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1.
Carcinogenesis ; 41(2): 194-202, 2020 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-31074772

RESUMO

Alcohol consumption is the key risk factor for the development of esophageal squamous cell carcinoma (ESCC), and acetaldehyde, a metabolite of alcohol, is an alcohol-derived major carcinogen that causes DNA damage. Aldehyde dehydrogenase2 (ALDH2) is an enzyme that detoxifies acetaldehyde, and its activity is reduced by ALDH2 gene polymorphism. Reduction in ALDH2 activity increases blood, salivary and breath acetaldehyde levels after alcohol intake, and it is deeply associated with the development of ESCC. Heavy alcohol consumption in individuals with ALDH2 gene polymorphism significantly elevates the risk of ESCC; however, effective prevention has not been established yet. In this study, we investigated the protective effects of Alda-1, a small molecule ALDH2 activator, on alcohol-mediated esophageal DNA damage. Here, we generated novel genetically engineered knock-in mice that express the human ALDH2*1 (wild-type allele) or ALDH2*2 gene (mutant allele). Those mice were crossed, and human ALDH2*1/*1, ALDH2*1/*2 and ALDH2*2/*2 knock-in mice were established. They were given 10% ethanol for 7 days in the presence or absence of Alda-1, and we measured the levels of esophageal DNA damage, represented by DNA adduct (N2-ethylidene-2'-deoxyguanosine). Alda-1 significantly increased hepatic ALDH2 activity both in human ALDH2*1/*2 and/or ALDH2*2/*2 knock-in mice and reduced esophageal DNA damage levels after alcohol drinking. Conversely, cyanamide, an ALDH2-inhibitor, significantly exacerbated esophageal DNA adduct level in C57BL/6N mice induced by alcohol drinking. These results indicate the protective effects of ALDH2 activation by Alda-1 on esophageal DNA damage levels in individuals with ALDH2 gene polymorphism, providing a new insight into acetaldehyde-mediated esophageal carcinogenesis and prevention.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Aldeído-Desidrogenase Mitocondrial/metabolismo , Benzamidas/administração & dosagem , Benzodioxóis/administração & dosagem , Carcinogênese/efeitos dos fármacos , Neoplasias Esofágicas/prevenção & controle , Carcinoma de Células Escamosas do Esôfago/prevenção & controle , Acetaldeído/metabolismo , Acetaldeído/toxicidade , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/genética , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Cianamida/administração & dosagem , Adutos de DNA/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/patologia , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/etiologia , Carcinoma de Células Escamosas do Esôfago/patologia , Etanol/metabolismo , Etanol/toxicidade , Técnicas de Introdução de Genes , Humanos , Masculino , Camundongos Transgênicos , Mutação , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/prevenção & controle , Polimorfismo Genético , Fatores de Risco
2.
Alcohol ; 58: 1-11, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28109342

RESUMO

Lead (Pb) is a developmental neurotoxicant that elicits differential responses to drugs of abuse. Particularly, ethanol consumption has been demonstrated to be increased as a consequence of environmental Pb exposure, with catalase (CAT) and brain acetaldehyde (ACD, the first metabolite of ethanol) playing a role. The present study sought to interfere with ethanol metabolism by inhibiting ALDH2 (mitochondrial aldehyde dehydrogenase) activity in both liver and brain from control and Pb-exposed rats as a strategy to accumulate ACD, a substance that plays a major role in the drug's reinforcing and/or aversive effects. To evaluate the impact on a 2-h chronic voluntary ethanol intake test, developmentally Pb-exposed and control rats were administered with cyanamide (CY, an ALDH inhibitor) either systemically or intracerebroventricularly (i.c.v.) on the last 4 sessions of the experiment. Furthermore, on the last session and after locomotor activity was assessed, all animals were sacrificed to obtain brain and liver samples for ALDH2 and CAT activity determination. Systemic CY administration reduced the elevated ethanol intake already reported in the Pb-exposed animals (but not in the controls) accompanied by liver (but not brain) ALDH2 inactivation. On the other hand, a 0.3 mg i.c.v. CY administration enhanced both ethanol intake and locomotor activity accompanied by brain ALDH2 inactivation in control animals, while an increase in ethanol consumption was also observed in the Pb-exposed group, although in the absence of brain ALDH2 blockade. No changes were observed in CAT activity as a consequence of CY administration. These results support the participation of liver and brain ACD in ethanol intake and locomotor activity, responses that are modulated by developmental Pb exposure.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Encéfalo/crescimento & desenvolvimento , Cianamida/administração & dosagem , Etanol/toxicidade , Chumbo/toxicidade , Locomoção/fisiologia , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído-Desidrogenase Mitocondrial/antagonistas & inibidores , Aldeído-Desidrogenase Mitocondrial/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Etanol/administração & dosagem , Feminino , Injeções Intraventriculares , Fígado/efeitos dos fármacos , Fígado/enzimologia , Locomoção/efeitos dos fármacos , Masculino , Gravidez , Ratos , Ratos Wistar
3.
Toxicology ; 302(1): 1-10, 2012 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-22835378

