Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 28
Filtrar
2.
PLoS One ; 9(6): e98658, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24892905

RESUMO

BACKGROUND: Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms. METHODS: Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods. RESULTS: CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3ß pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ. CONCLUSION: These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3ß pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.


Assuntos
Etanol/toxicidade , Quinase 3 da Glicogênio Sintase/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/metabolismo , Fatores de Transcrição/metabolismo , Acetilação/efeitos dos fármacos , Animais , Clormetiazol/uso terapêutico , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/tratamento farmacológico , Glicogênio Sintase Quinase 3 beta , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Transdução de Sinais/efeitos dos fármacos
3.
J Psychopharmacol ; 26(2): 205-12, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21742726

RESUMO

A number of compounds already in use as medications for various indications substitute for ethanol at clinically relevant brain pathways, in particular, at gamma-aminobutyric acid (GABA) receptors. Nevertheless, although substitute medications have been recognized for heroin and tobacco dependence, patients with alcohol dependence are rarely offered an analogous approach. Benzodiazepines may have paradoxical effects, and abuse and dependence are known. Baclofen (GABA(B) agonist) has not been associated with dependence or misuse and has been effective in several trials in preventing relapse, although research is required to establish the optimal dosing regimen. GABA-ergic anticonvulsants, helpful in treating withdrawal, have yet to emerge as effective in relapse prevention. Clomethiazole and sodium oxybate, the latter having been shown to be effective in relapse prevention, have incurred a reputation for dependence and abuse. However, data have emerged showing that the risk of abuse of sodium oxybate is lower than many clinicians had foreseen. For a condition where existing therapies are only effective in a proportion of patients, and which has high morbidity and mortality, the time now seems right for reappraising the use of substitute prescribing for alcohol dependence.


Assuntos
Alcoolismo/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Clormetiazol/efeitos adversos , Clormetiazol/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Agonistas dos Receptores de GABA-B/efeitos adversos , Agonistas dos Receptores de GABA-B/uso terapêutico , Redução do Dano , Humanos , Oxibato de Sódio/efeitos adversos , Oxibato de Sódio/uso terapêutico
4.
J Neural Transm (Vienna) ; 117(4): 513-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20191296

RESUMO

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been implicated in the pathogenesis of addictive behaviour and especially in alcohol craving. The pro-opiomelanocortin gene (POMC), encoding a 241 amino acids stretching polypeptide hormone precursor, plays an important role in the regulation of the HPA, and is prone to epigenetic regulation due to promoter-related DNA methylation. Aim of the present study therefore was to investigate possible differences in promoter-related DNA methylation in patients suffering from alcohol dependence compared to healthy controls. We analysed the DNA methylation of the 5' promoter of the POMC gene that is embedded in a CpG island using bisulfite sequencing in 145 alcohol-dependent patients and 37 healthy controls taken from the Franconian Alcoholism Research Studies. We found only marginal, hence significant differences at single CpG sites between patients and controls. We identified a cluster of CpGs showing a significant association with alcohol craving in the patients group. These results implicate that epigenetic changes possibly due to alcohol intake may contribute to craving via promoting HPA-axis dysfunction. Further studies should more closely investigate the impact of these changes on the several derivatives of the POMC gene.


Assuntos
Alcoolismo/genética , Alcoolismo/psicologia , Metilação de DNA , Processos Mentais , Pró-Opiomelanocortina/genética , Regiões Promotoras Genéticas , Adulto , Alcoolismo/tratamento farmacológico , Clormetiazol/uso terapêutico , Ilhas de CpG , Comportamento de Ingestão de Líquido , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Análise de Sequência de DNA , Adulto Jovem
5.
Pharmacopsychiatry ; 41(4): 134-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18651341

