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1.
Spinal Cord ; 47(10): 751-6, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19333246

RESUMO

STUDY DESIGN: Retrospective study. OBJECTIVES: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. METHODS: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. RESULTS: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (P<0.05), and then stabilized around a mean dose of 350 microg per day. Eight patients (22%) developed tolerance, defined as a dose increase of >100 microg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance. Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n=11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pump-related complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. CONCLUSIONS: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.


Assuntos
Baclofeno/administração & dosagem , Tolerância a Medicamentos/fisiologia , Agonistas GABAérgicos/administração & dosagem , Relaxantes Musculares Centrais/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Adolescente , Adulto , Idoso , Baclofeno/efeitos adversos , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Agonistas GABAérgicos/efeitos adversos , Humanos , Bombas de Infusão Implantáveis , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Relaxantes Musculares Centrais/efeitos adversos , Espasticidade Muscular/etiologia , Espasticidade Muscular/fisiopatologia , Inibição Neural/efeitos dos fármacos , Inibição Neural/fisiologia , Receptores de GABA-B/efeitos dos fármacos , Receptores de GABA-B/metabolismo , Estudos Retrospectivos , Medula Espinal/efeitos dos fármacos , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/complicações , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
2.
Neuropharmacology ; 44(3): 311-23, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12604091

RESUMO

Nucleotides can activate ionotropic P2X receptors that induce calcium-responses in rat midbrain synaptosomes. In this report, we show that ATP elicits Ca(2+) responses producing a monophasic dose-response curve with an EC(50) value of 24.24+/-1.42 micro M. In the presence of gamma-aminobutyric acid (GABA), the ATP dose-response curve becomes biphasic with EC(50) values of 3.69+/-0.44 nM and 59.65+/-8.32 micro M. Moreover, the maximal calcium response induced by ATP is 52.1% higher than the control. This effect is mimicked or blocked by the specific GABA(B) receptor agonist and antagonist, baclofen and saclofen, respectively. Presynaptic GABA(B) receptors, identified by immunocytochemistry are present in 62% of the total synaptosomal population. Adenylate cyclase and protein kinase A cascades are involved in the potentiatory effects mediated by baclofen and their activation or inhibition modifies calcium signalling and synaptosomal cAMP levels. The potentiatory action of baclofen was confirmed by microfluorimetry performed on single synaptic terminals. In its presence, 86% of the terminals responding to 100 micro M ATP, are also able to respond to nanomolar concentrations (100 nM) of this nucleotide. This potentiatory effect is reduced to 32% in the presence of pertussis toxin. Our data suggest that the activity of P2X receptors is modulated by GABA(B) receptors in midbrain synaptosomes.


Assuntos
Trifosfato de Adenosina/análogos & derivados , Baclofeno/análogos & derivados , Mesencéfalo/metabolismo , Receptores de GABA-B/metabolismo , Receptores Purinérgicos P2/metabolismo , Sinaptossomos/metabolismo , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Animais , Baclofeno/farmacologia , Cálcio/metabolismo , Colforsina/farmacologia , Proposta de Concorrência/métodos , AMP Cíclico/agonistas , AMP Cíclico/análogos & derivados , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fura-2/metabolismo , Agonistas GABAérgicos/farmacologia , Antagonistas GABAérgicos/farmacologia , Proteína Glial Fibrilar Ácida/metabolismo , Imuno-Histoquímica , Técnicas In Vitro , Mesencéfalo/efeitos dos fármacos , Muscimol/farmacologia , Proteínas do Tecido Nervoso/metabolismo , Picrotoxina/farmacologia , Ratos , Receptores de GABA-B/efeitos dos fármacos , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2X , Sinaptossomos/efeitos dos fármacos , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologia
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