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2.
Basic Clin Pharmacol Toxicol ; 126(2): 153-165, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31468699

RESUMO

Increased expression of CYP2E1 may represent the main factor contributing to oxidative stress-mediated liver damage in drug-induced liver injury (DILI). However, the regulation mechanism of CYP2E1 expression is poorly described. The present study was aimed to investigate the role of CYP2E1 in acetaminophen (APAP)- or tripterygium glycosides (TG)-induced hepatotoxicity as well as the regulation of CYP2E1 and miR-378a-3p expression by APAP or TG. Rats were randomly divided and treated with APAP, TG, chlormethiazole (CMZ), APAP + CMZ and TG + CMZ, respectively, for 4 weeks. Then, blood and liver samples were collected. Serum and hepatic biochemical parameters were measured using commercial kits. Liver histopathology was tested by H&E staining. Expression levels of CYP2E1 mRNA and miR-378a-3p were detected by qRT-PCR. CYP2E1 protein expression was determined by Western blot. Our results showed that CMZ effectively restored the hepatic histopathological changes, oxidative stress biomarkers and TNF-α levels induced by APAP or TG. CYP2E1 mRNA and/or protein expression levels were dramatically increased after chronic APAP or TG treatment, while this induction was significantly reversed by CMZ co-treatment. Of note, miR-378a-3p expression levels were significantly suppressed after APAP, TG and/or CMZ treatment. These results suggested that CYP2E1 were highly induced after chronic APAP or TG treatment, which in turn play an important role in APAP- or TG-induced hepatotoxicity. These inductions of CYP2E1 expression were probably carried out by inhibition of miR-378a-3p. Our findings might provide a new molecular basis for DILI.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Glicosídeos/toxicidade , Tripterygium/química , Animais , Doença Hepática Induzida por Substâncias e Drogas/genética , Clormetiazol/farmacologia , Citocromo P-450 CYP2E1/genética , Regulação Enzimológica da Expressão Gênica , Glicosídeos/isolamento & purificação , Masculino , MicroRNAs/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
3.
Biochem Biophys Res Commun ; 518(3): 513-518, 2019 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-31439375

RESUMO

Thiamin pyrophosphate (TPP) is an essential co-factor in amino acid and carbohydrate metabolic pathways. The TPP-related vitamin B1 biosynthetic pathway is found in most bacterial, plant and lower eukaryotic processes; however, it is not present in humans. In bacterial thiamin synthesis and salvage pathways, the 5-(hydroxyethyl)-methylthiazole kinase (ThiM) is essential in the pathway forming TPP. Thus, ThiM is considered to be an attractive antibacterial drug target. Here, we determined the crystal structures of ThiM from pathogenic Klebsiella pneumoniae (KpThiM) and KpThiM in complex with its substrate 5-(hydroxyethyl)-4-methylthiazole (TZE). KpThiM, consisting of an α-ß-α domain, shows a pseudosymmetric trimeric formation. TZE molecules are located in the interface between the KpThiM subunits in the trimer and interact with Met49 and Cys200. Superimposition of the apo and TZE-complexed structures of KpThiM show that the side chains of the amino acids interacting with TZE and Mg2+ have a rigid configuration. Comparison of the ThiM structures shows that KpThiM could, in terms of sequence and configuration, be different from other ThiM proteins, which possess different amino acids that recognize TZE and Mg2+. The structures will provide new insight into the ThiM subfamily proteins for antibacterial drug development.


Assuntos
Proteínas de Bactérias/metabolismo , Clormetiazol/análogos & derivados , Klebsiella pneumoniae/metabolismo , Proteínas Quinases/metabolismo , Tiamina/metabolismo , Sequência de Aminoácidos , Proteínas de Bactérias/química , Vias Biossintéticas , Clormetiazol/química , Clormetiazol/metabolismo , Cristalografia por Raios X , Humanos , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/química , Modelos Moleculares , Conformação Proteica , Proteínas Quinases/química , Multimerização Proteica , Especificidade por Substrato
4.
Drug Chem Toxicol ; 42(6): 600-607, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29648470

