RESUMEN
New bioanalytical SPE-HPLC-PDA-FL method for the determination of the neuroleptic drug tiapride and its N-desethyl metabolite was developed, validated and applied to xenobiochemical and pharmacokinetic studies in humans and animals. The sample preparation process involved solid-phase extraction of diluted plasma spiked with sulpiride (an internal standard) using SPE cartridges DSC-PH Supelco, USA. Chromatographic separation of the extracts was performed on a Discovery HS F5 250 mm × 4 mm (Supelco) column containing pentafluorophenylpropylsilyl silica gel. Mobile phase (acetonitrile-0.01 M phosphate buffer pH=3, flow rate 1 ml min(-1)) in the gradient mode was employed in the HPLC analysis. Tandem UV photodiode-arrayâfluorescence detection was used for the determination of the analytes. Low concentrations of tiapride and N-desethyl tiapride were determined using a more selective fluorescence detector (λ(exc.)/λ(emiss.)=232 nm/334 nm), high concentrations (500-6000 pmol ml(-1)) using a UV PDA detector at 212 nm with a linear response. Each HPLC run lasted 15 min. Lower limits of quantification (LLOQ) for tiapride (N-desethyl tiapride) were found to be 8.24 pmol ml(-1) (10.11 pmol ml(-1)). The recoveries of tiapride ranged from 89.3 to 94.3%, 81.7 to 86.8% for internal standard sulpiride and 90.9 to 91.8% for N-desethyl tiapride.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Fluorescencia/métodos , Espectrofotometría Ultravioleta/métodos , Clorhidrato de Tiapamilo/análogos & derivados , Clorhidrato de Tiapamilo/sangre , Animales , Humanos , Límite de Detección , Modelos Lineales , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Reproducibilidad de los Resultados , Extracción en Fase Sólida , Sulpirida/sangre , Clorhidrato de Tiapamilo/farmacocinética , Adulto JovenRESUMEN
The benzamide derivative tiapride (Tiapridex, Synthelabo) has a highly selective antagonistic effect on striatal adenylate cyclase-independent dopamine-2 receptors. Its in vitro binding affinity is especially high for dopamine receptors which have been sensitized by pre-incubation with dopamine. The involvement of altered dopamine receptor sensitivity in several extrapyramidal dys- and hyperkinesia has been hypothesized. By its high affinity for these receptors, without any affinity for other neurotransmitter receptors of the brain, tiapride is especially well suited for the treatment of movement disorders related to functional dopamine hyperactivity. Even at higher doses, tiapride does not exceed a D2-receptor occupancy of 80%, which is in accordance with the finding that tiapride rarely causes acute extrapyramidal syndromes and has, up to now, never implicated in inducing tardive dyskinesias. On the contrary, clinical studies demonstrate its excellent efficacy in neuroleptic-induced tardive dyskinesia, L-Dopa-induced dyskinesias, psychomotor agitation in geriatric patients and choreatic movement disorders. Since tiapride is not available in the USA as yet, most of the studies concerning tiapride have been carried out in Europe. In a recent study, based on objective measurements, tiapride effectively controlled choreatic movements in patients suffering from Huntington's disease (HD). Tiapride is well tolerated in daily doses between 300 and 1200 mg. Adverse events are generally rare and mild.
