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1.
J Clin Pharmacol ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32196692

RESUMO

Organic anion-transporting polypeptides (OATPs) 1B1 and 1B3 are the primary hepatic transporters responsible for uptake of drugs into the liver and, as such, an area of growing research focus. Currently, evaluation of these transporters as potential mediators of drug-drug interactions (DDIs) is recommended by regulatory agencies worldwide during the drug development process. Despite the growing focus on OATP1B1/1B3 as mediators of DDIs, only 2 drugs are recommended as index inhibitors for use in clinical studies, single-dose rifampin and cyclosporine, each with limitations for the utility of the resulting data. In this study a thorough analysis of the available in vitro and clinical data was conducted to identify drugs that are clinically relevant inhibitors of OATP1B1/1B3 and, from those, to select any novel index inhibitors. A total of 13 drugs and 16 combination products were identified as clinical inhibitors of OATP1B1/1B3, showing significant changes in exposure for sensitive substrates of the transporters, with strong supporting in vitro evidence. Although none of the identified inhibitors qualified as index inhibitors, this study confirmed the utility of cyclosporine and single-dose rifampin as index inhibitors to evaluate the effect of broad, multiple-pathway inhibition and more selective OATP1B1/1B3 inhibition, respectively.

2.
Epilepsy Res ; 153: 66-67, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30910314

RESUMO

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain from May 13th to 16th 2018. Again, presentations on new medical devices and neuromodulation and discussions on device-related regulatory aspects were included in the programme. The virtual special issue on "neuromodulation" summarises the presentations focusing firstly, on the pre-clinical developments and the difficulties of clinical trial designs for neuromodulatory therapies, including vagus nerve stimulation (VNS) and Brain-Responsive Neurostimulation (RNS), and the use of transcutaneous vagus nerve stimulation (tVNS) as a potential screening tool for determining the efficacy of neuromodulatory treatments in individual patients; secondly, on wearable devices for seizure monitoring through indices of peripheral sympathetic nervous activity, the use of such devices in combination with biofeedback for the treatment of epilepsy, and its potential for improving epilepsy specialist services, particularly in remote areas.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/terapia , Estimulação do Nervo Vago/métodos , Dispositivos Eletrônicos Vestíveis , Animais , Ensaios Clínicos como Assunto , Congressos como Assunto , Humanos , Espanha , Estimulação do Nervo Vago/instrumentação
3.
Clin Transl Sci ; 12(4): 379-387, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30706983

RESUMO

Organic anion transporting polypeptides (OATPs) 1B1 and 1B3 facilitate the uptake of drugs and endogenous compounds into the liver. In recent years, the impact of these transporters on drug-drug interactions (DDIs) has become a focus of research, and the evaluation of their role in drug disposition is recommended by regulatory agencies worldwide.1-3 Although sensitive substrates of OATP1B1/1B3 have been identified in the literature and probe drugs have been proposed by regulatory agencies, there is no general consensus on the ideal in vivo substrate for clinical DDI studies as analysis may be confounded by contribution from other metabolic and/or transport pathways.1-3 A thorough analysis of the available in vitro and in vivo data regarding OATP1B1/1B3 substrates was performed using the in vitro, clinical, and pharmacogenetic modules in the University of Washington Drug Interaction Database. A total of 34 compounds were identified and further investigated as possible clinical substrates using a novel indexing system. By analyzing the compounds for in vivo characteristics, including sensitivity to inhibition by known OATP1B1/1B3 inhibitors, selectivity for OATP1B1/1B3 compared with other transport and metabolic pathways, and safety profiles, a total of six compounds were identified as potential clinical markers of OATP1B1/1B3 activity.

