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1.
Bioorg Med Chem Lett ; 27(8): 1744-1749, 2017 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-28285914

RESUMO

We recently reported the development of a novel inhibitor of Rho-mediated gene transcription (1, CCG-203971) that is efficacious in multiple animal models of acute fibrosis, including scleroderma, when given intraperitoneally. The modest in vivo potency and poor pharmacokinetics (PK) of this lead, however, make it unsuitable for long term efficacy studies. We therefore undertook a systematic medicinal chemistry effort to improve both the metabolic stability and the solubility of 1, resulting in the identification of two analogs achieving over 10-fold increases in plasma exposures in mice. We subsequently showed that one of these analogs (8f, CCG-232601) could inhibit the development of bleomycin-induced dermal fibrosis in mice when administered orally at 50mg/kg, an effect that was comparable to what we had observed earlier with 1 at a 4-fold higher IP dose.


Assuntos
Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/uso terapêutico , Fator Rho/antagonistas & inibidores , Escleroderma Sistêmico/tratamento farmacológico , Pele/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Administração Oral , Animais , Modelos Animais de Doenças , Fibrose , Células HEK293 , Humanos , Camundongos , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/química , Fator Rho/metabolismo , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Elemento de Resposta Sérica/efeitos dos fármacos , Pele/metabolismo , Pele/patologia , Transativadores/antagonistas & inibidores , Transativadores/metabolismo
2.
PLoS One ; 11(10): e0164646, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27768695

RESUMO

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.


Assuntos
Compostos de Anilina/farmacologia , Ácidos Nipecóticos/farmacologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Administração Oral , Compostos de Anilina/farmacocinética , Animais , Voluntários Saudáveis , Humanos , Macaca fascicularis , Camundongos , Camundongos Transgênicos , Ácidos Nipecóticos/farmacocinética , Células U937
3.
Chem Biol ; 21(12): 1648-59, 2014 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-25500222

RESUMO

Inducible Hsp70 (Hsp70i) is overexpressed in a wide spectrum of human tumors, and its expression correlates with metastasis, poor outcomes, and resistance to chemotherapy in patients. Identification of small-molecule inhibitors selective for Hsp70i could provide new therapeutic tools for cancer treatment. In this work, we used fluorescence-linked enzyme chemoproteomic strategy (FLECS) to identify HS-72, an allosteric inhibitor selective for Hsp70i. HS-72 displays the hallmarks of Hsp70 inhibition in cells, promoting substrate protein degradation and growth inhibition. Importantly, HS-72 is selective for Hsp70i over the closely related constitutively active Hsc70. Studies with purified protein show HS-72 acts as an allosteric inhibitor, reducing ATP affinity. In vivo HS-72 is well-tolerated, showing bioavailability and efficacy, inhibiting tumor growth and promoting survival in a HER2+ model of breast cancer. The HS-72 scaffold is amenable to resynthesis and iteration, suggesting an ideal starting point for a new generation of anticancer therapeutics targeting Hsp70i.


Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/metabolismo , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Benzimidazóis/metabolismo , Benzimidazóis/farmacocinética , Disponibilidade Biológica , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Células HEK293 , Proteínas de Choque Térmico HSP70/química , Humanos , Camundongos , Modelos Moleculares , Ácidos Nipecóticos/metabolismo , Ácidos Nipecóticos/farmacocinética , Permeabilidade , Piperidinas/metabolismo , Piperidinas/farmacocinética , Agregados Proteicos/efeitos dos fármacos , Estrutura Terciária de Proteína , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Therapie ; 65(1): 51-5, 2010.
Artigo em Francês | MEDLINE | ID: mdl-20205996

RESUMO

Tiagabine, a second-generation anticonvulsant drug, is marketed in France since 1997. It is also prescribed outside marketing authorization in the treatment of anxiety. They are few studies allowing arguing a relation exposure efficiency or toxicity, but intra and inter individual important variations in serum concentrations are described. Hepatic insufficiency requires a dose adaptation. In patients treated with therapeutic dose, serum levels are between 20 and 100 microg/L (50-250 nmol/L). For this molecule, the level of proof of the interest of TDM was estimated in: remaining to estimate.