Asunto(s)
Antidiscinéticos/uso terapéutico , Enfermedades de los Ganglios Basales/tratamiento farmacológico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Clorhidrato de Tiapamilo/uso terapéutico , Animales , Antidiscinéticos/farmacocinética , Antidiscinéticos/farmacología , Química Encefálica/efectos de los fármacos , Humanos , Clorhidrato de Tiapamilo/farmacocinética , Clorhidrato de Tiapamilo/farmacologíaRESUMEN
Tiapride is a substituted benzamide with selective dopamine D2 and D3-antagonist properties which appears to have preferential affinity for extra-striatal dopamine receptors. Tiapride is used in the treatment of agitation, aggressiveness and anxiety in the elderly. To define the effects of a single dose of tiapride 100 mg on psychomotor performance and cognitive functions and electroencephalogram (EEG), a randomized, double-blind, three-way crossover, placebo-controlled study using lorazepam 1 mg as a positive control was carried out in 12 elderly individuals (six women and six men, mean age +/- SD: 69 +/- 3 years). A 1-week wash-out interval was allowed between each administration. Psychomotor and cognitive functions were assessed using both objective [EEG, critical flicker fusion, simple reaction time, tapping, body sway, continuous performance task (CPT), digit symbol substitution test, Sternberg memory scanning and a learning memory test using word lists] and subjective (visual analogue scales) measures before and up to 6 h after dosing. Tiapride was devoid of any detrimental or sedative effects on EEG and all of the performance tasks used and did not impair memory compared with-placebo. In contrast, a single dose of lorazepam produced significant deleterious effects on psychomotor performance (decrease in tapping and in sustained attention (CPT) and an increase in reaction time and body sway), and sedative effects on EEG (significant increase in delta and decrease in alpha waves) as well as significant impairment in working memory (Sternberg) and anterograde amnesia (decrease in immediate and delayed free recall) up to 6 h after dosing compared with placebo and tiapride. In conclusion, the present study showed that in contrast to lorazepam 1 mg there is no evidence to suggest that a single dose of tiapride 100 mg has any sedative and amnestic effects in the elderly which may interfere with everyday life activities.
Asunto(s)
Antipsicóticos/farmacología , Cognición/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Clorhidrato de Tiapamilo/farmacología , Anciano , Antipsicóticos/efectos adversos , Antipsicóticos/farmacocinética , Estudios Cruzados , Método Doble Ciego , Femenino , Fusión de Flicker/efectos de los fármacos , Humanos , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Clorhidrato de Tiapamilo/efectos adversos , Clorhidrato de Tiapamilo/farmacocinéticaRESUMEN
Tiapride dose-dependently attenuated the biphasic nociceptive responses induced by s.c. injection of formalin to the hindpaw of mice, and its activity on the first (ED50 = 110 mg/kg p.o.) and the second (ED50 = 32.0 mg/kg p.o.) phases paralleled that on the nociceptive response to intrathecal injection of substance P (ED50 = 190 mg/kg p.o.) and somatostatin (ED50 = 56.0 mg/kg p.o.), respectively. Moreover, a similar antinociceptive activity was observed in streptozotocin-induced diabetic or genetically diabetic (db/db) mice. The effects of tiapride (100 mg/kg p.o.) on both phases of the formalin test in normal mice were abolished by pretreatment with p-chlorophenylalanine (800 x 2 mg/kg p.o.), a 5-hydroxytryptamine (5-HT) depletor, or pindolol (1 mg/kg i.p.), a 5-HT1 antagonist, but were scarcely affected by 3-tropanyl-indole-3-carboxylate, a 5-HT3 antagonist. Ketanserin (1 mg/kg i.p.), a 5-HT2 antagonist, attenuated the effect of tiapride on the second phase but not on the first phase. This study on the antinociceptive mechanism of action of tiapride (that blocks painful neuropathy in diabetic patients) has led us to hypothesize that the drug attenuates pain transmission through an indirect activation of central 5-HT1 and 5-HT2 receptors.
