Lack of tolerance for the anti-dyskinetic effects of 7-nitroindazole, a neuronal nitric oxide synthase inhibitor, in rats

7-Nitroindazole (7-NI) inhibits neuronal nitric oxide synthase in vivo and reduces l-DOPA-induced dyskinesias in a rat model of parkinsonism. The aim of the present study was to determine if the anti-dyskinetic effect of 7-NI was subject to tolerance after repeated treatment and if this drug could interfere with the priming effect of l-DOPA. Adult male Wistar rats (200-250 g) with unilateral depletion of dopamine in the substantia nigra compacta were treated with l-DOPA (30 mg/kg) for 34 days. On the 1st day, 6 rats received ip saline and 6 received ip 7-NI (30 mg/kg) before l-DOPA. From the 2nd to the 26th day, all rats received l-DOPA daily and, from the 27th to the 34th day, they also received 7-NI before l-DOPA. Animals were evaluated before the drug and 1 h after l-DOPA using an abnormal involuntary movement scale and a stepping test. All rats had a similar initial motor deficit. 7-NI decreased abnormal involuntary movement induced by l-DOPA and the effect was maintained during the experiment before 7-NI, median (interquartile interval), day 26: 16.75 (15.88-17.00); day 28: 0.00 (0.00-9.63); day 29: 13.75 (2.25-15.50); day 30: 0.5 (0.00-6.25); day 31: 4.00 (0.00-7.13), and day 34: 0.5 (0.00-14.63), Friedman followed by Wilcoxon test,vs day 26, P < 0.05;. The response to l-DOPA alone was not modified by the use of 7-NI before the first administration of the drug (l-DOPA vs time interaction, F1,10 = 1.5, NS). The data suggest that tolerance to the anti-dyskinetic effects of a neuronal nitric oxide synthase inhibitor does not develop over a short-term period of repeated administration. These observations open a possible new therapeutic approach to motor complications of chronic l-DOPA therapy in patients with Parkinson’s disease.

Treatment of Parkinson's disease in Thailand: review of the literature and practical recommendations.

The mainstay of treatment for Parkinson's Disease (PD) remains symptomatic despite the rapid expansion in knowledge of its neurodegenerative process. Therapeutic options, both medical and surgical, have been markedly improved over the past decades, resulting in better motor function, activities of daily living, and quality of life for PD patients. The principle of PD management should be individualized and the selection of treatments should aim to control symptoms as well as to prevent or delay motor complications. In Thailand, various pharmacologic and surgical options are available, including different formulations of levodopa, dopamine agonists, monoamine oxidase B inhibitor, cathechol-O-methyltransferase inhibitor pallidotomy, and lastly deep brain stimulation. The use of dopamine agonists in early PD has a levodopa-sparing effect and reduces the incidence of motor complications. Continuous dopaminergic stimulation (CDS), which mimics physiological activation of dopaminergic receptors, has been proposed as a strategy to prevent motor complications. Based on current evidence, practical guidelines in the medical management of different types of motor complications are outlined in the present article according to what are available in Thailand. Surgical interventions should be reserved for patients with intractable motor complications after careful patient selection.

Use of clozapine in Brazilian patients with Parkinson's disease / Uso da clozapina em pacientes brasileiros com doença de Parkinson

Clozapine has been used as an attempt to manage levodopa complications in advanced Parkinson's disease (PD). To investigate the use of clozapine in this context in a Brazilian sample, a retrospective chart review was carried out at the Movement Disorders Clinic from the Federal University of Minas Gerais. This study enrolled 43 PD patients who used or were in use of clozapine. Patients had a mean age of 64 years and a mean UPDRS score of 55. Clozapine was indicated for dyskinesias in 17 patients, for psychosis in 15 and for both reasons in 11. The average maximum dose was 70 mg/day. Twenty six patients used it for a mean of 3.5 years. Twenty nine presented an improvement of their condition, 9 remained clinically stable. Twenty subjects interrupted the use of clozapine, being 9 due to adverse effects. Clozapine may play a role in the management of motor and psychiatric complications in PD, but it is associated with low tolerability.