RESUMO

Cyanamide has been used for decades for medical intentions in the treatment of alcoholism and for agricultural purposes as a plant growth regulator and bud-breaking agent. Its therapeutic effect is mediated by reversible inhibition of aldehyde dehydrogenase and it was reported to be metabolized in vivo mainly via coenzyme A dependent N-acetylation by N-acetyltransferases. Although described to be a substrate for N-acetyltransferases (NATs), cyanamide has a different molecular structure to arylamines and hydrazines, the preferred substrates for N-acetyltransferases. Therefore, a more detailed investigation of its interrelations with N-acetyltransferases was performed. We analyzed the impact of cyanamide on NAT1 activities of human monocytes (monocytic THP-1 cells) using the classical substrate p-aminobenzoic acid. We found that a 24h treatment with physiologically relevant concentrations of cyanamide decreased the NAT1 activity significantly. Based on this observation we performed additional experiments using recombinant human NAT1 and NAT2 to achieve further insights. In detail a significant dose- and time-dependent inhibition of NAT1 activity was observed for 100 and 1000µM cyanamide using recombinant human NAT1*4. However, cyanamide did not inhibit recombinant NAT2*4. Experiments testing cyanamide as substrate did not provide evidence that cyanamide is metabolized via coenzyme A dependent N-acetylation in vitro by human NAT1 or NAT2, THP-1 or human liver cytosol. Therefore we can conclude that the observed enzyme inhibition (around 50% and 25% after treatment with 0.5 and 0.25mM CA, respectively) is not based on substrate-dependent down-regulation of NAT1. Further mechanistic and kinetic studies indicated that cyanamide reacts with the active site cysteine residue of NAT1, leading to its rapid inhibition (significant inhibition after 30min and 2h for 1000 and 100µM CA, respectively). Addition of the reduction agent dithiothreitol (DTT) did not modify the effect, indicating that oxidative processes that can be reversed by 5mM DTT are not likely involved in the inhibition. Taken together our results show that cyanamide is able to inhibit NAT1 most likely via interaction with the active site cysteine residue. Thereby cyanamide might modulate NAT1 dependent detoxification and activation of arylamines.


Assuntos
Ácido 4-Aminobenzoico/metabolismo , Arilamina N-Acetiltransferase/antagonistas & inibidores , Arilamina N-Acetiltransferase/efeitos dos fármacos , Cianamida/farmacologia , Isoenzimas/antagonistas & inibidores , Acetilação , Arilamina N-Acetiltransferase/metabolismo , Linhagem Celular Tumoral , Coenzima A/metabolismo , Cianamida/administração & dosagem , Cianamida/metabolismo , Citosol/metabolismo , Ditiotreitol/farmacologia , Relação Dose-Resposta a Droga , Humanos , Fígado/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fatores de Tempo
4.
Alcohol Clin Exp Res ; 30(1): 86-95, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16433735

RESUMO

OBJECTIVE: (1) To perform a 9-year study of abstinence, lapse, and relapse in 180 chronic alcoholic patients, participants of the Outpatient Longterm Intensive Therapy for Alcoholics (OLITA); (2) To investigate the role of supervised alcohol deterrents (AD) in relapse prevention and as an adjunct for maintenance of long-term abstinence. METHOD: This prospective open treatment study evaluates the long-term course of drinking outcomes and AD use of 180 chronic alcoholics consecutively admitted from 1993 to 2002. Subsamples are compared for (1) sham-AD versus verum-AD (disulfiram/calcium carbimide), (2) coped lapses versus finally detrimental lapses versus malignant relapses, and (3) AD use for 13 to 20 versus >20 months. RESULTS: In this 9-year study, the cumulative probability of not having relapsed was 0.52, and that of not having consumed any alcohol was 0.26. Despite long-term use, disulfiram/calcium carbimide was well tolerated. Patients on sham-AD (due to contraindications to verum-AD) showed higher cumulative abstinence probability than patients on verum (S = 0.86 vs. S = 0.49, p = 0.03). Detrimental lapses and malignant relapses occurred earlier than successfully coped lapses (p < 0.001); patients with detrimental lapse and with malignant relapse had fewer days of AD intake and less subsequent days without AD than patients with coped lapse (p < 0.001). The cumulative abstinence probability was S = 0.75 for patients with long-term intake compared with S = 0.50 for patients who stopped AD between months 13 and 20 (p < 0.001). CONCLUSIONS: An abstinence rate of >50% in this 9-year study strongly supports the concept of comprehensive, long-term outpatient treatment of alcoholics. Supervised, guided intake of AD, also over extended periods, can be used as a predominantly psychologically acting ingredient of successful alcoholism therapy.