RESUMO

The effect of chlormethiazole (CMZ) at single and multiple doses on the toxicokinetics of diethylnitrosamine (DEN) was investigated in normal rats and those with DEN-induced liver fibrosis. Twelve rats were treated with DEN (50 mg/kg) alone and in combination with a single dose of CMZ (10, 50, or 100 mg/kg) by intraperitoneal (i.p.) injection. In a multiple dose test, six rats were treated with CMZ (50 mg/kg) for 7 d with addition of DEN (50 mg/kg) on days 1 and 7. Lastly, 12 rats were treated with DEN (50 mg/kg) by i.p. injection twice a week for 4 consecutive weeks, followed by weekly injections for another 8 weeks to build the model of liver fibrosis. Following this induction, the 12 rats were given CMZ (50 mg/kg) combined with DEN (50 mg/kg) to study the inhibitory effect of CMZ on DEN metabolism in hepatofibrotic rats. Serial blood samples were also collected and analyzed by a validated high-performance liquid chromatography (HPLC) method. A single-dose CMZ treatment decreased DEN clearance (CL), prolonged the t1/2, and increased the 'area under the curve' (AUC) for DEN in normal and hepatofibrotic rats relative to rats that did not receive CMZ. Treatment with CMZ for 7 d further prolonged the t1/2 for DEN but did not alter the CL and AUC relative to a single CMZ treatment. These results suggest that CMZ significantly inhibits the metabolism of DEN in normal and hepatofibrotic rats.


Assuntos
Clormetiazol/farmacologia , Dietilnitrosamina/farmacocinética , Cirrose Hepática/induzido quimicamente , Animais , Área Sob a Curva , Clormetiazol/administração & dosagem , Cromatografia Líquida de Alta Pressão , Dietilnitrosamina/toxicidade , Relação Dose-Resposta a Droga , Meia-Vida , Cirrose Hepática/patologia , Masculino , Ratos , Ratos Sprague-Dawley
5.
Intern Emerg Med ; 14(1): 143-160, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30187438

RESUMO

The chronic use of alcohol can lead to the onset of an alcohol use disorder (AUD). About 50% of subjects with an AUD may develop alcohol withdrawal syndrome (AWS) when they reduce or discontinue their alcohol consumption and, in 3-5% of them, convulsions and delirium tremens (DTs), representing life-threatening complications, may occur. Unfortunately, few physicians are adequately trained in identifying and treating AWS. The Italian Society on Alcohol has, therefore, implemented a task force of specialists to draw up recommendations for the treatment of AWS with the following main results: (1) while mild AWS may not require treatment, moderate and severe AWS need to be pharmacologically treated; (2) out-patient treatment is appropriate in patients with mild or moderate AWS, while patients with severe AWS need to be treated as in-patients; (3) benzodiazepines, BDZs are the "gold standard" for the treatment of AWS and DTs; (4) alpha-2-agonists, beta-blockers, and neuroleptics may be used in association when BDZs do not completely resolve specific persisting symptoms of AWS; (5) in the case of a refractory form of DTs, the use of anaesthetic drugs (propofol and phenobarbital) in an intensive care unit is appropriate; (6) alternatively to BDZs, sodium oxybate, clomethiazole, and tiapride approved in some European Countries for the treatment of AWS may be employed for the treatment of moderate AWS; (7) anti-convulsants are not sufficient to suppress AWS, and they may be used only in association with BDZs for the treatment of refractory forms of convulsions in the course of AWS.


Assuntos
Intoxicação Alcoólica/diagnóstico , Intoxicação Alcoólica/tratamento farmacológico , Benzodiazepinas/uso terapêutico , Síndrome de Abstinência a Substâncias/diagnóstico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Anticonvulsivantes/uso terapêutico , Clormetiazol/uso terapêutico , Humanos , Fenobarbital/uso terapêutico , Propofol/uso terapêutico , Oxibato de Sódio/uso terapêutico , Cloridrato de Tiaprida/uso terapêutico
6.
Rev Med Suisse ; 14(626): 2018-2023, 2018 Nov 07.
Artigo em Francês | MEDLINE | ID: mdl-30422422

RESUMO

Sleep disorders are a recurrent complaint in geriatrics. Of multifactorial origin, they have a significant impact on health and quality of life. However, the answer is (too) often the prescription of benzodiazepines or related-drugs (Z-pills), sedative antidepressant, or another psychotropic medication. More recently, melatonin, valerian and, in Switzerland, clomethiazol are widely considered as effective and more suitable alternatives for aged people. We present a systematic review of the literature on the efficacy and tolerance of these molecules, of which the main objective is to demonstrate that non-pharmacological approach must remain the first-line therapy of insomnia in geriatrics.