A clozapina vem sendo utilizada na doença de Parkinson (DP) avançada para controle das complicações causadas pela levodopa. Com o objetivo de investigar o emprego da clozapina nesse contexto em amostra de pacientes brasileiros, um estudo retrospectivo foi realizado no Ambulatório de Distúrbios do Movimento da Universidade Federal de Minas Gerais. Este estudo incluiu 43 pacientes que usaram clozapina, apresentando idade média de 64 anos e uma média de 55 pontos no UPDRS. A clozapina foi indicada para discinesias em 17 pacientes, para psicose em 15 e para ambos os motivos em 11. A média da dose máxima empregada foi de cerca de 70 mg/dia. Vinte e seis pacientes usaram a medicação por uma média de 3,5 anos. Houve melhora do quadro clínico em 29 pacientes, 9 permaneceram com quadro clínico estático. O tratamento foi interrompido em 20 pessoas, sendo 9 por efeitos adversos. Apesar de a clozapina ser eficaz no controle das complicações motoras e psiquiátricas na DP, seu uso está associado com baixa tolerabilidade.

Piridoxina en el manejo de disquinesias tardías: un estudio placebo controlado, randomizado, doble ciego y cruzado / Pyridoxine for drug induced dyskinesia: a placebo-controlled randomized cross-over trial

Las Disquinesias tardías son reacciones adversas frecuentes e invalidantes de aquellos fármacos relacionados con la transmisión dopaminérgica. Una proporción importante de pacientes que la padecen no responden a las terapias actualmente vigentes. En este estudio se randomizó a 28 pacientes portadores de Disquinesias tardías severas y refractarias a tratamiento habitual, provenientes del Instituto Psiquiátrico de Santiago, en dos grupos que recibieron Piridoxina (500 mg al día) o placebo por 4 semanas, siguiendo un periodo de lavado de 7 días tras los cuales ambos grupos se cruzaron, manteniendo tratamiento por 4 semanas adicionales. Se utilizó la escala AIMS (Abnormal Involuntary Movement Scale) para evaluar a cada paciente en la semana 2 y 4 de cada etapa del estudio. La Piridoxina fue bien tolerada y no hubo efectos adversos en el periodo de estudio, no encontrándose diferencias significativas en la mejoría de Disquinesias Tardía entre los grupos que recibieron Piridoxina o Placebo.

Tardive Dyskinesia is a common and disabling adverse effect of drugs acting on Dopaminergic pathways. An important proportion of patients does not respond to the conventional treatment. In this study 28 severe and refractory patients from a Psychiatric Hospital were randomized in a cross over design to placebo and high doses (500 mg per day) of Pyridoxine for 4 weeks each one. The patients were evaluated using the Abnormal Involuntary Movement Scale (AIMS) at 2 and 4 weeks of each cycle. Pyridoxine was well tolerated, and no adverse effect occurred during the study. No statistical differences between Pyridoxine and Placebo were found. Surprisingly, in both groups equally good responses were found.

Lithium - induced tardive dystonia.

Tardive dystonia is an uncommon form of chronic dystonia, which usually develops on exposure to neuroleptics. Tardive dystonia (Tdt) following lithium therapy has not been previously reported. The case of 38 year old man with bipolar affective disorder who developed tardive dystonia while on maintenance lithium treatment is described. Presentation of Tdt in this patient was fairly characteristic although there was no suggestion of recent neuroleptic exposure. Tdt known to have poor treatment response, responded very well to clozapine, a novel anti-psychotic, in this case. To conclude, Tdt may develop on exposure to drugs other than neuroleptics. An adequate trial to clozapine can prove to be a useful treatment option.

Remisión de diskinesia tardía inducida por fase maníaca de trastorno bipolar del estado de ánimo: comunicación de un caso clínico / Remision of tardive dyskinesia induced by maniac phase of bipolar disorder: communication of a clinical case

Se comunica el caso clínico de un paciente portador de un trastorno bipolar del estado de ánimo, quien ha sido hospitalizado en 10 oportunidades en el Instituto Psiquiátrico de Santiago. Su enfermedad se inició a la edad de 32 años y durante las internaciones ha sido tratado, durante las fases maníacas, con clorpormazina, tioridazina, haloperidol y terapia electroconsulsivante. En marzo de 1984 se indicó carbonato de litio como tratamiento profiláctico de las fases de manía y depresión. En marzo de 1991, estando el paciente eutímico, y en relación a la disminución de 50 a 25 mgrs/día de clorpromazina, aparecieron movimientos anormales cervicales y bucolinguales y se planteó el diagnóstico de Kiskinesia y Distonia Tardía. Con el objeto de controlar los movimientos anormales se indicaron: propanolol, ácido valproico, diazepam, clonazepam, trihexifenidilo, baclofeno, alprazolam, carbamazepina y, finalmente, terapia electroconvulsivante. La utilización de estas alternativas terapéuticas, trajo consigo una disminución leve y transitoria de los movimientos anormales. Una semana antes de su última hospitalización, a causa de una fase maníaca, desaparecieron de manera sorpresiva todos los movimientos anormales, los que reaparecieron cuando se trató la manía con litio y ácido valproico

