http://www.prous.com Prous Science is a leading multiple-media publishing and information services company in the health and pharmaceutical sciences. Prous Science (c). Created of RSS by Jesus Moya. http://www.prous.com/ http://www.prous.com/images/design/prousscience5.gif http://www.prous.com/molecules/default.asp?ID=190 <p align="center"><img src="http://www.prous.com/images/moleculas/164510.gif"></p><P>Tumor cells rely on the existence of a specialized vasculature for the oxygen and nutrients that they require in order to grow and survive. Targeting the tumor vasculature as a technique for inhibiting tumor growth was first attempted with angiogenesis inhibitors, a class of drugs that compromise the formation of new blood vessels. More recently a new class of drugs called vascular disrupting agents (VDAs) has been reported. Rather than preventing the formation of new blood vessels, VDAs target endothelial cells and pericytes in the already-established vascular network supporting the tumor. VDAs are designed to induce massive downstream tumor cell death in a tumor-specific manner, i.e. by shutting down the supporting vasculature. Two subtypes of VDAs have been described: ligand-directed VDAs, which incorporate a targeting moiety linked to an effector moiety, and small molecules. Small molecules have several potential advantages over ligand-directed VDAs, including lower cost, greater specificity and reduced toxicity (Gridelli, C. et al., The Oncologist 2009, 14(6): 612; Hinnen, P. and Eskens, F.A., Br J Cancer 2007, 96(8): 1159). </P> <P>Codevelopment partners Antisoma and Novartis are currently conducting two phase III trials of the small-molecule tumor vascular disrupting agent <B>vadimezan </B>(ASA-404) in non-small cell lung cancer (NSCLC). Vadimezan exerts its antitumor effects partly through inhibition of tumor blood flow, but unlike other small-molecule vascular-targeting agents under clinical investigation, it does not act through modulation of the tubulin cytoskeleton of vascular endothelial cells. While the molecular target of vadimezan is unknown, a hallmark of its preclinical activity is its induction of cytokine production within the tumor tissue. These cytokines confer a multiplicity of indirect effects, including vascular collapse and enhanced immune response, making this one of the most promising agents of its class under clinical development (Ching, L.M. et al., Drugs Fut 2008, 33(7): 561).</P> <P>Ongoing phase III studies of vadimezan are employing a dose of 1800 mg/m2. The results of a phase II study of this dose in previously untreated NSCLC patients have been described, revealing acceptable safety and activity. Thirty patients who had not received chemotherapy were given carboplatin AUC 6 mg/ml and paclitaxel 175 mg/m2 plus vadimezan every 21 days for up to 6 cycles. Coadministration with vadimezan did not appear to affect the pharmacokinetics of carboplatin or paclitaxel and was generally well tolerated. Safety was similar between squamous and nonsquamous patients. There were 15 treatment-emergent serious adverse events, and 5 withdrawals were adverse event-related. The most common grade 3-4 toxicities were neutropenia and leukopenia. For activity, 37.9&#37; of patients had a partial response, while 48.3&#37; had stable disease, according to independent assessment. These figures were 46.7 and 43.3&#37;, respectively, by investigator assessment. The median time to progression was 5.5 months by investigator assessment data and median survival was 14.9 months. The results were in line with those from a previous phase II study of vadimezan 1200 mg/m2 in similar patients (McKeage, M.J. et al. Lung Cancer 2009, 65(2): 192).</P> <P>Antisoma has completed enrollment in the randomized, double-blind, placebo-controlled, multicenter phase III ATTRACT-1 trial of vadimezan in non-small cell lung cancer. The trial is being conducted by Novartis and has enrolled 1,200 patients in the U.S., E.U., Japan and other territories. It opened in April 2008 and has enrolled patients with all NSCLC histologies, including squamous and nonsquamous cancers. Patients have been randomized 1:1 to receive either vadimezan plus chemotherapy (carboplatin/paclitaxel) or a placebo plus chemotherapy (carboplatin/paclitaxel) as a control. Phase II trials are also under way for the treatment of hormone-refractory prostate cancer.</P> http://www.prous.com/molecules/default.asp?ID=189 <P>The current pandemic of H1N1 influenza, the first cases of which were detected in Mexico in March 2009, has extended worldwide with astonishing speed, matched only by the speed of response by health authorities and the pharmaceutical industry. On April 27, slightly a month after the first cases were detected, the World Health Organization raised the pandemic alert level to phase 4, indicating confirmed human-to-human transmission of the virus resulting in community-level outbreaks. Just two days later, WHO raised the pandemic alert level to phase 5, thus acknowledging efficient community-level human-to-human transmission of the virus in at least two countries within a single WHO region. On June 11, the WHO raised the level of influenza pandemic alert from phase 5 to phase 6, reflecting the fact that, in addition to the criteria defined in phase 5, the virus has caused sustained community-level outbreaks in at least one other country in another WHO region. This marked the official start of the first global influenza pandemic in 41 years.</P> <P>The need for an influenza (H1N1) vaccine became clear just months after the first cases were registered. WHO Director-General Dr. Margaret Chan and United Nations Secretary-General Ban Ki-moon met on May 19, 2009 with more than 30 vaccine manufacturers from developing and developed countries. Industry representatives affirmed their cooperation in making vaccine supplies available to developing as well as developed countries, responding to WHO concerns that the pandemic would hit especially hard in low-resource nations. WHO and CDC subsequently provided samples of the seed virus (A/California/7/2009(H1N1)pdm) to pharma companies to use in the development of H1N1 vaccines. On September 15, the FDA approved injectable H1N1 vaccines made by CSL, Novartis and sanofi pasteur as well as an intranasal vaccine made by MedImmune. Regulatory authorities have also licensed pandemic vaccines in Australia, China and the European Union. Many governments are planning mass vaccination campaigns beginning in late September or early October.</P> <P>Based on preliminary data from adults participating in multiple clinical studies, the four FDA-approved 2009 H1N1 vaccines induce a robust immune response in most healthy adults 8-10 days after a single dose, as occurs with the seasonal influenza vaccine. Ongoing clinical studies will provide additional information about the optimal dose in children. The recommendations for dosing will be updated if indicated by findings from those studies. Potential side effects of the H1N1 vaccines are expected to be similar to those of seasonal flu vaccines.</P> <P>The following table presents an overview of H1N1 vaccines in late-stage development or approved for marketing. Together these vaccines, which have gone from the stage of conception to market in record time, have been selected as the October 2009 Molecules of the Month. </P> <table border="1" cellspacing="0" cellpadding="0"> <tr> <td width="576" colspan="3" valign="top"><CENTER><b>Influenza (H1N1) 2009 vaccines</b></CENTER></td> </tr> <tr> <td width="192" valign="top"><p><i>Vaccine and manufacturer</i></p></td> <td width="192" valign="top"><p><i>Description</i></p></td> <td width="192" valign="top"><p><i>Status of development</i></p></td> </tr> <tr> <td width="192" valign="top">PanFlu.1 (Sinovac)</td> <td width="192" valign="top">Influenza A/H1N1 vaccine </td> <td width="192" valign="top">Launched (China)</td> </tr> <tr> <td width="192" valign="top">Influenza A (H1N1) 2009 monovalent vaccine (CSL Ltd.) </td> <td width="192" valign="top">Monovalent unadjuvanted, inactivated, split-virus H1N1 influenza vaccine prepared from the reassortant virus NYMC X-179A, derived from the A/California/7/2009 (H1N1) virus, in embryonated chicken eggs </td> <td width="192" valign="top">Launched (Australia)<br /> Approved (U.S.)</p></td> </tr> <tr> <td width="192" valign="top">Influenza A (H1N1) 2009 monovalent vaccine (sanofi pasteur) </td> <td width="192" valign="top">Monovalent inactivated subvirion A/California/07/2009 (H1N1) influenza vaccine</td> <td width="192" valign="top">Launched (U.S.)</td> </tr> <tr> <td width="192" valign="top">Influenza A (H1N1) 2009 monovalent vaccine (MedImmune)</p></td> <td width="192" valign="top">Live attenuated intranasal vaccine (LAIV) against influenza A (H1N1) virus</td> <td width="192" valign="top">Launched (U.S.)</td> </tr> <tr> <td width="192" valign="top">Influenza A (H1N1) 2009 monovalent vaccine (Novartis) </td> <td width="192" valign="top">Cell culture influenza A (H1N1) vaccine consisting of influenza A/California/4/2009(H1N1) surface antigen adjuvanted with MF59 </td> <td width="192" valign="top">Approved (U.S., E.U.)</td> </tr> <tr> <td width="192" valign="top">H1N1 Influenza vaccine (Hualan Biological Bacterin)</td> <td width="192" valign="top">Split-virion A/H1N1 influenza vaccine </td> <td width="192" valign="top">Approved (China)</td> </tr> <tr> <td width="192" valign="top">Pandemrix&trade; (GlaxoSmithKline) </td> <td width="192" valign="top">Influenza A (H1N1) vaccine consisting of an antigen of H1N1strain adjuvanted with AS03 </td> <td width="192" valign="top">Approved (E.U.)</td> </tr> </table><P>Information current as of October 1, 2009</P> http://www.prous.com/molecules/default.asp?ID=188 <P><I>Bacillus anthracis</I>, the organism that causes anthrax infections, was the first bacterium demonstrated to cause a disease. The use of anthrax as a biological weapon dates back to World War I, when the German army is believed to have injected horses, mules and cattle with anthrax toxin. In 1937 Japan initiated a biological warfare program, and the U.S. and U.K. followed suit half a decade later. The United States' biological weapons program was terminated in 1969, and in 1972 the Biological Weapons and Toxins Convention outlawed the development and stockpiling of biological weapons. Since that time, however, this class of weapon has remained in the shadows, primarily developed and stockpiled by underground terrorist groups in addition to certain “renegade” countries. In the 1990s the Japanese terrorist group Aum Shinrikyo released anthrax on several occasions in Tokyo, with no victims. In late 2001, there was a rash of anthrax cases in the United States mostly involving inhalation of anthrax spores contained in envelopes sent through the U.S. postal system. Eleven confirmed cases and five resulting deaths were caused by inhalation anthrax infection in the period October 4-November 21, 2001. </P><P>While existing methods of fighting anthrax infection (vaccines and antibiotics) continue to be essential elements in the therapeutic armamentarium, both have their limitations. Vaccines take several weeks to produce a detectable immune response, during which time subjects remain susceptible to infection, and require booster immunizations in order to maintain protective immunity. Antibiotics are effective in killing anthrax bacteria, but have no effect against anthrax toxins once they have been released into the bloodstream. Antibiotics are furthermore ineffective or only partially effective against drug-resistant bacterial strains. New approaches are thus needed. In recent years, several potential treatment approaches based on disabling some or all three components of the anthrax toxin (lethal factor [LF], edema factor [EF] and protective antigen [PA]) have been described. </P><P>Human Genome Sciences is developing the novel antitoxin <B>raxibacumab</B> (ABthrax&trade;), a monoclonal antibody (MAb)-based product that specifically recognizes and neutralizes protective antigen (PA). By neutralizing PA, raxibacumab effectively blocks the binding of protective antigen to cell surfaces and prevents the anthrax toxins from entering and killing the cells. The results of clinical and preclinical studies to date provide strong support for the potential of raxibacumab to provide significant survival benefit with minimal side effects in the event of an anthrax attack. In July, Human Genome Sciences published the results of new animal and human studies evaluating the pharmacokinetics and efficacy of raxibacumab, both in the setting of prophylaxis and after the onset of respiratory disease. <I>Bacillus anthracis</I> spores were administered to rabbits and monkeys by aerosol at doses 100 (in prophylactic studies) and 200 (in treatment studies) times the median lethal dose. A single dose of the MAb was then administered to animals developing signs of anthrax disease (detectable PA in serum and/or significant increase in body temperature). Survival rates monkeys treated with raxibacumab were 64&#37; higher than in those given placebo, while survival rates in rabbits treated with the MAb were 44&#37; higher than in placebo-treated controls. In humans, the MAb was administered at a dose of 40 mg/kg i.v. to 333 healthy volunteers in order to study its safety and pharmacokinetics. The half-life of raxibacumab was 20-22 days, providing a maximum drug concentration that was greater than the dose exerting protective efficacy in animals (Migone, T.S. et al., New Engl J Med 2009, 361(2): 191-3).</P><P>Raxibacumab has received a Fast Track Product designation from the U.S. FDA for its potential use in the prevention and treatment of anthrax infection. Under the Bioterrorism Act of 2002, clinical trials are required to establish safety, tolerability and pharmacology, while efficacy need only be established in relevant animal models. In October 2005, Human Genome Sciences was awarded a two-phase contract to supply the product to the U.S. Government. In February 2009, the company began delivering raxibacumab to the U.S. Strategic National Stockpile. </P> http://www.prous.com/molecules/default.asp?ID=187 <P>Xoma recently presented new results from a phase I clinical trial of <B>XOMA-052</B>, a novel antiinflammatory approach for the treatment of type 2 diabetes. XOMA-052 is a humanized monoclonal antibody (MAb) against interleukin-1beta (IL-1beta), the elevated expression of which has been correlated with damage to insulin-producing beta cells in patients with type 2 diabetes. In this trial, a single intravenous infusion of XOMA-052 (0.01, 0.03 or 0.1 mg/kg) or placebo was administered to individuals with inadequately controlled type 2 diabetes who were subsequently assessed for safety, pharmacokinetics and various diabetes and inflammation-related parameters for up to a period of 3 months. Treatment with XOMA-052 was well tolerated without the incidence of any serious adverse events. A reduction in glycated hemoglobin A1c (HbA1c) was seen at 3 months following a single dose of XOMA-052 (median 1.1&#37;, maximum 2.2&#37;), whereas placebo-treated patients exhibited an increase of 0.1&#37; in HbA1c. Intravenous stimulation tests revealed a continuous increase in insulin production at 1 and 3 months following XOMA-052, but not placebo, administration. Future studies with monthly or less frequent dosing are planned (Donath, M.Y. et al. 69th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 5-9, New Orleans) 2009, Abst 113-OR). XOMA-052 clinical data also correlate with results obtained from studies in the diet-induced obesity (DIO) mouse model, where administration of twice weekly intraperitoneal doses of XOMA-052 (0.1 to 0.5 mg/kg) for up to 19 weeks led to significant reductions in fasting serum glucose, HbA1c, insulin resistance, fasting cholesterol, triglycerides and free fatty acid levels. The treatment was also found to improve glucose tolerance and beta-cell function (Owyang, A.M. et al. 69th Annu Meet Sci Sess Am Diabetes Assoc (ADA) (June 5-9, New Orleans) 2009, Abst 310-OR). Taken together, these data support the promising potential of XOMA-052 for the treatment of type 2 diabetes. </P> <P>In addition to type 2 diabetes, Xoma is developing XOMA-052 for the indications of rheumatoid arthritis, acute gout and systemic juvenile idiopathic arthritis. In March 2009, Xoma commenced a phase IIa clinical study evaluating XOMA-052 for the treatment of rheumatoid arthritis (RA). The U.S.-based clinical study is a randomized, placebo-controlled study designed to enroll up to 18 patients with moderate to severe RA and evaluate the safety, pharmacokinetics and disease-specific outcomes of XOMA-052. Standard rheumatoid arthritis clinical assessment scores will be calculated using the American College of Rheumatology (ACR) core criteria, which assess inflammatory status, joint physical exam and general patient functional status. Patients will be enrolled into one of three groups. Each group will include one patient who will receive standard-of-care-treatment plus placebo and five who will receive standard-of-care treatment plus a single dose of XOMA-052 at 0.3 mg/kg. In one group, XOMA-052 will be administered by s.c. injection and in the other two groups by i.v. infusion. Patients will be followed for eight weeks.</P> http://www.prous.com/molecules/default.asp?ID=186 <p align="center"><img src="http://www.prous.com/images/moleculas/386239.gif"></p><P>The tuberculosis (TB) epidemic constitutes a major global health threat. The steady emergence of <I>Mycobacterium tuberculosis</I> strains resistant to current anti-TB drugs, including multidrug-resistant and extensively drug-resistant tuberculosis (MDR-TB and XDR-TB, respectively), as well as the therapeutic obstacles presented by coinfection with HIV and the cumbersome nature of existing treatment protocols all demand the development of new, fast-acting, effective compounds that shorten and simplify the treatment of TB (Arjona, A. and Castaner, R., Drugs Fut 2008, 33(12): 1018). </P> <P>TMC-207 (R-207910) is a novel diarylquinoline with a unique biological target: the F0 subunit of mycobacterial ATP synthase. The inhibition of mycobacterial ATP synthase function may result in ATP depletion and upset pH homeostasis, thereby slowing the energy production of <I>M. tuberculosis</I> and subsequently reducing its survival. The ATP synthase of mycobacteria has been shown to have a unique sequence, indicating that this is a highly specific target that could be addressed by potentially safer, more potent drugs. TMC-207 exhibits high in vitro activity against a wide range of mycobacterial strains, both susceptible and resistant to all first-line and many second-line anti-TB drugs available. It has also shown remarkable in vivo efficacy against <I>M. tuberculosis</I> and other mycobacterial species in several animal models. Preliminary pharmacokinetic, safety and efficacy analyses in humans have reasserted the potential of this compound for treating TB. TMC-207 is currently undergoing phase II clinical evaluation at Tibotec, a subsidiary of Johnson &amp; Johnson. </P> <P>Encouraging results from the first part of an ongoing two-stage phase II, randomized, placebo-controlled trial evaluating TMC-207 in the treatment of MDR-TB were published in June. The data show that the addition of TMC-207 for eight weeks to a five-drug background regimen resulted in a significant increase in the proportion of patients achieving a negative sputum culture and a shorter time to sputum culture conversion as compared to the background regimen alone. In the present study, TMC-207 did not appear to be associated with serious adverse events. This study validates APT synthase as a target for tuberculosis (Diacon, A.H. et al., New Engl J Med 2009, 360(23): 2397). The second stage of the study, which will evaluate efficacy following 24 weeks of treatment, is currently ongoing and is actively recruiting patients with MDR-TB in South Africa, Peru, Latvia and Russia. Results from the second stage are expected to be available in 2010. </P> <P>In late June, Tibotec and the not-for-profit Global Alliance for TB Drug Development (TB Alliance) announced an agreement to collaborate and share their expertise and resources in order to speed the development of TMC-207, potentially the first TB drug with a new mechanism of action in 40 years. Under the terms of the agreement, Tibotec will continue to develop TMC-207 for the treatment of MDR-TB, and on approval, will establish an access program to ensure the compound reaches those in developing countries who are in need. The agreement grants the TB Alliance a royalty-free license for the worldwide development and access to TMC-207 in the field of drug-susceptible TB. In addition, Tibotec will collaborate with the TB Alliance on a discovery research program to identify new compounds for the treatment of TB. The rights for the newly discovered compounds for the treatment of tuberculosis will belong to the TB Alliance under a royalty free license. Costs for the development of TMC-207 will be shared. </P> http://www.prous.com/molecules/default.asp?ID=185 <P>Receptor activator of NF-kappaB ligand (RANKL) is a member of the tumor necrosis factor (TNF) family of cytokines that is produced by cells of osteoblastic lineage, and its cellular receptor RANK is present on the surface of hematopoietic osteoclast precursor cells as well as on mature osteoclasts. RANKL is now known to be the common and requisite factor intervening in osteoclast formation in response to all known catalysts. As such, the RANK/RANKL/osteoprotegerin pathway is essential for the process of osteoclastogenesis and modulates the differentiation, activation and survival of osteoclasts, thereby regulating bone resorption. Compounds acting on this pathway are being actively investigated for the treatment of osteoporosis (Integrity Disease Briefings: Osteoporosis [consulted May 28, 2009]). </P> <P>Several preclinical and clinical studies of the RANKL inhibitor <B>denosumab </B>(Amgen), a fully humanized monoclonal antibody to RANKL, were presented at the 36th European Symposium on Calcified Tissues, celebrated in late May in Vienna. </P> <P>A nonhuman primate study demonstrated the safety and efficacy of changing from alendronate to denosumab treatment: ovariectomized cynomolgus monkeys were treated for 6 months with vehicle or alendronate and then switched to denosumab. The transition was safe and while serum CTx and osteocalcin were reduced with denosumab and alendronate alone, further reductions were seen after the transition. Dynamic histomorphometry also showed greater reductions in bone turnover parameters at trabecular and cortical sites with denosumab alone or in animals switched from alendronate to denosumab compared to those given alendronate alone. Cortical and trabecular bone mass and strength were maintained or improved after treatment transition (Ominsky, M.S. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst P483). </P> <P>In a double-blind, phase II study, 247 postmenopausal women with low bone mass were randomized to placebo, denosumab 60 mg twice yearly or alendronate 70 mg weekly p.o. and given daily calcium and vitamin D. High-resolution peripheral quantitative computed tomography assessment of the ultradistal radius showed increased total bone mineral density (BMD) at 6 and 12 months with denosumab, while alendronate reduced the BMD loss seen in the placebo group (Seeman, E. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst OP14). In another double-blind study, 504 postmenopausal women with low bone mass received alendronate 70 mg weekly for 6 months and then continued that therapy or were transitioned to s.c. denosumab 60 mg every 6 months. Transition to denosumab was associated with greater increases in BMD at the total hip and lumbar spine as compared to continued alendronate, and the greatest increases were seen in patients with the highest levels of baseline bone turnover (Roux, C. et al. 36th Eur Symp Calcif Tissues (ECTS) (May 23-27, Vienna) 2009, Abst P476). </P> <P>Amgen has filed a BLA for denosumab in the U.S., where the proposed indication is the treatment and prevention of postmenopausal osteoporosis and treatment and prevention of bone loss in patients undergoing hormone ablation therapy for either prostate or breast cancer. The FDA has accepted the submission and has set a Prescription Drug User Fee Act action date for the application of October 2009. Amgen has also submitted marketing applications for use of denosumab for these indications in the E.U., Canada, Switzerland and Australia. Assuming approval is granted, denosumab will become the first-in-class member of this promising new class of antiosteoporosis agents. </P> http://www.prous.com/molecules/default.asp?ID=184 <P>Malignant ascites is a condition characterized by the abnormal accumulation of fluid in the abdominal cavity. It is caused by an imbalance between plasma flow into and out of the blood and lymphatic vessels, and may develop in patients with cancer &mdash;primarily ovarian, endometrial, breast, colorectal, gastric and pancreatic cancers. Generally, the development of malignant ascites can be traced back to the settlement of metastasizing cancer cells in the abdominal cavity. The infiltrating cancer cells disrupt the normal regulation of fluid flow in the peritoneal cavity by simultaneously causing greater plasma inflow as well as reduced lymphatic outflow. Symptoms of malignant ascites include increasing abdominal girth, abdominal pain, anorexia, nausea and vomiting. Patients with malignant ascites generally have poor prognosis, with a mean survival time of 1-4 months depending upon the underlying tumor and its stage. Until recently, nearly the only treatment option for malignant ascites was repeated peritoneal punctures and drainage of the ascites from the abdominal cavity to reduce symptoms. </P> <P>In April 2009, the European Union approved <B>catumaxomab</B> (Removab<SUP>&reg;</SUP>), the first treatment worldwide for malignant ascites. Specifically, it is indicated for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The approval was based on the results of a large international phase II/III pivotal study that demonstrated a statistically significant improvement of the primary endpoint puncture-free survival. Patients receiving catumaxomab had a four-fold increase in puncture-free survival over a therapy with peritoneal puncture alone. Catumaxomab was discovered by TRION Pharma and codeveloped with Fresenius Biotech.</P> <P>In addition to being the first treatment ever for this serious condition, catumaxomab is also the first and only approved antibody targeting EpCAM, an antigen expressed on almost all carcinomas, and the first approved bispecific, trifunctional antibody. Traditional monospecific antibodies can only recruit effector cells from the innate immune defense. TRION’s bispecific, trifunctional Triomab<SUP>&reg;</SUP> antibodies, including catumaxomab, additionally bind and activate cells from the adaptive immune system, including dendritic cells, macrophages and killer T cells. As a result, they destroy tumor cells at least 1,000-fold more effectively than conventional antibodies do. </P> <P>Epithelial cell adhesion molecule, or EpCAM, is a pan-epithelial differentiation antigen that is expressed on almost all carcinomas, including breast, lung, colorectal, gastric, prostate, head and neck, pancreatic and ovarian cancers. Catumaxomab is designed to specifically adhere with one binding arm to the EpCAM of carcinoma cells, with the second binding arm to CD3 receptors of T cells and with its Fc portion to the Fcgamma receptor of accessory cells such as macrophages and killer cells. The induction of a complex immune response appears to lead to an improved therapeutic effect. </P> <P>Fresenius Biotech and TRION expect to launch the product in Germany in May, with other European launches in the months to follow. </P> http://www.prous.com/molecules/default.asp?ID=183 <p align="center"><img src="http://www.prous.com/images/moleculas/415452.gif"></p><P>Orexins (hypocretins) are a class of hypothalamic neuropeptides first described in the late 1990s. They have since been shown to regulate the sleep/wake cycle by maintaining wakefulness, as well as being involved in appetite regulation and energy homeostasis. Orexins A and B bind to two CNS receptors, designated orexin-1 and orexin-2. The cell bodies of orexin-producing neurons are restricted to the dorsal, lateral and posterior hypothalamus and its perifornical nucleus. Axonal projections of these cells are dense in the hypothalamus and extend to the limbic system, thalamus, substantia nigra, raphe, locus coeruleus, ventral tegmental area, medullary reticular formation, nucleus of the solitary tract and other brain stem regions. Orexin neurons have been shown in electrophysiological studies to be regulated by monoamines, acetylcholine and metabolic triggers such as ghrelin, leptin and glucose. Blockade of orexin OX-1 and OX-2 receptors is being pursued as a promising and novel strategy for the treatment of sleep disorders --including insomnia, narcolepsy and restless legs syndrome-- and of obesity.</P><P>The RESTORA (REstore normal physiological Sleep with The Orexin Receptor antagonist Almorexant) program is evaluating the safety and efficacy of <B>almorexant</B>, the most advanced drug in this new drug class, in adult and elderly patients diagnosed with primary insomnia. Enrollment has commenced in the first phase III study of almorexant in primary insomnia, as part of the RESTORA program. First study results of the 700-patient study RESTORA 1 study, which includes a reference arm with zolpidem, are expected in the second half of 2009. In end-of-phase II discussions with the FDA, product originator Actelion provided additional four-week safety data generated in healthy volunteers as well as with results from a successful dose-finding study with almorexant in elderly patients. Actelion and codevelopment partner GlaxoSmithKline expect to initiate further clinical studies with almorexant upon conclusion of discussions with the FDA based on responses to the special protocol assessment (SPA) and results from additional trials.