Assuntos
Hipnóticos e Sedativos , Melatonina , Distúrbios do Início e da Manutenção do Sono , Valeriana , Benzodiazepinas/uso terapêutico , Clormetiazol/uso terapêutico , Humanos , Hipnóticos e Sedativos/uso terapêutico , Melatonina/uso terapêutico , Qualidade de Vida , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Suíça
7.
Cochrane Database Syst Rev ; 10: CD009622, 2018 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-30376593

RESUMO

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane Review first published in 2013, and previously updated in 2014 and 2016. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (accessed May 2018), the Cochrane Central Register of Controlled Trials (CENTRAL) 2018, Issue 4 (accessed May 2018), MEDLINE (from 1949 to May 2018), Embase (from 1980 to May 2018), CINAHL (from 1982 to May 2018), AMED (from 1985 to May 2018), and 11 Chinese databases (accessed May 2018). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trial registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: We included five trials with 3838 participants (acute ischemic or hemorrhagic stroke patients, 3758 analyzed). Most of the participants recruited had acute ischaemic stroke, with limited data available from participants with other stroke subtypes, including total anterior circulation syndrome (TACS). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. For death and dependency at three months, pooled results did not find a significant difference for chlormethiazole versus placebo (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11; four trials; 2909 participants; moderate-quality evidence) and for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07; one trial; 849 participants; moderate-quality evidence). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; 2527 participants; moderate-quality evidence) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; 2527 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.


Assuntos
Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Agonistas GABAérgicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Doença Aguda , Clormetiazol/efeitos adversos , Diazepam/efeitos adversos , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Agonistas GABAérgicos/efeitos adversos , Humanos , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinite/induzido quimicamente , Acidente Vascular Cerebral/mortalidade
8.
CNS Neurosci Ther ; 24(12): 1231-1240, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30039924

RESUMO

AIMS: 2-(4-methyl-thiazol-5-yl) ethyl nitrate maleate (NMZM), a derivative of clomethiazole (CMZ), had been investigated for the treatment of Alzheimer's disease (AD). The beneficial effects of NMZM in AD included reversing cognitive deficit, improving learning and memory as well as neuroprotection. The pharmacological effects of NMZM on GABAA receptors were reported previously; however, the mechanisms were unclear and were explored therefore. RESULTS: In this study, we demonstrated that NMZM improved learning and memory by alleviating scopolamine-induced long-term potentiation (LTP) suppression in the dentate gyrus of rats, indicating that NMZM had protective effects against scopolamine-induced depression of LTP. Next, we investigated the action of NMZM on GABAA receptors in hippocampal neurons and the binding site of NMZM on GABAA receptors. NMZM directly activated GABAA receptors in hippocampal neurons in a weak manner. However, NMZM could potentiate the response of GABAA receptors to GABA and NMZM positively modulated GABAA receptors with an EC50 value of 465 µmol/L at 3 µmol/L GABA while this potentiation at low concentration of GABA (1, 3 µmol/L) was more significant than that at high concentration (10, 30 µmol/L). In addition, NMZM could enhance GABA currents after using diazepam and pentobarbital, the positive modulators of GABAA receptors. NMZM could not affect the etomidate-potentiated GABAA current. It suggested that the binding site of NMZM on GABAA receptors is the same as etomidate. CONCLUSIONS: These results provided support for the neuroprotective effect of NMZM, which was partly dependent on the potentiation of GABAA receptors. The etomidate binding site might be a new target for neuronal protection and for drug development.


Assuntos
Clormetiazol/farmacologia , Moduladores GABAérgicos/farmacologia , Hipocampo/citologia , Neurônios/efeitos dos fármacos , Receptores de GABA/metabolismo , Regulação Alostérica , Animais , Animais Recém-Nascidos , Bicuculina/farmacologia , Células Cultivadas , Clormetiazol/química , Antagonistas Colinérgicos/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Flumazenil/farmacologia , Moduladores GABAérgicos/química , Antagonistas de Receptores de GABA-A/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Escopolamina/farmacologia , Fatores de Tempo , Ácido gama-Aminobutírico/farmacologia
9.
Psychiatr Prax ; 45(2): 95-102, 2018 03.
Artigo em Alemão | MEDLINE | ID: mdl-28371954