Assuntos
Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Epilepsia/tratamento farmacológico , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/uso terapêutico , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/análise , Anticonvulsivantes/farmacocinética , Interações Medicamentosas , Monitoramento de Medicamentos , França , Humanos , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/análise , Ácidos Nipecóticos/farmacocinética , Tiagabina
5.
Pharmacol Rep ; 61(5): 819-26, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19904004

RESUMO

Caffeine has been reported to be proconvulsant and to reduce the anticonvulsant efficacy of a variety of antiepileptic drugs (carbamazepine, phenobarbital, phenytoin, valproate and topiramate) in animal models of epilepsy and to increase seizure frequency in patients with epilepsy. Using the mouse maximal electroshock model, the present study was undertaken so as to ascertain whether caffeine affects the anticonvulsant efficacy of the new antiepileptic drugs lamotrigine, oxcarbazepine and tiagabine. The results indicate that neither acute nor chronic caffeine administration (up to 46.2 mg/kg) affected the ED(50) values of oxcarbazepine or lamotrigine against maximal electroshock. Similarly, caffeine did not modify the tiagabine electroconvulsive threshold. Furthermore, caffeine had no effect on oxcarbazepine, lamotrigine and tiagabine associated adverse effects such as impairment of motor coordination (measured by the chimney test) or long-term memory (measured by the passive avoidance task). Concurrent plasma concentration measurements revealed no significant effect on lamotrigine and oxcarbazepine concentrations. For tiagabine, however, chronic caffeine (4 mg/kg) administration was associated with an increase in tiagabine concentrations. In conclusion, caffeine did not impair the anticonvulsant effects of lamotrigine, oxcarbazepine, or tiagabine as assessed by electroconvulsions in mice. Also, caffeine was without effect upon the adverse potential of the studied antiepileptic drugs. Thus caffeine may not necessarily adversely affect the efficacy of all antiepileptic drugs and this is an important observation.


Assuntos
Anticonvulsivantes/farmacologia , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Epilepsia Tônico-Clônica/tratamento farmacológico , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Cafeína/administração & dosagem , Carbamazepina/efeitos adversos , Carbamazepina/análogos & derivados , Carbamazepina/farmacocinética , Carbamazepina/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Eletrochoque , Lamotrigina , Masculino , Camundongos , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/farmacologia , Oxcarbazepina , Tiagabina , Triazinas/efeitos adversos , Triazinas/farmacocinética , Triazinas/farmacologia
6.
Eur J Pharmacol ; 605(1-3): 87-94, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19168049

RESUMO

To characterize the interactions between levetiracetam and the antiepileptic drugs gabapentin, tiagabine, and vigabatrin in suppressing pentylenetetrazole-induced clonic seizures in mice, type II isobolographic analysis was used. Clonic seizures were evoked in Albino Swiss mice by subcutaneous injection of pentylenetetrazole at its CD(97)(98 mg/kg). Adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured along with total brain antiepileptic drug concentrations. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 were supra-additive (synergistic) in terms of seizure suppression whilst the combination at the fixed-ratio of 4:1 was additive. Tiagabine with levetiracetam and vigabatrin with levetiracetam at the fixed-ratios of 1:25, 1:50, 1:100, 1:200, and 1:400 and at 2:1, 3:1, 4:1, 6:1, 8:1, and 16:1 were additive, respectively. No acute adverse effects were observed. Measurement of total brain antiepileptic drug concentrations revealed that levetiracetam in combination with gabapentin at the fixed-ratio of 1:4 significantly elevated (21%) total brain gabapentin concentrations. In contrast, levetiracetam was without affect on tiagabine or vigabatrin concentrations and co-administration with gabapentin, tiagabine or vigabatrin had no effect on levetiracetam brain concentrations, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse pentylenetetrazole model. The combination of gabapentin with levetiracetam at the fixed-ratios of 2:1, 1:1, 1:2, and 1:4 appears to be particularly favorable combination exerting supra-additive interaction in suppressing pentylenetetrazole-induced seizures, although there is a pharmacokinetic contribution to the interaction between levetiracetam and gabapentin at the fixed-ratio of 1:4. Levetiracetam in combination with tiagabine and vigabatrin appear to be neutral combinations producing only additivity in the mouse pentylenetetrazole model.


Assuntos
Anticonvulsivantes/farmacologia , Piracetam/análogos & derivados , Convulsões/prevenção & controle , Aminas/efeitos adversos , Aminas/farmacocinética , Aminas/farmacologia , Animais , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Ácidos Cicloexanocarboxílicos/efeitos adversos , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacologia , Modelos Animais de Doenças , Interações Medicamentosas , Sinergismo Farmacológico , Gabapentina , Levetiracetam , Masculino , Camundongos , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/farmacologia , Pentilenotetrazol , Piracetam/efeitos adversos , Piracetam/farmacocinética , Piracetam/farmacologia , Tiagabina , Distribuição Tecidual/efeitos dos fármacos , Vigabatrina/efeitos adversos , Vigabatrina/farmacocinética , Vigabatrina/farmacologia , Ácido gama-Aminobutírico/efeitos adversos , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/farmacologia
7.
Acta Neurol Scand ; 119(1): 55-60, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18616622

RESUMO

OBJECTIVES: We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively. METHODS: We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital. RESULTS: There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. CONCLUSIONS: Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.