</P> http://www.prous.com/molecules/default.asp?ID=182 <p align="center"><img src="http://www.prous.com/images/moleculas/355544.gif"></p><P><B>Riociguat</B> (BAY-63-2521) is an oral soluble guanylate cyclase stimulator in phase III clinical development at Bayer Schering Pharma for the treatment of chronic thromboembolic pulmonary hypertension and for the treatment of pulmonary arterial hypertension (PAH). The compound stimulates sGC, which leads to the catalyzing of cyclic guanosine monophosphate (cGMP), resulting in the dilation of blood vessels, lowering of blood pressure and the mediation of tissue-protective effects. </P> <P>In February, Bayer Schering Pharma initiated two phase III clinical trials of riociguat: CHEST-1 (chronic thromboembolic pulmonary hypertension sGC stimulator trial) and PATENT-1 (pulmonary arterial hypertension sGC stimulator trial). CHEST-1 is a multicenter, double-blind, randomized, placebo-controlled trial in patients with inoperable chronic thromboembolic pulmonary hypertension. The trial will involve 270 patients who will be randomized to receive either riociguat or placebo for 16 weeks. The treatment success will be measured as the change from baseline in patients' exercise capacity, using the six-minute walking distance test. After the 16-week treatment in CHEST-1, all patients will have the opportunity to participate in an open-label, long-term study (CHEST-2) during which longer-duration safety and efficacy aspects will be assessed. PATENT-1 is a multicenter, double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension who are either treatment-naive or are being treated with an endothelin receptor antagonist or a prostacyclin analogue. The trial will involve 460 patients who will be randomized to receive either riociguat or placebo. The primary endpoint will be the change from baseline in the six-minute walking distance test after 12 weeks of treatment with riociguat compared to the change in the placebo group. After this study, all patients will have the opportunity to participate in an open-label, long-term study (PATENT-2) during which longer-duration safety and efficacy aspects will be assessed. First results from both trials are expected in 2011.</P> <P>In 2007, orphan drug designation was received in the E.U. for the treatment of pulmonary arterial hypertension, including treatment of chronic thromboembolic pulmonary hypertension.</P> http://www.prous.com/molecules/default.asp?ID=181 <p align="center"><img src="http://www.prous.com/images/moleculas/387102.gif"></p><P>The calcitonin gene-related peptide (CGRP) is a 37-amino acid vasodilatory neuropeptide that mediates inflammation and belongs to a family of peptides that includes calcitonin, adrenomedullin and amylin. It appears to involved in the pathophysiology of migraine. Migraine headache is thought to be associated with dilatation of cranial vessels and activation of the trigeminovascular system and stimulation of the trigeminal ganglion leads to the release of CGRP. Increased CGRP levels are also observed during a migraine attack. Antagonists of CGRP may thus be effective in the treatment of acute migraine and headache. One such compound, Merck &amp; Co.’s <B>telcagepant</B> (MK-0974), has reached phase III clinical testing and has been selected as this month’s Molecule of the Month. </P> <P>In a randomized, double-blind, placebo- and active-controlled dose-ranging phase II study published last year, telcagepant significantly improved migraine pain relief two hours after dosing compared to placebo, and the relief was sustained through 24 hours. For the primary endpoint, the overall treatment effect of telcagepant in relieving migraine pain two hours after dosing was significant compared to placebo. The proportion of patients reporting pain relief at two hours for those treated with the CGRP antagonist was 68.1&#37;, 48.2&#37; and 67.5&#37; (300, 400 and 600 mg, respectively); and 69.5&#37; for rizatriptan compared to 46.3&#37; for placebo. A similar pattern was observed for secondary measures in which the overall treatment effect of telcagepant for each measure was significant compared to placebo. The proportion of patients experiencing two-hour pain freedom was 45.2&#37;, 24.3&#37; and 32.1&#37; for 300, 400 and 600 mg of telcagepant, respectively; 33.4% for rizatriptan and 14.3&#37; for placebo. Twenty-four hour sustained pain relief was reported in 52.6&#37;, 37.8&#37; and 52.5&#37; of subjects taking 300, 400 and 600 mg of telcagepant, respectively; 35.3&#37; for rizatriptan and 23.5&#37; for placebo. Twenty-four hour sustained pain freedom was recorded in 39.6&#37;, 22.0&#37; and 32.0&#37; of patients treated with 300, 400 and 600 mg telcagepant, respectively, compared to 18.4&#37; for rizatriptan and 11.0&#37; for placebo. Telcagepant provided relief of migraine-associated symptoms, including nausea and sensitivity to light and sound, and improved functional disability two hours post-dose, and was relatively well tolerated (Ho, T.W. et al., Neurology 2008, 70(16): 1304). </P> <P>Similarly positive results were obtained in a randomized, double-blind, parallel-treatment, placebo-controlled trial conducted at more than 80 centers in the U.S. and Europe. In this study, 1,380 patients diagnosed with moderate to severe migraine according to International Headache Society (IHS) criteria were treated with telcagepant (150 or 300 mg), zolmitriptan (5 mg) or placebo. Five co-primary endpoints were evaluated at 2 hours postdosing: pain freedom, pain relief, absence of photophobia, absence of phonophobia and absence of nausea. Telcagepant was significantly more effective than placebo in terms of all five endpoints. Furthermore, while the efficacy of the CGRP antagonist was comparable to that of the zolmitriptan, telcagepant was associated with fewer adverse events (Ho, T.W. et al., Lancet 2008, 372(9656): 2115). </P> <P>Merck plans to file an NDA for telcagepant later this year in the U.S.</P> http://www.prous.com/molecules/default.asp?ID=180 <p align="center"><img src="http://www.prous.com/images/moleculas/339576.gif"></p><P>The emergence of multidrug-resistant Gram-positive pathogens has created a need for newer antibacterial agents with improved efficacy. Researchers have focused on modifying the antibiotic vancomycin and other glycopeptides by adding hydrophobic substituents in order to improve activity, absorption, distribution, metabolism and excretion. <B>Telavancin</B> is one such novel antibiotic that was found to have multiple mechanisms of action, including inhibition of bacterial cell wall formation and disruption of cell membrane integrity. The agent showed potent activity <I>in vitro</I> and <I>in vivo</I> against methicillin-resistant <I>Staphylococcus aureus</I> (MRSA) and vancomycin-resistant enterococci, among other bacterial species. Telavancin was also shown to have good pharmacokinetics and was effective in clinical trials in patients with Gram-positive skin and soft tissue infections and hospital-acquired pneumonia. </P> <P>Telavancin was associated with a rate of clinical response (87.9 vs. 86.5&#37;) statistically equivalent to that of vancomycin in patients with complicated skin and skin structure infections (cSSSI) in the ATLAS I study. The randomized, double-blind, phase III trial included 855 patients at multiple centers. Treatment consisted of vancomycin 1 g i.v. every 12 hours or telavancin 10 mg/kg i.v. every day for 7-14 days. A clinical response was seen in 85.5 and 87&#37;, respectively, of microbiologically evaluable patients with MRSA infection and in 84.6 and 89.9&#37;, respectively, of those with methicillin-susceptible <I>S. aureus</I> infection. Safety was similar between treatments and noninferiority in efficacy was demonstrated. </P> <P>Efficacy was also demonstrated in the double-blind, randomized, ATTAIN 1 and ATTAIN 2 phase III clinical studies of telavancin for the treatment of hospital-acquired pneumonia (HAP), including patients with ventilator-associated pneumonia (VAP) caused by Gram-positive bacteria such as MRSA. In each study, telavancin achieved its objective of noninferiority in the all-treated and clinically evaluable patient populations. In the clinically evaluable population from ATTAIN 1 and ATTAIN 2 combined, the clinical cure rate for telavancin was 82.7&#37; compared with 80.9&#37; for vancomycin. In the microbiologically evaluable patients who were infected with MRSA alone, treatment with telavancin resulted in cure rates of 82&#37; compared with 74&#37; for vancomycin; this difference did not reach statistical significance but is clinically meaningful. In clinically evaluable patients with VAP, the cure rate was 80&#37; for telavancin compared with 68&#37; for vancomycin. </P> <P>In November, telavancin received a favorable recommendation from the Anti-Infective Drugs Advisory Committee of the FDA with a vote of 21-5. The NDA was submitted for the indication of cSSSI. Astellas, who in-licensed the antibiotic from Theravance, is working closely with the company towards FDA approval. On the downside, Astellas has withdrawn its European marketing authorization application for telavancin, based on communications from the CHMP that the data submitted are insufficient to provide a proper benefit/risk assessment for the indication of complicated skin and soft tissue infections. The company plans to submit a new MAA with expanded clinical data, including data from hospital-acquired pneumonia phase III studies.</P> http://www.prous.com/molecules/default.asp?ID=179 <p align="center"><img src="http://www.prous.com/images/moleculas/193166.gif"></p><P>Tricyclic antidepressants, while effective in treating mild to severe forms of depression, are associated with an extensive tolerability profile, making them a nonviable option to many patients. The newer selective serotonin reuptake inhibitors (SSRIs) are better tolerated when compared with their tricyclic predecessors, and have recently become the most widely used antidepressant agents. However, problems with specific side effects (particularly affecting sexual function) have compromised treatment compliance in some patients. There is also evidence to suggest that while SSRIs are effective in mild to moderate forms of depression, they may not be as effective in patients exhibiting very severe forms of the disease. Therefore, research efforts are still being directed towards finding new antidepressant agents that are effective in all forms of depression and that are associated with a reduced side effect profile. </P> <P><B>Agomelatine </B>has been proposed as one such candidate for antidepressant therapy. Agomelatine is a metabolically stable analogue of melatonin that is known to act as a selective and specific agonist at melatonin MT1 and MT2 receptor sites in the hypothalamus. Agomelatine has also been shown to act as a competitive antagonist at serotonin (5-HT2C) receptors. Its ability to mimic the action of melatonin means that it is a potential candidate for the treatment of disorders characterized by dysfunction of biological rhythms (e.g., sleep disorders, depression). Disruption of circadian rhythm patterns has been implicated as an etiological factor in the pathophysiology of depression. This disorganization of internal rhythms is said to be characteristic of mood variation. Therefore, the normalization of such impairments has been heralded as a potential new therapeutic target for the treatment of depression.</P> <P>In late November, agomelatine (<I>Valdoxan<SUP>&reg;</SUP></I>) received a positive opinion from the EMEA's Committee for Medicinal Products for Human Use (CHMP) for its use in the treatment of adult patients with major depressive disorder (MDD). Both short-term and long-term results from the large, comprehensive, international development program including nearly 4,000 adult patients with MDD were presented to the CHMP to support the efficacy of agomelatine as compared with placebo, SSRIs and serotonin noradrenaline reuptake inhibitors (SNRIs). This program also showed that the drug’s antidepressant efficacy was combined with a favorable tolerability profile compared with other treatments, resulting in better adherence and remission in depressed patients. If approved, agomelatine is expected to be marketed by Servier in European countries in the following months. </P> http://www.prous.com/molecules/default.asp?ID=178 <p align="center"><img src="http://www.prous.com/images/moleculas/306794.gif"></p><P>Multiple sclerosis (MS) is one of the most common diseases of the central nervous system, affecting more than 2,500,000 people around the world. MS is the result of damage to myelin, a protective sheath surrounding nerve fibres of the central nervous system. When myelin is damaged, this interferes with messages between the brain and other parts of the body.</P> <P>Altered peptide ligands (APLs) are analogues of peptide determinants with one or more substitutions at the amino acid positions required for contact with the T cell receptor. APLs can act as either partial agonists or antagonists of the T cell receptor in question. In the case of multiple sclerosis, the peptide is an altered version of myelin basic protein (MBP), one of the most important proteins attacked by the immune system in MS. MPB-reactive T cells produce the proinflammatory Th1 cytokines TNF-alpha, IL-2 and IFN-gamma, leading to the supposition that they facilitate myelin-destructive inflammation in the CNS. Research indicates that the introduction of an altered form of MBP into MS patients --a process called T cell vaccination-- may cause the body to react to normal MBP in a protective rather than destructive fashion, thereby stopping flare-ups of the disease (Integrity&reg; Disease Briefing: Multiple Sclerosis) .</P> <P>Dirucotide (MBP-8298) is a synthetic peptide that consists of 17 amino acids linked in a sequence identical to that of a portion of human MBP. The apparent mechanism of action of dirucotide is the induction or restoration of immunological tolerance with respect to ongoing immune attack at this molecular site. High doses of antigen delivered periodically by the intravenous route are expected to suppress immune responses to the administered substance. The potential benefit of dirucotide for any individual patient is therefore expected to be related to the extent to which his or her disease process is dominated by autoimmune attack at the site represented by this synthetic peptide. </P> <P>BioMS Medical has designed an ambitious clinical trials program evaluating dirucotide in various phase II and phase III studies for the treatment of secondary progressive and relapsing-remitting forms of MS, including MAESTRO-01 (phase II/III, SPMS), MAESTRO-02 (follow-on, SPMS), MAESTRO-03 (phase III, SPMS) and MINDSET-01 (phase II, RRMS). Last month both MINDSET-01 and MAESTRO-03 underwent routine review by their respective independent data safety monitoring boards, both of which recommended that the trials continue without according to protocol. The U.S. FDA has granted fast-track designation to dirucotide for the treatment of secondary progressive multiple sclerosis. </P> http://www.prous.com/molecules/default.asp?ID=177 <p align="center"><img src="http://www.prous.com/images/moleculas/396437.gif"></p><P>In 1980, the World Health Organization declared that variola virus, the etiologic agent of smallpox, had been eradicated on a global level. However, two decades later concerns remain that this infectious agent, which has an alarmingly high morbidity and mortality rate, could be used as an agent of biological warfare. In recent years investigation into potential new vaccines and antiviral drugs for the treatment and prevention of smallpox virus infection has gained renewed strength, driven in part by support from the U.S. FDA and Centers for Disease Control and Prevention (CDC). </P> <P>Tecovirimat (ST-246), an inhibitor of orthopoxvirus egress from infected cells, is one promising agent to emerge from this new wave of research. The drug, an orally active inhibitor of core protein cysteine proteinase encoded by the poxvirus I7L gene, blocks the ability of the virus to spread to other cells, thus preventing it from causing disease. Tecovirimat has demonstrated significant antiviral activity in various animal models of poxvirus disease, including the complete protection of golden ground squirrels from lethal doses of monkeypox virus and protection of nonhuman primates from variola virus in lesional disease models. The agent demonstrated favorable safety, tolerability and pharmacokinetics in a double-blind, randomized, placebo-controlled phase I ascending-dose study in healthy human volunteers (Jordan, R. et al., Antimicrob Agents Chemother 2008, 52(5): 1721). These and other results support the use of tecovirimat to prevent smallpox disease in nonvaccinated individuals, as a postexposure therapeutic for use in nonsymptomatic individuals exposed to variola virus, as a treatment for confirmed smallpox infection, and as an adjuvant to vaccination with the smallpox vaccine. </P> <P>SIGA Technologies has received both orphan drug designation and fast-track status from the FDA supporting development of tecovirimat for the prevention and treatment of smallpox infections. In September 2008, SIGA was awarded a contract of USD &#36;55 million from the National Institute of Allergy and Infectious Diseases (NIAID) and The Office of the Biomedical Advance Research and Development Authority to support development of additional formulations and smallpox-related indications for tecovirimat. Later the same month, the company announced that it had received an additional USD &#36;20 million from the NIAID to further accelerate development of tecovirimat. This additional funding will be used to accelerate process development related to large-scale manufacturing and packaging of the drug and commercial-scale validation. </P> http://www.prous.com/molecules/default.asp?ID=176 <P>Mipomersen (ISIS-301012) is a 20-mer antisense chimeric phosphorothiate oligonucleotide that selectively targets apolipoprotein B (apoB), a protein critical to the synthesis and transport of LDL and VLDL cholesterol, both involved in the development of heart disease. It is in phase III clinical trials at Isis Pharmaceuticals for the subcutaneous treatment of familial hypercholesterolemia. The compound is also in phase II clinical development for the treatment of hypercholesterolemia, and in phase II in combination with simvastatin for the treatment of atherosclerosis in patients with high cholesterol. In June 2006, mipomersen received orphan drug status from the FDA for the treatment of homozygous familial hypercholesterolemia. In 2008, the compound was licensed by Isis to Genzyme for worldwide development and commercialization as a lipid-lowering treatment for high-risk cardiovascular patients.</P> <P>Results reported late last year from a phase II clinical trial of mipomersen administered at 200 mg/week for 3 months in patients with routine high cholesterol on stable doses of statins showed that mipomersen treatment resulted in a 42&#37; reduction in apoB and a 48&#37; reduction in LDL-cholesterol, beyond reductions achieved with statin therapy alone. Furthermore, results of an integrated safety analysis including data from more than 250 subjects treated with mipomersen in phase I and phase II studies demonstrated that mipomersen was well tolerated, with no evidence of liver toxicity. The most common adverse event to date has been mild to moderate injection-site reactions.</P> <P>In August 2008, Genzyme and Isis initiated a phase III study (NCT00706849) of mipomersen in patients with heterozygous familial hypercholesterolemia (heFH). This was the first of four new trials the companies plan to initiate by the end of this year. The trial will evaluate the safety and efficacy of mipomersen in patients who have heFH and coronary artery disease. The randomized, double-blind, placebo-controlled study will enroll around 100 patients at some 30 sites in the U.S. and Canada. Patients on a stable dose of other lipid-lowering agents are being randomized 2:1 to receive a 200 mg dose of mipomersen or placebo weekly for 26 weeks. The primary endpoint will be percent reduction in LDL cholesterol, and data are expected to be available in 2010. The initial indication to be sought for mipomersen will be for patients with homozygous FH, and enrollment in a phase III trial in this patient population is expected to be completed by the end of this year. Data are expected to be available in mid-2009 and a U.S. filing for this indication is anticipated during the second half of 2010. </P> <P>Genzyme and Isis plan to begin three additional trials evaluating mipomersen's safety and efficacy in reducing LDL cholesterol in high-risk patients during the second half of 2008. These trials will include one for apheresis-eligible patients, and two for high-risk high cholesterol patients. All three have anticipated trial designs that include a 2:1 randomization ratio of a 200 mg dose of mipomersen or placebo weekly for 26 weeks. Data from the trials will inform the design of the morbidity and mortality outcome study for potential expansion of mipomersen's label to include a broader group of at-risk, high cholesterol patients on maximally tolerated, currently available therapies. Following the finalization in June of the mipomersen license and collaboration agreement between Genzyme and Isis, the mipomersen IND and all regulatory authority has been transferred to Genzyme. Genzyme plans to begin discussions with the FDA and regulatory authorities in Europe. </P> http://www.prous.com/molecules/default.asp?ID=175 <p align="center"><img src="http://www.prous.com/images/moleculas/166737.gif"></p><P>Hereditary angioedema (HAE) is an uncommon hereditary disorder that can cause sudden and severe attacks of nonpitting edema that may affect any external or mucosal surface including the face, arms, legs, hands, feet, genitalia, digestive track and airway. Although it is uncomfortable and cosmetically unacceptable, it is rarely dangerous. Severe urticaria or angioedema, however, may sometimes cause swelling of mucous membranes of the respiratory or gastrointestinal tracts, resulting in anaphylaxis or asphyxiation. The pathogenesis of HAE is due to a mutation in the gene encoding for the plasma protein C1 inhibitor. Treatments for hereditary angioedema include C1 inhibitor concentrate, attenuated androgens (danazol, oxandrolone) or fresh frozen plasma (Integrity&reg; Disease Briefings: <I>Uricaria and Angioedema</I>). </P> <P>In July 2008, the European Commission approved Jerini's icatibant acetate (Firazyr&reg;), a first-in-class bradykinin B2 receptor antagonist, as a novel treatment of HAE. The European Commission's approval allows Jerini to market icatibant in the European Union's 27 member states, making it the first product to be approved in all EU countries for the treatment of HAE. Icatibant is a synthetic peptidomimetic that blocks the B2 receptor, thus inhibiting bradykinin, which is elevated in hereditary angioedema patients and responsible for edema formation during HAE attacks. Icatibant has been granted orphan drug status for the treatment of angioedema by the FDA and EMEA. The FDA, however, has issued a not-approvable letter for the product in the U.S.</P> <P>Combined analysis of the For Angioedema Subcutaneous Treatment (FAST)-1 and FAST-2 studies, both randomized, multicenter, phase III trials, revealed faster onset of symptom relief with icatibant acetate (median 2 hours) than with tranexamic acid (11.0 hours) or placebo (4.2 hours). The difference between icatibant and tranexamic acid was significant. The study treatments were icatibant 30 mg s.c. or placebo in FAST-1 (n = 56) and icatibant 30 mg s.c. or oral tranexamic acid 1000 mg in FAST-2 (n = 74), and patients had moderate to severe cutaneous and/or abdominal hereditary angioedema attacks. Onset of symptom relief occurred within 4 hours in 73&#37; of icatibant-treated patients and in 29&#37; of patients given tranexamic acid and in 45&#37; of patients given placebo. Time to almost complete symptom relief was significantly shorter with icatibant compared to the other groups, and icatibant was well tolerated (Riedl, M. et al., Annu Meet Am Acad Allergy Asthma Immunol (AAAAI) (Mar 14-18, Philadelphia) 2008: Abst 398).</P> http://www.prous.com/molecules/default.asp?ID=174 <p align="center"><img src="http://www.prous.com/images/moleculas/322926.gif"></p><P>Deposition of amyloid beta (Abeta) peptide into plaques is one of the two hallmark features of Alzheimer's disease. These plaques, typically concentrated in the spaces between nerve cells in the brain parenchyma and cerebral blood vessel walls, are thought to impede nerve cell function and promote neuronal degeneration in Alzheimer's disease brains. According to current thinking, AD etiology is explained by the amyloid cascade hypothesis, whereby overproduction of Abeta protein, or alternatively the failure to clear this protein, leads to the accumulation of amyloid deposits and contributes to the formation of neurofibrillary tangles. These lesions are associated with neuronal cell death, which manifests as loss of memory. Thus strategies to prevent the formation, accumulation or cytotoxic effects of Abeta are being actively pursued. Several potential interventions have been proposed to delay the onset or prevent the appearance of Alzheimer's disease, including Abeta production inhibitors (beta- and gamma-secretase inhibitors, statins, etc.); Abeta aggregation inhibitors; Abeta deposit-dissolving agents; and immunization with Abeta peptide. Furthermore, antiinflammatory therapies and metal chelating agents may minimize the brain's reaction to Abeta (Integrity<SUP>&reg;</SUP> Disease Briefings: <I>Alzheimer’s Disease</I>). </P> <P>In the spring of 2008, Lilly initiated its first phase III clinical trial of <B>semagacestat</B> (LY-450139) for the treatment of mild to moderate Alzheimer's disease. Semagacestat is being tested to see if it can slow the progression associated with Alzheimer's disease by inhibiting gamma-secretase, an enzyme that contributes to the formation of amyloid beta. The trial, called IDENTITY, is a randomized, double-blind, placebo-controlled trial that will be conducted in the U.S. and 21 additional countries and will evaluate 1,500 patients for 21 months. An open-label extension will be available to all participants completing the study. Patients who are taking currently available symptomatic treatments for Alzheimer's disease can continue treatment during their participation in IDENTITY. Because the IDENTITY study also incorporates a randomized delayed start design, even those subjects initially assigned to the placebo arm of the study will be started on active semagacestat treatment sometime before the end of the 21-month study period. Both the subjects and investigators will be blinded to the exact timing of this delayed start of study drug administration (ClinicalTrials.gov NCT00594568). Semagacestat was originally codeveloped by Lilly and Elan. </P> http://www.prous.com/molecules/default.asp?ID=173 <p align="center"><img src="http://www.prous.com/images/moleculas/313630.gif"></p><P>Thrombopoietin (TPO) is a glycoprotein hormone produced primarily by the liver that activates megakaryocytes in the bone marrow, causing them to differentiate and fragment into platelets. Under normal circumstances, the bloodstream platelet counts range from 150,000 to 400,000/mcl. However, under conditions of thrombocytopenia, platelet counts may drop below 50,000/mcl. Under these circumstances, patients are predisposed to bleeding, particularly at mucous membranes, and in some cases bleeding may become severe enough to require treatment.</P> <P>Thrombocytopenia is commonly associated with cancer chemotherapy and a number of other conditions, including AIDS, myelodysplastic syndrome, idiopathic thrombocytopenic purpura and chronic liver disease. The only treatment currently available for severe thrombocytopenia is platelet transfusion, but the known limitations and risks of this therapy have spurred investigation into novel methods of stimulating platelet production.</P> <P>A small-molecule, nonpeptide TPO agonist would be expected to offer several advantages over other therapies in terms of safety, cost and ease of administration. <B>Eltrombopag</B> (SB-497115, Promacta&reg;) an orally available small molecule that has been shown to activate the human TPO receptor, resulting in activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) signal transduction pathways to stimulate the proliferation and differentiation of megakaryocytes. Activity has been demonstrated in vitro in human bone marrow assays and in clinical trials.</P> <P>Last year, results were published from a phase II study that evaluated 118 patients with chronic ITP and low platelet levels (&lt; 30,000/mcl). The results showed a statistically significant increase in the number of patients achieving a platelet count of 50,000/mcl or higher and decreased bleeding following eltrombopag doses of &gt; 50 mg over six weeks. There was no increased incidence of adverse events compared to placebo across the 30 mg, 50 mg or 75 mg eltrombopag arms. All seven patients who received the study drug and bled were nonresponders (Bussel, J.B. et al., Lancet 2007, 357(22): 2237-47).</P> <P>Product developer GlaxoSmithKline has filed for approval in the U.S. of eltrombopag as a once-daily, oral agent for the short- and long-term treatment of adult patients with previously treated chronic idiopathic thrombocytopenic purpura. The FDA has granted the product priority review status. The agency's decision is expected in the second quarter; if approved, eltrombopag would be the first treatment of its type to be approved for this indication. Eltrombopag is also phase III clinical studies for the treatment of thrombocytopenia in patients with hepatitis C infection.