RESUMO

Whilst internationally benzodiazepines are first choice for treatment of alcohol withdrawal syndrome, Germany has a long tradition with clomethiazole. This study explores effectiveness of clomethiazole versus oxazepam in the treatment of alcohol withdrawal syndrome within an observational, stratified, non-inferiority study in routine care. Main outcome criterion was severity of the alcohol withdrawal syndrome (Alcohol Withdrawal Syndrome [AWS]) Scale in the first five days. Additionally, the association between the detoxification protocol (five vs. ten days) and AWS-Score was examined. 453 patients (74.2 % male, average age 47.1 years [±â€Š9.2]) took part; 249 received oxazepam (55.0 %) and 204 clomethiazole (45.0 %). The average duration of inpatient treatment was 14.0 days (±â€Š6.3) in both groups. The average AWS-score was lower in the oxazepam group compared to the clomethiazole group (50.0 [±â€Š26.5] vs. 56.2 [±â€Š31.5]; p < .05; effect size d = - .25). Patients with a shorter detoxification protocol had a lower AWS sum score compared to patients with a longer protocol (p < .001; d = - .46). In treatment of alcohol withdrawal syndrome in routine care oxazepam yields at least comparable results to clomethiazole.


Assuntos
Alcoolismo , Clormetiazol/uso terapêutico , Oxazepam/uso terapêutico , Síndrome de Abstinência a Substâncias , Alcoolismo/tratamento farmacológico , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/tratamento farmacológico
10.
Eur Addict Res ; 23(4): 211-218, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898879

RESUMO

BACKGROUND: The objective of this retrospective study was to compare the effectivity and tolerability of diazepam and clomethiazole in the treatment of alcohol withdrawal syndrome (AWS) in a large clinical sample. METHODS: The data of 566 patients admitted to an intensive care psychiatric unit in Germany (2010-2014) were evaluated. The course of withdrawal was analyzed on a matched sample (n = 152) consisting of a diazepam group (n = 76) and a clomethiazole group (n = 76). Medical assessment was based on a standardized point-based symptom rating scale called AESB (Alkoholentzugssymptom-Bogen), a German modified version of the Revised Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar). RESULTS: Although the mean daily symptom reduction did not differ significantly, patients treated with clomethiazole were treated significantly shorter and needed less concomitant antipsychotic medication. Numbers of complications and adverse events did not show significant differences. CONCLUSION: Both clomethiazole and diazepam were effective and equally safe in the treatment of AWS. Clomethiazole provided a faster withdrawal and required less concomitant antipsychotic medication and therefore might be the more favorable option for patients and physicians. Taken into account the methodological limitations of the study (retrospective design, secondary matching, missing randomization, use of clomethiazole as drug of first choice), further studies are needed to confirm this result.


Assuntos
Alcoolismo/tratamento farmacológico , Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Síndrome de Abstinência a Substâncias/terapia , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
11.
Cochrane Database Syst Rev ; 10: CD009622, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-27701753

RESUMO

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebrovascular disease. However, the sedative effects of GABA receptor agonists have limited their wider application in people with acute stroke, due to the potential risk of stupor. This is an update of a Cochrane review first published in 2013, and previously updated in 2014. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (accessed March 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 3, part of the Cochrane Library (accessed March 2016), MEDLINE (from 1949 to March 2016), Embase (from 1980 to March 2016), CINAHL (from 1982 to March 2016), AMED (from 1985 to March 2016), and 11 Chinese databases (accessed March 2016). In an effort to identify further published, unpublished, and ongoing trials we searched ongoing trials registers, reference lists, and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for people with acute stroke (within 12 hours after stroke onset), with the primary outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy, and assessed the risk of bias. MAIN RESULTS: We included five trials with 3838 participants (3758 analyzed). The methodological quality of the included trials was generally good, with an unclear risk for selection bias only. Four trials (N = 2909) measured death and dependency at three months for chlormethiazole versus placebo; pooled results did not find a significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.96 to 1.11). One trial (N = 849) measured this outcome for diazepam versus placebo (RR 0.94, 95% CI 0.82 to 1.07). The most frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95; two trials; N = 2527) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46; two trials; N = 2527). AUTHORS' CONCLUSIONS: This review provides moderate-quality evidence that fails to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of people with acute stroke. More well-designed RCTs with large samples of participants with total anterior circulation syndrome are required to determine if there are benefits for this subgroup. Somnolence and rhinitis are frequent adverse events related to chlormethiazole.