Assuntos
Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Epilepsia/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aminas/farmacocinética , Aminas/uso terapêutico , Criança , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácidos Cicloexanocarboxílicos/uso terapêutico , Epilepsia/classificação , Epilepsia/etiologia , Feminino , Finlândia , Frutose/análogos & derivados , Frutose/farmacocinética , Frutose/uso terapêutico , Gabapentina , Meia-Vida , Humanos , Lamotrigina , Levetiracetam , Licenciamento em Farmácia , Masculino , Pessoa de Meia-Idade , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/uso terapêutico , Piracetam/análogos & derivados , Piracetam/farmacocinética , Piracetam/uso terapêutico , Estudos Retrospectivos , Tiagabina , Topiramato , Resultado do Tratamento , Triazinas/farmacocinética , Triazinas/uso terapêutico , Adulto Jovem , Ácido gama-Aminobutírico/farmacocinética , Ácido gama-Aminobutírico/uso terapêutico
8.
Naunyn Schmiedebergs Arch Pharmacol ; 378(5): 483-92, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18566800

RESUMO

The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.


Assuntos
Anticonvulsivantes/farmacologia , Etossuximida/farmacologia , Ácidos Nipecóticos/farmacologia , Convulsões/tratamento farmacológico , Animais , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacocinética , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Interações Medicamentosas , Etossuximida/administração & dosagem , Etossuximida/farmacocinética , Imunoensaio de Fluorescência por Polarização , Masculino , Camundongos , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/farmacocinética , Pentilenotetrazol , Tiagabina , Distribuição Tecidual
9.
J Neural Transm (Vienna) ; 115(5): 661-7, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18193378

RESUMO

This study evaluated the interactions between tiagabine (TGB) and three conventional antiepileptic drugs (AEDs): valproate (VPA), carbamazepine (CBZ), and phenobarbital (PB) in amygdala-kindled rats, a reliable model of complex partial seizures in humans. Isobolographic analysis of interactions revealed that TGB interacted additively with all tested conventional AEDs for the fixed-ratio combinations of 1:3, 1:1, and 3:1. Evaluation of pharmacokinetic interactions between AEDs revealed that the observed additivity was pharmacodynamic in nature. TGB did not affect the plasma and brain concentrations of VPA, CBZ and PB. Similarly, none of the studied conventional AEDs changed the plasma or brain levels of TGB. Also, TGB, VPA, CBZ, and PB administered alone (at their median effective doses) and in combinations at the fixed-ratio of 1:1 did not impair motor performance evaluated in the chimney test. In conclusion, additivity between TGB and conventional AEDs in amygdala-kindled rats and lack of bidirectional pharmacokinetic interactions suggest that TGB appears to be a valuable drug for an add-on therapy of refractory complex partial seizures in humans.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Ácidos Nipecóticos/uso terapêutico , Tonsila do Cerebelo/fisiopatologia , Análise de Variância , Animais , Anticonvulsivantes/farmacocinética , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Epilepsias Parciais/etiologia , Epilepsias Parciais/patologia , Masculino , Ácidos Nipecóticos/farmacocinética , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Tiagabina
10.
Expert Opin Pharmacother ; 7(14): 1977-87, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17020423

RESUMO

GABA has been implicated in both the aetiology and treatment of anxiety. Tiagabine is currently the only selective GABA reuptake inhibitor available in US markets; it exerts its action via GAT-1 transporter blockade presynaptically, facilitating GABA neurotransmission. Preclinical studies and current human studies suggest tiagabine possesses anxiolytic properties. The anxiolytic properties of tiagabine have also been suggested in a number of case series, open-label studies and placebo-controlled studies in patients with different anxiety disorders. Throughout these studies, tiagabine has been reasonably tolerated; the most commonly reported adverse events include dizziness, headache and nausea. Tiagabine may be a useful addition to currently available drugs for anxiety; however, the data from small open-label investigations remain to be confirmed in larger controlled studies.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Agonistas GABAérgicos/uso terapêutico , Ácidos Nipecóticos/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Feminino , Agonistas GABAérgicos/efeitos adversos , Agonistas GABAérgicos/farmacocinética , Humanos , Masculino , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Tiagabina , Ácido gama-Aminobutírico/fisiologia
11.
Clin Pharmacokinet ; 45(11): 1061-75, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-17048972