</P> http://www.prous.com/molecules/default.asp?ID=172 <p align="center"><img src="http://www.prous.com/images/moleculas/349654.gif"></p><P>Cathepsin K is a cysteine protease that is selectively and highly expressed by osteoclasts and secreted into the extracellular compartment, where it cleaves important bone matrix proteins, acting as the principal effector of bone degradation during the process of bone resorption. Activated cathepsin K degrades various bone matrix components including type I collagen, osteopontin and osteonectin. It is an attractive target for modulation in osteoporosis and other disorders caused by excessive bone resorption, because while it is expressed at high levels in bone, it is present at extremely low levels in the heart, liver, lung and other tissues. At the present time several cathepsin K inhibitors are under active development for the treatment of osteoporosis, including Merck & Co.’s <B>odanacatib</B> (formerly MK-0822), which has been selected as the Molecule of the Month. </P> <P>In a phase IIb study reported at last year’s meeting of the American Society of Bone and Mineral Research, odanacatib dose-dependently improved bone mineral density (BMD) in postmenopausal women with low BMD. The study included 399 women who were randomized in double-blind fashion to placebo or odanacatib 3, 10, 25 or 50 mg p.o. once weekly for 12 months. While the lowest odanacatib dose had no effect on BMD, the 10-, 25- and 50-mg doses were associated with dose-related increases in BMD at the lumbar spine, total hip, femoral neck and hip trochanter. The 50-mg dose significantly increased lumbar spine BMD at 12 months by 3.4&#37;, while this measure declined 0.1&#37; with placebo. Femoral neck BMD was also increased 2.5&#37; and the urinary N-telopeptide/creatinine ratio was reduced 58&#37; with the 50-mg odanacatib dose. Odanacatib was generally safe and well tolerated, with similar discontinuation rates due to adverse events in the active treatment and placebo groups (Bone, H.G. et al. J Bone Miner Res [29th Annu Meet Am Soc Bone Miner Res (ASBMR) (Sept 16-19, Honolulu) 2007] 2007, 22(Suppl. 1): Abst 1128). </P> <P>Based on these and other positive findings, Merck has begun enrolling patients in a phase III trial to evaluate odanacatib in postmenopausal women. The three-year study will determine the incidence of radiographic spine fractures and fractures at other body sites in patients taking odanacatib compared to placebo, as well as the drug’s effects on bone mineral density over the three-year study period (ClinicalTrials.gov identifier NCT00529373). In addition, several ongoing phase II trials are assessing the cathepsin K inhibitor for the treatment of osteoarthritis in the knee, arthritis and cancer, specifically for the treatment of women with breast cancer and metastatic bone disease. Banyu is developing the compound for the treatment of osteoporosis in Japan.</P> http://www.prous.com/molecules/default.asp?ID=171 <P>Cryopyrin-Associated Periodic Syndromes (CAPS) are a recently identified group of rare, inherited auto-inflammatory disorders characterized by life-long, recurrent symptoms of rash, fever/chills, joint pain, eye redness/pain and fatigue. Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to cooling temperatures, stress, exercise or other unknown stimuli. Three related conditions fall under the classification of CAPS: Familial Cold Auto-inflammatory Syndrome (FCAS), Muckle-Wells Syndrome (MWS) and Neonatal-Onset Multisystem Inflammatory Disease (NOMID). The incidence of CAPS has been reported to be approximately 1 in 1,000,000 people in the United States.</P> <P>CAPS are generally caused by mutations in the <I>NLRP-3</I> (previously known as <I>CIAS1</I>) gene and resultant alterations in the protein, cryopyrin, which it encodes. Cryopyrin, active in circulating, infection-fighting, white blood cells, controls the production of a protein called interleukin-1 (IL-1). As part of the body's infection-fighting defense system, IL-1 circulates throughout the body and can trigger inflammatory reactions when it binds to inflammatory cells. Researchers have found that alterations in the cryopyrin protein lead to over-production of IL-1, resulting in an inflammatory response and the symptoms of CAPS. Most, but not all, patients with CAPS have the <I>NLRP-3</I> gene mutation.</P> <P>Rilonacept, a targeted inhibitor of IL-1 discovered and developed by Regeneron, has been shown throughout its clinical development program to improve overall CAPS symptom scores. Last month at the AAAAI meeting in Philadelphia, results were reported from a 24-week extension of a 24-week study. Administered to patients with cryopyrin-associated periodic syndromes, including FCAS and MWS, rilonacept treatment was associated with sustained improvement in signs and symptoms. Of 47 patients initially treated with placebo or rilonacept 160 mg s.c. weekly, 44 entered the open-label extension study. The percentages of patients with at least 30&#37;, 50&#37; and 75&#37; improvement in key symptom scores at week 6 were 96&#37;, 87&#37; and 70&#37;, respectively, with rilonacept and 29&#37;, 8&#37; and 0&#37;, respectively, with placebo. At week 48, these percentages were 93&#37;, 91&#37; and 68&#37;, respectively, for rilonacept-treated patients receiving the treatment for 33-48 weeks. Key symptoms included rash, fever/chills, joint pain, eye redness/pain and fatigue. Large reductions in C-reactive protein and serum amyloid A were seen with rilonacept treatment at week 6 (92&#37; and 94&#37;, respectively) and after 33-48 weeks (77&#37; and 84&#37;, respectively) (Hoffman, H.M. et al. Annu Meet Am Acad Allergy Asthma Immunol (March 14-18, Philadelphia) 2008, Abst 669).</P> <P>In February the U.S. FDA approved rilonacept (Arcalyst&trade;) for the treatment of CAPS, including FCAS and MWS, in adults and children aged 12 years and older. The drug has not been evaluated in patients with NOMID. The product, which has orphan drug status in the U.S. for this indication, was launched in late March.</P> http://www.prous.com/molecules/default.asp?ID=169 <P>Overexpression of proinflammatory cytokines --especially IFN-gamma, TNF-alpha, IL-2, IL-6, IL-8, IL-12 and IL-23-- at the systemic and cutaneous level has been established in the context of psoriasis and is believed to underlie the initiation, maintenance and recurrence of skin lesions. Interleukin-12 (IL-12) is a heterodimeric cytokine (p70) comprised of two independently regulated protein subunits, p35 and p40. The well-documented biological functions of IL-12 are the induction of IFN-gamma expression from T-cells and natural killer (NK) cells, and the differentiation of naïve T-cells to a Th1 cell type. In addition, the p40 subunit of IL-12 can dimerize with a p19 subunit and form IL-23, a more recently discovered member of the IL-12 family that also promotes a Th1 response but has distinct functions from IL-12. IL-23 is required for the generation of effector memory T-cells and IL-17-producing T-cells (Th17), which play a significant role in the inflammatory response (<A HREF="http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=1158296&p_IsPs=N"><U>Wada, Y., Drugs Fut 2008, 33(1): 49</U></A>). </P> <P><B>Ustekinumab</B> (formerly CNTO-1275) is a human monoclonal antibody targeting IL-12 and IL-23. It has recently been shown that ustekinumab downregulates type 1 cytokines, chemokines and IL-12/IL-23 in psoriatic lesions of treated patients. Phase III trial results indicate that ustekinumab is effective with infrequent administration in patients with psoriasis and that efficacy is maintained with long-term treatment. In the PHOENIX 1 study, 766 patients were randomized to placebo or s.c. ustekinumab given in two 45- or 90-mg doses 4 weeks apart followed by 45 or 90 mg every 12 weeks. Placebo patients crossed over to ustekinumab 45 or 90 mg at weeks 12 and 16 and were than treated every 12 weeks. At week 12, 67&#37; and 60&#37; of patients given ustekinumab 45 and 90 mg, respectively, achieved the primary endpoint of an improvement of at least 75&#37; in Psoriasis Area and Severity Index (PASI 75) scores. A dose response was seen after week 12 with a peak response at week 24, with 76&#37; and 85&#37; of the ustekinumab 45 and 90 mg groups, respectively, achieving a PASI 75 response. Ustekinumab was generally well tolerated, with 57&#37; and 51&#37; of the ustekinumab 45 and 90 mg groups, respectively, experiencing at least one adverse event compared to 48&#37; of the placebo group (Papp, K. et al., J Am Acad Dermatol 2008, 58(2, Suppl. 2): Abst P2621). In this study, patients responding to ustekinumab at week 40 were randomized to either continue treatment or switch to placebo. At week 52, 87&#37; and 91&#37; of patients receiving ustekinumab 45 and 90 mg, respectively, maintained a PASI 75 response, compared to 64&#37; and 62&#37; of placebo-treated patients. Long-term maintenance therapy was generally well tolerated, with 46&#37; and 49&#37; of patients in the 45 and 90 mg dose groups, respectively, experiencing at least one adverse event after randomization at week 40, compared to 56&#37; and 48&#37; of patients switched to placebo (Gordon, K.B. et al., J Am Acad Dermatol 2008, 58(2, Suppl. 2): Abst P2620). </P> <P>Centocor and Jassen-Cilag have filed for regulatory approval of ustekinumab in the U.S. and European Union, respectively, for the subcutaneous treatment of adult patients with chronic moderate to severe plaque psoriasis. Medarex, originator of the therapeutic agent, is conducting phase III trials for the treatment of severe plaque-type psoriasis and Centocor is conducting additional phase II trials in patients with psoriatic arthritis. </P> http://www.prous.com/molecules/default.asp?ID=168 <p align="center"><img src="http://www.prous.com/images/moleculas/313738.gif"></p><P>Despite the availability of several approved drugs for the treatment of human immunodeficiency virus (HIV) infection, the limited effectiveness of current antiretroviral regimens, mainly due to the emergence of resistance, makes the development of new agents necessary. Several novel compounds are being added to existing classes, but the discovery and development of newer classes of antiretroviral drugs, such as HIV entry inhibitors, represents a significant advance in the treatment of AIDS and HIV. </P> <P>HIV enters the host cell by a sequential process that requires engagement with CD4 followed by binding to a coreceptor: either the chemokine CCR5 receptor (R5 strains) or CXCR4 (RX strains). The chemokine CCR5 receptor is a G-protein-coupled, 7-transmembrane receptor expressed on monocytes, macrophages, T cells and B cells that binds the CC chemokines MIP-1-alpha, MIP-1-beta and RANTES with high affinity. It also binds viral MIP-2 with high affinity and has been shown to bind cyclophilin-18 and histidyl-tRNA synthetase. CCR5 acts as a coreceptor with CD4 for HIV-1 infection and functions as a fusion cofactor for macrophage-tropic and T-cell line-tropic isolates of HIV-1. In general, during the early stages of HIV infection, viral isolates use CCR5 for viral entry, while later isolates use CXCR4. Antagonism of this receptor may therefore be effective in the prevention and treatment of HIV infection. </P> <P><B>Maraviroc</B> (<I>Selzentry</I>&trade;; Pfizer), the first member of the CCR5 antagonist class to cross the finish line, received accelerated approval from the U.S. FDA last August and was launched for the first time in September 2007. The drug acts by blocking the CCR5 coreceptor, thereby blocking viral entry into T cells. It is indicated for use in combination antiretroviral treatment of adults infected with CCR5-tropic HIV-1, evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. The FDA approval was based on 24-week data from the ongoing double-blind, controlled MOTIVATE clinical trials, in which approximately twice as many patients receiving maraviroc plus optimized background therapy achieved undetectable viral load at 24 weeks compared to those on optimized background therapy alone. In September, Pfizer presented 48-week data supporting these initial findings, and announced the commercial availability of maraviroc in the U.S. Pfizer has also filed for regulatory approval of maraviroc in Europe, where it will be known as <I>Celsentri</I>, and has received a positive opinion from the CHMP. </P> http://www.prous.com/molecules/default.asp?ID=167 <p align="center"><img src="http://www.prous.com/images/moleculas/390240.gif"></p><P>Obatoclax mesylate (GX15-070) is a small-molecule indole bipyrrole drug compound and pan-Bcl-2 family inhibitor being developed at Gemin X Biotechnologies for the treatment of cancer. Recently published studies have confirmed the mechanism of action of the compound, demonstrating that it specifically disrupts the survival of cancer cells as a result of inhibiting the Bcl-2 pro-survival protein Mcl-1. Elevated expression of members of the Bcl-2 pro-survival family of proteins can confer resistance to apoptosis in cancer cells, and obatoclax overcomes Bcl-2 pro-survival proteins' resistance to the pro-apoptotic proteins BAX and BAK. The anti-apoptotic protein Mcl-1 plays a particularly central role in conferring cancer cell resistance in certain instances, and obatoclax potently interferes with the direct interaction between Mcl-1 and BAK in the intact mitochondrial outer membrane and inhibited the association between Mcl-1 and BAK in intact cells. It is thought that Mcl-1 regulates BAK within the mitochondrial outer membrane (Nguyen, M. et al. Proc Natl Acad Sci USA 2007, 104(49): 19512).</P> <P>During the recent annual meeting of the American Society of Hematology, results were presented from several preclinical and clinical studies evaluating obatoclax. Obatoclax inhibited cell proliferation and induced apoptosis in drug-resistant non-Hodgkin's B-cell lymphoma cell lines, including those resistant to rituximab. No cytotoxicity was seen with obatoclax in human peripheral blood leukocytes from different donors (Martinez-Paniagua, M.A. et al., Abst 1402). Experiments in chronic lymphocytic leukemia cells showed that increased levels of phosphorylated Bcl-2 reduced obatoclax cytotoxic activity. The synergistic activity seen with obatoclax and bortezomib was also regulated by Bcl-2 phosphorylation, and combination with ERK inhibitors showed potential in increasing the activity of the compound (Galan, P.P. et al., Abst 3464). </P> <P>A phase I study was conducted in patients with relapsed or refractory mantle cell lymphoma to evaluate the combination of obatoclax and bortezomib. The dosage selected for further assessment was 45 mg/1.3 mg/m2, administered i.v. on days 1, 4, 8, and 11 of a 21-day cycle which displayed acceptable tolerability. Evidence of activity was seen (Goy, A. et al., Abst 2569). Prolonged infusions of obatoclax were assessed in patients with hematological malignancies enrolled in a phase I trial, with 21 patients receiving obatoclax 20-28 mg/m2/day weekly or 20 mg/m2/day for 2, 3 or 4 consecutive days every 2-3 weeks. Multiple-day infusions were well tolerated. A patient with acute myelogenous leukemia achieved a cytogenetic complete response with complete hematological recovery and transfusion independence on day 9 after starting weekly obatoclax infusions (Schimmer, A.D., Abst 892). </P> <P>Obatoclax is currently being evaluated in a phase II trial in patients with chronic idiopathic myelofibrosis (CIMF). Patients are given a dose of 60 mg by 24-hour infusion every 2 weeks. In 14 patients with data available after administration of 102 cycles, grade 3 adverse events included peripheral edema, dyspnea, fatigue, diarrhea and chest pain. Plasma obatoclax concentrations appeared to reach steady state before the end of the infusion. Of 8 previously treated patients, 2 had a Clinical Improvement Response lasting 6 months with increases in hemoglobin and red blood cell transfusion independence while continuing chronic recombinant erythropoietin therapy to which they had not previously responded. Of 6 previously untreated patients, 3 were still on therapy with stable disease at the time results were reported (Verstovsek, S. et al., Abst 3553). </P> <P>Obatoclax is also undergoing phase II clinical evaluation for the treatment of Hodgkin's lymphoma, myelofibrosis with myeloid metaplasia, myelodysplasia and follicular lymphoma. Early clinical studies are also under way for the treatment of chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute myeloid leukemia, relapsed or refractory non-small cell lung cancer, relapsed or refractory mantle cell lymphoma and solid tumors. The NCI is conducting studies of obatoclax in combination with topotecan in patients with relapsed or refractory small cell lung cancer and solid tumors. Obatoclax was granted orphan drug designation by the FDA in 2004 for the CLL indication.</P> http://www.prous.com/molecules/default.asp?ID=166 <p align="center"><img src="http://www.prous.com/images/moleculas/343476.gif"></p><P>Synta Pharmaceuticals' <B>elesclomol</B> (STA-4783), a first-in-class small-molecule oxidative stress inducer, has been selected as the Molecule of the Month. Elesclomol induces an oxidative stress response in cancer cells by inducing heat shock protein 70 (Hsp70), thereby inducing apoptosis and enhancing the activity of certain anticancer agents such as paclitaxel. In October, Synta signed a global collaboration agreement with GlaxoSmithKline for the joint development and commercialization of elesclomol. Under the terms of the agreement, the companies will share responsibility for development and commercialization of elesclomol in the U.S. and GSK will have exclusive responsibility for development and commercialization of the product outside the U.S. In addition, Synta will also be eligible to receive potential milestone payments for events leading to approval of elesclomol in metastatic melanoma, and further development and regulatory milestones across various indications. Elesclomol was granted fast-track designation by the FDA in 2006 for the treatment of metastatic melanoma.</P> <P>In a double-blind, randomized, multicenter phase II trial reported last summer at ASCO, 81 patients with metastatic melanoma were randomized to receive paclitaxel (80 mg/m2) plus elesclomol (213 mg/m2) or paclitaxel alone for three weeks on a four-week schedule. Intent-to-treat analysis revealed a median progression-free survival (PFS) of 3.68 and 1.84 months, respectively, for the combination versus paclitaxel alone and a response rate of 15.1&#37; and 3.6&#37;, respectively. Chemotherapy-naive patients showed an even greater benefit on the combination, with a median PFS of 8.28 and 2.40 months, respectively, for the combination and paclitaxel alone. Moreover, several patients progressing on paclitaxel alone showed a delay in the time to progression when elesclomol was added. Adverse event rates were similar in both treatment groups, the most common events in the combination group being fatigue, alopecia, constipation, nausea, arthralgia, insomnia, diarrhea, anemia and hypoesthesia (O'Day, S. et al., 43rd Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2007: Abst 8528; Kirshner, J. et al. 43rd Annu Meet Am Soc Clin Oncol (ASCO) (June 1-5, Chicago) 2007: Abst 14107).</P> <P>In mid-November, Synta announced that the first patients had been treated in the SYMMETRY(SM) (Synta Metastatic Melanoma Elesclomol Trial) trial, a global, pivotal phase III clinical trial to evaluate the safety and efficacy of elesclomol in patients with stage IV metastatic melanoma. Synta has also successfully completed the special protocol assessment process, reaching agreement with the FDA on the design, conduct and planned analyses of the trial. The trial is enrolling patients with stage IV metastatic melanoma who have not received prior chemotherapy but who may have already been treated with non-chemotherapeutic agents such as biologics. Approximately 630 patients will be enrolled in the blinded, randomized, controlled study, which will be conducted at approximately 150 centers worldwide. Patients will be randomized (1:1) to elesclomol (213 mg/m2) plus paclitaxel (80 mg/m2) or paclitaxel alone (80 mg/m2) and will receive three weekly treatments and one week without treatment per each four-week cycle. If tolerated, treatment will continue until disease progression. The control arm treatment, the combination arm treatment, the doses, the schedule and the primary endpoint of progression-free survival (PFS), are the same as in the above phase IIb trial. There are two planned analyses for the primary endpoint of PFS: an interim analysis to assess safety and non-futility will be conducted and reviewed by an independent data safety monitoring board, and the final analysis for PFS will be initiated when enrollment is close to completion. At the time of the final analysis for PFS, a first interim analysis will also be performed for overall survival (OS), a secondary endpoint. Following these, two additional analyses for OS are planned: a second interim analysis and a third and final OS analysis. Synta expects to complete the primary endpoint analysis by the end of 2008 and file an NDA with the FDA by the first half of 2009. </P> http://www.prous.com/molecules/default.asp?ID=165 <p align="center"><img src="http://www.prous.com/images/moleculas/356099.gif"></p><P>Sodium-dependent glucose transport proteins (SGLTs) play a key role in maintaining glucose homeostasis in the human body. SGLTs are found in the intestine (SGLT1) and the kidney (SGLT1 and SGLT2). Renal SGLT reabsorbs glucose from the renal filtrate, thus preventing loss of glucose in urine. Renal SGLTs are found in the pars convoluta of the nephron's proximal tubule. SGLTs use the energy from a positive sodium gradient to transport glucose across the membrane. SGLT2 has a 1:1 ratio of sodium-glucose transport. SGLT1 works similarly but has a 2:1 ratio of sodium-glucose transport. SGLT2 accounts for 98&#37; of renal glucose reabsorption, whereas SGLT1 accounts for the remaining 2&#37;. Transcellular glucose transport is facilitated by the basolateral membrane glucose transporters GLUT2 and GLUT1. Binding of glucose to one side provokes a conformational change that causes the release of glucose into the other side of the membrane. SGLT2 inhibitors are being developed as potential antidiabetic agents because of their ability to specifically reduce transcellular epithelial glucose reabsorption.</P> <P>Clinical studies of <B>dapagliflozin</B> (BMS-512148; Bristol-Myers Squibb/AstraZeneca), an inhibitor of the sodium-glucose cotransporter (SGLT2), were presented at the 2007 meeting of the European Association for the Study of Diabetes (EASD). Two studies of dapagliflozin in healthy subjects were reported. In one, 40 subjects received doses of 2.5, 10, 20, 50 or 100 mg p.o. o.d. or placebo for 14 days. Dapagliflozin was safe and well tolerated, with rash the most common adverse event. Maximal inhibition of renal glucose resorption was seen with doses of 20-100 mg (Brenner, E. et al. 43rd Eur Assoc Study Diabetes (EASD) Annu Meet (Sept 17-21, Amsterdam) 2007, Abst 0765). Single dapagliflozin doses of 2.5-500 mg or placebo were given to healthy fasted subjects (n = 64) in a second study, and the dapagliflozin doses were well tolerated. Administration of dapagliflozin 250 mg after a high-fat meal delayed the tmax but did not greatly affect the AUC (Li, L. et al. 43rd Eur Assoc Study Diabetes (EASD) Annu Meet (Sept 17-21, Amsterdam) 2007, Abst 0764).</P> <P>An exclusive animation depicting SGLT-2 as a target for the development of antidiabetic drugs has been published on Prous Science’s LifeSciChannel and in the Integrity&reg; Disease Briefings knowledge area, where it can be found in the “Diabetes” report. Dapagliflozin, the most advanced compound in this novel class of oral antidiabetic agents, is currently in phase III clinical testing for the treatment of type 2 diabetes. The drug was discovered by Bristol-Myers Squibb and has been licensed to AstraZeneca for development and commercialization. Two trials are currently recruiting participants: one in diabetic subjects not adequately controlled on metformin alone (NCT00528879) and the other in those not adequately controlled with diet and exercise alone (NCT00528372).</P> http://www.prous.com/molecules/default.asp?ID=164 <p align="center"><img src="http://www.prous.com/images/moleculas/306386.gif"></p><P><B>Sugammadex sodium</B>, a reversal agent used during general anesthesia, is the first selective relaxant binding agent (SRBA), a drug-specific cyclodextrin that is specifically designed to reverse the effects of the muscle relaxant rocuronium bromide (Esmeron<SUP>&reg;</SUP>/Zemuron<SUP>&reg;</SUP>) when the latter is used as a component of general anesthesia during surgical procedures. Current reversal agents can only be administered when muscle relaxation is starting to wear off naturally; however, sugammadex can achieve reversal following rocuronium bromide administration within three minutes, regardless of the depth of block. Furthermore, in studies to date, sugammadex has shown less adverse effects than the currently available agents. Sugammadex encapsulates the muscle relaxant and forms a very tight, water-soluble host-guest complex, removing the drug from its site of action and rendering it inactive. A chemically modified gamma-cyclodextrin compound, sugammadex alone does not have an appreciable activity in the body. </P> <P>Drug developer Organon has described safety and efficacy data obtained in more than 1,700 patients, including data from ten global phase III trials. In these studies, sugammadex has generally demonstrated the ability to reverse shallow and profound depths of rocuronium-induced neuromuscular blockade within three minutes, thereby enabling control of the onset and offset of skeletal muscle relaxation through the use of both drugs. In the pivotal phase III Aurora trial, reported last summer, sugammadex induced a 9-12 times faster reversal of neuromuscular blockade as compared to neostigmine, without evidence of postoperative residual curarization (PORC) or reoccurrence of muscle relaxation. The Aurora trial compared the efficacy of sugammadex and neostigmine for the reversal of shallow neuromuscular blockade induced by single or multiple doses of either rocuronium or vecuronium, another neuromuscular blocking agent. The international, randomized, multicenter, parallel-group trial was conducted at 13 European centers and enrolled 198 patients. In the trial sugammadex was administered at reappearance of T2 and achieved significantly faster recovery of the T4/T1 ratio to 0.9 compared with neostigmine. Median time to recovery was 1.4 minutes for sugammadex versus 17.6 minutes for neostigmine following rocuronium administration and 2.1 minutes versus 18.9 minutes respectively following vecuronium administration. There were no clinical events due to PORC or recurarization reported for either group. Data from three other phase III trials demonstrated that sugammadex was effective and well tolerated in pediatric patients, in patients with mild or moderate impaired renal function and in comparison with neostigmine-glycopyrrolate after cisatracurium. Based on data from these and other studies, Organon has filed for approval of sugammadex in the E.U. Filings are proceeding according to plan in Japan and the U.S.</P> http://www.prous.com/molecules/default.asp?ID=163 <p align="center"><img src="http://www.prous.com/images/moleculas/196024.gif"></p><P>The chemokine CXCR4 (SDF-1) antagonist <B>plerixafor hydrochloride</B> (AMD-3100, Mozobil&trade;) is in phase III clinical development at Genzyme, which acquired the product through its acquisition of AnorMED in late 2006. AnorMED had been developing plerixafor for the treatment of HIV, but discontinued the trials in 2001 due to abnormal cardiac activity and lack of efficacy. </P> <P>By blocking CXCR4, a specific cellular receptor, plerixafor triggers the rapid movement of stem cells out of the bone marrow and into circulating blood, where they can be collected for use in stem cell transplant. The current standard of care for stimulating the mobilization of stem cells from the bone marrow is with granulocyte colony-stimulating factor (G-CSF). Plerixafor is being developed in combination G-CSF as a novel stem cell mobilization regimen in patients undergoing stem cell transplantation for the treatment of non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). The trials are designed to evaluate the ability of plerixafor plus G-CSF to rapidly increase the number of peripheral blood stem cells capable of engraftment, thereby increasing the proportion of patients reaching a peripheral blood stem cell target and, as a result, reducing the number of apheresis sessions required for patients to collect a target number of peripheral blood stem cells. </P> <P>In July, Genzyme announced that it had successfully completed a first phase III trial of plerixafor in non-Hodgkin's lymphoma, and that the trial had met its primary and secondary endpoints. The randomized, double-blind, placebo-controlled trial examined the effectiveness of plerixafor in increasing the number of hematopoietic stem cells collected for a transplant in 298 patients undergoing a hematopoietic stem cell transplant (HSCT) for NHL at medical centers in the U.S. and Canada. The study compared the hematopoietic stem cell yields from patients treated with plerixafor plus G-CSF to patients treated with G-CSF in combination with placebo. In the primary efficacy endpoint, 59&#37; of patients treated with plerixafor/G-CSF achieved the target threshold for collection of at least 5 million CD34+ cells/kg from the peripheral blood with 4 or fewer days of apheresis sessions, compared with 20&#37; of patients in the G-CSF/placebo group. The three-fold increase was highly statistically significant in favor of the study drug. The 40&#37; absolute difference between the two treatment groups was nearly double the target that Genzyme had prospectively defined in the protocol for the study, which was reviewed by the FDA as part of the Special Protocol Assessment (SPA) process. In the secondary efficacy endpoint, nearly 87&#37; of patients treated with plerixafor/G-CSF achieved the minimum level of stem cells generally associated with a successful transplant in 4 or fewer days of apheresis sessions, compared with approximately 47&#37; in the placebo arm. The other secondary efficacy endpoints were supportive of these findings, including number of days needed to reach target ranges for stem cell mobilization, success of engraftment, number of days needed to engraft and durability of the engraftment for the first 100 days. </P> <P>A few weeks later, Genzyme announced similar positive results from a separate phase III trial comparing plerixafor/G-CSF to G-CSF/placebo for stem cell mobilization prior to autologous HSCT in patients with multiple myeloma. Similar to the NHL results above, plerixafor was shown to enable 72&#37; of patients to achieve target thresholds for stem cell collection (&ge; 6 million CD34+ cells/kg) from peripheral blood with two days or fewer of apheresis sessions, as compared to only 34&#37; of patients in the G-CSF/placebo group. The study's secondary outcomes were also met, showing a statistically significant result in favor of plerixafor in the number of patients reaching the target threshold within 4 days of apheresis, and the number of patients who reached at least 2 million cells collected in 4 days. Other secondary outcomes were also supportive, including success of engraftment, number of days needed for engraftment, and durability of engraftment for the first 100 days. The trial also robustly met the primary endpoint specified by EMEA, which is a composite of successful mobilization and engraftment. The study drug was well tolerated in both trials.