RESUMO

INTRODUCTION: Numerous investigations have shown that premature discharge against medical advice from alcohol detoxification treatment is associated with poor outcome. The aim of the present study was to assess the risk of different possible influencing factors. PATIENTS AND METHOD: 168 in-patients admitted for detoxification treatment were included in the study. All patients were detoxified using clome-thiazole and/or carbamazepine in individual, symptom-triggered dosages. Possible influencing factors were recorded using a standardised interview. RESULTS: Cox regression revealed a lower risk of premature discharge being significantly asso-ciated with few preceding withdrawals, intoxication at admission and treatment with clomethiazole. Kaplan-Meier survival statistics showed a significantly lower risk only for being treated with clomethiazole (premature discharge until day 7: chi2=25.07; p<0.001; premature discharge until day 14: chi2=5.19; p=0.023). Other included demographic factors like daily intake of ethanol before admission, duration of alcohol dependence, age or smoking status were not associated with the risk of premature discharge. DISCUSSION: The present findings show that pharmacotherapy with clomethiazole may positively influence the risk of premature discharge. This might be a consequence of the psychoactive properties of the drug which leads to positive reinforcement.


Assuntos
Alcoolismo/tratamento farmacológico , Clormetiazol/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Alta do Paciente/estatística & dados numéricos , Adulto , Alcoolismo/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Análise de Sobrevida
6.
Neuroscience ; 144(2): 547-61, 2007 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-17112678

RESUMO

Mitochondria play a central role in both the physiological and pathophysiological regulation of cell survival/death. Increasing evidence places mitochondrial dysfunction at the center of many neuropathological conditions. The present study investigates the extent of mitochondrial dysfunction in cortical, hippocampal and cerebellar tissues in a rat model of hypoxia-ischemia (HI). We hypothesized that; mitochondrial dysfunction in situ may be prevented by treatment with clomethiazole (CMZ), a GABA(A) receptor agonist. Assessment of mitochondrial FAD-linked respiration at both 1- and 3-day post-HI revealed a marked decrease in activity from ipsilateral cortical and hippocampal regions (P<0.001). In addition, small changes were seen in contralateral cortical and hippocampal tissues as well as in the cerebellum at 3-days (P<0.05). Assessment of the mitochondrial electron transport chain (complexes I-V), and mitochondrial markers of integrity (citrate synthase) and oxidative stress (aconitase) confirmed mitochondrial impairment in ipsilateral regions following HI. Complexes I, II-III, V and citrate synthase were also impaired in contralateral regions and cerebellum 3-days post-HI. Treatment with CMZ (414 mg/kg/day via minipumps) provided marked protection to all aspects of neuronal tissue assessed. Circulating cytokine (interleukin [IL]-1alpha, IL-1beta, tumor necrosis factor [TNF]-alpha, granulocyte macrophage colony-stimulating factor [GM-CSF], IL-4 and IL-10) levels were also assessed in these animals 3-days post-HI. Plasma IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels were significantly increased post-HI. Treatment with CMZ ameliorated the increases in IL-1alpha, IL-1beta, TNF-alpha and GM-CSF levels while increasing plasma IL-4 and IL-10 levels. This study provides evidence of the extent of mitochondrial damage following an HI-insult. In addition, we have shown that protection afforded by CMZ extends to preservation of mitochondrial function and integrity via anti-inflammatory mediated pathways.


Assuntos
Clormetiazol/uso terapêutico , Lateralidade Funcional/efeitos dos fármacos , Isquemia/tratamento farmacológico , Isquemia/patologia , Mitocôndrias , Fármacos Neuroprotetores/uso terapêutico , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Citocinas/metabolismo , Imunoensaio , Técnicas In Vitro , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitocôndrias/fisiologia , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Wistar , Fatores de Tempo
7.
J Extra Corpor Technol ; 39(4): 296-301, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18293824

RESUMO

Dozens of drugs have been studied in an attempt to mitigate the adverse cerebral consequences of cardiac surgery. The targets for these drugs have focused on pathways identified through the cascade of events that occurs once cerebral ischemia is initiated. In addition, inflammatory targets specific to cardiopulmonary bypass have also been addressed. Although no drugs are yet approved as specific neuroprotective agents, trials continue of increasingly unique targets, with fewer unwanted side effects and acting through novel mechanisms of action. This review summarizes the past, present, and future of pharmacologic neuroprotection for cardiac surgery.


Assuntos
Isquemia Encefálica/etiologia , Ponte Cardiopulmonar/efeitos adversos , Fármacos Neuroprotetores , Cirurgia Torácica , Aprotinina/uso terapêutico , Isquemia Encefálica/prevenção & controle , Clormetiazol/uso terapêutico , Humanos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
8.
Anesth Analg ; 97(1): 13-8, table of contents, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12818935

RESUMO

UNLABELLED: Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass. IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.