Assuntos
Dissuasores de Álcool/administração & dosagem , Alcoolismo/reabilitação , Assistência Ambulatorial , Cianamida/administração & dosagem , Dissulfiram/administração & dosagem , Adulto , Estudos de Casos e Controles , Terapia Combinada , Esquema de Medicação , Feminino , Seguimentos , Alemanha , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Prospectivos , Psicoterapia , Prevenção Secundária , Detecção do Abuso de Substâncias , Temperança
5.
Eur J Clin Pharmacol ; 61(5-6): 467-9, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15991038

RESUMO

OBJECTIVE: To report a case of aplastic anemia in a patient treated with cyanamide, an alcohol-aversive drug. A 67-year-old man was admitted to hospital because of fever and pancytopenia. He had taken cyanamide for 6 months as an alcohol deterrent. No other risk factors for aplastic anemia were identified by interviewing the patient using a structured validated questionnaire. The results of bone-marrow biopsy showed severe aplastic anemia. Cyanamide was discontinued and the patient was treated according to a prespecified treatment protocol. One year after hospital admission, the patient was completely recovered with no need of immunosuppressive therapy. An objective causality assessment revealed that an adverse drug reaction was probable. DISCUSSION: As the efficacy of cyanamide has been questioned, due to the failure of various trials to show any benefit over placebo, its overall benefit/risk ratio should be reconsidered. The complete and rapid hematological recovery after discontinuation of the drug, and the absence of other factors that could explain the condition support the association of the present case of aplastic anemia with cyanamide. The mechanism remains unknown. Aplastic anemia is a rare but potentially serious adverse drug effect of cyanamide treatment. CONCLUSIONS: Given the poor evidence on the efficacy of cyanamide and the associated risk of aplastic anemia, its use in reducing alcohol consumption should be reconsidered.


Assuntos
Anemia Aplástica/etiologia , Cianamida/efeitos adversos , Idoso , Alcoolismo/tratamento farmacológico , Cianamida/administração & dosagem , Humanos , Masculino , Fatores de Tempo
6.
Leg Med (Tokyo) ; 5 Suppl 1: S79-82, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12935558

RESUMO

To assess the dose-dependent effect of cyanamide (CY, a potent aldehyde dehydrogenase inhibitor) on salsolinol release in the striatum, rats were treated with CY (25, 50 and 100 mg/kg) plus ethanol (EtOH,1 g/kg) intraperitoneally. Striatal salsolinol was detected using in vivo microdialysis coupled with high-performance liquid chromatography with an electrochemical detector in free-moving rats, and blood acetaldehyde (AcH) and EtOH were detected using the head-space gas chromatographic method. With the increase in the doses of CY following EtOH, the peak concentrations of striatal salsolinol and blood AcH were increased significantly. Our study indicated that the magnitude of striatal salsolinol levels may depend on the concentration of blood AcH, and that there is a correlation between the blood AcH and striatal salsolinol.


Assuntos
Depressores do Sistema Nervoso Central/administração & dosagem , Corpo Estriado/metabolismo , Cianamida/administração & dosagem , Etanol/administração & dosagem , Isoquinolinas/metabolismo , Acetaldeído/sangue , Animais , Cromatografia Líquida de Alta Pressão , Cianamida/farmacocinética , Relação Dose-Resposta a Droga , Infusões Parenterais , Masculino , Microdiálise , Ratos , Ratos Wistar
7.
Addict Biol ; 8(2): 181-9, 2003 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12850777