RESUMO

A new generation of antiepileptic drugs (AEDs) has reached the market in recent years with ten new compounds: felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin and zonisamide. The newer AEDs in general have more predictable pharmacokinetics than older AEDs such as phenytoin, carbamazepine and valproic acid (valproate sodium), which have a pronounced inter-individual variability in their pharmacokinetics and a narrow therapeutic range. For these older drugs it has been common practice to adjust the dosage to achieve a serum drug concentration within a predefined 'therapeutic range', representing an interval where most patients are expected to show an optimal response. However, such ranges must be interpreted with caution, since many patients are optimally treated when they have serum concentrations below or above the suggested range. It is often said that there is less need for therapeutic drug monitoring (TDM) with the newer AEDs, although this is partially based on the lack of documented correlation between serum concentration and drug effects. Nevertheless, TDM may be useful despite the shortcomings of existing therapeutic ranges, by utilisation of the concept of 'individual reference concentrations' based on intra-individual comparisons of drug serum concentrations. With this concept, TDM may be indicated regardless of the existence or lack of a well-defined therapeutic range. The ten newer AEDs all have different pharmacological properties, and therefore, the usefulness of TDM for these drugs has to be assessed individually. For vigabatrin, a clear relationship between drug concentration and clinical effect cannot be expected because of its unique mode of action. Therefore, TDM of vigabatrin is mainly to check compliance. The mode of action of the other new AEDs would not preclude the applicability of TDM. For the prodrug oxcarbazepine, TDM is also useful, since the active metabolite licarbazepine is measured. For drugs that are eliminated renally completely unchanged (gabapentin, pregabalin and vigabatrin) or mainly unchanged (levetiracetam and topiramate), the pharmacokinetic variability is less pronounced and more predictable. However, the dose-dependent absorption of gabapentin increases its pharmacokinetic variability. Drug interactions can affect topiramate concentrations markedly, and individual factors such as age, pregnancy and renal function will contribute to the pharmacokinetic variability of all renally eliminated AEDs. For those of the newer AEDs that are metabolised (felbamate, lamotrigine, oxcarbazepine, tiagabine and zonisamide), pharmacokinetic variability is just as relevant as for many of the older AEDs. Therefore, TDM is likely to be useful in many clinical settings for the newer AEDs. The purpose of the present review is to discuss individually the potential value of TDM of these newer AEDs, with emphasis on pharmacokinetic variability.


Assuntos
Anticonvulsivantes/farmacocinética , Monitoramento de Medicamentos , Epilepsia/sangue , Aminas/farmacocinética , Anticonvulsivantes/sangue , Carbamazepina/análogos & derivados , Carbamazepina/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Interações Medicamentosas , Epilepsia/tratamento farmacológico , Felbamato , Frutose/análogos & derivados , Frutose/farmacocinética , Gabapentina , Humanos , Isoxazóis/farmacocinética , Lamotrigina , Levetiracetam , Ácidos Nipecóticos/farmacocinética , Oxcarbazepina , Fenilcarbamatos/farmacocinética , Piracetam/análogos & derivados , Piracetam/farmacocinética , Pregabalina , Propilenoglicóis/farmacocinética , Tiagabina , Topiramato , Triazinas/farmacocinética , Vigabatrina/farmacocinética , Zonisamida , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacocinética
12.
J Med Toxicol ; 2(4): 160-2, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18072137

RESUMO

INTRODUCTION: Tiagabine (TGB) is a novel antiepileptic that decreases GABA uptake. The literature contains one report of an adult with epilepsy who ingested up to 1 gram of TGB and developed status epilepticus. We reported on a pediatric patient who ingested significantly less TGB but still developed tonic-clonic seizures. CASE REPORT: A previously healthy, 13 kg, two-year-old girl developed generalized tonic-clonic seizure activity at home approximately 1 hour after ingesting 90 mg of her grandmother's TGB (forty five 2 mg tablets). At the hospital she had two 5 minute seizures at 1.5 and 3.5 hours post ingestion. Her serum TGB levels were 530 and 130 ng/ml approximately 5 and 11 hours post-ingestion (5-70 ng/ml trough levels with most probable range for seizure control). She was discharged 27 hours post ingestion, and she was in good condition. CONCLUSION: An overdose of TGB, a novel anti-epileptic, can cause convulsive seizures.


Assuntos
Anticonvulsivantes/intoxicação , Epilepsia Tônico-Clônica/induzido quimicamente , Ácidos Nipecóticos/intoxicação , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Pré-Escolar , Overdose de Drogas , Feminino , Humanos , Ácidos Nipecóticos/sangue , Ácidos Nipecóticos/farmacocinética , Tiagabina
13.
Pharm Res ; 22(4): 556-62, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15846463