Assuntos
Moléculas de Adesão Celular/biossíntese , Clormetiazol/uso terapêutico , Circulação Extracorpórea/efeitos adversos , Interleucinas/sangue , Fármacos Neuroprotetores/uso terapêutico , Neutrófilos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Equilíbrio Ácido-Base , Gasometria , Antígenos CD18/sangue , Humanos , Interleucina-1/sangue , Interleucina-6/sangue , Interleucina-8/sangue , Selectina L/biossíntese , Neutrófilos/efeitos dos fármacos
9.
ILAR J ; 44(2): 153-60, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12652010

RESUMO

The Stroke Therapy Academic Industry Roundtable noted the need for standardized, well-accepted primate models of stroke to help develop both neuroprotective and restorative therapies. One primate model has been developed using the marmoset, a small New World species of monkey, in which long-term functional deficits can be assessed. The surgery and postoperative care of the animals is described, as well as the behavioral tests used to quantify the postoperative disability. The types of deficits seen are illustrated by reference to some of the findings with neuroprotective treatments. Nevertheless, the long-term nature and consistency of the motor deficits make this model ideal for assessing the worth of restorative therapies.


Assuntos
Callithrix/fisiologia , Cognição/fisiologia , Modelos Animais de Doenças , Atividade Motora/fisiologia , Fármacos Neuroprotetores/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Benzenossulfonatos , Callithrix/cirurgia , Clormetiazol/farmacologia , Clormetiazol/uso terapêutico , Cognição/efeitos dos fármacos , Feminino , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Óxidos de Nitrogênio/farmacologia , Óxidos de Nitrogênio/uso terapêutico , Desempenho Psicomotor/efeitos dos fármacos , Desempenho Psicomotor/fisiologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia
10.
Anesthesiology ; 97(3): 585-91, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12218524

RESUMO

BACKGROUND: The neuroprotective property of clomethiazole has been demonstrated in several animal models of global and focal brain ischemia. In this study the authors investigated the effect of clomethiazole on cerebral outcome in patients undergoing coronary artery bypass surgery. METHODS: Two hundred forty-five patients scheduled for coronary artery bypass surgery were recruited at two centers and prospectively randomized to clomethiazole edisilate (0.8%), 225 ml (1.8 mg) loading dose followed by a maintenance dose of 100 ml/h (0.8 mg/h) during surgery, or 0.9% NaCl (placebo) in a double-blind trial. Coronary artery grafting was completed during moderate hypothermic (28-32 degrees C) cardiopulmonary bypass. Plasma clomethiazole was measured at several intervals during and up to 24 h after the end of infusion. A battery of eight neuropsychological tests was administered preoperatively and repeated 4-7 weeks after surgery. Analysis of the change in neuropsychological test scores from baseline was used to determine the effect of treatment. RESULTS: Neuropsychological assessments were completed in 219 patients (110 clomethiazole; 109 placebo). The mean plasma concentration of clomethiazole during surgery was 66.2 microm. There was no difference between the clomethiazole and placebo group in the postoperative change in neuropsychological test scores. CONCLUSION: Clomethiazole did not improve cerebral outcome following coronary artery bypass surgery.


Assuntos
Clormetiazol/uso terapêutico , Ponte de Artéria Coronária , Fármacos Neuroprotetores/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/psicologia , Afeto/efeitos dos fármacos , Idoso , Clormetiazol/administração & dosagem , Clormetiazol/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Embolia e Trombose Intracraniana/prevenção & controle , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/sangue , Testes Neuropsicológicos , Estudos Prospectivos , Resultado do Tratamento
11.
Proc Soc Exp Biol Med ; 224(4): 302-8, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10964266