5.
Drug Metab Dispos ; 47(2): 135-144, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30442649

RESUMO

Pharmacokinetic-based drug-drug interaction (DDI) data for drugs approved by the U.S. Food and Drug Administration in 2017 (N = 34) were analyzed using the University of Washington Drug Interaction Database. The mechanisms and clinical relevance of these interactions were characterized based on information from new drug application reviews. CYP3A inhibition and induction explained most of the observed drug interactions (new drugs as victims or as perpetrators), and transporters mediated about half of all DDIs, alone or with enzymes. Organic anion transporting polypeptide (OATP)1B1/1B3 played a significant role, mediating more than half of the drug interactions with area under the time-plasma curve (AUC) changes ≥5-fold. As victims, five new drugs were identified as sensitive substrates: abemeciclib, midostaurin, and neratinib for CYP3A and glecaprevir and voxilaprevir for OATP1B1/1B3. As perpetrators, three drugs were considered strong inhibitors: ribociclib for CYP3A, glecaprevir/pibrentasvir for OATP1B1/1B3, and sofosbuvir/velpatasvir/voxilaprevir for OATP1B1/1B3 and breast cancer resistance protein. No strong inducer of enzymes or transporters was identified. DDIs with AUC changes ≥5-fold and almost all DDIs with AUC changes 2- to 5-fold had dose recommendations in their respective drug labels. A small fraction of DDIs with exposure changes <2-fold had a labeling impact, mostly related to drugs with narrow therapeutic indices. As with drugs approved in recent years, all drugs found to be sensitive substrates or strong inhibitors of enzymes or transporters were among oncology or antiviral treatments, suggesting a serious risk of DDIs in these patient populations for whom effective therapy is already complex because of polytherapy.


Assuntos
Área Sob a Curva , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antivirais/farmacologia , Antivirais/uso terapêutico , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Aprovação de Drogas , Quimioterapia Combinada/efeitos adversos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Neoplasias/tratamento farmacológico , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Estados Unidos , United States Food and Drug Administration , Viroses/tratamento farmacológico
6.
Epilepsia ; 59(10): 1842-1866, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30368788

RESUMO

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from both preclinical studies and studies in patients were presented. The compounds reviewed include anakinra, cannabidiol, cannabidivarin, fenfluramine, ganaxolone, medium-chain fatty acids, padsevonil, and the valproic derivatives valnoctamide and sec-butylpropylacetamide. On June 25, 2018, the US Food and Drug Administration approved a standardized formulation of cannabidiol oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome in patients 2 years and older. The report shows that there continues to be a steady flow of potential antiepileptic drugs progressing to clinical development. Many of these compounds show innovative mechanisms of action, and some have already been tested in placebo-controlled randomized controlled trials, with promising efficacy and safety results.


Assuntos
Anticonvulsivantes/uso terapêutico , Ensaios Clínicos como Assunto , Congressos como Assunto , Desenvolvimento de Medicamentos , Epilepsia/tratamento farmacológico , Drogas em Investigação , Humanos , Espanha
7.
Epilepsia ; 59(10): 1811-1841, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30368792

RESUMO

The Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV) took place in Madrid, Spain, on May 13-16, 2018 and was attended by 168 delegates from 28 countries. The conference provided a forum for professionals involved in basic science, clinical research, regulatory affairs, and clinical care to meet and discuss the latest advances related to discovery and development of drugs and devices aimed at improving the management of people with epilepsy. This progress report provides a summary of findings on investigational compounds for which data from preclinical or early (phase I) clinical studies were presented. The compounds reviewed include adenosine and adenosine kinase inhibitors, BIS-001 (huperzine A), 2-deoxy-d-glucose, FV-082, FV-137, JNJ-40411813, JNJ-55511118 and analogs, ketone-enhanced antiepileptic drugs, oxynytones, OV329, TAK-935 (OV935), XEN901, and XEN1101. Many innovative approaches to drug development were presented. For example, some compounds are being combined with traditional antiepileptic drugs based on evidence of synergism in seizure models, some act as inhibitors of enzymes involved in modulation of neuronal activity, and some interact in novel ways with excitatory receptors or ion channels. Some of the compounds in development target the etiology of specific epilepsy syndromes (including orphan conditions) through precision medicine, and some offer hope of producing disease-modifying effects rather than symptomatic seizure suppression. Overall, the results summarized in the report indicate that important advances are being made in the effort to develop compounds with potentially improved efficacy and safety profiles compared with existing agents.


Assuntos
Anticonvulsivantes/uso terapêutico , Ensaios Clínicos como Assunto , Congressos como Assunto , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/química , Anticonvulsivantes/farmacologia , Desenvolvimento de Medicamentos , Drogas em Investigação , Humanos , Espanha
8.
Drug Metab Dispos ; 46(6): 835-845, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29572333