RESUMO

We tested the hypothesis that phospholipids are altered in skeletal muscles of rats exposed to ethanol for either acute (2.5 hours) or prolonged (6 weeks) periods. In acute studies, rats were dosed with saline (0.15 mmol/l; controls) or ethanol (75 mmol/kg body weight; treated). There were four groups: (A) saline (control); (B) cyanamide (an aldehyde dehydrogenase inhibitor); (C) ethanol; and (D) cyanamide + ethanol. In prolonged studies, two groups of rats were fed liquid diets containing 35% of total dietary energy as either glucose [group (E)] or ethanol [group (F)]. At the end of the treatments, membrane phospholipids were measured in soleus (Type I fibre-predominant) and plantaris (Type II fibre-predominant) muscle. In acute studies, ethanol alone [(A) vs. (C)] and cyanamide + ethanol [(A) vs. (D)] significantly increased 18 : 2 in plantaris (p < 0.05), whereas in soleus none of the treatments had any effect on the phospholipids. In prolonged studies [(E) vs. (F)], there were decreases in 16 : 0 (p < 0.05) and 18 : 1 (p < 0.01) and increases in 18 : 2 (p < 0.001) in plantaris. In soleus, decreases in 18 : 1 (p < 0.05) and increases in 18 : 2 (p < 0.01) occurred. In conclusion, alterations in the proportions of 16 : 0, 18 : 1 and 18 : 2 provide evidence of an altered membrane domain which may contribute to the pathogenesis of alcohol-induced muscle disease. Changes due to prolonged exposure are more profound than those in acute exposure and the preferential effects in Type II plantaris may reflect the greater susceptibility of this muscle to alcohol.


Assuntos
Etanol/farmacologia , Ácidos Graxos/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Aldeído Desidrogenase/antagonistas & inibidores , Animais , Cianamida/administração & dosagem , Cianamida/farmacologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Etanol/administração & dosagem , Masculino , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Ratos , Ratos Wistar , Cloreto de Sódio/administração & dosagem , Fatores de Tempo
8.
Alcohol Alcohol ; 38(3): 197-201, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12711651

RESUMO

AIMS: The in vivo formation of salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquionoline), an endogeneous condensation product of dopamine (DA) with acetaldehyde (AcH), was examined following the administration of cyanamide (CY) plus ethanol (EtOH) using microdialysis-high-performance liquid chromatography with electrochemical detection. METHODS: After the insertion of a microdialysis probe into the striatum, rats were treated with CY (a potent inhibitor of aldehyde dehydrogenase, 50 mg/kg), 4-methylpyrazole (4-MP, a strong inhibitor of alcohol dehydrogenase, 82 mg/kg), and CY + 4-MP, followed 1 h later by EtOH (1 g/kg), CY and 4-MP only by intraperitoneal administration. RESULTS: In the CY + EtOH group, salsolinol was detected in striatal dialysates and high AcH concentrations were found in the blood. The time course of changes in salsolinol concentrations correlated with blood AcH concentrations. In the other experimental groups, salsolinol in the dialysates and high AcH concentrations in the blood were not detected. CONCLUSIONS: These observations indicate that: (1) high AcH concentrations induce the formation of salsolinol in the rat striatum; (2) there is no effect of EtOH or AcH on striatal dialysate concentrations of DA and 5-hydroxytryptamine.


Assuntos
Acetaldeído/farmacologia , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Etanol/farmacologia , Isoquinolinas/metabolismo , Acetaldeído/sangue , Animais , Cromatografia Líquida de Alta Pressão , Corpo Estriado/metabolismo , Cianamida/administração & dosagem , Dopamina/análise , Etanol/sangue , Isoquinolinas/análise , Masculino , Microdiálise/métodos , Ratos , Ratos Wistar
9.
Psychopharmacology (Berl) ; 167(2): 130-6, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12655465

RESUMO

RATIONALE: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. OBJECTIVES: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. METHODS: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. RESULTS: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. CONCLUSIONS: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA.


Assuntos
Acetaldeído/farmacologia , Consumo de Bebidas Alcoólicas/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Etanol/farmacologia , Acetaldeído/administração & dosagem , Acetaldeído/metabolismo , Dissuasores de Álcool/administração & dosagem , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/psicologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Cianamida/administração & dosagem , Cianamida/farmacologia , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Etanol/administração & dosagem , Etanol/metabolismo , Masculino , Ratos , Ratos Wistar , Sacarina/administração & dosagem , Cloreto de Sódio/administração & dosagem , Água/administração & dosagem
10.
Lipids ; 36(3): 267-71, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11337982