Asunto(s)
Sistema Nervioso Central/fisiología , Antagonistas de Dopamina/farmacología , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Dolor/tratamiento farmacológico , Serotonina/fisiología , Transmisión Sináptica/efectos de los fármacos , Clorhidrato de Tiapamilo/farmacología , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/tratamiento farmacológico , Neuropatías Diabéticas/fisiopatología , Antagonistas de Dopamina/farmacocinética , Femenino , Fenclonina/análogos & derivados , Indoles , Inyecciones Espinales , Ketanserina , Masculino , Ratones , Dolor/inducido químicamente , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Pindolol , Antagonistas de la Serotonina , Somatostatina , Sustancia P , Clorhidrato de Tiapamilo/farmacocinética , TropisetrónRESUMEN
Tiapride, an atypical neuroleptic agent, is a selective dopamine D2-receptor antagonist with little propensity for causing catalepsy and sedation. It shows preferential activity at receptors previously sensitised to dopamine and those located extrastriatally. Tiapride demonstrates antidyskinetic activity reflecting antidopaminergic actions, and also anxiolytic activity mediated by mechanisms that are poorly understood. Unlike the benzodiazepines, tiapride does not affect vigilance and has a low potential for interaction with alcohol (ethanol), and possibly for abuse. Tiapride facilitates management of alcohol withdrawal, but its use in patients at risk of severe reactions in acute withdrawal should be accompanied by adjunct therapy for hallucinosis and seizures. Since it may prove difficult to identify such patients and there is also a small risk of neuroleptic malignant syndrome (particularly with parenteral administration), the usefulness of tiapride in this setting is likely to be limited. Nevertheless, relative freedom from the complications associated with benzodiazepine therapy suggest a possible role for the drug in the treatment of individuals suitable for alcohol detoxification as outpatients. Preliminary clinical studies in alcoholic patients following detoxification have shown that tiapride ameliorates psychological distress, improves abstinence, and reduces drinking behaviour, and in the short term facilitates reintegration within society. These benefits were associated with reduced consumption of health care resources. However, the potential risk of tardive dyskinesia at the dosage employed (300 mg/day) requires evaluation and necessitates medical supervision. Thus, with its lack of adverse effects on vigilance and low propensity for interaction with alcohol and possibly for abuse, tiapride will probably find particular use in the management of alcoholic patients suitable for detoxification in an outpatient setting; and, if initial findings are confirmed in large well-designed trials, in the short term (< or = 6 months) therapy of reformed alcoholic patients under medical supervision.
Asunto(s)
Etanol/efectos adversos , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Clorhidrato de Tiapamilo/uso terapéutico , Administración Oral , Delirio por Abstinencia Alcohólica/prevención & control , Animales , Disponibilidad Biológica , Semivida , Humanos , Inyecciones Intramusculares , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores Dopaminérgicos/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Síndrome de Abstinencia a Sustancias/rehabilitación , Clorhidrato de Tiapamilo/farmacocinética , Clorhidrato de Tiapamilo/farmacologíaRESUMEN
Tiapride is a substituted benzamide derivative with selective dopamine D2-receptor antagonist properties which appears to have preferential affinity for extrastriatal dopamine receptors. Animal and clinical studies show that tiapride has anxiolytic properties but the mechanism of action is uncertain. Results from limited studies indicate that the clinical efficacy of tiapride in the treatment of agitation, aggressiveness, anxiety and sleep disorders in the elderly appears superior to that of placebo, chlorpromazine, lorazepam and meprobamate. Tiapride also exerts a beneficial effect on vigilance and alertness in elderly patients and causes less sedation than chlorpromazine. Tiapride is well tolerated at the dosages recommended for elderly patients. Further well designed comparative studies with newer drugs are needed to determine the relative place of tiapride in the treatment of geriatric agitation, and such studies should also address the quality-of-life benefits for the patient. Additional clinical experience to determine the efficacy of tiapride in elderly patients with more than one disease condition, receiving concomitant medications, and/or with renal impairment is also required. However, despite these current limitations, tiapride may have potentially important applications in this difficult area of clinical medicine.
Asunto(s)
Antagonistas de los Receptores de Dopamina D2 , Agitación Psicomotora/tratamiento farmacológico , Clorhidrato de Tiapamilo/farmacología , Anciano , Animales , Humanos , Clorhidrato de Tiapamilo/efectos adversos , Clorhidrato de Tiapamilo/farmacocinética , Clorhidrato de Tiapamilo/uso terapéuticoRESUMEN
The pharmacokinetic properties of a single oral dose of 100 mg of tiapride were studied in six patients with Huntington's disease. The results for five patients were consistent with a two compartment open model. Peak plasma concentrations were observed within 2 h following drug administration with a mean value of 0.92 micrograms/ml being recorded. The drug was rapidly eliminated as unmetabolised tiapride in the urine, 51% of the dose was recovered in 24 h. The plasma elimination half-life was 5.3 h and the average apparent plasma clearance was 16.6 l/h.