Assuntos
Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Agonistas GABAérgicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Doença Aguda , Clormetiazol/efeitos adversos , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Agonistas GABAérgicos/efeitos adversos , Humanos , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinite/induzido quimicamente , Acidente Vascular Cerebral/mortalidade
12.
Dtsch Med Wochenschr ; 141(15): 1113-4, 2016 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-27464286

RESUMO

Most of the patients addicted to alcohol are socially well integrated. The offer of a low threshold ambulant withdrawal therapy opens an opportunity to build a sustainable therapeutic relationship. The so started empathic addiction therapy will be well accepted and will lead to a satisfying outcome. Using Clomethiazole or Oxazepam in a daily reduced dose and with daily personal contacts, the ambulant withdrawal in patients without seizures or delir in medical history is a secure and successful therapeutic option.


Assuntos
Delirium por Abstinência Alcoólica/terapia , Alcoolismo/terapia , Assistência Ambulatorial/métodos , Relações Médico-Paciente , Síndrome de Abstinência a Substâncias/terapia , Delirium por Abstinência Alcoólica/psicologia , Alcoolismo/psicologia , Assistência Ambulatorial/psicologia , Anticonvulsivantes/uso terapêutico , Clormetiazol , Terapia Combinada/métodos , Aconselhamento Diretivo/métodos , Empatia , Humanos , Oxazepam , Cooperação do Paciente/psicologia , Síndrome de Abstinência a Substâncias/psicologia
13.
Drug Metab Dispos ; 44(8): 1424-30, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27149898

RESUMO

The sedative clomethiazole (CMZ) has been used in Europe since the mid-1960s to treat insomnia and alcoholism. It has been previously demonstrated in clinical studies to reversibly inhibit human CYP2E1 in vitro and decrease CYP2E1-mediated elimination of chlorzoxazone. We have investigated the selectivity of CMZ inhibition of CYP2E1 in pooled human liver microsomes (HLMs). In a reversible inhibition assay of the major drug-metabolizing cytochrome P450 (P450) isoforms, CYP2A6 and CYP2E1 exhibited IC50 values of 24 µM and 42 µM, respectively with all other isoforms exhibiting values >300 µM. When CMZ was preincubated with NADPH and liver microsomal protein for 30 minutes before being combined with probe substrates, however, more potent inhibition was observed for CYP2E1 and CYP2B6 but not CYP2A6 or other P450 isoforms. The substantial increase in potency of CYP2E1 inhibition upon preincubation enables the use of CMZ to investigate the role of human CYP2E1 in xenobiotic metabolism and provides advantages over other chemical inhibitors of CYP2E1. The KI and kinact values obtained with HLM-catalyzed 6-hydroxylation of chlorzoxazone were 40 µM and 0.35 minute(-1), respectively, and similar to values obtained with recombinant CYP2E1 (41 µM, 0.32 minute(-1)). The KI and kinact values, along with other parameters, were used in a mechanistic static model to explain earlier observations of a profound decrease in the rate of chlorzoxazone elimination in volunteers despite the absence of detectable CMZ in blood.


Assuntos
Clormetiazol/farmacologia , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Citocromo P-450 CYP2E1/metabolismo , Hipnóticos e Sedativos/farmacologia , Fígado/efeitos dos fármacos , NADP/metabolismo , Biotransformação , Clormetiazol/toxicidade , Clorzoxazona/metabolismo , Inibidores do Citocromo P-450 CYP2E1/toxicidade , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Hidroxilação , Hipnóticos e Sedativos/toxicidade , Cinética , Fígado/enzimologia , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Medição de Risco , Especificidade por Substrato
14.
Pharmacopsychiatry ; 49(5): 199-203, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27101233

RESUMO

Introduction: Despite the fact, that symptom-triggered alcohol withdrawal treatment is recommended by German guidelines on alcoholism, many hospitals continue to use fixed-schedule protocols, as they have been successfully applied for many years. Methods: This retrospective study compared all patients' records of alcohol withdrawal treatment from October 2010 to November 2011 at Magdeburg's University Department of Psychiatry (n=120). A symptom-triggered protocol with clomethiazole (AESB, n=46) was used in parallel with the existing fixed-schedule protocol with diazepam (n=74). Results: The symptom-triggered group showed less need of pharmacological treatment duration (p<0.001) and cumulative dosage of medication compared to the fixed-schedule protocol (p<0.006). No difference was observed regarding the need of clonidine or haloperidol (to treat blood pressure derailment or delirium) and the incidence of epileptic seizures. Discussion: Based on the shorter treatment duration and a similar rate of complications our department has switched to the symptom-triggered protocol to improve the quality of patient care.