RESUMO

We tested the hypotheses that ethanol sensitivities of muscle and liver can be discerned in the initial periods of ethanol exposure, especially when acetaldehyde levels are markedly raised with cyanamide, an aldehyde dehydrogenase inhibitor. To test this, we measured cholesterol hydroperoxides in soleus (Type I) and plantaris (Type II) muscle in four groups of rats acutely (i.e., 2.5 h) exposed to: [S] saline (control), [Cy] cyanamide, [EtOH] ethanol, or [Cy + EtOH] cyanamide + ethanol. Comparative reference was also made to the response of the liver. After 2.5 h, ethanol alone significantly increased 7 alpha-hydroperoxycholest-5-en-3 beta-ol (7 alpha-OOH) and 7 beta-hydroperoxycholest-5-en-3 beta-ol (7 beta-OOH) levels in plantaris muscle. Identical qualitative effects were seen in rats treated with cyanamide + ethanol, but there was no discernible difference between groups [EtOH] and [Cy + EtOH]. In both the soleus muscle and liver, none of the treatments with either ethanol or cyanamide + ethanol had any effect on any of the measured parameters. This is the first report of a differential response of 7 alpha-OOH and 7 beta-OOH in Type II, compared to Type I predominant muscles, and the first time that muscle has been shown to be more sensitive than the liver in terms of its lipid marker response to oxidative stress. Perturbations in the muscle membrane lipid domain may contribute to impairment of muscle in alcoholism.


Assuntos
Colesterol/metabolismo , Etanol/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Acetaldeído/sangue , Acetaldeído/metabolismo , Animais , Colesterol/análogos & derivados , Colesterol/análise , Cianamida/administração & dosagem , Cianamida/farmacologia , Interações Medicamentosas , Etanol/administração & dosagem , Masculino , Fibras Musculares de Contração Rápida/efeitos dos fármacos , Fibras Musculares de Contração Rápida/metabolismo , Fibras Musculares de Contração Lenta/efeitos dos fármacos , Fibras Musculares de Contração Lenta/metabolismo , Ratos , Ratos Wistar
11.
Alcohol Clin Exp Res ; 24(4 Suppl): 39S-42S, 2000 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10803778

RESUMO

BACKGROUND: To identify the pharmacological effectiveness of cyanamide, 144 alcoholics treated with cyanamide were subjected to a test that used an acetaldehyde dehydrogenase (ALDH) inhibitor, the ethanol patch test, which is considered to be a good indicator of ALDH2 phenotype. METHODS: We placed 100 microl of 70% ethanol on a lint pad and, as a control, placed the same volume of distilled water on a second pad. The ethanol patch test was performed on 144 alcoholics more than 2 weeks after abstinence from alcohol before and after treatment with cyanamide for 1 week. The dose of cyanamide was increased up to 150 mg until the patch test yielded a positive result. RESULTS: In the ethanol patch test, 36 alcoholics (25.0%) gave a positive result before treatment with cyanamide and might have been ALDH2(1)/2(2) heterozygotes. Among 108 alcoholics who were not positive, the distribution of the cyanamide dose that yielded a positive ethanol patch test result was 30 mg in 42 cases (38.9%), 50 mg in 33 cases (30.6%), 70 mg in 5 cases (4.6%), 100 mg in 6 cases (5.6%), and 150 mg in 2 cases (1.9%). Prevalence of liver cirrhosis was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of less than 50 mg cyanamide than those at doses more than 70 mg (p = 0.029). The prevalence of adverse effects was significantly higher in alcoholics who showed a positive ethanol patch test result at doses of more than 70 mg than at doses of less than 50 mg cyanamide (p = 0.002). CONCLUSIONS: The ethanol patch test is a useful method for identifying pharmacological effectiveness of cyanamide and may reduce the prevalence of side effects in cyanamide-treated alcoholics.


Assuntos
Alcoolismo/tratamento farmacológico , Aldeído Desidrogenase/antagonistas & inibidores , Cianamida/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Etanol , Testes do Emplastro , Adulto , Idoso , Aldeído Desidrogenase/genética , Cianamida/administração & dosagem , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
12.
J Neuroendocrinol ; 12(3): 255-62, 2000 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-10718921

RESUMO

The present study investigated the effects of acute administration of cyanamide (a potent inhibitor of aldehyde dehydrogenase used to treat alcoholics), on the hypothalamo-pituitary adrenal (HPA)-axis. Cyanamide resulted in a significant increase in arginine vasopressin mRNA and corticotrophin releasing factor (CRF) mRNA in the parvocellular cells of the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. Plasma corticosterone concentrations were elevated by a range of doses of cyanamide which were maintained in the high dose group at 4 h following administration. These results suggest that cyanamide is able to activate the HPA axis at all levels of the axis. Arginine vasopressin mRNA, in the parvocellular cells of the paraventricular nucleus is an important component of the stress response. Silver grain counting of emulsion dipped slides is commonly used for its evaluation following in-situ hybridization. This method is however, not entirely satisfactory and very time-consuming. We compared this method with a film autoradiographic method, and show that the film autoradiographic method is valid for the determination of arginine vasopressin mRNA in the parvocellular cells of the paraventricular nucleus.