RESUMO

PURPOSE: The purpose of this research was to characterize nipecotic acid pharmacokinetics in blood and brain after intravenous (i.v.) and nasal administration of nipecotic acid and its n-butyl ester. METHODS: Nipecotic acid and its n-butyl ester were administered to rats i.v. and intranasally (n = 5 rats/drug per route), and nipecotic acid pharmacokinetics in blood were characterized. Nipecotic acid concentration-time profiles were determined in blood by noncompartmental and compartmental methods. Nipecotic acid was also dosed i.v. and its n-butyl ester was dosed by nasal and i.v. routes, and brain levels of nipecotic acid over the subsequent 4 h (n = 5 rats/time point per route) were assessed. RESULTS: The absolute systemic availability of nipecotic acid after nasal dosing was 14%. After i.v. and nasal dosing of the n-butyl ester, nipecotic acid systemic availability was 97% and 92%, respectively. Both i.v. and nasal administration of the n-butyl ester resulted in a significantly longer terminal half-life and larger mean resident time and volume of distribution for nipecotic acid than was observed after an i.v. nipecotic acid dose. Total brain exposure to nipecotic acid was not significantly different after nasal and i.v. dosing of the n-butyl ester. However, the brain/blood nipecotic acid ratio declined significantly with time after i.v. and nasal dosing of the ester prodrug. Nipecotic acid was not detectable in brain after i.v. dosing of nipecotic acid. CONCLUSIONS: The use of an ester formulation was crucial to delivering nipecotic acid to the brain. Preliminary evidence strongly suggests ester hydrolysis is rate limiting to nipecotic acid brain delivery. Once nipeoctic acid was formed, it displayed tissue trapping in brain. Parenteral dosing of nipecotic acid esters is unnecessary for systemic or brain delivery of nipecotic acid and possibly other CNS active zwitterion esters.


Assuntos
Encéfalo/metabolismo , Ácidos Nipecóticos/farmacocinética , Pró-Fármacos/farmacocinética , Administração Intranasal , Animais , Disponibilidade Biológica , Injeções Intravenosas , Masculino , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/sangue , Ratos , Ratos Sprague-Dawley
14.
Seizure ; 13(8): 574-81, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15519917

RESUMO

PURPOSE: Tiagabine is a unique antiepileptic drug with a novel mechanism of action. Whilst some limited data are available as to the peripheral blood pharmacokinetics of tiagabine, data regarding the kinetics of tiagabine in the central brain compartment are very limited. We therefore sought to investigate serum, cerebrospinal fluid (CSF) and frontal cortex and hippocampal extracellular fluid (ECF) kinetic inter-relationship of tiagabine in a freely moving rat model. METHODS: Adult male rats were implanted with either a jugular vein catheter and a cisterna magna catheter for blood and CSF sampling, respectively, or a blood catheter and a microdialysis probe in the hippocampus and frontal cortex (for ECF sampling). Tiagabine was administered intraperitoneal (i.p.) at 20 or 40 mg/kg and blood, CSF and ECF were collected at timed intervals for the measurement of tiagabine concentrations by high performance liquid chromatography. RESULTS: Tiagabine concentrations in blood and CSF rose linearly and dose-dependently and time to maximum concentration (Tmax) was 15 and 29 min, respectively. Mean CSF/serum tiagabine concentration ratios (range, 0.008-0.01) were much smaller than the mean free/total tiagabine concentration ratios in serum (0.045 +/- 0.003). Entry of tiagabine into brain ECF (frontal cortex and hippocampus) was rapid with Tmax values of 31-46 min. Distribution of tiagabine in brain was not brain region specific with values in the frontal cortex and hippocampus being indistinguishable. Whilst elimination from CSF was comparable to that of serum, half-life (t(1/2)) values in ECF were three times longer. CONCLUSIONS: Tiagabine is associated with linear kinetic characteristics and with rapid brain penetration. However, CSF concentrations are not reflective of free non-protein-bound concentrations in serum. The observation that tiagabine elimination from the brain is threefold slower than that seen in blood, may explain as to the relatively long duration of action of tiagabine.


Assuntos
Anticonvulsivantes , Epilepsia/tratamento farmacológico , Líquido Extracelular/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Ácidos Nipecóticos , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/líquido cefalorraquidiano , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Técnicas In Vitro , Masculino , Microdiálise , Ácidos Nipecóticos/sangue , Ácidos Nipecóticos/líquido cefalorraquidiano , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/uso terapêutico , Ratos , Ratos Sprague-Dawley , Tiagabina
15.
Epilepsia ; 45(5): 424-35, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15101823