RESUMO

A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database, and the clinical relevance of these observations was characterized based on information from new drug application reviews. CYP3A was involved in approximately two-thirds of all drug-drug interactions (DDIs). Transporters (alone or with enzymes) participated in about half of all interactions, but most of these were weak-to-moderate interactions. When considered as victims, eight new molecular entities (NMEs; cobimetinib, ibrutinib, isavuconazole, ivabradine, naloxegol, paritaprevir, simeprevir, and venetoclax) were identified as sensitive substrates of CYP3A, two NMEs (pirfenidone and tasimelteon) were sensitive substrates of CYP1A2, one NME (dasabuvir) was a sensitive substrate of CYP2C8, one NME (eliglustat) was a sensitive substrate of CYP2D6, and one NME (grazoprevir) was a sensitive substrate of OATP1B1/3 (with changes in exposure greater than 5-fold when coadministered with a strong inhibitor). Approximately 75% of identified CYP3A substrates were also substrates of P-glycoprotein. As perpetrators, most clinical DDIs involved weak-to-moderate inhibition or induction. Only idelalisib showed strong inhibition of CYP3A, and lumacaftor behaved as a strong CYP3A inducer. Among drugs with large changes in exposure (≥5-fold), whether as victim or perpetrator, the most-represented therapeutic classes were antivirals and oncology drugs, suggesting a significant risk of clinical DDIs in these patient populations.


Assuntos
Interações Medicamentosas/fisiologia , Preparações Farmacêuticas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Indutores das Enzimas do Citocromo P-450/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Proteínas de Membrana Transportadoras/metabolismo , Estados Unidos , United States Food and Drug Administration
9.
J Pharm Sci ; 106(9): 2312-2325, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28414144

RESUMO

In recent years, an increasing number of clinical drug-drug interactions (DDIs) have been attributed to inhibition of intestinal organic anion-transporting polypeptides (OATPs); however, only a few of these DDI results were reflected in drug labels. This review aims to provide a thorough analysis of intestinal OATP-mediated pharmacokinetic-based DDIs, using both in vitro and clinical investigations, highlighting the main mechanistic findings and discussing their clinical relevance. On the basis of pharmacogenetic and clinical DDI results, a total of 12 drugs were identified as possible clinical substrates of OATP2B1 and OATP1A2. Among them, 3 drugs, namely atenolol, celiprolol, and fexofenadine, have emerged as the most sensitive substrates to evaluate clinical OATP-mediated intestinal DDIs when interactions with P-glycoprotein by the test compound can be ruled out. With regard to perpetrators, 8 dietary or natural products and 1 investigational drug, ronacaleret (now terminated), showed clinical intestinal inhibition attributable to OATPs, producing ≥20% decreases in area under the plasma concentration-time curve of the co-administered drug. Common juices, such as apple juice, grapefruit juice, and orange juice, are considered potent inhibitors of intestinal OATP2B1 and OATP1A2 (decreasing exposure of the co-administered substrate by ∼85%) and may be adequate prototype inhibitors to investigate intestinal DDIs mediated by OATPs.


Assuntos
Interações Medicamentosas/fisiologia , Mucosa Intestinal/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Preparações Farmacêuticas/metabolismo , Bebidas , Interações Alimento-Droga/fisiologia , Humanos , Absorção Intestinal/fisiologia
10.
Epilepsy Res ; 130: 27-36, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28113141

RESUMO

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain from June 26th to 29th 2016. For the first time, the last day of the conference focused solely on new medical devices and neuromodulation. The current article summarises the presentations of that day, focusing first on EEG- and ECG based methods and devices for seizure detection. These methodologies form the basis for novel cardiac-based methods of vagal nerve and responsive deep brain stimulation that rely on the prediction or early detection of seizures and that are also included in this article.


Assuntos
Convulsões/diagnóstico , Convulsões/terapia , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Coração/fisiopatologia , Humanos , Convulsões/fisiopatologia , Espanha
11.
Epilepsia ; 58(2): 181-221, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28111749

RESUMO

The Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII) took place in Madrid, Spain, on June 26-29, 2016, and was attended by >200 delegates from 31 countries. The present Progress Report provides an update on experimental and clinical results for drugs presented at the Conference. Compounds for which summary data are presented include an AED approved in 2016 (brivaracetam), 12 drugs in phase I-III clinical development (adenosine, allopregnanolone, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-d-glucose, everolimus, fenfluramine, huperzine A, minocycline, SAGE-217, and valnoctamide) and 6 compounds or classes of compounds for which only preclinical data are available (bumetanide derivatives, sec-butylpropylacetamide, FV-082, 1OP-2198, NAX 810-2, and SAGE-689). Overall, the results presented at the Conference show that considerable efforts are ongoing into discovery and development of AEDs with potentially improved therapeutic profiles compared with existing agents. Many of the drugs discussed in this report show innovative mechanisms of action and many have shown promising results in patients with pharmacoresistant epilepsies, including previously neglected rare and severe epilepsy syndromes.