Assuntos
Glândulas Suprarrenais/efeitos dos fármacos , Cianamida/farmacologia , Hipotálamo/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Glândulas Suprarrenais/fisiologia , Adrenalectomia , Aldeído Desidrogenase/antagonistas & inibidores , Animais , Arginina Vasopressina/genética , Autorradiografia , Corticosterona/sangue , Hormônio Liberador da Corticotropina/genética , Cianamida/administração & dosagem , Inibidores Enzimáticos/farmacologia , Hipotálamo/fisiologia , Hibridização In Situ , Cinética , Masculino , Hipófise/fisiologia , Pró-Opiomelanocortina/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Alcohol ; 15(3): 239-47, 1998 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9539382

RESUMO

A key question related to the role of acetaldehyde and aldehyde adducts in alcoholism concerns their relationship to the genetic mechanisms underlying drinking. Experimentally, the low-alcohol-drinking (LAD) rat represents a standard rodent model having a strong aversion to alcohol. In these experiments, preferences for water vs. alcohol, offered in concentrations from 3% to 30%, were determined over 10 days in adult LAD rats (N = 6 per group). Then a saline vehicle or either 10 or 20 mg/kg of the aldehyde dehydrogenase (AIDH) inhibitor, cyanamide, was injected s.c. twice daily for 3 days. Secondly, either 0.5 or 1.0 microg of tetrahydropapaveroline (THP) was infused i.c.v. twice daily for 3 days in LAD rats (N = 8) and, as a genetic control, THP also was infused identically in Sprague-Dawley (SD) rats (N = 8). The results showed that the lower and higher doses of cyanamide augmented alcohol intakes in 33% and 50% of the LAD rats, respectively, with the patterns of drinking resembling that of genetic high-alcohol-drinking HAD or P rats. Although i.c.v. infusions of THP had little effect on alcohol preference of LAD rats, alcohol drinking was enhanced significantly in the SD rats. In a supplementary study, 200 microg of 6-hydroxydopamine (6-OHDA) also was infused i.c.v. in LAD rats (N = 7) on two consecutive days; no change occurred in the characteristic aversion to alcohol. These findings suggest that in certain individuals, a perturbation in the synthesis of AIDH can modify the genetically based aversion to alcohol, thus precipitating the liability for alcoholism. In that neither THP nor 6-OHDA lesioning exerted any effect on the genetic nondrinking LAD animal suggests that an unknown endogenous factor in the brain must underlie the cyanamide-induced shift to alcohol preference. We conclude that the genetic elements that normally prevent the progression to addictive drinking in most individuals appear to be invariant and irreversible.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Cianamida/farmacologia , Oxidopamina/farmacologia , Tetra-Hidropapaverolina/farmacologia , Animais , Cianamida/administração & dosagem , Preferências Alimentares , Injeções Intraventriculares , Masculino , Oxidopamina/administração & dosagem , Ratos , Ratos Mutantes , Ratos Sprague-Dawley , Tetra-Hidropapaverolina/administração & dosagem
15.
Pol J Pharmacol ; 46(5): 445-9, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7894532

RESUMO

The effects of the aldehyde dehydrogenase (ALDH) inhibitors: cyanamide (CY) and disulfiram (DS) and the alcohol dehydrogenase (ADH) inhibitor, pyrazole (PY) and the combination of these drugs with ethanol (ET, 3.5 g/kg, ip 6 h before decapitation) on the concentrations of rat blood and liver ketone bodies were studied. We found a 2-fold increase in acetone 12 h after PY, 4-fold elevation 30 h after DS and a 14-fold rise 12 h after CY administration. While DS and PY had no pronounced effects on the blood acetoacetate and 3-hydroxybutyrate concentrations, CY increased both of them 5.5 and 3.4-fold, respectively. After combined PY+CY, DS+ET and CY+ET injection, the effect became potentiated and the blood acetone levels rose more than 20-fold. The ET injection increased the concentrations of liver ketone bodies. The DS pretreatment did not change the acetoacetate and 3-hydroxybutyrate concentrations found after ET, but CY increased that of acetoacetate. Thus, the DS- and PY-induced acetonemia may be related to decreased acetone catabolism, whereas the CY effect--to increased formation of acetone from its metabolic precursor, acetoacetate. The ALDH inhibitors potentiated the ethanol-induced acetonemia probably by a combination of disturbances in ketone bodies production and acetone metabolism.