RESUMO

PURPOSE: The pharmacodynamic interaction between the antiepileptic drugs (AEDs) tiagabine (TGB) and lamotrigine (LTG) was characterized on basis of the anticonvulsant effect in the cortical stimulation model in the rat. METHODS: The study was conducted according to a partial crossover design, in which both drugs were infused intravenously to achieve linear increases in the plasma concentration in the absence and presence of a steady-state concentration of the second drug. The anticonvulsant effect was quantified by counts of four specific ictal signs (eye closure, forelimb clonus, forelimb extension, and head jerk). A potential pharmacokinetic interaction was accounted for by determination of total plasma concentrations of both drugs. RESULTS: When given separately, both TGB and LTG suppressed all ictal signs in a concentration-dependent manner, with the exception of eye closure, which was not suppressed by LTG. The interaction between both drugs was estimated by response surface analysis by using the difference between the observed effect and the additive effect to identify synergistic drug concentrations. This analysis showed that the pharmacodynamic interaction between TGB and LTG is synergistic for the ictal signs of eye closure and head jerk. In contrast, the interaction was additive for the ictal signs of forelimb clonus and forelimb tonus. CONCLUSIONS: This study demonstrates the usefulness of ictal-component analysis for studying the pharmacodynamic interaction between AEDs. Quantification of both the nature and the magnitude of the interaction between TGB and LTG led to the identification of two ictal signs that were synergistically suppressed. This approach offers a theoretical basis to identify and optimize drug combinations that are useful to treat refractory epilepsy.


Assuntos
Anticonvulsivantes/farmacologia , Córtex Cerebral/efeitos dos fármacos , Ácidos Nipecóticos/farmacologia , Convulsões/prevenção & controle , Triazinas/farmacologia , Animais , Anticonvulsivantes/sangue , Anticonvulsivantes/farmacocinética , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Sinergismo Farmacológico , Eletroencefalografia/efeitos dos fármacos , Eletrochoque , Epilepsia/tratamento farmacológico , Humanos , Lamotrigina , Masculino , Ácidos Nipecóticos/sangue , Ácidos Nipecóticos/farmacocinética , Ratos , Ratos Wistar , Tiagabina , Triazinas/sangue , Triazinas/farmacocinética
16.
Epilepsia ; 45(3): 204-10, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15009220

RESUMO

PURPOSE: To examine the inhibitory effect of anticonvulsants (AEDs) on carnitine transport by the human placental carnitine transporter. METHODS: Uptake of radiolabeled carnitine by human placental brush-border membrane vesicles was measured in the absence and presence of tiagabine (TGB), vigabatrin (VGB), gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), valproic acid (VPA), and phenytoin (PHT). The mechanism of the inhibitory action of TGB was determined. RESULTS: Most of the AEDs inhibited placental carnitine transport. Kinetic analyses showed that TGB had the greatest inhibitory effect [50% inhibitory concentration (IC50, 190 microM)], and the order of inhibitory potency was TGB > PHT > GBP > VPA > VGB, TPM > LTG. Further studies showed that TGB competitively inhibited carnitine uptake by the human placental carnitine transporter, suggesting that it may be a substrate for this carrier. CONCLUSIONS: Although the involvement of carnitine deficiency in fetal anticonvulsant syndrome requires further evaluation, potential interference with placental carnitine transport by several AEDs was demonstrated. Despite the higher inhibitory potency of TGB, given the therapeutic unbound concentrations, the results for VPA and PHT are probably more clinically significant.


Assuntos
Aminas , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/farmacocinética , Carnitina/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Ácidos Cicloexanocarboxílicos , Epilepsia/tratamento farmacológico , Frutose/análogos & derivados , Proteínas de Transporte de Cátions Orgânicos , Placenta/efeitos dos fármacos , Placenta/metabolismo , Complicações na Gravidez/tratamento farmacológico , Ácido gama-Aminobutírico , Acetatos/administração & dosagem , Acetatos/efeitos adversos , Acetatos/farmacocinética , Ácidos Aminoisobutíricos/metabolismo , Anticonvulsivantes/classificação , Carnitina/metabolismo , Técnicas de Cultura , Relação Dose-Resposta a Droga , Esquema de Medicação , Epilepsia/metabolismo , Feminino , Frutose/administração & dosagem , Frutose/efeitos adversos , Frutose/farmacocinética , Gabapentina , Humanos , Lamotrigina , Modelos Biológicos , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/efeitos adversos , Ácidos Nipecóticos/farmacocinética , Fenitoína/administração & dosagem , Fenitoína/efeitos adversos , Fenitoína/farmacocinética , Placenta/citologia , Gravidez , Complicações na Gravidez/metabolismo , Proteínas da Gravidez/metabolismo , Membro 5 da Família 22 de Carreadores de Soluto , Tiagabina , Topiramato , Triazinas/administração & dosagem , Triazinas/efeitos adversos , Triazinas/farmacocinética , Ácido Valproico/administração & dosagem , Ácido Valproico/efeitos adversos , Ácido Valproico/farmacocinética , Vigabatrina/administração & dosagem , Vigabatrina/efeitos adversos , Vigabatrina/farmacocinética
17.
Br J Pharmacol ; 141(1): 152-62, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14662729