</P> <P>Based on these results, Genzyme expects to file for U.S. and European approval in both the lymphoma and multiple myeloma indications in the first half of 2008. Plerixafor has been granted SPA and orphan drug status in the U.S. and the E.U., and the pivotal trials have undergone special protocol assessment by the FDA and protocol assistance by the EMEA. </P> http://www.prous.com/molecules/default.asp?ID=162 <p align="center"><img src="http://www.prous.com/images/moleculas/398997.gif"></p><P><B>Dimebolin hydrochloride</B> (Dimebon&trade;) is an orally-available, small-molecule agent that is in clinical testing for the treatment of Alzheimer's and Huntington's diseases-two progressive, devastating conditions with limited treatment options. Based on clinical and preclinical data generated to date, developer Medivation believes that dimebolin operates via a novel mechanism of action and may exert a neuroprotective effect in multiple areas of the central nervous system. Dimebolin appears to block a new target that involves mitochondrial pores, which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process. Dimebolin also blocks both cholinesterase and the NMDA receptor simultaneously. These two targets provide the mechanism of action for all FDA-approved drugs for Alzheimer's disease, although no marketed drug is known to have an effect on both pathways.</P> <P>In July, the Huntington Study Group (HSG) reported that recruitment of participating sites for the DIMOND phase II trial (ClinicalTrials.gov identifier: NCT00497159), which will evaluate dimebolin in subjects with mild to moderate Huntington's disease (HD), is currently in progress. The randomized, double-blind, placebo-controlled phase II trial will enroll up to 90 patients at some 15 research centers in the U.S. and U.K. It is designed to evaluate the safety and tolerability of dimebolin during three months of treatment, as well as its effects on cognition, motor signs and overall functioning of HD patients aged 18 years or older. Patient enrollment will begin during the summer of 2007. </P> <P>In June, the company reported that benefits of dimebolin hydrochloride over placebo in a double-blind, placebo-controlled phase II study in mild to moderate Alzheimer's disease (AD) were statistically significant on all five study endpoints at 12 months. In the multicenter, double-blind trial, 183 patients with mild to moderate AD were randomized to oral dimebolin (60 mg/day) or placebo for six months. Of these patients, 134 subsequently consented to continue treatment for up 12 months in their same treatment group. On the primary endpoint, the ADAS-cog, dimebolin caused an improvement over placebo of 6.9 points at one year. On the global function endpoint used in this study, the CIBIC-plus, dimebolin's benefit over placebo was 0.8 points at 12 months. Global function improved or remained stable in 69&#37; of treated Alzheimer's disease patients after one year of dimebolin therapy. Dimebolin produced an aggregate benefit over placebo in this study that was larger at 12 months than at six. After a year of treatment, dimebolin's benefit over placebo was greater than six-month levels on the ADAS-cog (6.9 points vs. 4.0 points), CIBIC-plus (0.8 points vs. 0.6 points), and ADCS-ADL (5.2 points vs. 2.9 points) scales; however, only the ADAS-cog difference reached statistical significance. Dimebolin's benefit over placebo on the other two endpoints (the Mini Mental State Exam, [MMSE] and the Neuropsychiatric Inventory [NPI]) at six months was maintained at one year. Dimebolin-treated patients experienced significantly fewer serious adverse events than placebo-treated patients (3.4&#37; vs. 11.7&#37;). The most frequent adverse events associated with treatment were dry mouth, depressed mood/depression and sweating. Six-month phase III studies of dimebolin in AD will begin next year.</P> <P>Dimebolin hydrochloride, which also acts as an antihistamine, is marketed in Russia by the Russian Academy of Sciences for the treatment of skin allergy and allergic rhinitis. <P> <P><FONT COLOR="Navy"><I>The information in this summary was derived from company sources and the Prous Science Integrity&reg; and is current as of July 16, 2007. For continuously updated information on dimebolin, including new bibliographical references, Disease Briefings, clinical trials, regulatory information, patents and more, consult Integrity&reg;.</I></FONT></P> http://www.prous.com/molecules/default.asp?ID=161 <p align="center"><img src="http://www.prous.com/images/moleculas/218793.gif"></p><P>The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that belongs to a family of phosphatidylinositol kinase-related kinases, which mediate cellular responses to stresses such as DNA damage and nutrient deprivation. mTOR acts as a target for the cell cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. mTOR plays a critical role in controlling cell growth, since it receives stimulatory signals from Ras and PI-3 kinase downstream from growth factors, as well as information on nutrient levels in the form of amino acid, glucose and oxygen availability. Its function is to integrate extracellular signals with amino acid availability and energy status of the cell and modulate translation rates of the proteins and other metabolic events accordingly. mTOR phosphorylates eIF4E binding proteins and the ribosomal protein S6 kinases to regulate protein translation rates, and its activity is closely associated with a 12-kDa immunophilin FK506-binding protein (FKBP12). mTOR inhibitors have been identified as promising agents for cancer prevention and/or therapy. </P> <P>The cell cycle inhibitor <B>temsirolimus</B> (CCI-779) works by specifically inhibiting mTOR-driven cell proliferation. Based on its promising anticancer activity, temsirolimus has been evaluated in a range of oncology indications including renal cell carcinoma, lymphoma, leukemia, sarcoma, glioblastoma, melanoma, non-small cell lung, ovarian, prostate, breast and endometrial cancers and more. In late May, the U.S. FDA approved temsirolimus for the treatment of renal cell carcinoma (RCC). The rapid approval of temsirolimus in the U.S. was facilitated by both fast-track and priority review status. Temsirolimus has orphan drug status in both the U.S. and E.U. for the renal cell carcinoma indication. </P> <P>In a three-arm, phase III trial of 626 patients with advanced RCC and poor prognosis who had received no prior systemic therapy, temsirolimus significantly increased median overall survival by 49&#37; compared to interferon alpha (10.9 months vs. 7.3 months). The mTOR inhibitor also was associated with a statistically significant improvement over interferon alpha in the secondary endpoint of progression-free survival (5.5 months vs. 3.1 months). The combination of temsirolimus and interferon alpha did not result in a significant increase in overall survival when compared with interferon alpha alone (Hudes, G. et al., New Engl J Med 2007, 356(22): 2271-81). </P> <P>Drug manufacturer Wyeth plans to launch temsirolimus (<I>Torisel</I>&trade;) in July. As part of a postmarketing commitment, Wyeth has agreed to submit two completed study reports and data sets: one on a thorough QT prolongation study and one on an ongoing hepatic impairment study. </P> <P><FONT COLOR="Navy"><I>The information in this summary was derived from Prous Science Integrity&reg; and is current as of June 26, 2007. For continuously updated information on temsirolimus, including new bibliographical references, clinical trials, regulatory information, patents and more, consult Integrity&reg;. </I></FONT></P> http://www.prous.com/molecules/default.asp?ID=160 <P>Paroxysmal nocturnal hemoglobinuria (PNH, also sometimes called Marchiafava-Micheli Syndrome) is a rare, incurable acquired blood disorder characterized by a decreased number of red blood cells (anemia) and the presence of blood in the urine (hemoglobinuria) and plasma (hemoglobinemia), which is most evident after sleeping. PNH is associated with a high risk of major thrombotic events, most commonly thrombosis of large intra-abdominal veins. Thrombosis is an important cause of mortality among PNH patients. The disease may arise in relation to aplastic anemia, and may progress to acute myelogenous leukemia. The prognosis for patients with PNH is bleak, and most patients do not survive more than ten years from the time of diagnosis. Prior to 2007, there were no drugs specifically approved for the indication of paroxysmal nocturnal hemoglobinuria.</P> <P><B>Eculizumab</B> (Soliris&trade;), developed by Alexion Pharmaceuticals, was approved and launched earlier this year in the U.S., becoming the first treatment ever for PNH, as well as the first ever marketed therapeutic with a novel mechanism of action: complement inhibition. Eculizumab is a recombinant humanized monoclonal antibody that blocks the complement cascade through binding to the terminal complement protein C5. The European Committee for Human Medicinal Products has also recommended the E.U. approval of the product. Eculizumab has orphan drug status in both the U.S. and the E.U.</P> <P>PNH is caused by an acquired mutation in a gene (<I>PIG-A</I>) encoding a protein essential for the synthesis of glycosylphosphatidylinositol (GPI), a plasma membrane lipid that allows the anchoring of several proteins to the cell surface. Patients with PNH produce hematopoietic clones with complete or partial deficiency of GPI-linked proteins such as CD55 and CD59, two proteins that protect cells from complement attacks. This lack of protection and the resulting susceptibility to complement-mediated cell destruction is the primary cause of the symptoms commonly found in PNH (i.e., intravascular hemolysis, venous thrombosis and hemoglobinuria). Eculizumab specifically targets this defect.</P> <P>Eculizumab proved to be a safe and effective therapy for PNH in three multinational clinical studies: TRIUMPH, a placebo-controlled 26 week phase III study involving 87 PNH patients; SHEPHERD, an open-label, 52-week phase III trial involving 97 PNH patients; and E05-001, a long-term extension study. These studies showed that the complement inhibitor reduced hemolysis in every treated patient. Hemolysis was dramatically reduced from a baseline LDH of 2,032 U/l to 239 U/l at week 26. The reductions in hemolysis occurred within one week of initiating treatment and were sustained for periods of up to 54 months with continued dosing of eculizumab. The reduction in hemolysis expands the number of circulating PNH cells, and thereby increases the hemoglobin level. Hemoglobin stabilization and the number of transfused packed red blood cell units, the pivotal study's coprimary endpoints, were both achieved; half of the eculizumab-treated patients achieved hemoglobin stabilization compared with none of the patients in the placebo group, and the median number of transfusions was reduced from 10 units/patient to 0 units/patient, respectively. Patients receiving eculizumab therapy reported less fatigue and improved health-related quality of life. There were fewer thrombotic events with the treatment than during the same period of time prior to treatment.</P> http://www.prous.com/molecules/default.asp?ID=159 <p align="center"><img src="http://www.prous.com/images/moleculas/162578.gif"></p><p><b>Paliperidone</b>, the active metabolite of the known atypical antipsychotic risperidone, was launched in the U.S. in 2007 for the treatment of schizophrenia. The product, known as Invega&trade;, was developed by Johnson &amp; Johnson based on Alza's OROS drug delivery system, which is designed to deliver paliperidone over a 24-hour period. </p> <p>Data from several studies adding detail to previously released clinical trial data on the effects of paliperidone extended-release tablets in schizophrenia were made available at the 11th International Congress on Schizophrenia Research, celebrated March 8-April 1, 2007 in Colorado Springs. Data pooled from three 52-week, open-label extension studies of paliperidone ER in 1,083 patients with acute schizophrenia, treatment-related adverse events occurred in 76&#37; of patients and were most often insomnia, headache, akathisia, anxiety and psychotic disorder. Long-term safety was consistent with results from short-term studies, and efficacy was maintained (Eerdekens, M. et al., Abst P2-290). Data from clinical studies was used to compare paliperidone to risperidone in an analysis conducted to fill the absence of a direct comparison. The reduction in PANSS total score was greater with paliperidone than with risperidone, and paliperidone was associated with lower rates of akathisia, restlessness, anxiety, insomnia, somnolence, dizziness and gastrointestinal disturbances (Schooler, N. et al., Abst P2-373). Patients who had been treated with risperidone were treated with fixed doses of paliperidone or placebo. Paliperidone was associated with a significant improvement in mean PANSS total score, mean PANSS factor change scores, mean PSP and CGI scores at endpoint (Canuso, C. et al., Abst P2-372). The efficacy of paliperidone was also investigated in 199 patients previously treated with olanzapine. The mean PANNS total score improved significantly with paliperidone as compared to placebo, and all mean PANSS factor change scores, PSP and CGI scores were significantly improved at endpoint with paliperidone (Dirks, B. et al., Abst P2-371).</p> <p>A regulatory application has been filed in the E.U. for the schizophrenia indication. Phase III trials are under way for the treatment of bipolar disorder and schizoaffective disorder. Paliperidone enters a market currently dominated by five antipsychotic drugs, which together reap worldwide sales of more than US $14 billion annually, according to Integrity&reg;. </p> http://www.prous.com/molecules/default.asp?ID=158 <p align="center"><img src="http://www.prous.com/images/moleculas/283279.gif"></p><P>Oral antiplatelet drugs form the cornerstone of treatment for patients with vascular disease, due to their demonstrated beneficial effects on reducing cardiovascular morbidity and mortality. AstraZeneca’s <b>ticagrelor</b> (formerly AZD-6140), the first reversible oral P2Y12 receptor antagonist, is being developed as an alternative to clopidogrel, currently a market leader among antiplatelet drugs. Ticagrelor is expected to be especially indicated for the treatment of the approximately 15-30&#37; of all atherosclerosis patients who do not respond to clopidogrel, as well as those patients who must undergo surgery and thus are not candidates for treatment with clopidogrel, which has long-acting and irreversible antiplatelet effects. </p> <p>Antiplatelet drugs such as clopidogrel and ticagrelor inhibit platelet activation by ADP, while leaving the final common platelet aggregation pathway, which is mediated by the fibrinogen receptor, intact. This provides the advantage of a wider therapeutic window between the desired inhibition of unwanted thrombosis and the undesirable clinical bleeding that occurs through less targeted inhibition. Unlike clopidogrel, ticagrelor is a non-thienopyridine that acts directly on the P2Y12 receptor, with a rapid onset of action of approximately 2 hours. Being a reversible antagonist, it also has a rapid offset of action of approximately 12 hours. Using a twice-daily dosing regimen, the DISPERSE and DISPERSE2 clinical studies have demonstrated more potent and consistent platelet aggregation inhibition as compared to clopidogrel. Some unwanted but self-limited side effects (dyspnea, bradycardic effect and increases in uric acid) have been observed that will require further evaluation in phase III trials. </p> <p>Ticagrelor is currently being evaluated in a randomized, double-blind, parallel-group, international phase III efficacy and safety study in comparison with clopidogrel for the prevention of vascular events in patients with non-ST or ST elevation acute coronary syndromes (ACS) (ClinicalTrials.gov identifier NCT00391872). </p> http://www.prous.com/molecules/default.asp?ID=157 <p align="center"><img src="http://www.prous.com/images/moleculas/377425.gif"></p><P>Attention deficit/hyperactivity disorder (ADHD; also known as attention deficit disorder or hyperkinetic disorder) is a complex neuropsychiatric and behavioral disorder characterized by inattentive, hyperactive and impulsive behavior. Although estimates vary widely, the Centers for Disease Control and Prevention (CDC) estimates that nearly 8&#37; of school-age children in the U.S. have ADHD, making this one of the most common behavioral and psychological disorders encountered in pediatric medicine.</P> <P>Psychostimulant drugs have been used in the treatment of attention deficit/hyperactivity disorder for more than 60 years. The most widely used and well studied psychostimulant is methylphenidate (<em>Ritalin</em>); other drugs in this class include dextroamphetamine and pemoline. Nine out of ten patients improve with psychostimulants. Through their predominantly dopaminergic mechanism of action, drugs in this class produce beneficial effects on the defining symptoms of ADHD (overactivity, attention span, impulsivity, self-control) and associated aggressiveness, although they may not correct all behavior problems. However, psychostimulants may be addictive to adolescents and adults if misused, and this concern has generated significant debate among individuals with ADHD and their families. These drugs are not considered to be addictive in young children; nonetheless, administration of stimulants in the U.S. is closely controlled.</P> <P>In an attempt to reduce the potential liability of addiction and abuse, New River Pharmaceuticals developed <strong>lisdexamfetamine dimesilate</strong>, an amphetamine prodrug consisting of d-amphetamine conjugated to L-lysine. The drug is therapeutically inactive until it is hydrolyzed in the digestive tract, and furthermore has a prolonged duration of effect, with efficacy lasting for a full treatment day. Data from phase II and III trials, conducted by New River in collaboration with development partner Shire, demonstrated statistically significant improvements in ADHD symptoms in patients aged 6-12 years receiving lisdexamfetamine at all doses tested (30, 50 and 70 mg) as compared to those given placebo. In human drug abuse studies, oral and intravenous administration of lisdexamfetamine produced subjective responses on a scale of &quot;drug-liking effects&quot; (DLE, a measure of relative preference among substance abusers, used in clinical abuse studies) that were less than those reported for d-amphetamine at equivalent doses.</P> <P>In February, the U.S. FDA approved lisdexamfetamine dimesilate (<em>Vyvanse</em>&reg;) for the treatment of attention deficit/hyperactivity disorder in pediatric patients. The label received with the approval letter includes information about the drug’s extended duration of effect and abuse-related drug-liking characteristics, which differentiate <em>Vyvanse</em>&reg; from other ADHD medications. The FDA has proposed that <em>Vyvanse</em>&reg; be classified as a Schedule II controlled substance, and this proposal has been accepted by the U.S. Drug Enforcement Administration (DEA). Pending final scheduling designation, product launch is anticipated in the second quarter of 2007. In related news, Shire announced just days prior to the NDA approval that it would acquire New River and, as a result, all rights to the product.</P> http://www.prous.com/molecules/default.asp?ID=156 <P>GlaxoSmithKline is developing <B>Daronrix&reg;</B>, a “mock-up” pandemic influenza vaccine for the prophylaxis of influenza infection. The vaccine candidate, an inactivated whole-virion H5N1 vaccine formulated with an alum salt adjuvant, is intended for use once a pandemic has officially been declared by the WHO/E.U. and would be modified to include the exact pandemic strain, once such a strain has been identified. The vaccine has been filed for approval in the E.U. In December 2006, a positive opinion was received in the E.U. for the treatment of influenza.</P> <P>Daronrix&reg; represents a first step in the preparation against a possible H5N1 pandemic. The benefit of this vaccine, according to the Committee for Medicinal Products for Human Use summary of positive opinion, “can mount an appropriate immune response in individuals that are immunologically naïve against the mock-up virus strain.” The submission dossier was based on a series of data, including a pivotal clinical trial involving 400 healthy adults that evaluated the safety, reactogenicity and immunogenicity of different doses of the candidate vaccine and compared it to different doses of nonadjuvanted H5N1 influenza vaccine. It was concluded from the study, that two doses containing at least 15 mg of H5N1 HA antigen are required to meet the European Medicines Agency (EMEA)'s licensing criteria for seroprotection rate (SP(3)70&#37;), seroconversion rate (SC(3)40&#37;) and seroconversion factor (2.5). The vaccine also had a safety and reactogenicity profile similar to non-adjuvanted vaccine. </P> <P>GSK has also submitted a second file to the European regulatory authorities for its second-generation H5N1 candidate vaccine. Upon licensure, this second vaccine could potentially be used as part of a proactive pre-pandemic vaccination campaign in advance of a pandemic and give broad protection against different H5N1 strains. This new-generation vaccine candidate could also be adapted for use as a pandemic vaccine once the flu strain causing the pandemic has been identified. Other companies known to be working on potential pandemic influenza vaccines (according to Integrity&reg;) include Novartis, whose MF59-adjuvanted H5N1 vaccine is also under review in the E.U.; as well as Baxter, CSL, Crucell, sanofi pasteur, Generex, Sinovac, PowderMed, MedImmune and the National Institute of Allergy and Infectious Diseases (NIH), each of which has a proprietary H5N1 pandemic influenza vaccine in early clinical testing.</P> http://www.prous.com/molecules/default.asp?ID=155 <P>Roche's R-744 (CERA, Mircera&reg;), the first continuous erythropoietin receptor activator, is in late-stage development for the treatment of renal anemia in chronic kidney disease (CKD) patients, including those on dialysis and not on dialysis. Unlike traditional erythropoietin-stimulating agents (ESAs), Mircera has a greatly reduced affinity for the receptors involved in stimulating red blood cell production, allowing it to stimulate red cell production without immediate internalization and degradation. This is believed to play a role in providing targeted, stable and sustained control of anemia. Recently released phase III study data, including data presented in November at the American Society of Nephrology (ASN)'s 39&trade; annual meeting, highlighted Mircera's ability to extend dosing intervals up to once monthly while maintaining stable hemoglobin levels in dialysis patients. Current antianemia treatments must be administered as frequently as three times weekly. </P> <P>The ARCTOS and AMICUS studies, presented at the ASN meeting, examined the effectiveness of intravenous and subcutaneous Mircera at extended administration intervals in correcting anemia and maintaining hemoglobin (Hb) levels in treatment-naive patients with CKD either on dialysis or not. The studies used epoetin alfa/beta or darbepoetin alfa as comparator agents in a noninferiority design. In the first study, ARCTOS (Administration of C.E.R.A. in CKD Patients to Treat Anaemia with a Twice Monthly Schedule), CKD patients not on dialysis (n = 324) were randomized to s.c. CERA once weekly (0.6 mcg/kg) or s.c. darbepoetin alfa once weekly (0.45 mcg/kg), with responders to CERA at week 28 randomized to CERA given once every 2 or 4 weeks for 24 weeks. Response rates at week 28 were 97.5 and 96.3&#37; with CERA and darbepoetin alfa, respectively, and monthly administration of CERA proved effective in maintaining Hb levels (Macdougall, I.C. et al. 39th Annu Meet Am Soc Nephrol (Nov 16-19, San Diego) 2006, Abst SA-PO208). The second study, AMICUS (C.E.R.A. AdMinistered Intravenously for Anaemia Correction and SUStained Maintenance in Dialysis), examined intravenous Mircera once every two weeks epoetin alfa in 181 dialysis patients. The response rate at the end of the correction period was 93.3&#37; with CERA and 91.3&#37; with epoetin; the median CERA dose at the time of response was 0.6 mcg/kg every 2 weeks (Klinger, M. et al. 39th Annu Meet Am Soc Nephrol (Nov 16-19, San Diego) 2006, Abst SA-PO212).</P> <P>Regulatory filings occurred in the U.S. and E.U. in April of last year. In December, Roche submitted additional data to the FDA to support its BLA for Mircera. As a result, the FDA has granted Roche a three-month extension to the review period. Roche is seeking approval for Mircera in the treatment of anemia associated with chronic kidney disease (CKD), including patients on dialysis or not on dialysis. The BLA is based on data from all six studies that comprise the phase III program. This included treating anemia in previously untreated patients and maintaining hemoglobin after conversion from epoetin alfa/beta or darbepoetin alfa. The program consisted of two treatment/correction and four conversion/maintenance studies of both intravenous and subcutaneous Mircera at extended administration intervals of up to once monthly.</P> http://www.prous.com/molecules/default.asp?ID=154 <p align="center"><img src="http://www.prous.com/images/moleculas/276526.gif"></p><P>The treatment of bacterial infections is increasingly complicated by the emergence of resistant strains, which lends an urgency to the development of new drug classes that would circumvent said resistance. <B>Retapamulin</B> is the first in one new class of antibiotics called the pleuromutilins and demonstrates a unique mechanism of action. By binding to a distinct site on the 50s sub-unit of the bacterial ribosome, retapamulin inhibits protein synthesis. <I>In vitro</I>, retapamulin has shown no target-specific cross-resistance to other established classes of antibiotics. GlaxoSmithKline has filed for marketing approval of the drug, which will have the trade name Altabax&trade;, in the U.S. and expects to receive FDA approval by year-end. </P> <P>The clinical trials program for retapamulin involved 2,450 patients worldwide. The U.S. NDA is based on phase III data involving 712 patients across the U.S. Retapamulin has been developed for the topical treatment of uncomplicated skin and skin structure infections (SSSI) due to susceptible strains of <I>Staphylococcus aureus</I> and <I>Streptococcus pyogenes</I>. It has been studied for use twice a day for a five-day period. Recently presented laboratory studies demonstrated that retapamulin showed a high degree of <I>in vitro</I> potency against key pathogens commonly associated with skin and skin structure infections, consistently showing potent activity when compared to other commonly prescribed topical and oral antimicrobial agents. Retapamulin also demonstrated a low propensity for development of resistance in target pathogens. </P> <P>In a randomized clinical trial presented last summer at the International Congress on Infectious Diseases in Lisbon, retapamulin demonstrated efficacy equal to that of oral cephalexin (Keflex&reg;) in patients with secondarily infected dermatitis. The treatments compared were retapamulin ointment 1&#37; b.i.d. for 5 days and oral cephalexin 500 mg b.i.d. for 10 days. Clinical success rates in these groups were 85.9 and 89.7&#37;, respectively. Microbiological success rates at follow-up were 87.2 and 91.8&#37;, respectively. Microbiological success was similar between treatments for patients with <I>Staphylococcus aureus</I> and <I>Streptococcus pyogenes</I> isolates. Adverse events occurred with equal frequency in the two groups, and events related to retapamulin treatment were application site irritation, pruritus or pain (Parish, L. et al., 12th Int Cong Infect Dis (June 15-18, Lisbon) 2006, Abst 68.025). </P> <P>Attendees at the ICAAC meeting in September learned that against isolates from phase III trials, retapamulin was highly active against <I>Staphylococcus aureus, S. Pyogenes</I> and other Streptococcus spp. with MIC90 values of 0.12, 0.06 and 0.06 mcg/ml, respectively. The agent was also active against isolates of <I>S. Aureus</I> resistant to methicillin, mupirocin and fusidic acid (MIC90 values of 0.12-0.25 mcg/ml) and was more active than comparators against all staphylococci and streptococci tested (Scangarella, N. et al. 46th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Sept 27-30, San Francisco) 2006, Abst E-1861).