Assuntos
Transtornos Induzidos por Álcool/tratamento farmacológico , Transtornos Induzidos por Álcool/prevenção & controle , Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Moduladores GABAérgicos/uso terapêutico , Adulto , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Estudos Retrospectivos
15.
Fortschr Neurol Psychiatr ; 84(2): 83-7, 2016 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-26953547

RESUMO

INTRODUCTION: For alcohol withdrawal during hospitalization, often a medication as means for withdrawal needs to be chosen. Modern, score-controlled processes that can be used by the nursing staff after instruction by physicians are frequently not used and even unknown in hospitals. One reason for this is that some of the scores require checking several criteria and are therefore more time-consuming and complicated than use of a fixed-dosage strategy. The SAB-P and HAES are short with only 6 items that can be checked by the nursing staff. METHODS: Safety of the Hamburg Alcohol Withdrawal Scale (Hamburger Alkoholentzugs-Skala (HAES)) was analyzed retrospectively and prospectively with regard to score-controlled alcohol-withdrawal treatment after rating by the nurse staff (Scoregesteuerte Alkoholentzugsbehandlung nach Rating durch das Pflegepersonal (SAB-P)). RESULTS: Incidence of complications in patients treated with SAB-P and HAES was nearly similar with 1% start of delirium and 3% seizures (SAB-P) and 0.5 to 1.5% start of delirium and 0 to 0.5% seizures in the HAES group. With both scales it was possible to start medical treatment while still under falling alcohol levels (0.93 and 0.91%, respectively). Medication dosage was initially higher using the HAES, so that the time needed to monitor withdrawal symptoms could be reduced (3.8 vs. 3.1 days). DISCUSSION: Using a score-controlled strategy for alcohol withdrawal leads to a lower complication rate than found in literature. The structured procedure was helpful for the nursing staff as well as for the physicians. SAB-P as well as HAES made withdrawal for the patients more comfortable and led to fewer complaints. Because of rapid reaction and faster symptom reduction of HAES, there was less time necessary for monitoring. Simple handling, clomethiazol, oxazepam or diazepam as applicable medication and clear documentation are the advantages of HAES.


Assuntos
Alcoolismo/terapia , Síndrome de Abstinência a Substâncias/terapia , Adulto , Idoso , Delirium por Abstinência Alcoólica/epidemiologia , Delirium por Abstinência Alcoólica/terapia , Alcoolismo/psicologia , Depressores do Sistema Nervoso Central/sangue , Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Etanol/sangue , Feminino , Humanos , Hipnóticos e Sedativos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Convulsões/epidemiologia , Convulsões/etiologia , Convulsões/terapia , Síndrome de Abstinência a Substâncias/complicações , Síndrome de Abstinência a Substâncias/psicologia , Adulto Jovem
16.
Epileptic Disord ; 18(1): 87-91, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26842397

RESUMO

We report a retrospective case study of the use of clomethiazole for treatment of non-convulsive status epilepticus in a patient not responding to benzodiazepines, illustrated by EEG and video. Clomethiazole can be considered as a safe oral option for management of non-convulsive status epilepticus when conventional treatment has failed. [Published with video sequences online].