RESUMO

The purpose of this investigation was to assess the effect of chlormethiazole treatment on liver damage in the experimental rat intragastric ethanol-feeding model of alcoholic liver disease. Chlormethiazole has been used in the treatment of alcoholic withdrawal and has been shown to inhibit cytochrome P4502E1. Since treatment of experimental alcoholic liver disease with CYP2E1 inhibitors had an ameliorating effect on liver injury in the rat, chlormethiazole was used to see if it had a similar effect. Rats fed ethanol for 2 months had significantly less liver injury when chlormethiazole was added to the diet, fed intragastrically. The CYP2E1 apoprotein levels, which were increased by ethanol feeding, were also increased when chlormethiazole was fed with ethanol. Chlormethiazole inhibited the increase in the ethanol-induced CYP2E1 activity in vivo, as measured by chlorzoxazone 6-hydroxylation, but did not affect the level of CYP2E1 apoprotein. Likewise, the reduction in proteasome proteolytic enzyme activity produced by ethanol feeding was blunted in chlormethiazole-fed rats. These results support the conclusion that chlormethiazole treatment partially protects the liver from injury by inhibiting CYP2E1 activity in vivo.


Assuntos
Clormetiazol/uso terapêutico , Modelos Animais de Doenças , Etanol/antagonistas & inibidores , Hepatopatias Alcoólicas/tratamento farmacológico , Fígado/patologia , Animais , Apoenzimas/antagonistas & inibidores , Apoenzimas/metabolismo , Peso Corporal/efeitos dos fármacos , Clormetiazol/administração & dosagem , Clormetiazol/farmacologia , Clorzoxazona/análogos & derivados , Clorzoxazona/metabolismo , Quimotripsina/metabolismo , Cisteína Endopeptidases/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Inibidores do Citocromo P-450 CYP2E1 , Etanol/administração & dosagem , Etanol/farmacologia , Hidroxilação/efeitos dos fármacos , Imuno-Histoquímica , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Hepatopatias Alcoólicas/enzimologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Masculino , Complexos Multienzimáticos/metabolismo , Tamanho do Órgão/efeitos dos fármacos , Complexo de Endopeptidases do Proteassoma , Ratos , Ratos Wistar , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Tripsina/metabolismo
12.
Exp Neurol ; 156(1): 121-9, 1999 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10192783

RESUMO

Clomethiazole (CMZ) (Zendra) is neuroprotective in rodents following focal and global ischemia. However, its neuroprotective effects in other species, particularly on functional outcome, have not been reported. We have therefore examined the ability of CMZ to ameliorate the functional deficits produced by a focal cerebral ischemic lesion in the marmoset, a New World primate. Six monkeys received permanent middle cerebral artery occlusion (pMCAO); six further monkeys received pMCAO with administration of CMZ, 5 min after the arterial occlusion, by intraperitoneal bolus injection and by subcutaneous implantation of an osmotic minipump, which released CMZ for 24 h. The monkeys were trained and tested preoperatively on a number of behavioral tasks which were repeated 3 and 9 weeks after surgery. CMZ-treated monkeys were better than non-drug-treated monkeys at using the disabled arm contralateral to the lesion and also showed a reduction in contralateral spatial hemineglect. Postmortem histopathological analysis at several stereotaxic levels showed a significant reduction in the area of ischemic damage in CMZ-treated monkeys compared to that in untreated animals. CMZ treatment reduced the overall volume of damage by 31.8% (MCA group, 370.8 +/- 37.4 mm3 of damage; CMZ group, 253.0 +/- 38.0 mm3 of damage). This study demonstrates that CMZ is neuroprotective in a nonhuman primate species and is able to ameliorate the level of functional disability and reduce the size of infarct produced by focal cerebral ischemia.


Assuntos
Clormetiazol/uso terapêutico , Ataque Isquêmico Transitório/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Animais , Arteriopatias Oclusivas/complicações , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal , Encéfalo/patologia , Callithrix , Doenças Arteriais Cerebrais/complicações , Clormetiazol/administração & dosagem , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ataque Isquêmico Transitório/etiologia , Ataque Isquêmico Transitório/patologia , Ataque Isquêmico Transitório/fisiopatologia , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Rotação
13.
Exp Neurol ; 148(1): 110-23, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9398454