Assuntos
Álcool Desidrogenase/antagonistas & inibidores , Aldeído Desidrogenase/antagonistas & inibidores , Etanol/toxicidade , Corpos Cetônicos/sangue , Fígado/efeitos dos fármacos , Ácido 3-Hidroxibutírico , Acetoacetatos/sangue , Acetoacetatos/metabolismo , Acetona/sangue , Acetona/metabolismo , Animais , Glicemia/metabolismo , Cianamida/administração & dosagem , Cianamida/toxicidade , Modelos Animais de Doenças , Dissulfiram/administração & dosagem , Dissulfiram/toxicidade , Sinergismo Farmacológico , Etanol/sangue , Hidroxibutiratos/sangue , Hidroxibutiratos/metabolismo , Injeções Intraperitoneais , Corpos Cetônicos/metabolismo , Fígado/metabolismo , Masculino , Pirazóis/administração & dosagem , Pirazóis/toxicidade , Ratos
16.
Biopharm Drug Dispos ; 14(5): 419-28, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-8218960

RESUMO

The inhibition of rat hepatic mitochondrial aldehyde dehydrogenase (ALDH) isozymes was studied in apparent steady-state conditions after repeated intra-peritoneal cyanamide administration. The low-Km mitochondrial ALDH isozyme was more susceptible to cyanamide-induced inhibition (DI50 = 0.104 mg kg-1) than the high-Km isozyme (DI50 = 8.52 mg kg-1), with almost complete inhibition occurring at 0.35 mg kg-1 total cyanamide administered for the low-Km isozyme. The relationships between plasma and liver cyanamide concentrations and the inhibition of high-Km ALDH were established by means of the sigmoid Imax model. The effect of dosing rate on the plasma concentration of cyanamide at apparent steady-state showed non-linearity, indicating that clearance or first-pass metabolism of cyanamide during its absorption after intraperitoneal administration did not remain constant throughout the range of doses studied.


Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Cianamida/farmacologia , Mitocôndrias Hepáticas/enzimologia , Animais , Cianamida/administração & dosagem , Esquema de Medicação , Isoenzimas , Cinética , Masculino , Modelos Biológicos , Ratos , Ratos Sprague-Dawley
17.
Pharmacol Toxicol ; 70(1): 41-5, 1992 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-1594534

RESUMO

A study was undertaken to examine the relationship between blood acetaldehyde levels and clinical responses in volunteers receiving the anti-alcohol drugs disulfiram and calcium cyanamide. In the first part of this study volunteers received different doses of disulfiram (125 mg and 500 + 250 mg), of calcium cyanamide (25 mg, 50 mg and 100 mg) and of ethanol (0.2 g/kg orally and 0.5 g/kg intravenously). The ensuing interactions ranged from no reaction at all to an intense hypotensive cyanamide-ethanol reaction (CER). A blood acetaldehyde concentration-effect relationship was suggested. In the second part of this study seven subjects received 50 mg of calcium cyanamide 4 hr prior to an intravenous ethanol dose of 0.2 g/kg. The maximum blood level of acetaldehyde ranged from 16 to 241 microM. Aversive interactions started to occur at acetaldehyde levels around 40-60 microM. Changes in flushing reaction and diastolic blood pressure appeared best to reflect changing blood acetaldehyde levels. As a rule, however, the expected cyanamide-ethanol and disulfiram-ethanol reactions are more clearly registered as an increase in acetaldehyde levels than as the ensuing physiological responses.