Assuntos
Anticonvulsivantes/uso terapêutico , Drogas em Investigação/uso terapêutico , Epilepsia/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Congressos como Assunto , Descoberta de Drogas , Drogas em Investigação/farmacologia , Humanos , Relatório de Pesquisa
12.
Epilepsy Res ; 111: 85-141, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25769377

RESUMO

The Twelfth Eilat Conference on New Antiepileptic Drugs (AEDs) - EILAT XII, took place in Madrid, Spain from August 31st to September 3rd 2014. About 130 basic scientists, clinical pharmacologists and neurologists from 22 countries attended the conference, whose main themes included "Conquering pharmacoresistant epilepsy", "Innovative emergency treatments", "Progress report on second-generation treatment" and "New methods and formulations". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 2004. Like the EILAT X and EILAT XI reports, the current article focuses on the preclinical and clinical pharmacology of AEDs that are currently in development. These include adenosine-releasing silk, allopregnanolone (SAGE-547), AMP-X-0079, brivaracetam, bumetanide, cannabidiol, cannabidivarin, 2-deoxy-glucose, everolimus, ganaxolone, huperzine A, imepitoin, minocycline, NAX 801-2, pitolisant, PRX 0023, SAGE-217, valnoctamide and its homologue sec-butyl-propylacetamide (SPD), and VLB-01. Since the previous Eilat conference, perampanel has been introduced into the market and twelve novel potential epilepsy treatments are presented for the first time.


Assuntos
Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Ensaios Clínicos como Assunto , Congressos como Assunto , Preparações de Ação Retardada/efeitos adversos , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Preparações de Ação Retardada/uso terapêutico , Descoberta de Drogas , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Drogas em Investigação/farmacologia , Drogas em Investigação/uso terapêutico , Humanos , Relatório de Pesquisa
13.
Epilepsy Res ; 103(1): 2-30, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23219031

RESUMO

The Eleventh Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT XI, took place in Eilat, Israel from the 6th to 10th of May 2012. About 100 basic scientists, clinical pharmacologists and neurologists from 20 countries attended the conference, whose main themes included "Indications overlapping with epilepsy" and "Securing the successful development of an investigational antiepileptic drug in the current environment". Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the EILAT X report, the current manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, 2-deoxy-glucose, ganaxolone, ICA-105665, imepitoin, NAX 801-2, perampanel and other AMPA receptor antagonists, tonabersat, valnoctamide and its homologue sec-propylbutylacetamide (SPD), VX-765 and YK3089. Since the previous Eilat conference, retigabine (ezogabine) has been marketed and four newer AEDs in development (NAX 810-2, SPD, tonabersat and VX-765) are included in this manuscript.


Assuntos
Anticonvulsivantes/uso terapêutico , Congressos como Assunto , Drogas em Investigação/uso terapêutico , Epilepsia/tratamento farmacológico , Relatório de Pesquisa/tendências , Animais , Ensaios Clínicos como Assunto/tendências , Congressos como Assunto/tendências , Epilepsia/epidemiologia , Humanos , Israel
14.
Chem Res Toxicol ; 25(11): 2285-300, 2012 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-22823924

RESUMO

Drugs that are mainly cleared by a single enzyme are considered more sensitive to drug-drug interactions (DDIs) than drugs cleared by multiple pathways. However, whether this is true when a drug cleared by multiple pathways is coadministered with an inhibitor of multiple P450 enzymes (multi-P450 inhibition) is not known. Mathematically, simultaneous equipotent inhibition of two elimination pathways that each contribute half of the drug clearance is equal to equipotent inhibition of a single pathway that clears the drug. However, simultaneous strong or moderate inhibition of two pathways by a single inhibitor is perceived as an unlikely scenario. The aim of this study was (i) to identify P450 inhibitors currently in clinical use that can inhibit more than one clearance pathway of an object drug in vivo and (ii) to evaluate the magnitude and predictability of DDIs caused by these multi-P450 inhibitors. Multi-P450 inhibitors were identified using the Metabolism and Transport Drug Interaction Database. A total of 38 multi-P450 inhibitors, defined as inhibitors that increased the AUC or decreased the clearance of probes of two or more P450s, were identified. Seventeen (45%) multi-P450 inhibitors were strong inhibitors of at least one P450, and an additional 12 (32%) were moderate inhibitors of one or more P450s. Only one inhibitor (fluvoxamine) was a strong inhibitor of more than one enzyme. Fifteen of the multi-P450 inhibitors also inhibit drug transporters in vivo, but such data are lacking on many of the inhibitors. Inhibition of multiple P450 enzymes by a single inhibitor resulted in significant (>2-fold) clinical DDIs with drugs that are cleared by multiple pathways such as imipramine and diazepam, while strong P450 inhibitors resulted in only weak DDIs with these object drugs. The magnitude of the DDIs between multi-P450 inhibitors and diazepam, imipramine, and omeprazole could be predicted using in vitro data with similar accuracy as probe substrate studies with the same inhibitors. The results of this study suggest that inhibition of multiple clearance pathways in vivo is clinically relevant, and the risk of DDIs with object drugs may be best evaluated in studies using multi-P450 inhibitors.


Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores Enzimáticos/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Estrutura-Atividade
15.
Epilepsia ; 53(1): 207-14, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22221159

RESUMO

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).


Assuntos
Síndrome de Imunodeficiência Adquirida/tratamento farmacológico , Antirretrovirais/farmacocinética , Anticonvulsivantes/farmacocinética , Epilepsia/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Guias de Prática Clínica como Assunto , Comitês Consultivos/organização & administração , Antirretrovirais/uso terapêutico , Anticonvulsivantes/uso terapêutico , Comorbidade , Interações Medicamentosas , Medicina Baseada em Evidências , Saúde Global/normas , Humanos , Neurologia/organização & administração , Sociedades Médicas/organização & administração
16.
Hum Genomics ; 5(5): 506-15, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21807605

RESUMO

e-PKGene (www.pharmacogeneticsinfo.org) is a manually curated knowledge product developed in the Department of Pharmaceutics at the University of Washington, USA. The tool integrates information from the literature, public repositories, reference textbooks, product prescribing labels and clinical review sections of new drug approval packages. The database's easy-to-use web portal offers tools for visualisation, reporting and filtering of information. The database helps scientists to mine pharmacokinetic and pharmacodynamic information for drug-metabolising enzymes and transporters, and provides access to available quantitative information on drug exposure contained in the literature. It allows in-depth analysis of the impact of genetic variants of enzymes and transporters on pharmacokinetic responses to drugs and metabolites. This review gives a brief description of the database organisation, its search functionalities and examples of use.


Assuntos
Internet , Bases de Conhecimento , Preparações Farmacêuticas/metabolismo , Software , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Bases de Dados Factuais , Interações Medicamentosas/genética , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Variação Genética , Humanos , Preparações Farmacêuticas/química , Farmacocinética , Farmacologia , Interface Usuário-Computador
17.
Hum Genomics ; 5(1): 61-72, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21106490

RESUMO

The Metabolism and Transport Drug Interaction Database (http://www.druginteractioninfo.org) is a web-based research and analysis tool developed in the Department of Pharmaceutics at the University of Washington. The database has the largest manually curated collection of data related to drug interactions in humans. The tool integrates information from the literature, public repositories, reference textbooks, guideline documents, product prescribing labels and clinical review sections of new drug approval (NDA) packages. The database's easy-to-use web portal offers tools for visualisation, reporting and filtering of information. The database helps scientists to mine kinetics information for drug-metabolising enzymes and transporters, to assess the extent of in vivo drug interaction studies, as well as case reports for drugs, therapeutic proteins, food products and herbal derivatives. This review provides a brief description of the database organisation, its search functionalities and examples of use.


Assuntos
Bases de Dados Factuais , Interações Medicamentosas , Internet , Preparações Farmacêuticas/metabolismo , Farmacocinética , Humanos , Receptores Citoplasmáticos e Nucleares , Ferramenta de Busca , Universidades , Washington
18.
Epilepsy Res ; 92(2-3): 89-124, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20970964

RESUMO

The Tenth Eilat Conference on New Antiepileptic Drugs (AEDs)-EILAT X, took place in Eilat, Israel from the 25th to 29th of April 2010. About 200 basic scientists, clinical pharmacologists and neurologists from 25 countries attended the conference, whose main themes included learning from the past: Lessons learnt after 18 years of Eilat Conferences and Detecting assessing and preventing adverse effects of AEDs. Consistent with previous formats of this conference, a large part of the program was devoted to a review of AEDs in development, as well as updates on AEDs introduced since 1994. Like the previous EILAT (EILAT IX) manuscript, the current (EILAT X) manuscript focuses only on the preclinical and clinical pharmacology of AEDs that are currently in development. These include brivaracetam, carisbamate, 2-deoxy-glucose, ganaxolone, huperizine A, ICA-105665, NAX-5055, retigabine, perampanel, T-2007, valnoctamide and YK3089. Since the previous Eilat Conference (EILAT IX-2008) two new AEDs; eslicarbazepine acetate and lacosamide have been marketed and three new AEDs in development not included in the EILAT IX manuscript were added: ICA-105665, perampanel and valnoctamide. The CNS efficacy of these compounds in anticonvulsant animal models as well as other disease model systems are presented in Tables 1 and 2 and their proposed mechanism of action at summarized in Table 3.