RESUMO

1. In order to ascertain whether both GABA(A) and GABA(B), or only GABA(B) receptors, directly modulate thermoregulation in conscious rabbits, GABA(A)/GABA(B) agonist and antagonist agents were injected intracerebroventricularly in conscious rabbits while monitoring changes in rectal temperature (RT), gross motor behaviour (GMB) and electrocorticogram (ECoG) power spectra (ps) from sensorimotor cortices. 2. GABA (48 micromol), nipecotic acid (50 nmol), THIP (60 nmol), muscimol (18 nmol) and baclofen (8 nmol) induced hypothermia (-deltaRTmax values of 1.70+/-0.1, 1.4+/-0.2, 1.0+/-0.4, 1.1+/-0.2 and 1.6+/-0.3 degrees C, respectively), accompanied by inhibition of GMB and ECoG synchronization. THIP increased ps at delta frequency band (1.1-3.3 Hz), while GABA, nipecotic acid, muscimol and baclofen did the same at both delta and (4.6-6.5 Hz) frequency bands. ECoG ps changes were concomitant or even preceded hypothermia. 3. Bicuculline (1.8 nmol) induced hyperthermia (deltaRTmax 1.2+/-0.5 degrees C) and slight excitation of GMB, while CGP35348 (1.2 micromol) did not affect RT nor GMB. Both compounds did not affect ECoG ps. 4. Bicuculline potentiated muscimol-induced hypothermia, inhibition of GMB and synchronization of ECoG, while CGP35348 fully antagonized these effects. 5. In conclusion, the present results, while confirming the prevailing role of GABA(B), also outline a direct involvement of GABA(A) receptors in the central mechanisms of thermoregulation. Ascending inhibition towards discrete cortical areas controlling muscular activity and thermogenesis may result from GABA receptor activation in neurones proximal to the ventricles, thus contributing to hypothermia, although hypothermia-induced reduction of neuronal activity of these cortical areas cannot be ruled out.


Assuntos
Regulação da Temperatura Corporal/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Agonistas GABAérgicos/farmacocinética , Antagonistas GABAérgicos/farmacocinética , Córtex Somatossensorial/efeitos dos fármacos , Animais , Baclofeno/administração & dosagem , Baclofeno/farmacocinética , Comportamento Animal/efeitos dos fármacos , Bicuculina/administração & dosagem , Bicuculina/farmacocinética , Regulação da Temperatura Corporal/fisiologia , Eletroencefalografia/métodos , Agonistas GABAérgicos/administração & dosagem , Antagonistas GABAérgicos/administração & dosagem , Injeções Intraventriculares , Isoxazóis/administração & dosagem , Isoxazóis/farmacocinética , Ventrículos Laterais/efeitos dos fármacos , Masculino , Muscimol/administração & dosagem , Muscimol/farmacocinética , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/farmacocinética , Área Pré-Óptica/efeitos dos fármacos , Área Pré-Óptica/fisiologia , Coelhos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-B/efeitos dos fármacos , Reto , Córtex Somatossensorial/fisiologia
18.
J Pharm Sci ; 93(1): 78-85, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14648638

RESUMO

Continuing our studies on SVCT2 ascorbic acid (AA) transporter-mediated drug delivery of neurotropic agents, we have now investigated the in vitro intracellular uptake of Diclofenac (Diclo) and its conjugate (AA-Diclo), both characterized by high affinity for the SVCT2 transporter. We have also investigated the in vivo uptake mechanism of AA-conjugate of Nipecotic acid (AA-Nipec) and the implication of the transporter-mediated effects of Diclo and AA-Diclo. Diclo resulted as a noncompetitive inhibitor of AA transport, but also showed a sodium-dependent and ascorbate-independent uptake, thus implying the possible involvement of specific transporters in the delivery to the brain of Diclo. This result opens a perspective in the discovery of new strategies in the targeting of this drug to the brain. Inhibitory effects of Diclo and AA-Diclo on the SVCT2 transporter were used to study anticonvulsant effects of AA-Nipec, confirming our hypothesis of an SVCT2-mediated transport in its neurotropic activity. AA-Diclo stability has been also investigated: it is hydrolyzed following a first-order kinetics in buffer, plasma (t(1/2) at about 10 h) and whole blood (t(1/2) at about 3 h), suggesting AA-Diclo as a potential candidate to enhance the short half-life of Diclo in vivo.


