RESUMEN
BACKGROUND: Tiagabine is a novel antiepileptic that acts by increasing synaptic and extracellular gamma-aminobutyric acid concentrations. Information concerning overdose of tiagabine is limited. After introduction, an increasing number of off-label uses suggested that tiagabine use would increase. However in 2005 and 2008, warnings from the Food and Drug Administration (FDA) were issued on the risk of seizures in non-epileptic and increased suicide ideation. We evaluated the temporal trends associated with these two warnings as well as clinical outcomes from tiagabine overdose. METHOD: A retrospective review of all single substance tiagabine exposures in National Poison Data System (NPDS) from 2000 to 2012. RESULTS: A total of 2147 patients had ingested tiagabine, with a mean of 165 year(-1). This was disproportionally distributed, with a steep rise leading up to 2004 (max 559 year(-1)) and then a significant decline (p < 0.05) between 2005 and 2006. The number of cases reported to NPDS mirrored the sales of tiagabine. Clinical effects were predominantly neurological, with the most commonly reported effects being drowsiness (27%), agitation (19%), confusion (12%), seizures (11%), and tachycardia (10%). In all, 758 patients (35%) showed a major or moderate medical outcome, with no deaths reported. A disproportionate share of the major outcomes was in the suicide attempt group (73%). The majority of patients (75%) were treated in a health-care facility (HCF). CONCLUSIONS: The HCF usage is likely due to high rate of symptomatic patients (59%) and the large proportion of suicide attempt cases. The frequency of tiagabine cases in NPDS mirrored pharmaceutical sales, with steep declines temporally related to the 2005 FDA warning.
Asunto(s)
Anticonvulsivantes/toxicidad , Ácidos Nipecóticos/toxicidad , Centros de Control de Intoxicaciones/estadística & datos numéricos , Anticonvulsivantes/envenenamiento , Sobredosis de Droga , Humanos , Ácidos Nipecóticos/envenenamiento , Intento de Suicidio , Tiagabina , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Losartan and telmisartan, angiotensin AT1 receptor antagonists, are widely used antihypertensive drugs in patients. It is also known that arterial hypertension is often present in people with epilepsy, therefore, drug interactions between AT1 receptor antagonists and antiepileptic drugs can occur in clinical practice. OBJECTIVES: The aim of the current study was to assess the effect of losartan and telmisartan on the anticonvulsant activity of tiagabine, a second-generation antiepileptic drug, in mice. Additionally, the effect of the combined treatment with AT1 receptor antagonists and TGB on long-term memory and motor coordination has been assessed in animals. MATERIAL AND METHODS: The study was performed on male Swiss mice. Convulsions were examined in the maximal electroshock seizure threshold test. Long-term memory was measured in the passive-avoidance task and motor coordination was evaluated in the chimney test. AT1 receptor antagonists and TGB were administered intraperitoneally. RESULTS: Losartan (50 mg/kg) or telmisartan (30 mg/kg) did not influence the anticonvulsant activity of TGB applied at doses of 2, 4 and 6 mg/kg. However, both AT1 receptor antagonists in combinations with TGB (6 mg/kg) impaired motor coordination in the chimney test. The concomitant treatment of the drugs did not decrease retention in the passive avoidance task. CONCLUSIONS: It is suggested that losartan and telmisartan should not affect the anticonvulsant action of TGB in people with epilepsy. Because the combined treatment with AT1 receptor antagonists and TGB led to neurotoxic effects in animals, caution is advised during concomitant use of these drugs in patients.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Anticonvulsivantes/farmacología , Conducta Animal/efectos de los fármacos , Bencimidazoles/farmacología , Benzoatos/farmacología , Losartán/farmacología , Memoria a Largo Plazo/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ácidos Nipecóticos/farmacología , Desempeño Psicomotor/efectos de los fármacos , Convulsiones/prevención & control , Bloqueadores del Receptor Tipo 1 de Angiotensina II/toxicidad , Animales , Anticonvulsivantes/toxicidad , Bencimidazoles/toxicidad , Benzoatos/toxicidad , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Electrochoque , Losartán/toxicidad , Masculino , Ácidos Nipecóticos/toxicidad , Polifarmacia , Convulsiones/etiología , Convulsiones/metabolismo , Convulsiones/psicología , Telmisartán , Tiagabina , Factores de TiempoRESUMEN