Assuntos
Benzodiazepinas/uso terapêutico , Encéfalo/fisiopatologia , Clormetiazol/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Adolescente , Clormetiazol/administração & dosagem , Eletroencefalografia/métodos , Humanos , Masculino , Estudos Retrospectivos , Estado Epiléptico/diagnóstico , Estado Epiléptico/fisiopatologia , Resultado do Tratamento
17.
Drug Alcohol Depend ; 159: 142-51, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26790823

RESUMO

BACKGROUND: Previous research indicated the complexity of autonomic dysfunction during acute alcohol withdrawal. This study aimed to investigate the pupillary light reflex as an indicator of midbrain and brainstem regulatory systems in relation to cardiovascular autonomic function. METHODS: Thirty male patients were included in the study. They were investigated during acute alcohol withdrawal syndrome and 24h later during clomethiazole treatment and compared to healthy controls. Parameters of pupillary light reflex of both eyes as well as heart rate variability, blood pressure variability and baroreflex sensitivity (BRS) were studied. RESULTS: We observed significantly reduced sympathetic (small diameter, e.g., left eye: 5.00 in patients vs. 5.91 mm in controls) and vagal modulation (e.g., prolonged latencies, left eye: 0.28 vs. 0.26 ms) regarding both pupils during acute alcohol withdrawal syndrome. Cardiovascular parameters showed reduced vagal modulation (e.g., b-slope of BRS: 7. 57 vs. 13.59 ms/mm Hg) and mixed results for sympathetic influence. After 24h, autonomic dysfunction improved significantly, both for the pupils (e.g., left diameter: 5.38 mm) and the heart (e.g., b-slope of BRS: 9.34 ms/mm Hg). While parameters obtained from the pupil correlated with cardiac autonomic function (e.g, BRS and left diameter: r=0.564) in healthy controls, no such pattern was observed in patients. CONCLUSION: Results obtained from the pupil during acute alcohol withdrawal do not simply mirror autonomic dysfunction regarding the heart. Pupillary and cardiovascular changes after 24h indicate state dependencies of the results. The findings are discussed with respect to autonomic mechanisms and potentially involved brain regions.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Reflexo Pupilar/fisiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Adulto , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/fisiologia , Pressão Sanguínea/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Clormetiazol/uso terapêutico , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome de Abstinência a Substâncias/tratamento farmacológico
18.
BMC Neurosci ; 16: 67, 2015 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-26480871

RESUMO

BACKGROUND: Synaptic dysfunction is a key event in pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD) where synapse loss pathologically correlates with cognitive decline and dementia. Although evidence suggests that aberrant protein production and aggregation are the causative factors in familial subsets of such diseases, drugs singularly targeting these hallmark proteins, such as amyloid-ß, have failed in late stage clinical trials. Therefore, to provide a successful disease-modifying compound and address synaptic dysfunction and memory loss in AD and mixed pathology dementia, we repurposed a clinically proven drug, CMZ, with neuroprotective and anti-inflammatory properties via addition of nitric oxide (NO) and cGMP signaling property. RESULTS: The novel compound, NMZ, was shown to retain the GABAA potentiating actions of CMZ in vitro and sedative activity in vivo. Importantly, NMZ restored LTP in hippocampal slices from AD transgenic mice, whereas CMZ was without effect. NMZ reversed amnestic blockade of acetylcholine receptors by scopolamine as well as NMDA receptor blockade by a benzodiazepine and a NO synthase inhibitor in the step-through passive avoidance (STPA) test of learning and working memory. A PK/PD relationship was developed based on STPA analysis coupled with pharmacokinetic measures of drug levels in the brain: at 1 nM concentration in brain and plasma, NMZ was able to restore memory consolidation in mice. CONCLUSION: Our findings show that NMZ embodies a promising pharmacological approach targeting synaptic dysfunction and opens new avenues for neuroprotective intervention strategies in mixed pathology AD, neurodegeneration, and dementia.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Clormetiazol/análogos & derivados , Reposicionamento de Medicamentos/métodos , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Animais , Proteína de Ligação a CREB/metabolismo , GMP Cíclico/metabolismo , Modelos Animais de Doenças , Agonistas de Receptores de GABA-A/farmacocinética , Masculino , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacocinética , Óxido Nítrico/metabolismo , Nootrópicos/farmacocinética , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/patologia , Xenopus laevis
19.
Cochrane Database Syst Rev ; (8): CD009622, 2014 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-25097101