</P> <P>In October, the results obtained with retapamulin in children and adults with impetigo in two randomized, phase III clinical studies were described at another congress. In this multicenter study, retapamulin ointment (1&#37; given b.i.d. for 5 days) was compared to fusidic acid ointment (2&#37; given t.i.d. for 7 days) in 517 children and adults. A clinical response to therapy was seen in 99.1 and 94.0&#37; of patients in the retapamulin and fusidic acid groups, respectively. Microbiological success was noted in 98.3 and 93.9&#37; of protocol-adherent patients in these groups, respectively. Retapamulin was also well tolerated and more convenient than fusidic acid (Chosidow, O. et al. 15th Cong Eur Acad Dermatol Venereol (EADV) (Oct 4-8, Rhodes) 2006, Abst PO41.11). A double-blind study also evaluated retapamulin ointment (1&#37; given b.i.d. for 5 days) in comparison to placebo in 210 children and adults with impetigo. Clinical success rates 7 days after beginning treatment were 85.6 and 52.1&#37; in the retapamulin and placebo groups, respectively. Microbiological success occurred in 91.2 and 50.9&#37; of these groups, respectively. Retapamulin ointment was again well tolerated, with application-site pruritis the most common treatment-related adverse event (van der Wouden, J.C. et al. 15th Cong Eur Acad Dermatol Venereol (EADV) (Oct 4-8, Rhodes) 2006, Abst. PO41.74).</P> http://www.prous.com/molecules/default.asp?ID=153 <p align="center"><img src="http://www.prous.com/images/moleculas/234995.gif"></p><P>Within the diuretic drug class, one of the newer mechanisms of action to emerge in recent years is that of vasopressin antagonists. Vasopressin, a peptide hormone that is also known as antidiuretic hormone (ADH), is synthesized in the hypothalamus and released from the posterior pituitary. There are 2 forms which differ only in the amino acid at position 8: arginine vasopressin (AVP) which is widespread, and lysine vasopressin which is found only in pigs. Circulating AVP is a potent vasoconstrictor, and high levels of AVP may contribute to systemic vasoconstriction and hyponatremia. AVP activity is mediated via V1 (consisting of V1A and V1B subtypes) and V2 receptors. V1A receptors are located on blood vessels, where they exert vasoconstrictor effects, and in the myocardium, where they act as a myocardial stimulant. V2 receptors mediate the effects of AVP on water retention. V1B receptors have only indirect circulatory effects and thus do not constitute an important target. </P> <P>Late last year, the first vasopressin antagonist was granted marketing approval by the U.S. FDA: Astellas Pharma's Vaprisol&reg; (YM-087, <B>conivaptan hydrochloride</B>), indicated for the intravenous treatment of euvolemic hyponatremia in hospitalized patients. Conivaptan is the first drug specifically indicated for the treatment of euvolemic hyponatremia, a condition that occurs when the body's blood sodium level falls significantly below normal. The drug blocks the activity of AVP, resulting in increased urine output without loss of valuable electrolytes such as sodium and potassium. This aquaresis helps to correct serum sodium levels in patients with hyponatremia due to increased body water. In a randomized, double-blind, placebo-controlled study, intravenous administration of conivaptan hydrochloride (40 mg/day for four days) corrected the balance of sodium and water in hospitalized patients with mild to moderate euvolemic hyponatremia. Significant improvements in serum sodium levels were observed within the first day of treatment. The drug was launched in April 2006. The FDA also issued an approvable letter for conivaptan as a treatment for hypervolemic hyponatremia. </P> <P>In October 2006, the second vasopressin V2 antagonist -Otsuka's mozavaptan- was launched in Japan, where it is indicated for the treatment of hyponatremia in subjects with inappropriate antidiuretic hormone (ADH) secretion syndrome due to tumors with ectopic ADH production. </P> http://www.prous.com/molecules/default.asp?ID=152 <p align="center"><img src="http://www.prous.com/images/moleculas/302308.gif"></p><P>Although effective antiretroviral therapies do exist and treatment (although not cure) of many infected patients is feasible, significant impediments continue to hinder the treatment of the majority of HIV-infected patients worldwide. This fact means that prevention remains an important unmet goal. While an effective AIDS vaccine is generally considered to be the ideal preventive strategy, no such product has yet been successfully developed. One of the most promising alternative approaches being pursued at the present time is that of topical microbicides. </P> <P>Topical microbicides act as chemical, biological and/or physical barriers to virus entry in the host, and may constitute an effective method for preventing HIV and other sexually transmitted infections. A modeling study conducted by the Pharmaco-Economics Working Group of the Rockefeller Foundation's Microbicides Initiative has demonstrated the strong impact that even a partially effective microbicide could have on reducing the numbers of new HIV infections. For example, a first-generation microbicide with approximately 60&#37; efficacy against HIV and other sexually transmitted infections could prevent 2.5 million HIV infections in women, men and children over a three-year period. In order to be widely used, however, a microbicide must be effective as well as acceptable, safe, affordable, not contribute to the emergence of resistant viral strains, and not interfere with the efficacy of antiviral drugs or vaccines. </P> <P>Microbicides can be broken down into three major groups: non-HIV-specific, moderately specific or highly specific to HIV. <I>Nonspecific microbicides</I> include buffering agents, detergents and surfactants. Buffering agents alter the local pH, thereby inactivating the microorganism. Detergents act by solubilizing membrane proteins, which destroys the viral envelope. However, they may also disrupt the protective membranes of the vaginal epithelium, causing lesions that facilitate viral entry. Another drawback of the nonspecific microbicides is their limited therapeutic window. Products classified as <I>moderately specific microbicides</I> target the processes of viral adsorption and fusion, and have a somewhat wider therapeutic window. Due to their mechanism of action, they may prevent infection by other enveloped viruses such as herpes, in addition to HIV. <I>Highly specific microbicides</I> are based on compounds that target viral replication at a step prior to virus integration into the target cell. They may act at the level of virus entry, reverse transcription of the viral RNA, or proviral DNA integration into the host cells. These compounds have been shown in experimental studies to block both virus-cell infection and cell-cell transmission of the virus. </P> <P><B>SPL-7013</B> (VivaGel&trade;) is a polyvalent, polylysine dendrimer-based topical microbicide being evaluated in early clinical trials through a collaboration between Starpharma and the National Institute for Allergy &amp; Infectious Diseases (NIAID). Formulated as a water-based topical gel, SPL-7013 binds to surface proteins on HIV, preventing the virus from infecting human T-cells. SPL-7013 is expected to prevent HIV as well as other sexually transmitted diseases (genital herpes, Chlamydia, hepatitis B and human papillomavirus). Following successful completion of a safety study in women, a second safety study is now evaluating the tolerability of the product in men, both in terms of effects of exposure to the product among male partners of women who use the microbicide, as well as the potential development of a male protection application, should the company decide to pursue it in the future. SPL-7013 has been granted fast-track status by the FDA for the prevention of HIV. </P> http://www.prous.com/molecules/default.asp?ID=151 <p align="center"><img src="http://www.prous.com/images/moleculas/273686.gif"></p><P>Adenosine 5'-diphosphate (ADP) is an important physiological and pathological platelet agonist. Upon vascular injury, ADP is released into the bloodstream from damaged cells and activated platelets, and in turn acts on other platelets. ADP induces a number of platelet responses, including shape change from disc to sphere, aggregation and secretion of granule contents. These ADP-induced platelet responses contribute to hemostasis, pathological thrombus formation and vascular occlusion. These responses are considered to be mediated by the interaction of ADP with specific binding sites on the platelet membrane designated as P2Y12 (or P2T) receptors. <B>Prasugrel</B> (CS-747) is a new prodrug-type antiplatelet agent that acts as a P2Y12 receptor antagonist via its active metabolite R-138727.</P> <P>Oral prasugrel was about 10 times more potent than the marketed P2Y12 antagonist clopidogrel in inhibiting ex vivo ADP-induced platelet aggregation in rats. Plasma levels of the active metabolite of prasugrel were also 10 times higher than those of the active metabolite of clopidogrel, suggesting that prasugrel's greater potency may be due to a faster metabolization rate (Ogawa, T. et al. Eur Soc Cardiol [ESC] Cong (Sept 3-7, Stockholm) 2005, Abst P2954). </P> <P>A trial compared the effects of prasugrel and clopidogrel in 101 aspirin-treated patients with atherosclerotic disease. Following treatment with 325 mg of acetylsalicylic acid, the patients were randomized to receive clopidogrel (300 mg on day 1, 75 mg/day on days 2-28) or prasugrel (40 mg on day 1 and 5 or 7.5 mg/day on days 2-28, or 60 mg on day 1 and 10 or 15 mg/day on days 2-28). Lack of response was defined as failure to achieve at least 20&#37; inhibition. The percentage of patients who were nonresponders was higher with clopidogrel both at four hours after the loading dose (52&#37; vs. 3&#37;) and before administration of the maintenance dose scheduled for day 28 (45&#37; vs. 0&#37;). No study regimen had any significant effects on the inflammation and coagulation markers of the patients (Jernberg. T. et al., Eur Heart J 2006, 27(10): 1166). The JUMBO-TIMI 26 (Joint Utilization of Medication to Block Platelets Optimally - Thrombolysis in Myocardial Infarction 26) was a multicenter, double-blind, randomized, phase II clinical trial that evaluated the effects and safety of prasugrel. A total of 904 patients undergoing elective or urgent percutaneous coronary intervention were given the standard clopidogrel regimen above or one of three prasugrel regimens (loading doses of 40 or 60 mg, followed by 7.5, 10 or 15 mg/day) for 29-34 days, starting after the diagnostic angiogram. Prasugrel-treated patients showed a lower incidence of major adverse cardiac events than clopidogrel-treated patients, although the difference among study regimens did not reach statistical significance. Only 0.7&#37; of patients had major bleeding, whereas 1.1&#37; had minor bleeding and 2.4&#37; experienced minimal bleeding in all study groups combined. No significant differences among study treatments were found in the incidence of an endpoint combining major and minor hemorrhage unrelated to coronary artery bypass graft. Hemorrhage rates were lower than those expected from historical controls (Wiviott, S.D. et al., Circulation 2005, 111(25): 3366).</P> <P>Prasugrel was discovered through a collaboration between Sankyo and Ube. Sankyo subsequently entered into a codevelopment agreement with Lilly in 2000. The compound is currently in phase III clinical development for the prevention of thrombosis in patients with unstable angina pectoris and for the prevention of cardiovascular events during percutaneous coronary intervention. The companies plan to file with the U.S. FDA for approval of prasugrel later this year. </P> http://www.prous.com/molecules/default.asp?ID=150 <P>Chronic idiopathic constipation is a form of constipation that is characterized by the infrequent or difficult passage of stools for a period of at least three months. It is caused by abnormal colonic motility, which can delay the movement of intestinal contents and impede evacuation. Current treatment options include lifestyle and dietary changes, laxatives and stool softeners.</P> <P>The CIC-2 chloride channel activator <B>lubiprostone</B> (SPI-0211), a bicyclic fatty acid derivative, represents a novel treatment for constipation. A preclinical study conducted in rats revealed that oral lubiprostone dose-dependently increased intestinal fluid volume measured at 30 minutes after dosing. This effect was associated with dose-dependent increases in the chloride concentration of the intestinal fluid (Ueno, R. et al. 13th World Cong Gastroenterol (Sept 10-14, Montreal) 2005, Abst R.0663). </P> <P>A total of 308 patients with chronic constipation participated in a multicenter, open-label trial that determined the safety and efficacy of lubiprostone in this indication. Administration of lubiprostone (24 mcg p.o.) twice daily with food and water for 24 weeks significantly improved constipation severity, bloating and abdominal discomfort. The most common adverse events were nausea and headache, but no reported events were considered to be serious (Johanson, J.F. et al., 70th Annu Sci Meet Am Coll Gastroenterol (Oct 28-Nov 2, Honolulu) 2005, Abst 903). </P> <P>A multicenter, double-blind, phase III trial randomized 244 patients with chronic idiopathic constipation to receive placebo or the same dose of lubiprostone, twice daily with food and water for 28 days. Compared to placebo, lubiprostone significantly improved stool consistency, degree of straining and severity of constipation (Johanson, J.F. et al., 70th Annu Sci Meet Am Coll Gastroenterol (Oct 28-Nov 2, Honolulu) 2005, Abst 899). The percentage of patients who showed one spontaneous bowel movement (SBM) was greater in the lubiprostone group both within 24 hours (61.3&#37; vs. 31.4&#37; with placebo) and within 48 hours after the first dose (79.3&#37; vs. 65.5&#37;) (Johanson, J.F. et al., 70th Annu Sci Meet Am Coll Gastroenterol (Oct 28-Nov 2, Honolulu) 2005, Abst 884). The average increase in SBM frequency was significantly higher with lubiprostone (4.61 per week) than with placebo (2.47 per week) after one week of treatment; this difference was maintained throughout the study. The incidence of nausea was higher with lubiprostone (21&#37; vs. 4.2&#37;), but most cases were mild or moderate. No patients experienced serious treatment-related adverse events (Johanson, J.F. et al., 70th Annu Sci Meet Am Coll Gastroenterol (Oct 28-Nov 2, Honolulu) 2005, Abst 896).</P> <P>Treatment for as long as 48 weeks was effective in the population of 828 constipation patients enrolled in 3 open-label trials. Constipation severity was significantly improved during treatment (by a mean 1.38 points at week 48), as was abdominal bloating (by a mean 1.00 point at week 48) and abdominal discomfort (by a mean 0.87 points at week 48) (Johanson, J.F. et al., Dig Dis Week (May 20-25, Los Angeles) 2006, Abst M1171).</P> <P>Lubiprostone was also associated with significant improvements in SBM in elderly subjects compared to placebo, with weekly improvements of 4.6-5.4 compared to 1.29-1.27. <BR>Adverse events were less frequent in lubiprostone-treated patients (46.2 vs. 61.3&#37;) (Ueno, R. et al., Dig Dis Week (May 20-25, Los Angeles) 2006, Abst S1262).<BR> In February 2006, the U.S. FDA granted marketing approval for lubiprostone as a treatment for chronic idiopathic constipation in adult patients. The product is the first selective chloride channel activator approved for therapeutic use. It was launched by Sucampa and marketing partner Takeda in April. </P> http://www.prous.com/molecules/default.asp?ID=149 <p align="center"><img src="http://www.prous.com/images/moleculas/230535.gif"></p><P>Histone deacetylase (HDAC) inhibitors are emerging as a promising new class of targeted oncolytic drugs. They act by inducing apoptotic cell death in cancer cells but not in normal cells, which are comparatively resistant to the apoptosis-inducing effects of these agents. As such, they are associated with low toxicity and good tolerability, and hold potential in the treatment of both hematologic and solid tumor malignancies.</P><P>The HDAC inhibitor <B>vorinostat</B> (suberoylanilide hydroxamic acid, SAHA) is currently undergoing clinical development at Merck &amp; Co. for the treatment of various cancers. Preclinical and clinical trial results were featured at the AACR and ASCO meetings, as highlighted in <A HREF="http://www.dailydrugnews.com/" target="_blank">DailyDrugNews.com</A> and below.</P><P>A phase I study involving 23 patients with advanced cancer examined the safety, tolerability and pharmacokinetics of the agent (400 mg q.d. for 28 days) in fasted and fed states. Vorinostat was well tolerated. Adverse events related to treatment were thrombocytopenia, increased serum creatinine, anorexia/weight loss, nausea/vomiting and fatigue. Twenty-three and fourteen patients were evaluable for day 1, single-dose and day 28, multidose pharmacokinetics, respectively. The rate of absorption of the agent was reduced in the presence of a standard high-fat meal. In the fed states, most patients had a delay of a minimum of 15 minutes before levels of vorinostat could be detected in serum and the Tmax was slightly delayed. Mean apparent terminal t1/2 values were short and similar for both single- and multiple dosing and for the fed and fasted states (Rubin, E.H. et al. 97th Annu Meet Am Assoc Cancer Res: Abst 2907).</P><P>Vorinostat (400 mg o.d.) was administered to 74 patients with advanced, refractory cutaneous T-cell lymphoma in a phase IIb study. The objective response rate was 30&#37;, and safety was acceptable (Olsen, E. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 7500). </P><P>Vorinostat was combined with carboplatin and paclitaxel in a phase I study in patients with advanced solid tumors. The recommended dose for further evaluation of the combination was vorinostat 300 mg/day plus carboplatin 6 AUC and paclitaxel 175 mg/m2. Vorinostat pharmacokinetics were not affected by the other agents, and 4 partial response and 2 examples of stable disease were seen (Ramalingam, S. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 2077).</P><P>Vorinostat doses of 100, 200 and 300 mg were combined with FOLFOX in 9 patients with advanced colorectal cancer included in a phase I study. No dose-limiting toxicities were seen and accrual to the highest dose level is ongoing. Evidence of activity includes 3 patients with stable disease and downregulation of thymidylate synthase with the lowest dose (Fakih, M.G. et al. 42nd Annu Meet Am Soc Clin Oncol: Abst 3592). </P><P>The FDA has accepted for review Merck &amp; Co.'s NDA for vorinostat (Zolinza&trade;) for the treatment of advanced cutaneous T-cell lymphoma (CTCL) (orphen drug designation). The filing has been granted priority review and the company expects FDA action on the NDA by early October 2006. If approved, vorinostat would potentially be the first in the HDAC inhibitor class of anticancer therapies.</P> http://www.prous.com/molecules/default.asp?ID=148 <p align="center"><img src="http://www.prous.com/images/moleculas/267580.gif"></p><P>Renin is a proteolytic enzyme synthesized in the kidney. The blockade of angiotensin II production through the inhibition of renin has received considerable attention due to the specificity of the enzyme; angiotensinogen is the only known substrate for renin. A disadvantage of conventional therapies which act on the renin-angiotensin system (RAS) is that they provide incomplete RAS suppression due to indirect pathways and compensatory feedback mechanisms which eventually result in increased plasma renin activity (PRA). A possible advantage of renin inhibitors is that they may have few side effects due to their specific nature. The first renin inhibitors studied were peptide compounds and had poor bioavailability. Subsequent efforts to develop orally active renin inhibitors were met with many difficulties. Novartis' <B>aliskiren fumarate</B> (SPP-100) works by lowering renin enzyme activity in the bloodstream, thereby reducing PRA and optimizing suppression of the RAS. Aliskiren fumarate, potentially the first renin inhibitor to reach the market, is being rapidly developed through an ambitious fast-track program.</P> <P>In studies reported last month at the American Society of Hypertension’s 21st annual meeting, aliskiren lowered blood pressure when administered alone or in combination with hydrochlorothiazide (Villamil, A. et al., Abst P-228). It reduced plasma renin activity and neutralized hydrochlorothiazide-induced activation of the renin-angiotensin-aldosterone system in a placebo-controlled study in 2,776 hypertensive patients (Calhoun, D. et al., Abst P-168). Data from 672 patients revealed that the drug’s efficacy was maintained for 24 hours, with optimal end-organ protection (Mitchell, J. et al., Abst P-209). In animals, persistence of aliskiren in the kidneys after stopping treatment was demonstrated, suggesting long-term renal protective effects (Feldman, D.L. et al., Abst P-178).</P> <P>Speedel licensed all rights to aliskiren fumarate from Novartis in 1999 and subsequently completed 18 phase I and II clinical trials with the drug candidate. In 2002, Novartis exercised a license-back option regaining development and commercialization rights to the compound. Phase III trials were conducted by Speedel and Novartis for the treatment of hypertension as a monotherapy or in combination with other antihypertensive therapies. In addition, Novartis is conducting phase II and phase III trials for the treatment of diabetic nephropathy and heart failure, respectively. In April 2006, The FDA accepted for review Novartis' application for aliskiren (Rasilez&reg;) as a treatment for high blood pressure. European submission remains on track for 2006.</P> http://www.prous.com/molecules/default.asp?ID=147 <p align="center"><img src="http://www.prous.com/images/moleculas/303902.gif"></p><P>Talabostat is an orally-active small molecule inhibitor of dipeptidyl peptidases, such as fibroblast activation protein (FAP), found in the stroma of epithelial tumors. Inhibition of these proteins results in the inhibition of the growth of certain malignant tumors. Talabostat also stimulates a variety of cytokines and chemokines, which provide upregulation of both innate and acquired immune systems, thereby accelerating the reconstitution of the hematopoietic system. </P> <P>In October 2005, originator Point Therapeutics initiated the phase III program for talabostat in metastatic non-small cell lung cancer (NSCLC). The program will evaluate talabostat in patients with stage IIIB/IV NSCLC after failure of a platinum-based chemotherapy. Two randomized, double-blind, placebo-controlled trials will enroll up to 800 patients at approximately 100 sites in North America. The first 400-patient trial will evaluate talabostat in combination with docetaxel versus docetaxel with placebo. The second 400-patient trial will evaluate talabostat in combination with pemetrexed versus pemetrexed with placebo. The primary study endpoint is progression-free survival, while secondary endpoints include overall survival, objective response rate, complete response, duration of response and quality of life. In February of this year, Point Therapeutics reported that six clinical responses had been observed to date in a phase II metastatic NSCLC study, for an overall response rate of 14.3&#37;. Of the six responding patients, two experienced complete responses persisting for at least eight months. In addition, of the first 40 patients enrolled in the study, 48&#37; have survived for at least 12 months. </P> <P>In addition to the NSCLC indication, phase II trials are also under way with the compound as monotherapy for the treatment of advanced metastatic melanoma. chronic lymphocytic leukemia (CLL), metastatic melanoma and metastatic pancreas cancer. In the phase II study combining talabostat with cisplatin in patients with metastatic melanoma, five total responses have been observed to date, for an overall response rate of 11.9&#37;. Additional phase I/II trials are evaluating talabostat in combination with other chemotherapy in the treatment of non-Hodgkin's lymphoma (NHL) and chemotherapy-induced neutropenia. Furthermore, due to its mechanisms of action, the company believes that, in addition to the combination with chemotherapy, talabostat has potential in combination with monoclonal antibodies and/or vaccine for the treatment of solid tumors and hematologic malignancies as well as hematopoietic disorders, including both neutropenia and anemia and as an adjuvant to enhance the efficacy of certain vaccines for infectious diseases.</P http://www.prous.com/molecules/default.asp?ID=146 <p align="center"><img src="http://www.prous.com/images/moleculas/291074.gif"></p><P>The naturally occurring incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are potent insulinotropic hormones which are vital in the control of glucose homeostasis. GLP-1 stimulates the body's ability to produce insulin in response to raised blood glucose levels, inhibits the release of glucagon following meals and slows the rate of nutrient absorption into the bloodstream. The development of type 2 diabetes may be slowed, or even prevented, by extending the duration of action of endogenous GLP-1. The serine protease dipeptidyl-peptidase IV (DPP-IV) inactivates GLP-1, and acts as a catalyst in the processes of signal transduction during the immune response leading to the development of type 2 diabetes. By preserving GLP-1 levels, DPP-IV inhibition stimulates insulin gene expression and biosynthesis and increases the expression of the glucose-sensing mechanism in beta-cells. It also promotes genes involved in the differentiation of beta-cells and may play a role in mediating peripheral glucose uptake. In recent years, the development of DPP-IV inhibitors has been actively pursued by the pharmaceutical industry in an attempt to develop novel antidiabetic agents.</P> <P>The efficacy of this approach has been confirmed in clinical studies. In one randomized, double-blind trial in patients with type 2 diabetes, treatment for 12 weeks with Novartis' DPP-IV inhibitor <B>vildagliptin</B> (LAF-237), at doses of 50 and 100 mg/day, significantly reduced HbA1c levels compared with placebo. Beta-cell function was significantly increased compared to placebo with vildagliptin 100 mg once daily, although the drug had no consistent effect on insulin resistance. Vildagliptin was safe and well tolerated, with a similar incidence of adverse events noted in the vildagliptin and placebo groups. Most events were mild to moderate in severity (Ristic, S. et al. Diabetes Obes Metab 2005, 7(6): 692). In another study, vildagliptin 50 mg once daily was found to improve beta-cell function when combined with metformin in 107 patients with type 2 diabetes enrolled in a randomized, double-blind, placebo-controlled study. After 52 weeks of treatment, HbA1c and fasting glucose decreased in the vildagliptin group but increased in those given metformin and placebo. Insulin secretion increased in the vildagliptin group but decreased in patients given placebo, and insulin sensitivity during meal ingestion increased with vildagliptin while remaining unchanged in the placebo group. Furthermore, an increase in the adaptation index (the relation of insulin secretion to insulin sensitivity) in the vildagliptin group was correlated with the change in HbA1c (Ahren, B. et al., Diabetes Care 2005, 28(8): 1936).</P> <P>Based on these and other positive clinical studies, Novartis has filed with the U.S. FDA for approval of vildagliptin (Galvus&reg;) as a once-daily oral treatment for type 2 diabetes. The company plans to complete filing in the Europe later this year.</P> http://www.prous.com/molecules/default.asp?ID=145 <p align="center"><img src="http://www.prous.com/images/moleculas/330290.gif"></p><P>Nicotine addiction is one of the most prevalent addictive behaviors worldwide. According to the World Health Organization, 1.3 billion men, women and children worldwide are smokers. In spite of increased awareness and action on the part of both governments and individuals, tobacco continues to be the leading cause of preventable disease and death in the U.S., as well as many other countries. According to WHO, there are nearly 5 million tobacco-related deaths worldwide each year and nearly half of the smokers in the world today will die as a cause of their addiction. </P> <P>Although the development of pharmacotherapies for nicotine addiction has traditionally centered on nicotine replacement, more recent discoveries have led to a new line of research into non-nicotine therapies, including the antidepressant bupropion. </P> <P>Nicotine works upstream of dopamine to reinforce smoking behavior by activating nicotinic acetylcholine (AChE) receptors located in dopamine reward centers in the midbrain. Nicotine receptor modulation has thus been identified as a mechanism for treating nicotine addiction. </P> <P>New data reported late last year show that Pfizer's varenicline tartrate, a neuronal nicotinic alpha4beta 2 receptor partial agonist, is a more effective antismoking agent than bupropion. In two double-blind, placebo-controlled studies involving about 2,000 smokers, patients received either varenicline (1 mg b.i.d.), bupropion (150 mg b.i.d.), or placebo for 12 weeks. Patients were followed for an additional 40 weeks without treatment. In both studies, 44&#37; of varenicline-treated patients quit by the end of the 12-week treatment period, significantly more than the 30&#37; of bupropion-treated patients who quit. Among patients who received placebo, 18&#37; had quit by the end of the 12-week treatment period. The odds of quitting smoking for patients taking varenicline were approximately two times higher than those on bupropion, and four times higher than those on placebo. After one year, patients who received varenicline were significantly more likely to remain smoke-free compared to patients who received bupropion or placebo. A third study randomized smokers who successfully quit smoking after 12 weeks of varenicline to 12 weeks of either placebo or an additional 12 weeks of varenicline. These patients were followed for 28 weeks after the treatment period. A total of 71&#37; of patients who received the additional course of varenicline remained abstinent after six months, compared to 50% who received placebo as the second course. </P> <P>Pfizer has submitted regulatory submissions in the U.S. and Europe seeking approval of varenicline for smoking cessation; in the U.S., the FDA has granted priority review status to the product. Upon approval, Pfizer intends to market varenicline under the brand name Champix&reg;. </P> http://www.prous.com/molecules/default.asp?ID=144 <p align="center"><img src="http://www.prous.com/images/moleculas/301618.gif"></p><P>Last December the U.S. FDA approved the novel oncolytic drug <strong>sorafenib</strong> (<I>Nexavar&reg;</I>) for the treatment of patients with advanced renal cell carcinoma. Codeveloped by Bayer and Onyx, sorafenib is the first, oral multikinase inhibitor that targets serine/threonine and receptor tyrosine kinases in both the tumor cell and tumor vasculature. In preclinical models, the drug targeted members of two classes of kinases known to be involved in both tumor cell proliferation and tumor angiogenesis. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT and FLT-3. The companies made the drug available to patients within 24 hours of approval. </P> <P>The FDA approved sorafenib based on data from the largest ever randomized, placebo-controlled, international trial in patients with advanced renal cell carcinoma, in which 130 centers participated. As reported at the ECCO 13 meeting in Paris last October, treatment with sorafenib in this phase III trial resulted in approximately a doubling of progression-free-survival. A total of 900 patients who failed to respond to at least one previous systemic therapy were randomized to receive best supportive care combined with oral sorafenib (400 mg b.i.d.) or placebo. Preliminary data from the first 769 patients enrolled into the study revealed that sorafenib was associated with a longer median progression-free survival (24 vs. 12 weeks with placebo) and a greater percentage of progression-free patients at three months after randomization (75&#37; vs. 43&#37;). Tumor shrinkage was detected in 74&#37; of sorafenib-treated patients and 20&#37; of placebo-treated patients. A second interim analysis on the first 220 patient deaths recorded found that sorafenib improved survival by 39&#37; compared to placebo. Most common drug-related adverse events were rash/desquamation, diarrhea, hand-foot skin reaction and hypertension (Escudier, B. et al. 13th Eur Cancer Conf (ECCO 13) (Oct 30-Nov 3, Paris) 2005, Abst 794).</P> <P>Bayer has also filed for regulatory approval in Europe, Switzerland, Australia, Brazil, Canada and Mexico. Sorafenib has been studied in more than 20 tumor types and in more than 4,000 patients to date. It is currently in phase III trials for the treatment of advanced hepatocellular carcinoma and metastatic melanoma. A phase III trial in non-small cell lung cancer (NSCLC) is planned for the first half of 2006. In addition, the National Cancer Institute (NCI) is evaluating the compound both as a single therapy agent and in combination with other oncology agents in phase II trials for several indications, including metastatic breast cancer, head and neck cancer, NSCLC, ovarian cancer, pancreatic cancer, prostate cancer, uterus cancer, thyroid cancer, as well as malignant mesothelioma. An NCI-sponsored phase I trial is ongoing for the treatment of anaplastic astrocytoma and glioma, including glioblastoma. Sorafenib has orphan drug status in the U.S. and E.U. for the renal cell carcinoma indication. </P> http://www.prous.com/molecules/default.asp?ID=143 <p align="center"><img src="http://www.prous.com/images/moleculas/277136.gif"></p><P><strong>Tramiprosate</strong> (Alzhemed&trade;) is an antiamyloidogenic agent from Neurochem that is in phase III trials for the oral treatment of mild to moderate Alzheimer's type dementia and in phase II trials (as Cerebril&trade;) for the treatment of hemorrhagic stroke due to cerebral amyloid angiopathy (CAA). If ongoing clinical trials are successful, tramiprosate could become the first in a new class of orally available therapeutics developed to stop the progression of Alzheimer’s disease (AD). Phase II results demonstrated that the drug produced no apparent safety concerns and was well tolerated in individuals with mild to moderate AD. </P> <P>In the context of Alzheimer's disease, the disease-modifying drug candidate is thought to act by preventing and slowing the formation and the deposition of amyloid fibrils in the brain, and by binding to soluble beta-amyloid protein to reduce the amyloid-induced toxicity on neuronal and brain inflammatory cells. These actions also benefit hemorrhagic stroke patients by inhibiting deposition of cerebrovascular AB and lowering AB plasma concentration. </P> <P>In November 2005, Neurochem began enrolling patients in a multicenter European phase III trial designed to investigate the safety and efficacy of tramiprosate in treating Alzheimer's disease, with some 930 mild to moderate Alzheimer's patients expected to take part. They will be randomized to receive either placebo or one of two different dose levels of tramiprosate for a period of 18 months, in addition to their regular treatment with one of a number of acetylcholinesterase inhibitors. A North American phase III trial is also ongoing, following a third consecutive recommendation from its Independent Safety Review Board on the safety and tolerability of the product candidate. Neurochem recently completed the enrollment of 1,052 patients with mild to moderate AD for the trial being conducted in 51 U.S. and 17 Canadian centers across North America, over a period of 18 months. Both the European and North American trials are designed to demonstrate the disease-modifying potential of tramiprosate. </P> http://www.prous.com/molecules/default.asp?ID=142 <p align="center"><img src="http://www.prous.com/images/moleculas/210860.gif"></p><P>The European Medicines Agency (EMEA) has granted marketing authorization in 27 European countries for Servier's <strong>Ivabradine hydrochloride</strong> (Procoralan&reg;), the first selective and specific I(f) inhibitor, for the symptomatic treatment of chronic stable angina pectoris in patients with normal sinus rhythm who have a contraindication or intolerance to beta-blockers. Ivabradine, discovered and developed by Servier, is the first pure heart rate-lowering agent and acts by selective inhibition of the cardiac pacemaker I(f) current, which controls spontaneous diastolic depolarization in the sinus node and regulates heart rate. Ivabradine's effects are selective to the sinus node; it has no effect on intracardiac conduction, myocardial contractility or ventricular repolarization. Unlike beta-blockers, ivabradine is free from sexual disturbances, respiratory side effects caused by constriction or spasm of the airways, bradycardia or rebound phenomena. </P> <P>The efficacy and tolerability of ivabradine was demonstrated by a large program including almost 5,000 patients. The antianginal and antiischemic efficacy of the compound was evaluated using a standardized exercise tolerance test in four double-blind, randomized trials (two versus placebo, and one each versus the beta-blocker atenolol and the calcium channel blocker amlodipine) involving 3,222 patients with chronic stable angina. Ivabradine (5 and 7.5 mg twice daily) was associated with a significant decrease in angina attacks, and the twice-daily dosage regimen provided uniform efficacy over 24 hours. A sustained reduction in heart rate was demonstrated in patients treated for at least one year and no rebound effect occurred following withdrawal of treatment. Moreover, no influence on glucose or lipid metabolism was observed. Ivabradine will be launched in the coming months in Europe.</P> <P>Servier intends to continue studying ivabradine for additional indications. To this end, the morbidity/mortality BEAUTIFUL trial recently commenced with the aim of demonstrating the prognostic benefits of the compound in coronary patients with left ventricular dysfunction. This large study will include more than 10,000 patients from 33 countries and is expected to report findings in 2008. The efficacy of ivabradine in other indications such as heart failure or acute coronary syndrome will also be explored in the future.</P> <P>According to Prous Science’s Integrity&reg;, ivabradine is the first and only I(f) blocker to reach this advanced stage of development. Three other compounds with this mechanism of action had been studied in clinical trials (Boehringer Ingelheim’s zatebradine and alinidine, and AstraZeneca’s ZD-7288), but none are in active development at this time. Other compounds with the same mechanism of action have been reported in patent literature, nearly all by Astellas Pharma.</P> http://www.prous.com/molecules/default.asp?ID=141 <p align="center"><img src="http://www.prous.com/images/moleculas/241104.gif"></p><P><CENTER><B><I>WHO’s Pandemic Preparedness Plan recommends that countries stockpile the antiviral drugs oseltamivir and zanamivir</I></B> </CENTER></P> <P>The H5N1 strain of influenza A, first detected in South Africa in 1961, has spread rapidly throughout avian species since 1997, when it first became a health concern in Hong Kong. Although transmission from birds to humans is rare, it is a cause for serious concern due to the extremely high mortality associated with human H5N1 disease. According to the World Health Organization (consulted October 27, 2005), to date the virus has infected 121 people worldwide, killing 62 of them. Although human-to-human transmission has yet to be established, health officials are on high alert worldwide in the face of a potential influenza pandemic caused by this highly deadly virus. Such a pandemic could occur when a virus such as H5N1 begins to infect humans on a massive scale. </P> <P>Mutations in two of the membrane proteins of influenza A and B, hemagglutinin (H) and neuraminidase (N), cause antigenic variation ("antigenic drift"); those mutations are the result of the low fidelity of the RNA polymerase of influenza, which lacks a proofreading capacity. Much larger antigenic variations of these proteins ("antigenic shift"), especially in H, are known to occur in influenza A; these latter changes cause pandemics. Most likely, the antigenic shifts are due to the segmented nature of the genome: a cell infected with multiple A viruses of different subtypes, for example from different hosts, may produce virus with a hitherto unknown combination of H and N subtypes. As a previously unencountered virus in humans, the new strain will encounter no innate resistance and will thus spread easily, causing widespread mortality. </P> <P>WHO and CDC define six stages of a pandemic: <UL> <LI> <B>Interpandemic period</B></LI><P> <UL> <LI> <B>Phase 1</B>: No new influenza virus subtypes detected in humans. An influenza virus subtype that has caused human infection may be present in animals, although the risk of transmission to humans is considered to be low. </LI><P> <LI> <B>Phase 2</B>: No new influenza virus subtypes detected in humans. However, a circulating animal strain poses substantial human risk.</LI><P> </UL> <LI> <B>Pandemic alert period</B></LI><P> <UL> <LI> <B>Phase 3</B>: Human infection(s) with a new subtype, but no human-to-human spread. </LI><P> <LI> <B>Phase 4</B>: Small cluster(s) with limited human-to-human transmission; spread is highly localized, suggesting that the virus is poorly adapted to humans. </LI><P> <LI> <B>Phase 5</B>: Larger cluster(s) but human-to-human spread is still localized, suggesting that the virus is becoming better adapted to humans but may not yet be fully transmissible (substantial pandemic risk). </LI><P> </UL> <LI> <B>Pandemic period</B></LI><P> <UL> <LI> <B>Phase 6</B>: Pandemic: increased and sustained transmission in the general population. </LI><P> </UL> </UL></P> <P>The first line of effective defense against any influenza strain is vaccination. However, in order to develop a vaccine, the strain of pandemic virus must first be determined; this cannot happen until antigenic shift takes place. In the intervening period, health officials are concerned with establishing proper protocols for providing the most effective treatment for infected individuals and for preventing widespread transmission to healthy people. </P> <P>Preclinical testing of Roche's Tamiflu&reg; (<B>oseltamivir phosphate</B>) against a wide range of influenza virus strains suggests it may be effective in treating avian influenza. Despite the lack of clinical data, the findings indicate that Tamiflu can be expected to be active against any influenza virus neuraminidase enzyme subtype, including the H5N1 strain. Oseltamivir, codeveloped by Roche and Gilead Sciences, is a systemic drug for all common strains of influenza (types A and B), which targets the neuraminidase protein preventing the virus from infecting new cells. The drug is approved for the treatment of influenza in over 50 countries worldwide. It is also approved in many countries for the prevention of influenza in adolescents and adults and for the treatment of influenza in children aged 1 year and older. </P> <P>However, a report published recently in <I>Nature</I> indicates that emergence of viral resistance may be a problem with oseltamivir (Le, Q.M. et al., Nature 2005, 437: 1108), suggesting that alternative antiviral drugs such as <B>zanamivir</B> (Relenza&reg;), a related neuraminidase inhibitor, should also be available in quantities sufficient to address pandemic conditions. </P> <P>Roche has stated its willingness to enter discussions with governments and other manufacturers on the production of oseltamivir for emergency pandemic use. The FDA has granted approval of an additional capsule manufacturing site in the U.S. for the supply of the oseltamivir, expanding worldwide production capacity. The company has also said that it is prepared to discuss all available options, including granting sub-licenses, with any government or private company who approaches them to manufacture oseltamivir or to collaborate with them in its manufacturing. WHO has recommended as part of its Pandemic Preparedness Plan that countries establish stockpiles of antiviral treatments such as oseltamivir and zanamivir, which are effective against all strains of the influenza virus. </P> <P><B>Note</B>: Zanamivir was featured as Molecule of the Month in August 1999. </P> http://www.prous.com/molecules/default.asp?ID=140 <p align="center"><img src="http://www.prous.com/images/moleculas/310717.gif"></p><P>Gap junction modulation is a promising and completely novel mechanism of action for the treatment of cardiovascular disorders. Gap junctions are a class of protein channels that are responsible for conducting electrical impulses between cells in the heart to maintain normal rhythm. <B>Rotigaptide</B> (ZP-123, GAP-486), a stable antiarrhythmic peptide analogue that has been shown to increase gap junction intercellular conductance in cardiomyocytes, is currently under clinical investigation by Wyeth for the treatment of arrhythmias. This novel compound was the subject of presentations at two recent conferences. </P> <P>The mechanism of action of rotigaptide and preclinical study results were presented at the International Gap Junction Conference in Whistler, British Columbia in August. Rotigaptide increased gap junction-mediated intercellular communication in cultures of cells expressing connexin43, without inducing any significant changes in the overall phosphorylation status of connexin43 (Martin, P.E.M. et al. Int Gap Junction Conf (Aug 13-18, Whistler) 2005, Abst 93). Studies in isolated perfused rat hearts established that global no-flow ischemia for 30 minutes induced dephosphorylation of three serine sites (Ser297, Ser306 and Ser368) in the carboxy-terminal domain of connexin43 and resulted in the development of asystole. Treatment with rotigaptide suppressed dephosphorylation and significantly increased time to asystole (Axelsen, L.N. et al., Abst). Incubation of isolated rat left atria with rotigaptide dose-dependently prevented atrial conduction velocity (CV) slowing and completely reverted established atrial CV slowing induced by metabolic stress, but had no significant effects on atrial CV during physiological conditions (Haugan, K. et al., Abst). The <I>in vivo</I> effects of rotigaptide were evaluated in dogs with ventricular arrhythmias associated with ischemia/reperfusion injury. All the animals first received a single intravenous bolus of vehicle or rotigaptide 10 minutes before reperfusion, followed by an i.v. infusion of vehicle or active drug. Compared to vehicle, the two highest rotigaptide doses employed were associated with significant reductions in the total incidence of ventricular tachycardia during the first 60 minutes of reperfusion and in the total number of premature ventricular complexes. Infarct size also decreased dose-dependently with roptigaptide, and the difference compared to vehicle was statistically significant with the highest dose tested. The compound had no significant effects on regional myocardial blood flow, blood pressure or heart rate (Hennan, J.K. et al. Int Gap Junction Conf (Aug 13-18, Whistler) 2005, Abst 52). </P> <P>Chronic volume overload (CVO) has been reported to slow atrial conduction and increase susceptibility to the induction of atrial tachyarrhythmia in the heart. The <I>in vivo</I> effects of rotigaptide were further studied in rabbits with CVO induced by arterio-venous shunt formation. Compared to sham-operated rabbits, the expression of atrial gap junction proteins connexin40 and connexin43 in the heart of rabbits with CVO decreased by 32&#37; and 72&#37;, respectively. Treatment with rotigaptide significantly increased atrial conduction velocity, but had no effects on the incidence of atrial tachyarrhythmias. These results suggest that closure of gap junction channels contributes to slowing of atrial conduction in this model, but is not responsible for the increased susceptibility to arrhythmia (Haugan, K. et al. Eur Soc Cardiol Cong (Sept 3-7, Stockholm) 2005, Abst P3064).</P> <P>Rotigaptide has reached phase II clinical trials at Wyeth. Earlier this year, Zealand Pharma and Wyeth expanded their existing research collaboration in the field of gap junction modulation. This is the third research agreement between the two companies following the initial licensing agreement in 2003 concerning rotigaptide. The focus of the expanded three-year agreement is research and development of new gap junction modulators targeting cardiovascular disorders.</P> http://www.prous.com/molecules/default.asp?ID=139 <p align="center"><img src="http://www.prous.com/images/moleculas/308000.gif"></p><P>Schizophrenia is a severe disabling and chronic form of psychosis that develops in approximately 1&#37; of the population. Schizophrenia is characterized by positive, negative, affective and cognitive symptoms. Positive symptoms comprise, among others, delusions and hallucinations. The negative symptoms include social withdrawal, blunted affects and diminished capacity of speech. Affective symptoms are mainly depression and anxiety. Typical cognitive deficits are impaired attention and memory and some times disorganized speech. While most widely used treatments may be effective in controlling acute symptoms of schizophrenia, they are all associated with a variety of side effects that negatively influence their usefulness in long-term treatment. New treatments that improve symptomatology but with reduced side effects are therefore desirable.</P> <P><B>Bifeprunox mesilate</B> is a novel antipsychotic agent discovered by Solvay and codeveloped by Lundbeck. It is a putative full-spectrum atypical antipsychotic compound aimed at the treatment of both positive and negative symptoms of schizophrenia. Its mechanism of action couples highly potent partial dopamine D₂ receptor agonism with an additional 5-HT_1A receptor partial agonist effect.</P> <P>Phase II data have shown efficacy in patients with schizophrenia. Bifeprunox is expected to provide an improved safety profile with the advantages of no weight gain, increase in prolactin, glucose dysregulation or Q-Tc prolongation. In addition, the drug is expected to have a favorable lipid profile and extrapyramidal symptoms comparable to placebo. Phase III trials commenced in 2003 for the treatment of schizophrenia. Submissions are planned in a number of markets simultaneously in 2006, with expected market launch in 2007. Lundbeck has marketing rights to bifeprunox in Europe and a number of other markets, while Lundbeck and Solvay will jointly market the product in Brazil and Argentina. Solvay and Wyeth have entered a development and marketing agreement in the U.S., Mexico, Japan and Canada. In addition to schizophrenia, bifeprunox may also have potential in the treatment of bipolar disorder. </P> http://www.prous.com/molecules/default.asp?ID=138 <p align="center"><img src="http://www.prous.com/images/moleculas/280627.gif"></p><P>Blood transfusions are widely used to treat patients with chronic disorders such as sickle cell disease, beta-thalassemia and anemia. Because red blood cells contain iron, and there is no natural way for the body to eliminate it, patients who receive repeated blood transfusions can accumulate iron in the body until it reaches toxic levels. It is important to remove excess iron from the body, because it can gather in the heart, liver, and other organs and may lead to organ damage. Although treatments are available to eliminate iron overload, these are all accompanied by side effects and/or drawbacks, which makes the development of improved new chelating agents for the treatment of iron overload more urgent. </P> <P>Novartis has filed regulatory submissions for Exjade&reg; (<B>deferasirox</B>, ICL-670), the first and only once-daily oral iron chelator for the treatment of chronic iron overload due to blood transfusions, in the U.S. and the E.U. An easy-to-administer novel oral iron chelator, Exjade is simply taken once daily, after dispersing tablets in a glass of water. It benefits from ease of administration over deferoxamine (Desferal[R]), the current standard of care in iron chelation, which typically requires subcutaneous infusion lasting 8-12 hours per day, for 5-7 days a week for as long as the patient continues to receive blood transfusions. In the E.U., the filing for Exjade was submitted under the centralized procedure. Exjade was granted orphan drug status in both the U.S. and E.U. in 2002. Exjade also has fast-track and priority review status in the U.S. The Exjade global clinical trials program enrolled more than 1,000 patients and is the largest ever prospectively implemented for an investigational iron chelator. The regulatory filings are based on the results of pivotal clinical trials, including a phase III head-to-head trial versus deferoxamine, which showed that Exjade significantly reduced liver iron concentration (LIC), an accepted indicator for body iron content, in adult and pediatric patients receiving blood transfusions. Clinical studies demonstrated that Exjade led to the maintenance or reduction of absolute LIC in regularly transfused patients with different underlying diseases. </P> <P>Several studies evaluating deferasirox were presented at the 10<SUP>th</SUP> Congress of the European Hematology Association (June 2-5, Stockholm). The multicenter, open-label, phase II clinical trial CICL670A0108 showed that deferasirox was also effective in different subgroups of patients with transfusional iron overload. Oral deferasirox (5, 10, 20 or 30 mg/kg/day) given for an average of 51.6 weeks decreased mean LIC by 5.7 mg Fe/g dw and mean serum ferritin levels by 331 mcg/l compared to baseline in 47 patients with myelodysplastic syndrome (Cazzola, M. et al., Abst 0769; Tchernia, G. et al., Abst 0475).An open-label, crossover clinical trial determined that there is little potential for interaction between deferasirox and digoxin (Sechaud, R. et al., Abst 1130). Data from a multicenter, open-label, phase II clinical trial were used to determine the pharmacokinetic profile of deferasirox in pediatric subjects. The authors concluded that deferasirox was suitable for once-daily administration in pediatric patients (Piga, A. et al., Abst 0472).</P> http://www.prous.com/molecules/default.asp?ID=137 <p align="center"><img src="http://www.prous.com/images/moleculas/223488.gif"></p><P>Fibroids, also known as myoma or leiomyomata, are common benign growths of the uterine musculature which cause irregular and painful periods, bloating and lower abdominal pain, and can affect fertility. Uterine fibroids are extremely common. More than 75&#37; of women can be found to have small fibroids using MRI, although only about 30&#37; of all women will have fibroids large enough to be noted during a pelvic exam, and the vast majority of even these women will never have symptoms and will never require treatment. For the rare patient who does have problems, there are a number of sound and effective options available including laparoscopy or laparotomy. Hysterectomy should be performed only in patients with symptomatic disease. </P> <P>TAP and Schering AG are codeveloping <B>asoprisnil</B> (J867), the first product in a new class of drugs called selective progesterone receptor modulators (SPRMs). SPRMs exhibit partial progesterone agonist/antagonist effects, with high specificity for the progesterone receptor in both humans and experimental animals. Unlike compounds like RU-486, asoprisnil does not exert antiglucocorticoid activity at therapeutic doses. Asoprisnil has the potential to target the major clinical symptoms of fibroids related to excessive menstrual bleeding and fibroid size, thereby reducing or eliminating the need for surgery. If approved, asoprisnil would be the first long-term medical treatment for fibroids. Also being studied for the treatment of endometriosis, asoprisnil may reduce the associated pain and bleeding without affecting estrogen levels. Asoprisnil is currently in phase III clinical trials for treatment of symptomatic uterine fibroids and in phase II for endometriosis. Schering AG has announced plans to file for European marketing approval of the uterine fibroids indication in the fourth quarter of 2005.</P> http://www.prous.com/molecules/default.asp?ID=136 <p align="center"><img src="http://www.prous.com/images/moleculas/301036.gif"></p><P>The finding that the ErbB (HER) family of tyrosine receptor kinases is involved in the mediation of cell growth, survival and treatment resistance of different epithelial tumors led to the development of therapies that specifically target these proteins. ErbB2 (HER2/neu) is a member of this family that has been found to be especially relevant in some patients with breast cancer and other carcinomas. <B>Lapatinib</B> (GW-572016; GlaxoSmithKline) is a small molecule that inhibits the activity of both ErbB1 and ErbB2, and has shown clinical activity in breast cancer. As a reversible and dual-acting inhibitor, investigators hope that the drug will be able to overcome problems of resistance encountered with single inhibitors.</P> <P>Encouraging data regarding the antitumor activity of lapatinib were presented last December at the San Antonio Breast Cancer Symposium. Three phase I clinical trials have evaluated the feasibility of combining lapatinib with other antitumor drugs. In one of these trials, 26 patients with advanced or metastatic breast cancer overexpressing ErbB2 were given lapatinib plus standard trastuzumab therapy. Of 20 patients evaluable for response, four showed partial response for 1-4 months and another nine had stable disease for 1-5 months. The most common toxicities included grade 1-2 diarrhea, anorexia, fatigue and rash, and two patients experienced dose-limiting toxicities (grade 3 fatigue, grade 3 nausea) with 1500 mg/day of lapatinib (Burris, H.A. III. et al., Abst 3043). The efficacy and safety of lapatinib combined with letrozole were assessed in patients with advanced breast cancer or other tumors likely to respond to the combination therapy (e.g., ovarian or endometrial cancer). An interim analysis of data from the first 17 patients included in the study showed stable disease for at least two months in four patients and progressive disease within 2-4 months in another four patients. The combination regimen was generally well tolerated (Chu, Q. et al., Abst 6044). Forty-eight cancer patients participated in a clinical trial that compared the effects and safety of lapatinib combined with paclitaxel. Six of nine patients with metastatic breast cancer enrolled in the study responded to the lapatinib/paclitaxel regimens. Treatment-related adverse events were easily managed with supportive care (Jones, S.F. et al., Abst 1069).</P> <P>Other positive results were presented at meetings this spring, including phase II results in patients with FISH-positive advanced or metastatic breast cancer, reported at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO), and phase II results in patients with advanced, relapsed urothelial tumors, reported at the 3rd International Symposium on Targeted Anticancer Therapies.</P> <P>GlaxoSmithKline plans to file for U.S. marketing approval of lapatinib in the breast cancer indication later this year, with European filing to follow in 2006. </P> http://www.prous.com/molecules/default.asp?ID=135 <p align="center"><img src="http://www.prous.com/images/moleculas/207549.gif"></p><P>Postoperative ileus (POI) is defined as transient impairment of gastrointestinal motility and function characterized by abdominal distension and pain, nausea and vomiting, reduced desire to eat, and an inability to pass flatus (gas) or stool. POI may be brought on by manipulation of the bowel during surgery; and opioid use during and after surgery may prolong recovery from POI. Nearly all patients undergoing open abdominal surgery are at risk for the condition, which is associated with prolongation of hospital stay and increased healthcare costs. Currently there are no marketed treatments for postoperative ileus, and the condition has been identified by healthcare professionals as an important unmet medical need.