Assuntos
Ácido Ascórbico/farmacocinética , Diclofenaco/farmacocinética , Ácidos Nipecóticos/farmacocinética , Transportadores de Ânions Orgânicos Dependentes de Sódio/metabolismo , Pró-Fármacos/farmacocinética , Simportadores/metabolismo , Animais , Ácido Ascórbico/uso terapêutico , Encéfalo/metabolismo , Linhagem Celular , Diclofenaco/uso terapêutico , Humanos , Masculino , Camundongos , Ácidos Nipecóticos/uso terapêutico , Pró-Fármacos/uso terapêutico , Convulsões/induzido quimicamente , Convulsões/prevenção & controle , Transportadores de Sódio Acoplados à Vitamina C
19.
Arch Pharm Res ; 26(10): 785-95, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14609124

RESUMO

For the development of new anticonvulsive agents, GABAmimetics such as nipecotic acid, isonipecotic acid, gamma-aminobutyric acid (GABA), gamma-vinyl GABA (vigabatrin) and valproic acid were covalently coupled through an ester bond by a two-carbon linker chain as potential pro-drugs and evaluated for their anticonvulsive activities.


Assuntos
Anticonvulsivantes/síntese química , Anticonvulsivantes/farmacologia , Carbono/química , Dimerização , Desenho de Fármacos , Pró-Fármacos/síntese química , Pró-Fármacos/farmacologia , Animais , Convulsivantes/administração & dosagem , Convulsivantes/efeitos adversos , Convulsivantes/antagonistas & inibidores , Eletrochoque/efeitos adversos , Injeções Intraperitoneais , Injeções Subcutâneas , Ácidos Isonipecóticos/administração & dosagem , Ácidos Isonipecóticos/química , Ácidos Isonipecóticos/farmacocinética , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos ICR , Ácidos Nipecóticos/administração & dosagem , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacocinética , Pró-Fármacos/metabolismo , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/fisiopatologia , Ácido Valproico/administração & dosagem , Ácido Valproico/química , Ácido Valproico/farmacocinética , Vigabatrina/administração & dosagem , Vigabatrina/química , Vigabatrina/farmacocinética , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/química , Ácido gama-Aminobutírico/farmacocinética
20.
Epileptic Disord ; 5 Suppl 1: S17-26, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12915337

RESUMO

The pharmacokinetic properties of a drug are the primary deter-minant of the extent and duration of drug action, and influence susceptibility to clinically important drug interactions. Most of the older-generation antiepileptic drugs (AEDs) are far from ideal in terms of pharmacokinetics and interaction potential. For example, phenytoin, carbamazepine, and valproic acid exhibit non-linear kinetics; carbamazepine and valproic acid have relatively short half-lives; and most of these drugs cause either enzyme induction (phenytoin, phenobarbital, primidone, carbamazepine) or enzyme inhibition (valproic acid). Compared with older agents, certain new-generation AEDs offer a num-ber of pharmacokinetic advantages, particularly in terms of reduced inter-patient variability in drug clearance and a lower interaction potential. One of the most recently developed of these drugs, levetiracetam, comes especially close to fulfilling the desirable pharmacokinetic characteristics for an AED: (1) it has a high oral bioavailability, which is unaffected by food; (2) it is not significantly bound to plasma proteins; (3) it is eliminated partly in unchanged form by the kidneys and partly by hydrolysis to an inactive metabolite, without involvement of oxidative and conjugative enzymes; (4) it has linear kinetics; and (5) it is not vulnerable to important drug interactions, nor does it cause clinically significant alterations in the kinetics of concomitantly administered drugs. Although its half-life is relatively short (6 to 8 hours), its duration of action is longer than anticipated from its pharmacokinetics in plasma, and a twice-daily dosing regimen is adequate to produce the desired response.


Assuntos
Aminas , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapêutico , Carbamazepina/análogos & derivados , Ácidos Cicloexanocarboxílicos , Epilepsia/tratamento farmacológico , Frutose/análogos & derivados , Piracetam/análogos & derivados , Piracetam/farmacocinética , Piracetam/uso terapêutico , Ácido gama-Aminobutírico , Acetatos/farmacocinética , Acetatos/uso terapêutico , Animais , Carbamazepina/farmacocinética , Carbamazepina/uso terapêutico , Interações Medicamentosas , Epilepsia/metabolismo , Felbamato , Frutose/farmacocinética , Frutose/uso terapêutico , Gabapentina , Meia-Vida , Humanos , Isoxazóis/farmacocinética , Isoxazóis/uso terapêutico , Lamotrigina , Levetiracetam , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/uso terapêutico , Oxcarbazepina , Fenilcarbamatos , Propilenoglicóis/farmacocinética , Propilenoglicóis/uso terapêutico , Tiagabina , Topiramato , Triazinas/farmacocinética , Triazinas/uso terapêutico , Vigabatrina/farmacocinética , Vigabatrina/uso terapêutico , Zonisamida
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