PURPOSE: Vigabatrin (VGB) is an irreversible inhibitor of gamma-aminobutyric acid (GABA) transaminase. Its use as an antiepileptic drug (AED) has been limited because it causes retinal dysfunction, leading to visual field defects (VFDs). We performed this study to identify factors contributing to acute VGB retinotoxicity. METHODS: In ex vivo experiments, Sprague-Dawley rat retinas were isolated and incubated with VGB or GABA in the presence or absence of light. In in vivo experiments, Sprague-Dawley rats were given intraperitoneal injections of VGB and then exposed to light or kept in the dark. The retinas were analyzed histologically by using both light and electron microscopy. RESULTS: Incubating retinas with 50-500 microM VGB under 20,000 Lux white light for < or = 20 h caused a characteristic time- and dose-dependent degeneration limited to the outer retina. Incubating retinas with 500 microM VGB in darkness for 20 h caused no damage. Five hundred micromolar GABA and 50 microM tiagabine were not toxic in the presence or absence of light. Sprague-Dawley rats exposed to an intense white light for 20 h after a 1,000-mg/kg intraperitoneal injection of VGB showed damage in the outer retina, whereas those kept in the dark did not. CONCLUSIONS: Direct exposure of the retina to VGB causes acute retinotoxicity that depends on light exposure rather than GABA accumulation.
Asunto(s)
Anticonvulsivantes/toxicidad , Luz/efectos adversos , Estimulación Luminosa , Retina/efectos de los fármacos , Enfermedades de la Retina/inducido químicamente , Vigabatrin/toxicidad , Trastornos de la Visión/inducido químicamente , Ácido gamma-Aminobutírico/fisiología , Enfermedad Aguda , Animales , Oscuridad/efectos adversos , Masculino , Ácidos Nipecóticos/toxicidad , Estimulación Luminosa/efectos adversos , Células Fotorreceptoras/patología , Ratas , Ratas Sprague-Dawley , Retina/patología , Enfermedades de la Retina/patología , Escotoma/inducido químicamente , Escotoma/patología , Tiagabina , Trastornos de la Visión/patología , Campos Visuales/efectos de los fármacosRESUMEN
In the last decade, nine new antiepileptic drugs have reached the global marketplace. These new agents can be categorised according to their principal mechanisms of action. Vigabatrin and tiagabine are the only new compounds with selective effects on inhibitory neurotransmission. The principal inhibitory neurotransmitter in mammalian brain is gamma-aminobutyric acid (GABA). Both vigabatrin and tiagabine exert their pharmacological effects by reducing the inactivation of GABA. Vigabatrin attenuates the metabolism of GABA by inhibiting the enzyme GABA-transaminase, whereas tiagabine blocks the uptake of GABA from the synaptic cleft by an action on the GAT-1 transporter. These mechanistic differences are borne out in a range of experimental seizure models in which vigabatrin and tiagabine have very different anticonvulsant profiles. Pre-clinical neurotoxicity and pharmacokinetic profiles also differ. Long-term vigabatrin treatment is associated with intramyelinic oedema in white matter tracts of several brain regions and further studies have revealed an accumulation of vigabatrin in the retina. In contrast, it seems that tiagabine does not precipitate any significant neurotoxicity and does not appear to accumulate in the retina. The results of these pre-clinical investigations suggest that vigabatrin and tiagabine are pharmacologically distinct compounds with different anticonvulsant, neurotoxicity and pharmacokinetic profiles. It is possible that they will ultimately prove to have different clinical efficacies and spectra of activity.