</P> <P><B>Alvimopan hydrate</B> (Adolor/GlaxoSmithKline) is an investigational peripherally acting mu-opioid receptor antagonist designed to block the negative effects of opioids on the gastrointestinal system without interfering with their analgesic effects on the central nervous system. The company reported phase II clinical results for the compound in May 2005. Two ongoing multicenter, double-blind, randomized, placebo-controlled clinical trials are evaluating the effects and safety of alvimopan in the management of bowel dysfunction. Study SB-767905/011 is a phase IIb trial conducted in 522 noncancer patients with opioid-induced bowel dysfunction that showed that oral alvimopan (0.5 mg b.i.d., 1 mg o.d. or 1 mg b.i.d.) given for six weeks was significantly more effective than placebo in increasing weekly frequency of spontaneous bowel movements. Alvimopan was also associated with significant improvements in straining, stool consistency and incomplete evacuation, and was also well tolerated. The most common adverse events were abdominal pain, nausea and diarrhea. In the second study, SB-767905/007, 217 adult patients with chronic idiopathic constipation not caused by opioids were treated with alvimopan (1, 3 and 8 mg b.i.d.) or placebo for eight weeks. Preliminary data suggest that alvimopan is well tolerated at all doses tested and may induce therapeutic benefits in some patients.</P> <P>Nonetheless, in December 2004 the company reported disappointing top-line results from study SB-767905/001, an important phase III trial for the POI indication. The trial was conducted in Europe, Australia and New Zealand by GlaxoSmithKline (GSK) to support a marketing authorization application (MAA) in the E.U. The multicenter, randomized, double-blind, placebo-controlled parallel group trial enrolled 741 bowel resection patients and 170 radical hysterectomy patients. The top-line results reported concern only the bowel resection subjects, who were prespecified as the primary population for the analysis. Under the study protocol, patients were randomized into three arms to receive placebo or alvimopan (6 or 12 mg) orally two hours prior to surgery, and then twice a day beginning on the first postoperative day until hospital discharge or for a maximum of seven days. The primary endpoint (GI3) of the study was time to recovery of gastrointestinal function. Primary endpoint results did not reach statistical significance. Secondary endpoints included an additional measure of time to recovery of gastrointestinal function (GI2), which measures GI recovery based on tolerating solid food and bowel movement. Results in GI2 were statistically significant for the 6- and 12-mg groups as compared to the placebo group. Differences in favor of the alvimopan treatment groups as compared to placebo were observed in the secondary endpoint of time to hospital discharge, but were not statistically significant.</P> <P>In June 2004, Adolor completed submission of a rolling NDA for alvimopan hydrate (Entereg&trade;) capsules for the management of postoperative ileus. The FDA requested further information from the company regarding study SB-767905/001 and as a result has extended the target action date from April 25, 2005 to July 25, 2005 for the completion of review of the NDA. Adolor and GlaxoSmithKline are collaborating on the worldwide development and commercialization of alvimopan for POI and for several other gastrointestinal indications: opioid-induced bowel dysfunction (OBD) associated with extended use of opioids to treat chronic pain (phase II), chronic idiopathic constipation not associated with opioid use (phase II), and constipation-predominant irritable bowel syndrome (phase I).</P> http://www.prous.com/molecules/default.asp?ID=134 <p align="center"><img src="http://www.prous.com/images/moleculas/303122.gif"></p><P>Insulin sensitizers, or enhancers of insulin action, improve insulin resistance in patients with type 2 diabetes by increasing the sensitivity of cells to insulin, enabling the hormone to transport glucose from the blood into cells. Within the insulin sensitizer class, PPAR agonists have emerged as an especially promising class of antidiabetic agents, The peroxisome proliferator-activated receptor (PPAR) family of transcription factors plays a key role in regulating dietary fat storage and catabolism. Since they were first cloned just a decade ago, the PPARs have become established as an important target for the treatment of type 2 diabetes, obesity, cardiovascular disease, metabolic syndrome and other human health disorders associated with high intake of dietary fat. Three receptor subtypes have been identified: PPARalpha, PPARgamma and PPARdelta. The PPARgamma receptor, especially, has been identified as a master switch in adipocyte differentiation, and ligands for this receptor restore insulin sensitivity by down-regulating cytokines in adipose tissue (e.g., TNF-alpha) that are involved in insulin resistance. </P> <P>Since April 2004, Bristol-Myers Squibb and Merck &amp; Co. have been collaborating on the development of <B>muraglitazar</B> (BMS-298585), Bristol-Myers Squibb’s dual peroxisome proliferator-activated receptor agonist for treating blood glucose and lipid abnormalities in patients with type 2 diabetes. Muraglitazar works by targeting both PPARalpha and PPARgamma receptors. The companies submitted an NDA with the U.S. FDA seeking marketing approval of muraglitazar in December 2004. If approved, muraglitazar could become the first dual PPARalpha/PPARgamma agonist to be made available in the U.S. </P> <P>The therapeutic efficacy of was highlighted last year at the 64th Annual Scientific Sessions of the American Diabetes Association. The dual agonist was even more effective than the PPARgamma agonist pioglitazone in reducing lipid levels in patients with type 2 diabetes (T2DM), supporting its suitability as a future treatment for diabetic patients with associated dyslipidemia (Frost, C.E. et al., Abst 1988-PO). The compound was safe and well tolerated in a 28-day study of patients with T2DM, exerting favorable effects on 24-hour mean and fasting glucose levels and on fasting plasma insulin levels (Mosqued-Garcia, R. et al., Abst 138-OR). Muraglitazar improved metabolic abnormalities in a mouse model of obesity and diabetes, correcting levels of adiponectin and corticosterone (Harrity, T. et al., Abst 134-OR). </P> http://www.prous.com/molecules/default.asp?ID=133 <p align="center"><img src="http://www.prous.com/images/moleculas/253457.gif"></p><P>The Ras proteins have become a target for the development of anticancer drugs due to the fact that oncogenic mutations have been identified in approximately 30&#37; of all known human malignancies. Due to the crucial role farnesylation plays in Ras maturation, inhibitors of farnesyl protein transferase have emerged as a novel class of antineoplastic agents. Inhibitors of this enzyme ultimately interfere with ras-dependent cell transformation and therefore selectively inhibit the growth of ras-transformed cells. The investigational response has been the development of several farnesyl protein transferase inhibitors. Several of these agents are in the advanced stage of preclinical testing or in clinical trials, the most advanced being Johnson &amp; Johnson’s <B>tipifarnib</B>. Tipifarnib, administered orally, is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). </P> <P>Data from a multicenter phase II trial were reported last December at the annual meeting of the American Society of Hematology. In the study, 170 elderly, poor-risk AML patients were treated on an outpatient basis with oral tipifarnib for 21 days followed by 1-3 weeks of recovery. An overall response rate of 34&#37; was measured, with a complete response rate of 18&#37;. The mean duration of complete responses was 6.4 months. Drug-related non-hematologic adverse events occurred in 43&#37; of patients, and the hospitalization rate for tipifarnib-related toxicity was 18&#37;. </P> <P>In January 2005, completed the submission of an NDA for tipifarnib under the FDA’s Continuous Marketing Application (CMA) Pilot-1 Program. The company submitted the tipifarnib NDA based on data from a phase II trials conducted with the National Cancer Institute's Cancer Therapy Evaluation Program. In October 2004, J&amp;JPRD initiated an international phase III study designed to further substantiate the clinical benefit of tipifarnib in this condition. If approved, tipifarnib (Zarnestra&trade;) will be marketed in the U.S. by Tibotec Therapeutics, a division of Ortho Biotech. Tipifarnib has been granted orphan drug status in the United States for the indication of acute myeloid leukemia. J&amp;JPRD continues to investigate other potential uses of tipifarnib in solid and hematologic malignancies, including various stages of myeloid leukemia. </P> http://www.prous.com/molecules/default.asp?ID=132 <p align="center"><img src="http://www.prous.com/images/moleculas/274729.gif"></p><P>Alzheimer's disease is a degenerative neurological condition affecting nearly half of those over 85, with an estimated 4 million cases in the United States alone. Current approved treatments, such as cholinesterase inhibitors, temporarily relieve symptoms without meaningfully impacting progression of the underlying disease. Alzheimer's disease is marked by progressive cognitive decline and by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. The major structural component of these plaques is amyloid beta peptide, specifically amyloid beta-42 (Abeta42). Many researchers now believe that Abeta42 plays an essential role in initiating the neurodegeneration leading to the onset of Alzheimer's disease. Current research is focused on compounds that decrease levels of Abeta42 with the hope of preventing or slowing the progression of Alzheimer's disease.</P> <P><B>MPC-7869 (Flurizan&trade;)</B> is the pure (<I>R</I>)-enantiomer of flurbiprofen, an NSAID with 25 years of clinical experience. Unlike many NSAIDs, however, MPC-7869 is not an inhibitor of cyclooxygenase enzymes (COX-1 and COX-2). The compound modulates the signal transduction and transcription activation pathways associated with nuclear factor kappaB (NFkappaB), a principle transcription factor in the expression of many molecules involved in cell growth, cell death and inflammation. In addition, MPC-7869 has recently been shown to modulate gamma-secretase and selectively lower levels of Abeta42 peptide <I>in vitro</I> and <I>in vivo</I>, and to reduce amyloid pathology in the brain. MPC-7869 has an excellent safety profile and is very potent in animal models of cancer and Alzheimer's disease. In transgenic mouse studies, MPC-7869 reduced brain amyloid levels and prevented memory loss. </P> <P>Myriad Genetics has opened enrollment in a phase III trial of MPC-7869 in patients with Alzheimer's disease. The trial is designed to determine the ability of MPC-7869to alter the course of cognitive decline and behavioral change in AD patients. The double-blind, placebo-controlled, randomized trial will be conducted in approximately 750 patients with mild to moderate Alzheimer's disease, at approximately 100 U.S. centers. Patients will be randomized to one of three arms, to receive 400 or 800 mg of MPC-7869 twice daily or placebo twice daily for the duration of the 12-month study period. The primary efficacy endpoints will be the change in cognitive function, as measured by the ADAS-cog test, and the change in activities of daily living. Additionally, MPC-7869 is being studied in a phase II study in approximately 210 patients with mild to moderate Alzheimer's disease. All patients have now been on drug for more than nine months. The trial is expected to conclude its clinical study period in March 2005. </P> <P>At the same time, Myriad Genetics is developing MPC-7869 for the treatment of prostate cancer and potentially of other cancers as well. The efficacy of MPC-7869 in cancer indications is based on its ability to affect NFkappaB regulation and to slow the production of prostaglandins, thereby slowing or inhibiting carcinogenesis and potentially also enhancing apoptosis in cancer cells. In a preliminary phase II trial, MPC-7869 was administered to 23 late-stage prostate cancer patients who received up to 32 weeks of daily drug therapy. Of the 23 prostate cancer patients enrolled, 13 were hormone-refractory and the remaining 10 had not had hormone therapy but did have advanced disease. Although the study was open-label and not placebo-controlled, it was possible to examine efficacy by allowing each patient to act as their own control. The data were analyzed by examining each patient’s rate of PSA rise before and after treatment with MPC-7869. Overall, 12 of 23 (52&#37;) patients showed some benefit. Amongst the hormone-refractory, 5/13 (38&#37;) showed benefit and 7/10 (70&#37;) of the hormone-naive. The company is now conducting a phase IIb, multicenter, randomized, double-blind, placebo-controlled trial to assess the safety and efficacy of MPC-7869 in delaying the systemic progression of prostate cancer in patients with intermediate to high risk of recurrence with rising PSA levels after prostatectomy, prostatectomy and radiotherapy, or radiotherapy alone for localized disease. </P> http://www.prous.com/molecules/default.asp?ID=131 <p align="center"><img src="http://www.prous.com/images/moleculas/278582.gif"></p><P>Epilepsy constitutes a group of chronic disorders characterized by spontaneous disturbances of the normal electrical activity of the brain. About 5&#37; of the world population will have a seizure during the course of their lifetime and of these 10-20&#37; will develop repeated seizures. Only reoccurring seizures are called epilepsy. About 1&#37; of the world population suffers from epilepsy, making it second most prevalent neurological disorder. </P> <P>Most antiepileptic drugs increase the threshold of electrical energy in the epileptic focus required for a seizure to occur. Every human being has a brain seizure threshold, which makes people more or less resistant to seizures. Epileptic patients have an abnormally low seizure threshold that can be normalized with the help of treatment. Strategies include potentiating the inhibitory pathways within the CNS (predominantly enhancing the GABAergic system), inhibiting excitatory glutamatergic pathways or inhibiting excessive neuronal firing (predominantly by modulating cation conductance through sodium, calcium or potassium channels). The mechanisms of anticonvulsant action of many antiepileptic drugs, however, remain unknown. Nonpharmaceutical therapies for epilepsy include surgical treatment of the brain and vagus nerve stimulation. However, there are a large number of patients that do not respond to these treatments or experience severe side effects. </P> <P>There is compelling evidence to support the theory that alterations in NMDA receptors contribute to epileptogenesis, and NMDA antagonists have been studied extensively for this indication. The marketed drug felbamate, which is restricted to use in only the most severely affected patients due to life-threatening side effects, may work as an NMDA antagonist. <B>Lacosamide</B> (formerly known as harkoseride or SPM-927) is an NMDA glycine-site antagonist in development at Schwarz for both epilepsy and neuropathic pain, a condition that frequently responds favorably to anticonvulsant medications. Lacosamide is a functionalized amino acid that was identified as a promising anticonvulsive drug candidate from among 24,000 molecules in a comprehensive NIH screening program. Schwarz Pharma commenced a phase III program in epilepsy in May 2004. </P> <P>Results from a European and U.S. phase IIb trial of lacosamide for the treatment of epilepsy were reported in September, and demonstrated statistically significant and clinically relevant evidence of seizure frequency reduction. The multicenter, double-blind, placebo-controlled trial had a treatment duration of 12 weeks. A total of 497 patients with partial seizures suffering from refractory epilepsy were randomized for adjunctive treatment. The primary parameters were reduction of seizure frequency and a 50&#37; response rate. Both the primary endpoints for the U.S. and Europe were achieved. More than 90&#37; of patients who completed the trial entered the open-label follow-up trial. Favorable pharmacokinetic study results were described in a series of presentations at the 58th Annual Meeting of the American Epilepsy Society, celebrated in December 2004. </P> <P>Also in May 2004, Schwarz presented the results of a multicenter, double-blind, randomized, placebo-controlled dose-escalating clinical trial assessing the safety and analgesic effects of lacosamide in 119 patients with diabetic distal sensory polyneuropathy. Lacosamide was more effective than placebo in reducing pain scores (3.72 to 2.11), pain interference with sleep (3.1 vs. 2.06) and pain interference with function (2.96 vs. 2.00) in the Likert scale. No significant differences were found between the safety profiles of the two study groups (Rauck, R. et al., 56th Annu Meet Amer Acad Neurol (April 24-May 1, San Francisco) 2004, Abst S51.003). Lacosamide is also in phase III testing for the neuropathic pain indication. </P> http://www.prous.com/molecules/default.asp?ID=105 <p align="center"><img src="http://www.prous.com/images/moleculas/353520.gif"></p><P>With the emergence of organisms such as quinolone-resistant pneumococci and methicillin-, quinolone- and glycoprotein-intermediate and -resistant staphylococci, the need for novel agents to treat community-acquired respiratory and skin and soft tissue infections is a priority. A novel class of antibacterial agents to emerge from research efforts are the peptide deformylase inhibitors. Prokaryotic translation produces proteins that all begin with N-formyl methionine, a residue that is commonly removed in a multiple step process that begins with deformylation mediated by the enzyme, peptide deformylase (EC 3.5.1.88). Later steps in this process cannot proceed in the presence of the formyl group and often the resulting protein is not biologically active with the N-terminal Met in place. Inactivation of deformylase activity is lethal and thus an attractive antibiotic strategy. <B>LBM-415</B> (formerly NVP-PDF-713) is a novel peptide deformylase inhibitor discovered at Vicuron and being developed by Novartis that is advancing to phase II and III clinical trials. The agent has been tested in several studies, with results indicating that peptide deformylase inhibitors such as LBM-415 may be a highly effective novel antibacterial class in the clinic. This compound – the only compound with this mechanism of action to reach clinical trials – was discussed extensively at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Early clinical results were presented at the annual meeting of the American College of Clinical Pharmacology. </P> <P>LBM-415 was shown to be a selective peptide deformylase inhibitor (IC50 = &lt;10 nM) in experiments using enzymes from <I>Escherichia coli, Haemophilus influenzae and Streptococcus pneumoniae</I> (Lopez, S. et al. 44th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Oct 30-Nov 2, Washington, D.C.) 2004, Abst F-1960). LBM-415 was effective <I>in vitro</I> against several strains of antibiotic-resistant bacteria. The agent was equally effective against susceptible and multidrug-resistant isolates including penicillin-resistant <I>S. Pneumoniae</I>, methicillin-resistant <I>S. Aureus</I>, vancomycin-resistant enterococci, and clarithromycin-resistant <I>Helicobacter pylori </I> (Ryder, N.S. et al., Abst F-1959). The effects of LBM-415-induced inhibition of peptide deformylase on proteosomes of <I>S. Aureus</I> and <I>S. Pneumoniae</I> were examined, with results showing that inhibition of the enzyme resulted in dose- and time-dependent accumulation of N-terminal formylated peptide. When LBM-415 was removed, formylated peptides/proteins were depleted which may correlate with bacterial regrowth (Wang, W. et al. 44th Intersci Conf Antimicrob Agents Chemother (ICAAC) (Oct 30-Nov 2, Washington, D.C.) 2004, Abst F-1541). </P> <P>LBM-415 was effective in a murine model of <I>Mycoplasma pneumoniae</I> pneumonia, with MIC values of 0.005 mcg/ml or less (Fonseca-Aten, M. et al., Abst F-1966). The compound was also active in a pneumonia model using intranasal penicillin-susceptible <I>S. Pneumoniae</I>, and in a systemic methicillin-susceptible <I>S. Aureus</I> lethal sepsis model (Neckermann, G. et al., Abst F-1964; Osborne, C.S. et al., Abst F-1963). </P> <P>A placebo-controlled clinical trial evaluated the single- and multiple-dose pharmacokinetics of LBM-415. Single doses (100, 250, 500, 1000, 2000 and 3000 mg) or multiple doses (250, 500 and 1000 mg b.i.d. for 11 days) were given orally to healthy volunteers. All LBM-415 doses were quickly absorbed and showed a median time to peak plasma concentration of 1-1.75 hours. Other parameters, such as the peak plasma concentration and the area under the curve, increased with dose. Administering a single dose of 1000 mg of LBM-415 immediately after breakfast delayed the time to peak plasma concentration and reduced the peak to plasma concentration, but had no significant effects on systemic exposure. Multiple dose administration had no significant effects on the pharmacokinetics of LBM-415, did not result in drug accumulation, and steady-state was achieved after the first dose (Sun, H. et al. 33rd Annu Meet Amer Coll Clin Pharmacol (Oct 3-5, Phoenix) 2004, Abst 30). </P> http://www.prous.com/molecules/default.asp?ID=104 <p align="center"><img src="http://www.prous.com/images/moleculas/171120.gif"></p><P>Parkinson’s disease (PD) is an age-related, progressive, neurodegenerative disease affects as many as 1 million people in the U.S. alone and up to 4 million worldwide. It is caused by the death of cells that produce dopamine, a neurotransmitter necessary for normal motor function. Parkinson's patients suffer from tremors, rigidity, slow or uncontrolled muscle movement, speech disorders, and gait and postural disturbances. Administration of drugs designed to enhance or increase endogenous dopamine levels represents the most widely used and firmly established method of treating Parkinson's disease. Various dopamine-increasing strategies have been identified, although the most widely used continues to be administration of the dopamine precursor levodopa. Long-term use of levodopa can be associated with motor complications, however. New guidelines suggest the use of dopamine agonists as opposed to levodopa as a first-line treatment in Parkinson’s disease. Dopamine agonists have been shown to delay the onset of motor complications in early PD patients. </P> <P><B>Rotigotine hydrochloride</B> is a dopamine D2 agonist discovered by Aderis and developed by Schwarz Pharma. It has been formulated as a transdermal patch designed to circumvent one of the major problems encountered with oral medications, namely inconsistent pharmacokinetics, leading to fluctuating efficacy and side effects. The rotigotine transdermal patch delivers a constant drug level for 24 hours, at which time it is replaced with a new patch. In October, Schwarz Pharma submitted applications in the U.S. and E.U. seeking marketing approval for rotigotine (Neupro<SUP>TM</SUP>) for the treatment of patients in early stages of Parkinson's disease. Further testing is underway in patients with more advanced-stage disease. More than 1,500 patients with Parkinson's disease have been treated to date with rotigotine in 15 clinical trials. </P> <P> In one such study, results of which were also communicated in October, rotigotine showed a statistically significant and clinically relevant reduction in “off” time in patients with advanced PD. The reduction in off time following adjunctive therapy with rotigotine was not associated with an increase in undesirable dyskinesias. In the U.S. phase III trial, 351 patients with advanced-stage idiopathic PD received active drug or placebo in addition to stable levodopa treatment. The primary parameters were change from baseline in the absolute off time and response rate (response being defined as at least a 30% decrease in absolute off time from baseline). The most common adverse events associated with the use of rotigotine transdermal system were application site reactions, somnolence, nausea and dizziness. A total of 99&#37; of patients who completed the trial opted to continue treatment with rotigotine during an open-label extension trial. </P> <P> Earlier in the year, the Parkinson Study Group reported the results of a randomized, multicenter, double-blind, placebo-controlled study that included 242 patients older than 30 years with idiopathic PD and a Hoehm and Yahr stage equal to or lower than 3. Patients were treated with placebo or rotigotine administered transdermally for up to 11 weeks. Compared to placebo, patients treated with rotigotine showed significant improvements in UPDRS scores after only four weeks of treatment which were maintained throughout the study. Adverse events most frequently associated with rotigotine included nausea, application site reactions, dizziness, somnolence, insomnia, vomiting and fatigue. Four out of nine serious adverse events were considered to be drug-related. The authors concluded that transdermal rotigotine monotherapy was well tolerated and effective in improving the signs of early PD. </P> <P> Rotigotine is also being actively studied for the treatment of restless legs syndrome (RLS), another disorder that often responds favorably to dopaminergic therapy. In a multinational phase IIb study reported earlier this year, rotigotine therapy was associated with statistically significant and clinically relevant reductions in RLS symptoms. A meaningful clinical effect was observed within the first seven days of treatment, and the patch was well tolerated. The multicenter, double-blind, placebo controlled trial had a treatment duration of six weeks. In total, 310 patients with idiopathic moderate to very severe RLS completed the trial. Schwarz is now preparing the phase III program, which is scheduled to start in spring 2005. </P> http://www.prous.com/molecules/default.asp?ID=103 <p align="center"><img src="http://www.prous.com/images/moleculas/142924.gif"></p><P><B>Duloxetine hydrochloride</B>, a balanced and potent dual inhibitor of serotonin and norepinephrine reuptake, was developed simultaneously by Lilly for two apparently unrelated indications: depression and stress urinary incontinence (SUI). A huge body of clinical evidence supports its efficacy for both indications: duloxetine has been studied in more than 6,000 adults with major depression worldwide, showing improvements in both the emotional and physical symptoms of depression. Another 10 studies in more than 2,000 women with SUI across 5 continents demonstrated that duloxetine effectively reduces the frequency of incontinence episodes by up to 53% and is generally well tolerated. In patients with incontinence, duloxetine increases neurotransmitter concentrations; this is believed to increase the tone and contraction of the urethral sphincter, helping to prevent accidental urine leakage due to physical activities such as sneezing, coughing, laughing, lifting or exercising. </P> <P>Lilly has succeeded in recent months in launching the drug for both major depression (first approved and launched in the U.S. in August under the trade name Cymbalta&reg;) and for stress urinary incontinence in women (approved in the E.U. in August and introduced in the U.K., Germany, Denmark, Finland and Sweden in September under the trade name Yentreve&reg;). The European Committee for Medicinal Products in Human Use (CHMP) issued a positive opinion in mid-September recommending approval of duloxetine for the treatment of major depressive episodes. Duloxetine is copromoted by Boehringer Ingelheim for both indications in Europe, and in the U.S. for indications outside the area of neuroscience. </P> <P>Also in September, the FDA approved duloxetine for a completely new indication: the management of diabetic peripheral neuropathic pain. Duloxetine, which was subject to a six-month priority review, is the first and only FDA-approved treatment for pain caused by diabetic peripheral neuropathy. The drug's safety and efficacy in the treatment of pain caused by diabetic peripheral neuropathy was demonstrated at doses of 60 and 120 mg per day in two randomized, 12-week, double-blind, placebo-controlled, fixed-dose studies in nondepressed adults who had the disorder for at least 6 months. In both studies, duloxetine significantly reduced 24-hour average pain, with improvement noted as early as the first week of treatment and lasting throughout the duration of the studies. Although it does not change the underlying nerve damage caused by diabetic peripheral neuropathy, duloxetine helps relieve the pain often associated with the disorder by increasing levels of serotonin and norepinephrine. </P> <P>More recently, it was reported that duloxetine improved symptoms of fibromyalgia in patients enrolled in a randomized, double-blind, placebo-controlled trial, including those with major depressive disorder (Arnold, L.M. et al. Arthritis Rheum 2004, 50(9): 2974). In the multicenter study, 207 patients with primary fibromyalgia were treated with duloxetine or placebo for 12 weeks. The drug was well tolerated and significantly improved the Fibromyalgia Impact Questionnaire (FIQ) total score compared with placebo. Several other measures were improved significantly more with duloxetine than with placebo, including the FIQ stiffness score, the Brief Pain Inventory (BPI) average pain severity score, the BPI average interference from pain score, the number of tender joints, the mean tender joint pain threshold, the Clinical Global Impression of Severity scale and the Patient Global Impression of Improvement scale. Female patients experienced significant improvements in several efficacy measures with duloxetine compared with placebo, while male patients did not. Furthermore, the reduction in pain with duloxetine in female patients was independent of the drug's effect on mood. </P> http://www.prous.com/molecules/default.asp?ID=101 <p align="center"><img src="http://www.prous.com/images/moleculas/235379.gif"></p><P>Millions of people worldwide suffer from various forms of vascular disease. In the E.U. alone more than 2 million people are hospitalized and an estimated 4 million patients per year undergo invasive, catheter-based X-ray angiography (XRA), the most widely used method of vascular imaging. In the U.S., an estimated 62 million people have some form of cardiovascular disease, and approximately 4.8 million angiograms were performed in the US in 2002 in the cerebral, carotid, renal, and other peripheral arteries. It is currently estimated that only 25&#37; of the 10 million Americans affected by peripheral vascular disease have been diagnosed, however. Given the risks that are associated with catheter X-ray angiography, many patients are contraindicated for either the X-ray contrast agent or the procedure itself. </P> <P>Epix Medical and Schering AG have developed <B>gadofosveset sodium</B> (MS-325) as the first minimally invasive alternative to X-ray angiography for early diagnosis of vascular complications and disease. Gadofosveset, a contrast agent designed specifically for vascular imaging with magnetic resonance angiography (MRA), binds reversibly to human serum albumin, brightening the blood for an extended period and allowing for MRA imaging of multiple vascular beds. This feature may allow physicians to collect more meaningful clinical data using widely available MRI equipment to diagnose and characterize vascular disease. Earlier this year the partners filed for regulatory approval of gadofosveset in both the U.S. and E.U. Additional studies have been initiated to evaluate gadofosveset for high resolution vessel imaging and characterization of vascular wall structures and vulnerable plaque. </P> <P>Four phase III clinical trials determined the efficacy of gadofosveset sodium to detect vascular disease in different vascular territories by contrast-enhanced MRA. A total of 641 patients with known or suspected vascular disease were treated with single i.v. doses of gadofosveset and had their aortoiliac, renal and pedal arteries evaluated by twelve MRA readers. Compared to non-contrast 2D-TOF MRA, gadofosveset increased the average sensitivity, specificity and accuracy of the diagnosis of presence/absence of clinically significant stenoses by 16.4&#37;, 14.6&#37; and 13.9&#37;, respectively. Gadofosveset also increased the reproducibility of the procedure and reduced the number of uninterpretable blood vessels. Most drug-related adverse events were mild and transient (Kreitner, K.-F. Eur Cong Radiol (March 5-9, Vienna) 2004, Abst B-799). Notably, safety has been demonstrated in patients with renal impairment, who are at increased risk for cardiovascular disease. </P> http://www.prous.com/molecules/default.asp?ID=100 <p align="center"><img src="http://www.prous.com/images/moleculas/253430.gif"></p><P>Obesity is one of the most common metabolic disorders in the world. According to the Centers for Disease Control and Prevention, nearly two-thirds of the adult population of the United States, the country with the highest prevalence of obesity worldwide, is overweight and more than half of these are frankly obese. The World Bank estimates that obesity alone accounts for more than 12&#37; of the U.S. national health care budget. The National Institutes of Health estimated that direct costs for the treatment of obesity in 1998 had reached &#36;102.2 billion dollars. As these statistics illustrate, obesity is a rapidly growing, costly disease, for which there is currently no effective treatment. Existing medications for the treatment of obesity have significant side effects that limit their use. A safe, effective, orally administered compound that not only produces - but also sustains - weight loss would be a breakthrough in the treatment of obesity, and would represent a significant advantage over currently available treatments.</P> <P> <B>Oleoyl estrone</B> (OE), is an orally administered small molecule that has been shown to cause significant weight loss in extensive preclinical animal studies, without the need for dietary modifications. In such studies, OE appears to be safe and effective with no evidence of rebound weight gain after treatment has been discontinued. Developed by researchers at the University of Barcelona, OE has been tested in both obese and lean rats; treatment with OE resulted in significant weight loss even in the presence of abundant food and water. Manhattan Pharmaceuticals is the exclusive worldwide licensee of OE and its derivatives.</P> <P> Manhattan Pharmaceuticals has discovered that the levels of oleoyl estrone (OE), which appears to play a key role in communicating levels of stored body fat to the brain, are significantly lower in obese patients than predicted on the basis of body weight. The company theorizes that raising OE levels in the obese will therefore suppress appetite and cause weight loss. Animal studies support this theory, with body weight reductions of 20&#37;, and daily caloric intake reductions of 40&#37; or more during OE treatment. At the 13^th European Congress on Obesity, held in Prague during May 2004, the company presented further preclinical study results substantiating the safety of OE in both male and female rats. Safety observations were made over a 14-day period, including mortality, gross toxicity, blood, urine and carcass chemistries, blood and urine cellular counts, organ weights and histology. In groups treated at therapeutic dose levels of oleoyl estrone, there were no histological effects on endocrine-responsive tissues such as testes, epididymis, prostate, seminal vesicle, vagina, uterus or mammary glands. None of the doses tested resulted in mortality.</P> http://www.prous.com/molecules/default.asp?ID=99 <p align="center"><img src="http://www.prous.com/images/moleculas/217004.gif"></p><P>Cannabinoid receptors are members of the G-protein-coupled receptor superfamily. The cannabinoid-1 (CB1) receptor subtype is widely distributed in central and peripheral organs including the brain, adipose tissues, gastrointestinal, pulmonary, reproductive and cardiovascular systems. The CB1 receptor is involved in the regulation of energy balance and body weight but also in reinforcing reward. <B>Rimonabant hydrochloride</B> (Acomplia&trade;; Sanofi-Synth&eacute;labo), the first of a new class of selective CB1 receptor antagonists, is envisioned as an eventual cornerstone in the management of patients with cardiovascular risk factors. </P> <P>Rimonabant was evaluated in two programs, the RIO program and the STRATUS program. The RIO program has enrolled a total of over 6,600 patients in four phase III trials (RIO-US, RIO-Europe, RIO-Lipids and RIO-Diabetes) for the treatment of obesity and the STRATUS program has enrolled a total of over 6,500 patients in three worldwide phase III trials (STRATUS US, STRATUS Europe and STRATUS worldwide) for the treatment of nicotine dependence. </P> <P>Recently, researchers at the Laval Hospital of Quebec presented results of the RIO-Lipids obesity trial at the Metabolic Syndrome, Type II Diabetes and Atherosclerosis Congress. RIO-Lipids was a multinational, multicenter, double-blind, placebo-controlled one-year treatment study conducted in 1,036 overweight/obese patients who were randomly assigned to a once-daily dose of rimonabant (5 or 20 mg) or placebo. Treatment with rimonabant 20 mg significantly reduced body weight, waist circumference and plasma triglyceride levels, increased HDL cholesterol levels and improved plasma insulin and glucose levels. Rimonabant 20 mg also reduced the prevalence of patients meeting the NCEP-ATP III criteria for the presence of the metabolic syndrome from 52.9&#37; to 25.8&#37;. These findings indicate that rimonabant could be useful for the treatment of cardiovascular diseases in high-risk abdominally obese patients (Despres, J.-P. Metab Syndr Type II Diabetes Atheroscler Congr (May 19-May 23, Marrakesh) 2004, Abst LL-18 and P-42). </P> <P>In a separate study, 287 subjects with a body mass index of 29-41 were included in a randomized clinical trial that determined the effects of rimonabant on body weight and waist circumference. Each patient was given a mildly hypocaloric diet together with placebo or rimonabant (5, 10 or 20 mg) once daily for 16 weeks. Rimonabant dose-dependently reduced both body weight and waist circumference. Body weight reduction was significantly greater compared to placebo for all three rimonabant dose levels, but only the highest dose of rimonabant was significantly more effective than placebo in reducing waist circumference. All study treatments were well tolerated (Michael, J. et al. Intl J Obesity [13th Eur Cong Obesity (May 26-29, Prague) 2004] 2004, 28(Suppl. 1): Abst T5:O2-001). </P> <P>Results of the STRATUS US study were presented by researchers at the University of Cincinnati College of Medicine and Cincinnati VA Medical Center. STRATUS US was a randomized, multicenter, double-blind, placebo-controlled 10-week treatment study conducted in 784 smokers (at least 10 cigarettes/day) who received a once-daily dose of rimonabant (5 or 20 mg) or placebo accompanied by brief weekly counseling. Treatment with high-dose rimonabant doubled the odds of quitting smoking for at least the last four weeks of the study compared with placebo, significantly reduced post-cessation weight gain and was well tolerated (Anthenelli, R.M. Metab Syndr Type II Diabetes Atheroscler Congr (May 19-May 23, Marrakesh) 2004, Abst P-39). </P> <P>The rimonabant phase III program is expected to be completed in late 2004, with the first regulatory filings slated for early 2005. </P> http://www.prous.com/molecules/default.asp?ID=98 <p align="center"><img src="http://www.prous.com/images/moleculas/264763.gif"></p><P>Alteon’s <B>alagebrium chloride</B> (ALT-711) is the first in a new class of compounds that have been shown <I>in vitro</I> and <I>in vivo</I> to reverse advanced glycation end-product (AGE) crosslinking, thereby restoring more normal function to tissues, vessels and organs that have lost flexibility. Alagebrium's mechanism of action is believed to be new and novel, and unrelated to that of any pharmaceutical agent. Alagebrium does not disrupt the natural enzymatic glycosylation sites or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. In preclinical studies, alagebrium consistently demonstrates the ability to reverse the upregulation of genes for proteins and growth factors known to be associated with the pathological hypertrophy of tissues. Alagebrium has demonstrated safety and efficacy in several phase II trials and is being developed for systolic hypertension and heart failure.</P><P>Positive results were reported in February from the SAPPHIRE/SILVER study, a multicenter, double-blind, randomized, placebo-controlled clinical trial that evaluated the efficacy of alagebrium chloride in the treatment of hypertension. Approximately 800 patients suffering from systolic hypertension, with or without left ventricular hypertension, were randomized to receive placebo or alagebrium at doses up to 210 mg/day for six months. A first analysis reported in July 2003 suggested that none of the active drug dose levels tested induced significant antihypertensive effects compared to placebo, but these results were confounded by a 6-10 mmHg reduction in systolic blood pressure (SBP) in all study arms during the first two years after randomization. A post hoc analysis later revealed that alagebrium was well tolerated and significantly reduced SBP in patients with baseline systolic ambulatory blood pressure measurements equal or higher than 140 mmHg, but had no effects on diastolic blood pressure. The antihypertensive effects of alagebrium were also found in heavily pretreated patients and were greatest in patients with higher baseline SBP values.</P> <P>To build on these findings, Alteon has initiated a phase IIb trial of alagebrium chloride in patients with systolic hypertension. The SPECTRA trial is designed to evaluate alagebrium's ability to lower SBP in patients with a systolic blood pressure reading of greater than or equal to 140 mmHg. Alagebrium will be tested in approximately 390 male and female patients aged 45 and older at over 50 U.S. sites. Patients will undergo a wash-out period, when they are weaned from their existing antihypertensive treatment, followed by a run-in phase during which they will be stabilized on a diuretic. They will then receive alagebrium or placebo once a day for 12 weeks. The study will include three different dose levels of alagebrium (10, 50 or 150 mg) and placebo. Change from baseline in mean 24-hour systolic ambulatory blood pressure after 12 weeks of dosing as compared to placebo will be evaluated as the primary measure of efficacy. Secondary endpoints will include changes in diastolic, pulse and arterial pressures.</P> <P>The company has also initiated the open-label, exploratory PEDESTAL trial, which is designed to determine the effects of alagebrium at two oral doses (35 mg o.d. or 210 mg b.i.d.) for 6, 12, 16 and 24 weeks on diastolic function and left ventricular mass in 20 patients diagnosed with systolic heart failure and diastolic dysfunction. Safety and quality of life will also be evaluated. The study will enroll men and women at least 30 years of age with or without diabetes, who are classified as having grade II- IV heart failure under NYHA guidelines. The primary endpoints include quantification of left ventricular mass and complete Doppler evaluation of changes in diastolic function. Secondary endpoints include a quality of life assessment.</P> http://www.prous.com/molecules/default.asp?ID=97 <p align="center"><img src="http://www.prous.com/images/moleculas/301547.gif"></p><P>High-density lipoprotein (HDL) is one of the major lipid-transporting elements in the blood. It is known as the "good" cholesterol because it transports excess lipids from peripheral cells in the arterial walls to the liver, where they are subsequently eliminated in bile. Enhancement of this process --known as reverse cholesterol transport (RCT) or reverse lipid transport (RLT)—by boosting levels of HDL cholesterol has in recent years emerged as an attractive strategy for the control of atherosclerosis. </P> <P>Cholesteryl ester transfer protein (CETP) plays a pivotal role in the metabolism of HDL cholesterol, and has been identified as a potential factor influencing whether or not patients respond favorably to lipid-lowering therapy with statins and other drugs. CETP regulates the exchange of cholesterol and triglycerides between plasma lipoproteins, enabling the net transfer of cholesteryl ester from antiatherogenic HDL to proatherogenic apolipoprotein B-cointaining lipoproteins and the resulting uptake of cholesterol by hepatocytes via a process of receptor-mediated endocytosis. CETP promotes the atherogenicity of VLDL and LDL by increasing their cholesteryl ester content. Thus elevation of HDL levels via the inhibition of CETP has been proposed as a novel strategy for treating atherosclerosis. </P> <P><B>Torcetrapib</B>, a CETP inhibitor from Pfizer, is currently in advanced-stage clinical testing both as monotherapy and in combination with the HMG-CoA reductase inhibitor atorvastatin. In a recently reported single-blind, placebo-controlled clinical trial, the effects of torcetrapib were evaluated in 19 adult subjects with plasma HDL cholesterol levels below 40 mg/dl. The subjects were first treated with placebo for four weeks and were then randomized to receive torcetrapib (120 mg once daily) alone or combined with atorvastatin (20 mg/day) for another four weeks. Compared with placebo, trough CETP activity decreased by an average of 28&#37; with torcetrapib alone and by 38&#37; with torcetrapib plus atorvastatin, whereas plasma HDL cholesterol levels increased by 46&#37; and 61&#37;, apolipoprotein A-I levels increased by 16&#37; and 13&#37;, and apolipoprotein A-II levels increased by 12% and 10%, respectively. Six torcetrapib-treated patients continued receiving the drug (120 mg twice daily) for four more weeks. This additional treatment further reduced baseline trough CETP activity (by an average of 65&#37;) and increased HDL cholesterol levels by 106%, apolipoprotein A-I levels by 36% and apolipoprotein A-II levels by 21&#37;. The combination of torcetrapib and atorvastatin was more effective than torcetrapib once daily in reducing the plasma levels of triglycerides (18&#37; vs. a 1&#37; increase), LDL cholesterol (17&#37; vs. 8&#37;) and apolipoprotein B (14&#37; vs. 10&#37;), while torcetrapib twice daily reduced these parameters by 26&#37;, 17&#37; and 17&#37;, respectively. Torcetrapib also increased the mean particle size of HDL and LDL and was well tolerated. Only mild or moderate adverse events were found and included headache, asthenia, pain, dyspepsia, herpes simplex, herpes zoster, sweating, amnesia and abnormal thinking. Additional trials are needed to determine whether torcetrapib may be effective for atherosclerotic cardiovascular disease (Brousseau, M.E. et al. N Engl J Med 2004, 350(15): 1505). </P> http://www.prous.com/molecules/default.asp?ID=96 <p align="center"><img src="http://www.prous.com/images/moleculas/246885.gif"></p><P>The betulinic acid derivative <B>PA-457</B> is the first in the new class of antiretroviral agents called maturation inhibitors. It has a mechanism of action different from those of approved HIV drugs and potent activity against both wild-type HIV and strains resistant to current therapies, including inhibitors of reverse transcriptase and viral protease. PA-457 inhibits viral replication by disrupting a late stage in Gag processing, a series of events required for the process of structural rearrangement that is known as virus maturation. During maturation, the immature virus particle makes the transition to a mature, infectious virion. PA-457 prevents this event by interrupting the conversion of the capsid precursor (p25) to a mature capsid protein (p24), resulting in the formation of defective, noninfectious virus particles (Li, F. et al., Proc Natl Acad Sci USA 2003, 100(23): 13555). </P> <P>Preclinical studies demonstrated that the compound has favorable pharmacokinetics and anti-HIV activity in animals following oral administration. These studies indicated that it should be possible to achieve therapeutic drug concentrations following oral delivery in humans. </P> <P>In March 2004, Panacos initiated the first phase I trial of PA-457. The trial will evaluate the safety and pharmacokinetics of orally administered PA-457 in uninfected healthy volunteers. Studies testing PA-457's antiviral potency in HIV-infected individuals are expected to begin later in 2004. </P> http://www.prous.com/molecules/default.asp?ID=95 <p align="center"><img src="http://www.prous.com/images/moleculas/162123.gif"></p><P>Inhaled corticosteroids are the gold standard in asthma maintenance therapy, and systemic corticosteroids are used to treat severe exacerbations of asthma in the hospital setting. Corticosteroids have been marketed for this indication since the 1950s. In the asthmatic patient, corticosteroids decrease bronchial hyperreactivity and improve lung function, symptomatology and quality of life. Nonetheless, corticosteroids are not curative and their therapeutic benefits disappear when they are discontinued. </P> <P>Inhaled corticosteroids are considered to be safe and are generally well tolerated, although they can produce side effects. Even if a corticosteroid is properly inhaled, approximately 70-80&#37; of the dose is swallowed. This portion can be absorbed by the gastrointestinal tract and can cause side effects ranging from dysphonia and thrush to adrenal suppression, cataracts, glaucoma, osteoporosis and growth retardation. The benefits obtained through treatment with corticosteroids are felt to far outweigh the risks, which are comparatively minimal. </P> <P>In an attempt to overcome the limitations of existing corticosteroid therapies, researchers at Altana have developed <B>ciclesonide</B>, a new-generation nonhalogenated glucocorticoid with high local antiinflammatory properties. It is an ester prodrug, essentially devoid of oral bioavailability, which is activated upon cleavage by endogenous esterases. Advantages of on-site activation include targeted activation in the lung, minimal systemic adverse effects and minimal orpharyngeal side effects. Furthermore, its prolonged duration of action means that the compound is taken just once daily. </P> <P>The efficacy and safety of ciclesonide were evaluated in a double-blind, randomized, placebo-controlled clinical trial that enrolled 360 asthma patients with a FEV1 of 60-90&#37; and evidence of reversibility. Patients were pretreated with beclomethasone dipropionate and after two weeks were randomized to inhale ciclesonide (80 and 320 mcg) or placebo once daily in the morning for 12 weeks. The efficacy of the study regimens was estimated to be 62&#37; for 80-mcg ciclesonide, 77&#37; for 320-mcg ciclesonide and 45&#37; for placebo. Compared to baseline, morning peak expiratory flow (PEF) increased by 129 ml and 192 ml with the low and high ciclesonide doses, respectively, and decreased by 28 ml with placebo. No significant differences between treatments were found in the incidence of adverse events (Langdon, C.G. et al. 4th World Asthma Meet [Feb 16-19, Bangkok] 2004, Abst P-234). Similar efficacy was observed in a group of 283 persistent asthma patients who had received ciclesonide (160 and 640 mcg once daily) or placebo for 12 weeks were included in an open-label extension study that determined the long-term safety of ciclesonide. These patients first received a dose of 640 mcg of ciclesonide once daily or twice daily for four weeks, followed by an individualized dose ranging from 160 to 1280 mcg/day for another 36 weeks. The incidence of oropharyngeal adverse events during the extension study was low and consisted mainly of pharyngitis (4&#37;), voice alteration (2&#37;) and oral candidiasis (1&#37;). No relevant systemic or oral adverse events were reported, and most respiratory adverse events were considered to be unlikely or unrelated to ciclesonide. Long-term administration of ciclesonide was associated with a 28&#37; increase in 24-hour urine cortisol excretion (Chapman, K.R. et al. 4th World Asthma Meet [Feb 16-19, Bangkok] 2004, Abst P-232). The low frequency of oropharyngeal adverse effects found with ciclesonide may be associated with a low oropharyngeal deposition of the drug and its active metabolite, desisobutyryl-ciclesonide. A study in 18 healthy volunteers revealed that the oropharyngeal deposition of ciclesonide and its active metabolite was approximately half of that found for budesonide or fluticasone propionate (Richter, K. et al. 4th World Asthma Meet [Feb 16-19, Bangkok] 2004, Abst P-235). </P> <P>Shortly before the close of 2003, Altana's U.S. partner Aventis submitted an NDA to the FDA for the approval of <B>ciclesonide</B> (Alvesco[R]) in the treatment of asthma. Similarly, Teijin, Altana's partner for the Japanese market, submitted an application for approval for ciclesonide in Japan in January 2004. Concurrent with U.S. filing, Aventis initiated a Phase IIIb, 12-month trial to further profile the safety and tolerability of high doses of the steroid in adult patients with moderate to severe asthma. This trial will characterize the occurrence of lens opacity ocular events, as sometimes seen in patients who are treated with high doses of inhaled corticosteroids. The study was not a prerequisite for submission of the NDA to the U.S. FDA. In a separate ongoing phase I/II trial, ciclesonide is being evaluated in a fixed combination with a long-acting beta agonist. Dry powder inhaler and nasal spray formulations are being evaluated in phase I and phase II trials, respectively. </P> http://www.prous.com/molecules/default.asp?ID=94 <p align="center"><img src="http://www.prous.com/images/moleculas/210424.gif"></p><P>The rapamycin analogue <B>everolimus</B> (Certican[R]; formerly SDZ-RAD) is a novel proliferation signal (mTOR) inhibitor with immunosuppressive properties that targets the primary causes of allograft dysfunction. The drug has been repeated shown to reduce the incidence of acute rejection, reduce calcineurin inhibitor-induced nephrotoxicity, decrease the incidence of cytomegalovirus (CMV) infections and inhibit vascular remodeling. An extensive clinical trial program has demonstrated that everolimus is able to target primary causes of chronic rejection, including progressive vasculopathy, which eventually develops in approximately 50&#37; of all transplant recipients in the first several years after surgery. Twenty-four month data from a major international trial involving more than 600 heart transplant patients at 52 medical centers in Europe and the Americas has confirmed the superiority of everolimus over the current standard therapy, azathioprine, in terms of all-cause efficacy failure, acute rejection rates and cardiac allograft vasculopathy. Twelve-month results from another randomized, double-blind phase III study in over 200 lung transplant patients in nine countries show that everolimus is also more effective than azathioprine in preventing acute rejection and preserving pulmonary function in this patient population. </P> <P>In December 2003, Novartis successfully completed the European mutual recognition procedure in 15 countries (Austria, Belgium, Denmark, Finland, France, Germany, Greece, Iceland, Italy, Luxembourg, The Netherlands, Norway, Portugal, Spain and Sweden) for <I>Certican(R)</I> for the prevention of rejection episodes following heart or kidney transplantation. Sweden, which was the first country to approve the drug in July 2003, acted as reference member state. Everolimus will be indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant, and is to be used in combination with Neoral(R) (ciclosporin for microemulsion) to suppress T-lymphocyte proliferation, and with corticosteroids. All countries involved in the mutual recognition procedure are expected to issue a marketing authorization in the coming months. In the U.S., The FDA has issued an approvable letter for everolimus for the prevention of rejection episodes following heart or kidney transplantation in combination with ciclosporin. Final approval is contingent on the submission and review of additional clinical data. </P> http://www.prous.com/molecules/default.asp?ID=93 <p align="center"><img src="http://www.prous.com/images/moleculas/254767.gif"></p><P>Thrombin, a trypsin-like serine protease, is the final enzyme in the coagulation cascade formed from prothrombin via the serine protease factor Xa. Thrombin plays several key roles in the coagulation cascade. It induces platelet aggregation and, through positive feedback and activation of factors Va, VIIIa and XI, it enhances its own production. Small-molecule thrombin inhibitors are classified into two subtypes: tripeptide and peptide mimetics of the fibrinogen cleavage site and nonpeptide inhibitors. One of the more interesting compounds in this class is AstraZeneca's <B>ximelagatran</B> (H-376/95), a small-molecule double prodrug of the non-covalent peptide thrombin inhibitor melagatran, which exhibits poor bioavailability and absorption upon oral dosing. Following oral administration, the prodrug ximelagatran -- itself inactive as an anticoagulant -- is rapidly hydrolyzed and reduced to the active thrombin inhibitor melagatran. Ximelagatran is the first oral anticoagulant to reach late-stage clinical trials since the development of warfarin more than 50 years ago. Due to its predictable pharmacokinetics, antithrombotic efficacy and low potential for food and drug interactions, ximelagatran has been developed for the prevention and treatment of venous thrombosis and for the prevention of stroke in individuals with atrial fibrillation. </P> <P>On December 23, 2003, AstraZeneca received notification of the first approval worldwide for marketing of ximelagatran (Exanta(R)). French authorities approved the thrombin inhibitor for the indication of preventing venous thromboembolic events (VTE) in patients undergoing major elective orthopedic surgery, i.e., hip or knee replacement. France will now serve as Reference Member State for the European Union (EU) Mutual Recognition Procedure. Subject to approval, launches of ximelagatran for this first indication will take place in 2004. </P> <P>The French approval was based on the METHRO (Melegatran for Thrombin inhibition in Orthopedic surgery) study program, which compared injectable low-molecular-weight heparin, initiated in the evening before surgery, with preoperative (METHRO II) or postoperative (METHRO III) initiation of melagatran, followed by oral ximelagatran, in 4,688 patients undergoing total hip or knee replacement. </P> <P>On the same day, the company announced that filings had been made in the U.S. for three indications: prevention of VTE in patients undergoing knee replacement surgery; prevention of stroke and other thromboembolic complications associated with atrial fibrillation; and long-term secondary prevention of VTE after standard treatment for an episode of acute VTE. Additional filings were also made in France for two new indications in that and other E.U. markets: prevention of stroke and other thromboembolic complications associated with atrial fibrillation; and treatment of VTE. </P> http://www.prous.com/molecules/default.asp?ID=92 <p align="center"><img src="http://www.prous.com/images/moleculas/186290.gif"></p><P><B>Febuxostat</B> (TMX-67) is a selective inhibitor of xanthine oxidase/xanthine dehydrogenase under development for the treatment of gout and hyperuricemia. Febuxostat is expected to be safer and more effective than allopurinol, the only xanthine oxidase inhibitor presently on the market, at lower doses. The drug, discovered by Teijin, is currently in phase III trials in Japan (Teijin) and the U.S. (TAP Pharmaceutical) and it was recently licensed to Ipsen for Europe. Febuxostat was the focus of several presentations at the recent American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) meeting. </P> <P>A multicenter, double-blind, randomized, placebo-controlled clinical trial evaluated the efficacy and tolerability of febuxostat in 128 Japanese patients with gout or hyperuricemia