Assuntos
Acetaldeído/sangue , Cianamida/farmacologia , Dissulfiram/farmacologia , Etanol/farmacologia , Adulto , Cianamida/administração & dosagem , Dissulfiram/administração & dosagem , Interações Medicamentosas , Etanol/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
18.
Biopharm Drug Dispos ; 12(6): 425-34, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1932606

RESUMO

A pharmacokinetic study of carbimide, an inhibitor of aldehyde dehydrogenase, used as an adjuvant in the aversive therapy of chronic alcoholism, has been carried out in male human volunteers for intravenous and oral administration. Carbimide plasma concentrations were determined by a sensitive and specific high performance liquid chromatographic method. The intravenous doses administered were 0.1, 0.3, 0.6, and 1 mg kg-1 and linear pharmacokinetics were observed for this dose range. Elimination half-life and total plasma clearance values ranged from 42 to 52 min and from 14.4 to 20.5 ml kg-1 min-1, respectively. After oral administration of 1 and 1.5 mg kg-1 of carbimide, elimination half-life values were 75 and 61 min, respectively, being higher than the corresponding value obtained after 0.3 mg kg-1 doses, i.e. 39 min. In all cases, rapid absorption was indicated by tmax values ranging from 10.5 to 15.5 min. Absorption was not complete, the oral bioavailability being 53 per cent and 70 per cent for the 0.3 and 1 mg kg-1 carbimide dose, respectively. The data indicate that there is a first-pass effect for carbimide.


Assuntos
Cianamida/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Cianamida/administração & dosagem , Meia-Vida , Humanos , Masculino , Especificidade da Espécie
19.
Arch Toxicol ; 65(4): 268-72, 1991.
Artigo em Inglês | MEDLINE | ID: mdl-1953345

RESUMO

The main urinary metabolite of hydrogen cyanamide (syn.: cyanamide) in rat and man is acetylcyanamide (syn.: N-acetylcyanamide). An analytical method was developed to determine acetylcyanamide in the urine with a limit of quantification of less than 10 micrograms/l (mean recovery 96.1% using spikes of 20 micrograms/l; relative standard deviation less than 4%). This methodology is based upon ion chromatography using column-switch techniques and UV detection. It could be demonstrated that in rats an average of 45.6% of oral applied cyanamide (10 mg/kg) was excreted in the urine as acetylcyanamide. In male human volunteers a mean of 40% of oral administered cyanamide (mean dose 0.25 mg/kg body weight) was excreted via the urine as acetylcyanamide. The same group of volunteers participated in a skin absorption study with dermal application of the above cyanamide dose onto a skin surface area of 32 cm2. Within an application period of 6 h an average cyanamide quantity of 2.3 mg was available for skin absorption. A mean portion of 7.7% of this quantity was found as acetylcyanamide in the urine of the participants. Findings from literature state that cyanamide is metabolized in vitro to cyanide. According to examinations performed in vivo, however, such a metabolic pathway seems to be irrelevant for man. In comparison with the control values there was no significant increase of both the cyanide concentrations in the blood and the thiocyanate concentrations in the urine of the above volunteers after the described oral cyanamide administration.


Assuntos
Cianamida/metabolismo , Administração Oral , Administração Tópica , Adulto , Idoso , Animais , Cromatografia por Troca Iônica , Cianamida/administração & dosagem , Cianamida/urina , Cianetos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Endogâmicos , Absorção Cutânea , Tiocianatos/urina
20.
Arkh Anat Gistol Embriol ; 97(10): 13-20, 1989 Oct.
Artigo em Russo | MEDLINE | ID: mdl-2619564

RESUMO

The cerebral parietal cortex in rats subjected to an acute (single) and subacute (for 5 days) ethanol effect in combination with aldehyde dehydrogenase (AldDG) (enzymes classification 1.2.1.3 AldDG) inhibitors--disulfiram and cyanamide--has been investigated histochemically and electron microscopically. The inhibitors mentioned produce an essential decrease of AldDG activity in the cerebral cortex; it remains in some structures even 6 days after their single administration. Against the background of AldDG inhibitors alcohol produces more noticeable structural disorders in the cerebral cortex, they are possibly connected with accumulation of a highly toxic ethanol metabolite-acetaldehyde--in blood and with its easy penetration into the brain. This demonstrates an important role of AldDG in protection of the brain from alcoholic (aldehydic) lesions, as well as a peculiar danger for the brain of ethanol in combination with inhibitors of this enzyme.


Assuntos
Aldeído Desidrogenase/antagonistas & inibidores , Cianamida/toxicidade , Cianetos/toxicidade , Dissulfiram/toxicidade , Etanol/toxicidade , Neurônios/ultraestrutura , Lobo Parietal/patologia , Animais , Atrofia/induzido quimicamente , Cianamida/administração & dosagem , Dissulfiram/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Etanol/administração & dosagem , Masculino , Microscopia Eletrônica , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Lobo Parietal/efeitos dos fármacos , Lobo Parietal/enzimologia , Ratos
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