RESUMO

Systemically administered kainate (10 mg.kg-1) caused neuronal loss in both the hippocampus and the entorhinal regions of the rat brain. This resulted in a loss of 68.3 +/- 13.8 and 53.3 +/- 12.8% of pyramidal neurones in the hippocampal CA1 and CA3a regions, respectively. Chlormethiazole attenuated the loss of neurones in the hippocampal cell layers CA1 (cell loss 10 +/- 3.2%) and CA3a (cell loss 10 +/- 7.7%). The neuroprotective activity of chlormethiazole was apparent in the presence or absence of a low dose of clonazepam (200 micrograms.kg-1 i.p.). The kainate-induced damage could also be measured by the increase in binding of the peripheral benzodiazepine ligand ([3H]PK11195) in the hippocampus. In kainate-treated rats there was a 350-500% increase in binding indicative of reactive gliosis. Chlormethiazole prevented this elevation in a dose- and time-dependent manner, with an ED50 of 10.64 mg.kg-1 and an effective therapeutic window from 1 to 4 h posttreatment. Dizocilpine also attenuated damage significantly. The GABAA agonist muscimol was also able to attenuate the increase in [3H]PK11195 binding in a dose-dependent manner, with an ED50 of approximately 0.1 mg.kg-1. If muscimol, dizocilpine, or the adenosine A1 receptor agonist R-N6-phenylisopropyl-adenosine were administered together with chlormethiazole at their respective ED25 doses, a potentiation was apparent in the degree of neuroprotection. It is concluded that the combination of neuroprotective agents with different mechanisms of action can lead to a synergistic protection against excitotoxicity.


Assuntos
Adenosina/fisiologia , Clormetiazol/farmacologia , Maleato de Dizocilpina/farmacologia , Córtex Entorrinal/efeitos dos fármacos , Epilepsia Tônico-Clônica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Ácido Caínico/antagonistas & inibidores , Muscimol/farmacologia , Fármacos Neuroprotetores/farmacologia , Neurotoxinas/antagonistas & inibidores , Antagonistas de Receptores Purinérgicos P1 , Ácido gama-Aminobutírico/fisiologia , Animais , Temperatura Corporal , Clormetiazol/uso terapêutico , Maleato de Dizocilpina/uso terapêutico , Sinergismo Farmacológico , Quimioterapia Combinada , Córtex Entorrinal/patologia , Epilepsia Tônico-Clônica/induzido quimicamente , Epilepsia Tônico-Clônica/patologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Agonistas GABAérgicos/uso terapêutico , Gliose/induzido quimicamente , Gliose/patologia , Gliose/prevenção & controle , Hipocampo/patologia , Isoquinolinas/metabolismo , Ácido Caínico/farmacologia , Masculino , Muscimol/uso terapêutico , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/farmacologia , Ratos , Ratos Wistar , Xantinas/farmacologia
14.
Br J Anaesth ; 75(6): 734-9, 1995 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8672322

RESUMO

Prophylaxis of alcohol withdrawal syndrome (AWS) in alcohol-dependent patients shortens the duration of stay in the intensive care unit (ICU). The objective of this study was to assess the effect of four different prophylactic regimens on the duration of ICU stay, prevention of AWS and rate of major intercurrent complications in alcohol-dependent patients admitted to the ICU after tumour resection. A total of 197 alcohol-dependent patients, diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (third revised edition) with a daily ethanol intake of 60 g, were allocated randomly to one of the following regimens which were commenced on admission to the ICU: flunitrazepam-clonidine, chlormethiazole-haloperidol, flunitrazepam-haloperidol or ethanol. The duration of ICU stay, prevention of AWS, incidence of tracheobronchitis and major intercurrent complications such as pneumonia, sepsis, cardiac disorders, bleeding disorders and death were documented. On admission, patients did not differ significantly in age, APACHE II and multiple organ failure scores. ICU stay, incidence of AWS, severity of AWS (revised clinical institute withdrawal assessment for alcohol scale > 20) and major intercurrent complication rate did not differ significantly between groups. Although there was no advantage in any of the four regimens with respect to the primary outcome measures, pulmonary and cardiac patients were not included in the study. Patients in the chlormethiazole-haloperidol group had a significantly increased incidence of tracheobronchitis (P = 0.0023), probably because of an increased incidence of hypersecretion.