Asunto(s)
Anticonvulsivantes/uso terapéutico , Agonistas del GABA/uso terapéutico , Ácidos Nipecóticos/uso terapéutico , Vigabatrin/uso terapéutico , Animales , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/toxicidad , Agonistas del GABA/farmacocinética , Agonistas del GABA/toxicidad , Humanos , Ácidos Nipecóticos/farmacocinética , Ácidos Nipecóticos/toxicidad , Receptores de GABA/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Tiagabina , Vigabatrin/farmacocinética , Vigabatrin/toxicidad , Campos Visuales/efectos de los fármacosRESUMEN
RWJ-53308 is a novel nonpeptide glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist that inhibits fibrinogen binding to GPIIb/IIIa with an IC(50) of 0.4+/-0.3 nM. RWJ-53308 inhibits thrombin-induced platelet aggregation in human gel-filtered platelets (IC(50)=60+/-12 nM) and platelet aggregation in human platelet-rich plasma (PRP) in response to collagen, arachidonic acid, ADP, and SFLLRN-NH(2) (IC(50)=60+/-10, 150+/-30, 70+/-4, and 160+/-80 nM, respectively). The potency of RWJ-53308 in dog and guinea pig PRP is similar to human PRP. RWJ-53308 inhibits ex vivo collagen- and ADP-induced platelet aggregation in conscious dogs for up to 4 h following 0.3 mg/kg iv, and through 4 and 6 h following 1 and 3 mg/kg po. Oral bioavailability is 16+/-7%. RWJ-53308 reduces thrombus weight in a canine arteriovenous (AV) shunt model following intravenous (0.01-0.1 mg/kg) and oral (3 mg/kg) administration. In a guinea pig carotid artery pinch-injury model, RWJ-53308 completely suppresses thrombus-induced cyclic flow reductions (CFR) at 0.7 mg/kg iv. RWJ-53308 also blocks thrombus formation in photoactivation- and ferric chloride-induced models of thrombosis in guinea pigs at 0.3 and 1 mg/kg iv, respectively. In summary, RWJ-53308 is a potent orally active GPIIb/IIIa antagonist that may be useful for both acute and chronic treatment of arterial thrombotic disorders.
Asunto(s)
Ácidos Nipecóticos/farmacocinética , Inhibidores de Agregación Plaquetaria/farmacocinética , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria/antagonistas & inhibidores , Piridinas/farmacocinética , Animales , Disponibilidad Biológica , Modelos Animales de Enfermedad , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Fibrinógeno/efectos de los fármacos , Fibrinógeno/metabolismo , Cobayas , Humanos , Concentración 50 Inhibidora , Ácidos Nipecóticos/administración & dosificación , Ácidos Nipecóticos/toxicidad , Agregación Plaquetaria/efectos de los fármacos , Inhibidores de Agregación Plaquetaria/administración & dosificación , Inhibidores de Agregación Plaquetaria/toxicidad , Unión Proteica/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/toxicidad , Ratas , Trombosis/tratamiento farmacológicoRESUMEN
We studied in vitro the effects of Tiagabine on genomic DNA of cortical rat astrocytes. To evaluate DNA damage, we used a relatively simple technique called Single Cell Gel Electrophoresis or Comet assay. Tiagabine was dissolved in culture medium and added at concentration of 1, 10, 20 and 50 microg/ml on 12-day old cultured astrocytes. In presence of 1 and 10 microg/ml of Tiagabine, no DNA damage was observed after 48 h of treatment. A moderate DNA damage was instead observed for cells exposed to 20 microg/ml of antiepileptic drug. Finally, DNA fragmentation was more evident after treatment with 50 microg/ml of Tiagabine. We conclude that Tiagabine, at the usual recommended doses, does not appear to influence negatively the cortical rat astrocytes, inducing DNA fragmentation only at very high concentrations.
Asunto(s)
Astrocitos/efectos de los fármacos , Células Cultivadas/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Daño del ADN/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Agonistas del GABA/toxicidad , Ácidos Nipecóticos/toxicidad , Animales , Animales Recién Nacidos , Astrocitos/metabolismo , Astrocitos/patología , Células Cultivadas/metabolismo , Células Cultivadas/patología , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiopatología , Ensayo Cometa/métodos , Daño del ADN/fisiología , Relación Dosis-Respuesta a Droga , Genoma , Proteína Ácida Fibrilar de la Glía/metabolismo , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/metabolismo , Degeneración Nerviosa/fisiopatología , Ratas , TiagabinaRESUMEN
PURPOSE: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB). METHODS: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4-6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12 h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB x HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. RESULTS: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t(1/2)) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 l/h, and from 6.4 to 8.4 h, respectively. CONCLUSIONS: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.
Asunto(s)
Anticonvulsivantes/farmacocinética , Fallo Renal Crónico/metabolismo , Riñón/metabolismo , Ácidos Nipecóticos/farmacocinética , Adulto , Anticonvulsivantes/sangre , Anticonvulsivantes/toxicidad , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/metabolismo , Cromatografía Líquida de Alta Presión , Creatinina/orina , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Epilepsia/tratamiento farmacológico , Femenino , Semivida , Humanos , Riñón/efectos de los fármacos , Fallo Renal Crónico/sangre , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Ácidos Nipecóticos/sangre , Ácidos Nipecóticos/toxicidad , Unión Proteica , Tiagabina , UltrafiltraciónRESUMEN
In an effort to develop compounds with high antithrombotic activity and minimal toxicity, our laboratory has synthesized a number of nipecotamides. The effectiveness of one of these compounds, alpha,alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (A-1), in inhibiting both in vitro and in vivo platelet aggregation is reported here, along with its acute toxicity. The IC50 of A-1 in in vitro ADP- and PAF-induced platelet aggregation was 44.5 microM and 21.2 microM, respectively. Suppression of intraplatelet [Ca2+] is suggested as a likely mediator of the aggregation-inhibitory properties of A-1, since both the release of cytosolic Ca2+ and the influx of extracellular Ca2+ were decreased. The ED50 of A-1 in protecting mice against thromboembolism induced by a collagen-epinephrine challenge was 164 mumol/kg. The measurement of the acute toxicity of this compound as the LD50 was 691 mumol/kg, with the therapeutic index being 4.2. These data indicate that compounds in this family hold promise as clinically effective antithrombotic agents.
Asunto(s)
Fibrinolíticos/farmacología , Ácidos Nipecóticos/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Adenosina Difosfato/antagonistas & inhibidores , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Calcio/sangre , Fibrinolíticos/toxicidad , Humanos , Técnicas In Vitro , Dosificación Letal Mediana , Masculino , Ratones , Ratones Endogámicos ICR , Ácidos Nipecóticos/toxicidad , Factor de Activación Plaquetaria/antagonistas & inhibidores , Inhibidores de Agregación Plaquetaria/toxicidadRESUMEN
The nipecotic acid ester, (+/-)-m-nitrophenyl-3-piperidinecarboxylate hydrochloride (MNPC) is a potent inhibitor of uptake of GABA in vitro and should be able to penetrate into the brain much more readily than the parent compound nipecotic acid. A study of the effects of MNPC on convulsions induced by chemicals which interfere with GABA-mediated neurotransmission was carried out in the mouse, with MNPC being administered by subcutaneous injection 30, 60 or 90 min prior to challenge with bicuculline. It was found that MNPC protected against convulsions induced by bicuculline with ED50 values for clonic and tonic convulsions of 157.8 and 138.8 mg/kg, respectively, at the time of peak effect of 60 min and MNPC abolished both the clonic and tonic components of isoniazid convulsions with respective ED50 values of 255.3 and 76.7 mg/kg at 1 hr. Picrotoxin and pentylenetrazol-induced seizures were also blocked with corresponding ED50 values for clonic convulsions of 224.9 and 235.9 mg/kg at 1 hr. No serious side effects were observed during the 90 min period after the administration of MNPC in doses up to 600 mg/kg.