RESUMO

BACKGROUND: Gamma aminobutyric acid (GABA) receptor agonists have been shown to have a neuroprotectant effect in reducing infarct size and improving functional outcome in animal models of cerebral ischemia. However, the sedation effects of GABA receptor agonists have limited their wider application in acute stroke patients due to the potential risk of stupor. OBJECTIVES: To determine the efficacy and safety of GABA receptor agonists in the treatment of acute stroke. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (February 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 5), MEDLINE (1949 to June 2014), EMBASE (1980 to June 2014), CINAHL (1982 to June 2014), AMED (1985 to June 2014) and 11 Chinese databases (June 2014). In an effort to identify further published, unpublished and ongoing trials we searched ongoing trials registers, reference lists and relevant conference proceedings, and contacted authors and pharmaceutical companies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) investigating GABA receptor agonists versus placebo for acute stroke patients (within 12 hours after stroke onset), with the outcomes of death or dependency, functional independence and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts of identified records, selected studies for inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. MAIN RESULTS: We included five trials with 3838 patients. The methodological quality of the included trials was generally good, with low risk of bias. Four trials measured death and dependency at three months in chlormethiazole versus placebo without significant difference (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.95 to 1.11). One trial measured this outcome between diazepam and placebo (RR 0.94, 95% CI 0.82 to 1.07). In the subgroup analysis of total anterior circulation syndrome (TACS), a higher percentage of functional independence was found in the chlormethiazole group (RR 1.33, 95% CI 1.09 to 1.64). The frequent adverse events related to chlormethiazole were somnolence (RR 4.56, 95% CI 3.50 to 5.95) and rhinitis (RR 4.75, 95% CI 2.67 to 8.46). AUTHORS' CONCLUSIONS: This review does not provide the evidence to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of patients with acute ischemic or hemorrhagic stroke. Chlormethiazole appeared to be beneficial in improving functional independence in patients with TACS according to the subgroup analysis, but this result must be interpreted with great caution. More well-designed RCTs with large samples of TACS would be required for further confirmation. However, somnolence and rhinitis are frequent adverse events related to chlormethiazole.


Assuntos
Clormetiazol/uso terapêutico , Diazepam/uso terapêutico , Agonistas GABAérgicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Doença Aguda , Clormetiazol/efeitos adversos , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Agonistas GABAérgicos/efeitos adversos , Humanos , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Rinite/induzido quimicamente , Acidente Vascular Cerebral/mortalidade
20.
Chem Biol Interact ; 222: 18-26, 2014 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-25162931

RESUMO

Cytochrome P4502E1 (CYP2E1) has been demonstrated to play crucial roles in chronic ethanol-induced fatty liver, while its role in acute ethanol-induced fatty liver remains unclear. The current study was designed to evaluate the effects of chlormethiazole (CMZ), a specific inhibitor of CYP2E1, on acute ethanol-induced fatty liver, and to explore the mechanisms. Mice were pretreated with single dose of CMZ (50mg/kg body weight) by intraperitoneal injection or equal volume of saline, and then exposed to three doses of ethanol (5g/kg body weight, 25%, w/v) by gavage with 12h intervals. The mice were sacrificed at 4h after the last ethanol dosing. It was found that CMZ significantly attenuated acute ethanol-induced increase of the hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. Acute ethanol-induced increase of the hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels (two biomarkers for oxidative stress) and decrease of glutathione (GSH) level was significantly suppressed by CMZ. CMZ also suppressed ethanol-induced decline of serum adiponectin level, but did not significantly affect the serum tumor necrosis factor-α (TNF-α) and ethanol levels. Furthermore, a significant decline of p62 protein level was observed in CMZ/ethanol group mice liver compared with that of the ethanol group mice. However, acute ethanol-induced increase of peroxisome proliferator-activated receptor α (PPAR-α) protein level was suppressed by CMZ, while the protein levels of sterol regulatory element-binding protein-1c (SREBP-1) and diacylglycerol acyltransferase 2 (DGAT2) were not significantly affected by ethanol or CMZ. Collectively, the results of the current study demonstrated that CMZ could effectively attenuate acute ethanol-induced fatty liver possibly by suppressing oxidative stress and adiponectin decline, and activating autophagy, which suggest that CYP2E1 might also play important roles in acute ethanol-induced fatty liver.


Assuntos
Clormetiazol/farmacologia , Inibidores do Citocromo P-450 CYP2E1/farmacologia , Fígado Gorduroso Alcoólico/prevenção & controle , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/sangue , Animais , Autofagia/efeitos dos fármacos , Carbono-Carbono Ligases/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Modelos Animais de Doenças , Ácido Graxo Sintases/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
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