Síndrome a largo plazo por levodopa: enfoque clínico, profilaxis, avances terapéuticos / Long term levodopa syndrome: clinical approach, prophylaxis, therapeutical advances

El síndrome a largo plazo por levodopa (L-Dopa) corresponde a las manifestaciones adversas provocadas por el fármaco, que aparecen generalmente después de un año o más de su empleo y que afectan aproximadamente al 50 por ciento de los casos. Los síntomas son muy variados y polimorfos, los más habituales son de tipo motor (diskinesias, distonías posturales y disminución de la respuesta motora), se agregan otros, como trastornos mentales, neurovegetativos y sensitivos. Para la profilaxis de este síndrome debe considerarse el retraso en la iniciación de la terapia, usándose como alternativa: selegilina, bromocriptina, anticolinérgicos (thihexifenidilo) o antidepresivos. En casos severos de enfermedad de Prkinson y que no pueda obviarse el uso de L-Dopa, ésta debe emplearse inicialmente en la dosis mínima efectiva, la que se aumenta en forma lenta y progresiva en varias semanas. Otra variables es el uso de formulaciones de liberación controlada (Prolopa HBS o Sinemet CR). También es recomendable la asociación de agonistas dopaminérgicos que tendrían un efecto protector en el síndrome a largo plazo de L-Dopa

Vitamin E in the treatment of tardive dyskinesia.

In a double-blind placebo controlled trial, the efficacy of Vitamin E in the treatment of tardive dyskinesia (TD) was studied in 32 patients. After a two week wash-out phase a baseline (0 week) TD rating was assessed on the tardive dyskinesia rating scale (TDRS). Subsequently, the patients entered a four week treatment phase during which 17 patients received capsules of vitamin E (600 mg) and 15 patients received identical placebo capsules. In the first week the patients received 1 capsule daily which was then increased to two capsules per day from the second to the fourth week. All patients were rated on the TDRS at the end of each week. The baseline TDRS score in the vitamin E group was significantly higher than the placebo group. This was hence adjusted and the results were then subjected to analysis of co- variance. The TDRS score after four weeks treatment was significantly lower in the vitamin E group as compared to the placebo group (p = 0.03).

Discinesia tardia residual 24 meses após a suspensão do uso da flunarizina / Residual tardive syskinesia 24 months after suspension of flunarizine

O autor descreve um caso de discinesia tardia (DT) de aparecimento após a suspensão do uso da flunarizina (Fz). A paciente procurou atendimento por síndrome de Parkinson (SP) atípica, pelo parasitismo de movimentos córeo-atetósicos, refratária a L-dopa e anticolinérgicos. Usava a Fz para o tratamento de vertigens por provável insuficiência vértebro-basilar. Suspenso o uso da Fz houve melhora progressiva da SP mas na mesma medida que desaparecia a SP a DP se fez mais evidente e persiste 24 meses após a suspensão da Fz. O objetivo é alertar para esse efeito colateral grave da Fz, uma droga cuja comercialização não é liberada em vários países do mundo mas que se indica atualmente para afecções comuns como a enxaqueca como faz o Goodman e Gilman (1990) mas não aponta como efeitos colaterais nem a SP nem a DT

Discinesia tardia: aspectos clínicos; fisiopatologia e tratamento / Tardive dyskinesia: clinical aspects;physiopathology and treatment

A discinesia tardia (DT), uma complicaçäo do uso da medicaçäo antipsicótica por longo período em pacientes psiquiátricos, apresenta inúmeros fatores de risco, que podem a influenciar na prevalência. Embora sua fisiopatologia näo esteja bem esclarecida foram demonstrados distúrbios na neurotransmissäo dopaminérgica no estriado envolvendo vários mecanismos e neurotransmissores. Apesar de todas as tentativas terapêuicas, até o momento näo se encontrou uma medicaçäo que pudesse reverter totalmente o quadro hoje exitente