Assuntos
Anticonvulsivantes/uso terapêutico , Drogas em Investigação/uso terapêutico , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/classificação , Avaliação de Medicamentos , Drogas em Investigação/classificação , Humanos
19.
Anesth Analg ; 111(5): 1146-53, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20971961

RESUMO

BACKGROUND: Treatment of intense postoperative pain in patients with end-stage renal disease (ESRD) is a recurrent problem for anesthesiologists because of the risk of accumulation of numerous molecules and their metabolites. Nefopam is a potent analgesic metabolized by the liver and weakly eliminated intact in urine that may offer advantages for use in patients with ESRD because it lacks respiratory-depressive effects. However, the effects of renal failure on nefopam disposition have never been investigated. METHODS: We studied 12 ESRD patients (creatinine clearance < 20 mL/min, mean age 57 ± 13 years) having surgery under general anesthesia to create or repair an arteriovenous fistula. Postoperatively, after complete recovery from anesthesia, each patient received a single 20-mg dose of nefopam IV over 30 minutes. Nefopam and desmethyl-nefopam concentrations in plasma samples obtained over 48 hours were determined by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameter values obtained were compared with those of 12 healthy 50- to 60-year-old volunteers who also received a single 20-mg nefopam infusion over 30 minutes using a population pharmacokinetic approach. RESULTS: Healthy volunteers and ESRD patients had comparable demographic characteristics. In comparison with those volunteers, ESRD patients had a lower volume of central compartment (115 and 53 L vs. 264 L for patients not yet hemodialyzed and on chronic hemodialysis, respectively; P < 0.001) and lower mean nefopam clearance (37.0 and 27.3 L/h vs. 52.9 L/h, P < 0.001), resulting in higher mean nefopam peak concentration (121 and 223 ng/mL vs. 61 ng/mL, P < 0.001). CONCLUSIONS: Nefopam distribution and elimination are altered in patients with ESRD, resulting in heightened exposure. To avoid too-high concentration peaks, it is suggested that the daily nefopam dose be reduced by 50%.


Assuntos
Analgésicos não Entorpecentes/farmacocinética , Derivação Arteriovenosa Cirúrgica/efeitos adversos , Falência Renal Crônica/terapia , Nefopam/farmacocinética , Dor Pós-Operatória/prevenção & controle , Diálise Renal , Adulto , Idoso , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/efeitos adversos , Analgésicos não Entorpecentes/sangue , Biotransformação , Cromatografia Líquida , Feminino , França , Humanos , Infusões Intravenosas , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Nefopam/administração & dosagem , Nefopam/efeitos adversos , Nefopam/análogos & derivados , Nefopam/sangue , Dor Pós-Operatória/etiologia , Espectrometria de Massas em Tandem , Resultado do Tratamento
20.
Drug Metab Lett ; 3(4): 287-9, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19995331

RESUMO

Clopidogrel is an antiplatelet drug that requires bioactivation to its active metabolite to demonstrate its antiplatelet effect. Formation of the active metabolite involves multiple cytochrome P450 enzymes, with CYP2C19 playing an important role. Clopidogrel is often co-administered with proton pump inhibitors (PPIs) to decrease GI-tract bleeding, and decreased antiplatelet effect has been observed in these patients. This observation cannot be explained by the weak inhibitory effect of PPIs on CYP2C19. A hypothesis is proposed to interpret the phenomenon of PPI inhibition based in part on the finding that clopidogrel is itself an inhibitor of CYP2C19.


Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Inibidores da Agregação de Plaquetas/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Ticlopidina/análogos & derivados , Hidrocarboneto de Aril Hidroxilases/metabolismo , Clopidogrel , Citocromo P-450 CYP2C19 , Interações Medicamentosas , Humanos , Inibidores da Agregação de Plaquetas/metabolismo , Ticlopidina/metabolismo , Ticlopidina/farmacologia
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