Assuntos
Cuidados Críticos/métodos , Neoplasias do Sistema Digestório/cirurgia , Etanol/efeitos adversos , Cuidados Pós-Operatórios/métodos , Síndrome de Abstinência a Substâncias/prevenção & controle , Agonistas alfa-Adrenérgicos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Clormetiazol/uso terapêutico , Clonidina/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Combinação de Medicamentos , Etanol/uso terapêutico , Feminino , Flunitrazepam/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Haloperidol/uso terapêutico , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos
15.
J Int Med Res ; 22(1): 55-62, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-8187945

RESUMO

Two instances of successful treatment of the rare ocular dyskinesia, opsoclonus, with chlormethiazole are reported. A 65-year-old woman had the opsoclonus-myoclonus syndrome associated with carcinoma of the breast; her myoclonia and opsoclonus did not respond to intravenous diazepam or phenytoin. Treatment with intravenous chlormethiazole resulted in rapid control of her myoclonic attacks, followed by slower but complete resolution of the opsoclonus. Following control of the acute symptoms the patient was transferred to an oral chlormethiazole maintenance dose which was further reduced and subsequently discontinued after 5 months, when the patient's overall clinical status had improved. A 53-year-old man with opsoclonia, myoclonia, ataxia and encephalopathy, not associated with neoplasia, was given immunosuppressor drugs to establish basal control, and oral chlormethiazole for symptomatic treatment. Almost immediately after the initial dose of chlormethiazole the patient became more orientated; he was sedated and the agitation and myoclonic fits were brought under control quite quickly. The opsoclonus responded progressively and was completely resolved after a few days. The initial oral dose of chlormethiazole was gradually reduced and was discontinued after 5-6 months. Chlormethiazole was well tolerated; it may have an important role in the management of the rare opsoclonus-myoclonus syndrome.


Assuntos
Clormetiazol/uso terapêutico , Mioclonia/tratamento farmacológico , Transtornos da Motilidade Ocular/tratamento farmacológico , Idoso , Neoplasias da Mama/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos dos Movimentos/tratamento farmacológico , Síndrome
19.
Acta Psychiatr Scand Suppl ; 329: 189-93, 1986.
Artigo em Inglês | MEDLINE | ID: mdl-3092588

RESUMO

Epilepsy is an important problem in the period immediately following intracranial surgery. Rapid control of seizures is important to prevent damage to cerebral neuronal function. A method of managing epilepsy using intravenous chlormethiazole is reported. This regimen has proved to be safe and rapidly effective in the control of post-operative seizures.


Assuntos
Clormetiazol/uso terapêutico , Craniotomia , Epilepsias Parciais/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Encefalopatias/cirurgia , Esquema de Medicação , Humanos , Infusões Parenterais
20.
Psychopharmacology (Berl) ; 86(1-2): 142-6, 1985.
Artigo em Inglês | MEDLINE | ID: mdl-2862656

RESUMO

Dopamine (DA) sensitivity, assessed through maximal growth hormone (GH) response to stimulation by apomorphine (APO) (0.18-0.24 mg iv) was studied in 16 chronic alcoholics newly admitted after a period of heavy alcohol intake. Repeated hormonal tests were thereafter performed during a 2-month period under strictly controlled conditions to avoid relapse into alcohol consumption. Eight healthy volunteers with alcohol consumption slightly less than that of the general population were used as controls. It was found that DA sensitivity in the early abstinence phase was higher than later in the 2-month recovery period but not significantly different from control values. The relatively higher DA sensitivity in the early abstinence phase might be responsible for a lower threshold for psychotic symptoms and neuroleptic-induced extrapyramidal side effects. The results of this study give further evidence of a prolonged recovery phase after heavy alcohol intake.


Assuntos
Alcoolismo/fisiopatologia , Hormônio do Crescimento/metabolismo , Adeno-Hipófise/fisiopatologia , Receptores Dopaminérgicos/fisiologia , Adulto , Alcoolismo/tratamento farmacológico , Ansiolíticos/uso terapêutico , Anticonvulsivantes/uso terapêutico , Apomorfina , Benzodiazepinas , Clormetiazol/análogos & derivados , Clormetiazol/uso terapêutico , Etanol/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/fisiopatologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA