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Póvoa e Meadas, Portugal

Fortuna A.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | Soares-da-Silva P.,Bial | And 2 more authors.
Epilepsy Research

In silico approaches to predict absorption, distribution, metabolism and excretion (ADME) of new drug candidates are gaining a relevant importance in drug discovery programmes. When considering particularly the pharmacokinetics during the development of oral antiepileptic drugs (AEDs), one of the most prominent goals is designing compounds with good bioavailability and brain penetration. Thus, it is expected that in silico models able to predict these features may be applied during the early stages of AEDs discovery. The present investigation was mainly carried out in order to generate in vivo pharmacokinetic data that can be utilized for development and validation of in silico models.For this purpose, a single dose of each compound (1.4. mmol/kg) was orally administered to male CD-1 mice. After quantifying the parent compound and main metabolites in plasma and brain up to 12. h post-dosing, a non-compartmental pharmacokinetic analysis was performed and the corresponding brain/plasma ratios were calculated. Moreover the plasma protein binding was estimated in vitro applying the ultrafiltration procedure.The present in vivo pharmacokinetic characterization of the test compounds and corresponding metabolites demonstrated that the metabolism extensively compromised the in vivo activity of CBZ derivatives and their toxicity. Furthermore, it was clearly evidenced that the time to reach maximum peak concentration, bioavailability (given by the area under the curve) and metabolic stability (given by the AUC0-12h ratio of the parent compound and total systemic drug) influenced the in vivo pharmacological activities and must be considered as primary parameters to be investigated. All the test compounds presented brain/plasma ratios lower than 1.0, suggesting that the blood-brain barrier restricts drug entry into the brain. In agreement with in vitro studies already performed within our research group, CBZ, CBZ-10,11-epoxide and oxcarbazepine exhibited the highest brain/plasma ratios (>0.50), followed by eslicarbazepine, R-licarbazepine, trans-diol and BIA 2-024 (ratios within 0.05-0.50). BIA 2-265 was not found in the biophase, probably due to its high plasma-protein bound fraction (>90%) herein revealed for the first time.The comparative in vivo pharmacokinetic data obtained in the present work might be usefully applied in the context of discovery of new antiepileptic drugs that are derivatives of CBZ. © 2013 Elsevier B.V. Source

Fortuna A.,University of Coimbra | Alves G.,University of Coimbra | Alves G.,University of Beira Interior | Falcao A.,University of Coimbra | Soares-Da-Silva P.,Bial

Purpose: The rational discovery and development of new antiepileptic drugs (AEDs) with safer therapeutic index and better pharmacokinetic properties is still warranted nowadays. Because the long-term management of epilepsy is attained by means of orally administered AEDs, investigation of their potential to be well absorbed at the intestinal level is mandatory. Moreover, involvement of the efflux transport mediated by P-glycoprotein (P-gp) may compromise the systemic and central nervous system disposition of AEDs. Therefore, this study aimed at characterizing mouse jejunal passive transport and the possible active efflux mediated by P-gp of a series of dibenz[b,f]azepine-5-carboxamide derivatives (carbamazepine [CBZ], oxcarbazepine [OXC], S-licarbazepine [S-Lic], R-licarbazepine [R-Lic], carbamazepine-10,11-epoxide [CBZ-E], 10,11-trans-dihydroxy-10,11-dihydro-carbamazepine [trans-diol], and BIA 2-024), which comprise some AEDs and metabolites. Methods: Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P app) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance. Key Findings: The correlation obtained between P app(M-S) and Fa of references was high (r 2 = 0.9945), and could be used to classify the derivatives according to Biopharmaceutical Classification System: CBZ and OXC were the only classified as highly permeable. The P app(S-M) of OXC, CBZ-E, R-Lic, and BIA 2-024 were significantly higher than their P app(M-S). After verapamil addition, their P app(S-M) lowered while P app(S-M) increased, suggesting the involvement of P-gp on the transport of those compounds across mouse jejunum segments. In opposition, CBZ, S-Lic, and trans-diol presented no statistical differences between the P app values reported in both directions, with or without verapamil. The results reported herein suggest that differences in biodisposition of S-Lic and R-Lic might result from their distinct interaction with P-gp. Significance: The Ussing chamber model used herein showed to be useful for predicting Fa of AEDs and the involvement of efflux transport, namely P-gp, on their absorption. This is an important achievement as compounds that are not transported by P-gp may offer advantages when used in patients with pharmacoresistant epilepsy. © 2012 International League Against Epilepsy. Source

News Article
Site: http://cen.acs.org/news/ln.html

One man is dead and five men were hospitalized after participating in a Phase I clinical trial in Rennes, France. The clinical trial, conducted by the company Biotrial on behalf of the Portuguese pharmaceutical firm Bial, was evaluating a pain relief drug candidate called BIA 10-2474 that inhibits fatty acid amide hydrolase (FAAH) enzymes. Blocking these enzymes prevents them from breaking down cannabinoids in the brain, a family of compounds that includes the euphoria-inducing neurotransmitter anandamide and Δ9-tetrahydrocannabinol, the major psychoactive component of marijuana. Phase I clinical trials are conducted to check a drug candidate’s safety profile in healthy, paid volunteers. In this case, the drug caused hemorrhagic and necrotic brain lesions in five out of six men in a group who received the highest doses of the drug, said Gilles Edan, a neurologist at the University Hospital Center of Rennes. The most severely affected man was pronounced brain-dead after hospitalization and then died on Jan. 17. Four men remain in the hospital in stable condition. The only man in the high-dose group who had no adverse symptoms has been released from the hospital. Prior to the hospitalizations, 84 people had taken lower doses of BIA 10-2474 in the clinical trial without complications. A spokesperson for the European Medicines Agency told C&EN that, “since 2007, approximately 12,500 Phase I clinical trials have been conducted in the European Union without any major incidents being reported.” The last major Phase I clinical trial catastrophe took place in London in 2006, when six healthy men suffered permanent organ damage, and the loss of fingers, from unanticipated severe immune reactions during testing of an arthritis and cancer drug candidate called TGN1412. Multiple pharmaceutical companies, including Merck & Co. and Pfizer, have evaluated FAAH inhibitors as possible treatments for pain, mood disorders, and insomnia, among other applications, with no reports of significant adverse reactions until the Bial clinical trial. After the events in Rennes, Janssen, part of Johnson & Johnson Pharmaceutical Research & Development, voluntarily suspended a Phase II clinical trial of an FAAH inhibitor; no adverse events have been reported, the company noted in a press release, so it was a precautionary step . As news of the clinical trial tragedy broke, the online chemical community exploded with speculation about the nature of the putative drug. “What everybody wants to know now is its structure,” says Christopher Southan, a senior curator for the University of Edinburgh-based Guide to Pharmacology database. As C&EN went to press, Le Figaro posted a 96-page clinical study protocol for BIA 10-2474 that the French newspaper procured from an unnamed source. BIA 10-2474 “is designed to act as a long-active and reversible inhibitor of brain and peripheral FAAH,” notes the protocol. The compound “increases anandamide levels in the central nervous system and in peripheral tissues.” The clinical trial protocol also notes that the company tested BIA 10-2474 on mice, rats, dogs, and monkeys for effects on the heart, kidneys, and gastrointestinal tract, among other pharmacological and toxicological evaluations.

Patricio J.P.H.,Bial | Barbosa J.P.P.,Centro Hospitalar Of Lisbon Central | Ramos R.M.M.,Centro Hospitalar Cova da Beira | Antunes N.F.P.,Centro Hospitalar Do Porto Hospital Of Santo Antonio | De Melo P.C.S.,Instituto Portugues Of Oncologia Of Lisbon
Clinical Drug Investigation

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used in clinical practice, and are considered a first-line option for pain management. However, non-selective NSAIDs (nsNSAIDs) and new generation NSAIDs named cyclo-oxygenase-2 inhibitors (coxibs) are very different from one another and their cardiovascular and gastrointestinal safety profiles may influence prescribing. This article resulted from a search of MEDLINE/Pubmed, Cochrane Library, Bandolier, Medscape and Trip database, up to June 2011. Key words included non-steroidal anti-inflammatory, coxib and safety, with the purpose of reviewing the gastrointestinal and cardiovascular safety issues of NSAIDS and the main aspects that differentiate both classes. Selective coxibs are associated with a more favourable gastrointestinal safety profile than nsNSAIDs. In terms of the risk of cardiovascular events, there seems to be a class effect for all NSAIDs with the possible exception of naproxen. The proper usage guidelines for NSAIDs detail the importance of risk factors for each patient in addition to the differences between classes. Patients with high cardiovascular or gastrointestinal risk should avoid using NSAIDs. These medications should be used at the minimum effective dose and for the shortest time possible in all patients. © 2013 Springer International Publishing Switzerland. Source

News Article
Site: http://www.nature.com/nature/current_issue/

Clinical-trial death Five people were hospitalized and one has died after a French clinical trial went disastrously wrong. The phase I trial — designed to test the safety of new treatments in healthy people — involved a drug made by the company Bial near Porto, Portugal, and was conducted by a French contract-research organization, Biotrial, in Rennes. Neither the French authorities nor Biotrial has identified the drug, but Bial says that it was an inhibitor of the enzyme FAAH (fatty acid amide hydrolase). See page 263 for more. Ebola returns Health officials confirmed on 15 January that a 22-year-old woman in Sierra Leone had died of Ebola. The announcement comes two months after the World Health Organization declared that the disease had stopped spreading in Sierra Leone, and less than a day after it was announced that a similar resurgence of the virus in Liberia had ended. The source of the latest case is being investigated; other flare-ups have been traced to survivors who still harboured the virus in semen and other bodily fluids. Launch was a success, landing less so A joint US–European satellite that will track the surface height of the oceans was launched into orbit on 17 January. The oceanography mission Jason-3 will provide data for weather, climate and ocean researchers. But the Falcon 9 rocket that delivered the satellite into orbit had a less happy outcome. It was supposed to touch down on an ocean barge, but instead toppled over and was destroyed on landing. Turkish arrests Twenty-seven Turkish academics were arrested, and later released, on 15 January for signing a petition calling on their government to end violence in Turkey’s southeast, where government forces have been fighting Kurdish separatists. The researchers face prosecution for alleged defamation of the state and spreading of terrorist propaganda. Around 2,000 scientists from about 90 Turkish universities have signed the petition. Several of the universities have launched investigations into signatories in their faculty. See go.nature.com/gpcarv for more. Zika virus The US Centers for Disease Control and Prevention has issued a travel alert over the ongoing transmission of Zika virus in 14 countries in the Caribbean and in Central and South America. The alert — issued on 15 January — recommends that pregnant women consider postponing travel to any areas where Zika infection is occurring. It comes after evidence emerged that, since October, around 3,530 babies have been born in Brazil with unusually small heads and brains — a disorder called microcephaly. That is ten times more than the country usually sees in a year, and cases are concentrated in regions with Zika outbreaks. NASA spaceplane Starting in 2019, NASA will gain a third commercial partner for flying cargo to and from the International Space Station. The space agency announced on 14 January that it will use a miniature spaceplane owned by the Sierra Nevada Corporation in Sparks, Nevada, for a minimum of six missions by 2024. The craft can transport both pressurized and unpressurized loads, and lands on a runway back on Earth, improving NASA’s options for delivering and returning fragile scientific equipment. NASA also uses spacecraft from Orbital ATK in Dulles, Virginia, which burn up on re-entry, and from SpaceX in Hawthorne, California, which splash down into the ocean. Vaccine deal Gavi, the international vaccine alliance, announced on 20 January that it has paid US$5 million to Merck, manufacturer of the first Ebola vaccine shown to protect against the virus in a human clinical trial. The deal marks the first time that the public-health organization has moved to purchase a vaccine before it has been licensed. In return for the payment, Merck promises that it will seek to have the vaccine approved by a regulatory agency by 2017. See go.nature.com/ujcirz for more. Taiwanese election An epidemiologist famed for his work on the 2003 outbreak of severe acute respiratory syndrome (SARS) and for his studies on the health burden of arsenic and hepatitis is to become Taiwan’s vice-president. Chen Chien-Jen (pictured) assumes the role after Tsai Ing-Wen, his running mate, won the 16 January election. Chen is widely respected for his work as health minister in Taiwan during the SARS epidemic, and was vice-president of the nation’s premier research organization, the Academia Sinica. See go.nature.com/wwrrwn for more. Sentence upheld A former biomedical researcher at Iowa State University has failed to reduce his prison sentence for making false statements on successful funding applications to the US National Institutes of Health. On 11 January, a federal appeals court ruled against reducing the sentence of Dong Pyou Han, who pleaded guilty in 2015. At the time, Han was sentenced to 57 months in prison, but he appealed against the sentence two weeks later and argued that its length was unreasonable given his remorse and lawful past. The appeals court disagreed and upheld the sentence. Perpetrator named Nature and other sources confirmed last week that the faculty member suspended by the California Institute of Technology for harassing two female graduate students is theoretical astrophysicist Christian Ott. Caltech, in Pasadena, announced on 4 January that it had suspended an unnamed faculty member without pay for an academic year. Meanwhile, in a 12 January statement to the US House of Representatives, Congresswoman Jackie Speier (Democrat, California) highlighted sexual harassment in astronomy. She has called for universities to share information with each other on the outcome of harassment investigations. See go.nature.com/mnwdim for more. US coal pause The United States has halted any new coal mining on federal land as it begins a major review of the coal industry. Interior secretary Sally Jewell announced the review on 15 January and said it would ensure that the federal coal programme took into account the impact of the industry on climate change. Coal power is one of the most greenhouse-gas-intensive forms of electricity generation. The halt on new leases applies while the comprehensive review — which Jewell says is the first in 30 years — is under way. Iran sanctions The United States and the European Union lifted a broad array of sanctions against Iran on 16 January after it was confirmed that the country had taken steps to impair its ability to produce plutonium and enriched uranium, which are used in atomic bombs. The lifting of restrictions came within hours of confirmation by the International Atomic Energy Agency that Iran was in compliance with the deal it struck with six world powers in July over its nuclear programme. Sanctions have crippled Iran’s economy and contributed to the international isolation of its scientists. EU reprimand The ombudsman for the European Union (EU), Emily O’Reilly, has ruled that delays by the European Commission in dealing with 20 authorization applications for genetically modified (GM) foods and feedstuffs were a “systemic problem” and “constituted maladministration”. The ombudsman, who investigates complaints about EU bodies, said on 15 January that the commission had consistently failed to make decisions on the applications within the three-month deadline required by law. A review of EU decision-making on GM foods and feedstuffs is under way, and so O’Reilly did not make a recommendation related to the case. But she said that the commission should comply with current requirements until the review is complete. Reproducibility call A coalition representing more than 100,000 experimental biologists has released recommendations for enhancing the reproducibility of research. The Federation of American Societies for Experimental Biology, which includes 30 scientific groups, wants to see better characterization of antibodies, easier reporting of negative results, better training for graduate students and established scientists, and fuller descriptions of animal models. See page 256 for more. As the number of scientists and engineers in the United States jumped between 2003 and 2013, so too did the proportion of immigrants. A report from the US National Science Foundation (see go.nature.com/9hhf15) shows that immigrants made up just 15% of the 21.6-million-strong science workforce in 2003, rising to 18% of 29 million people in 2013. Asia remains the most likely region of birth for the immigrants; the number of Indian-born scientists nearly doubled, from 515,000 in 2003 to 960,000 in 2013. Annual amount needed to fight pandemics, says a group convened by the US National Academy of Medicine. Source: Commission on a Global Health Risk Framework for the Future

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