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1.
Expert Opin Drug Saf ; 19(1): 9-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31868031

RESUMO

Introduction: Reduced drinking has been debated as a treatment goal for heavy drinking alcohol-dependent patients, in whom treatment based on abstinence is not always an option. Nalmefene was the first drug approved by the European Medicines Agency (2013) with the indication of reduced drinking in high drinking risk level alcohol-dependent patients. Six years after its introduction in Europe, data from clinical experience can be compared with those from preclinical studies and pivotal registration studies to evaluate what nalmefene has added to the treatment of AUD.Areas covered: Systematic review of efficacy and safety data of nalmefene use in humans from preclinical, phase III and phase IV studies, including systematic reviews, meta-analyses, cost-effectiveness analyses, and other secondary analyses.Expert opinion: Nalmefene introduces a paradigm change in the treatment of AUD that makes it appealing to patients that are reluctant to embrace abstinence, and facilitate patient-centered care in heavy users. However, information regarding safety data in special populations (e.g., patients with alcohol-related diseases, pregnancy, psychiatric disease), and direct comparisons with other potential drugs for alcohol reduction are further needed. Despite the promising role of nalmefene, there are still some factors that limit its wide prescription further than in specialized settings.


Assuntos
Alcoolismo/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/administração & dosagem , Consumo de Bebidas Alcoólicas/prevenção & controle , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Aprovação de Drogas , Humanos , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/efeitos adversos
2.
Tijdschr Psychiatr ; 61(10): 692-701, 2019.
Artigo em Holandês | MEDLINE | ID: mdl-31907913

RESUMO

BACKGROUND: The co-occurrence of PTSD and alcohol use disorder (AUD) is common. Therefore, it is important to know which treatments are effective for the group of patients suffering from both disorders.
AIM: To explore the evidence of medical treatment options for PTSD and AUD.
METHOD: We systematically searched the literature using MEDLINE, Embase and psycINFO (PRISMA guideline).
RESULTS: Ten studies were included of which 9 were randomised controlled trials (RCT). Only one or a few RCTs examined several drugs. The combination of sertraline, naltrexone and disulfiram showed the biggest effect, although the results were limited and partly contradictory.
CONCLUSION: At the moment, there is little evidence for a clear pharmacological preference for the treatment of both PTSD and AUD. Based on the current studies there is, although limited, most evidence for the combination of naltrexone and sertraline or monotherapy with disulfiram. Further research is necessary in order to adequately treat this double diagnosis.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Dissulfiram/uso terapêutico , Quimioterapia Combinada , Humanos , Naltrexona/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Sertralina/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/epidemiologia
3.
Tidsskr Nor Laegeforen ; 138(18)2018 11 13.
Artigo em Norueguês | MEDLINE | ID: mdl-30421743

RESUMO

BACKGROUND: Alcohol use disorder can lead to serious illness and early death. The lifetime prevalence rate among the Norwegian population is estimated at 7-10 %. Many patients are never admitted to any kind of treatment programme, and it is assumed that few of those who are treated receive medicinal treatment. There are a variety of drugs on the market that can help reduce alcohol consumption and maintain abstinence. We wanted to gain an insight into the prescription prevalence rate and practice for these drugs. MATERIAL AND METHOD: We obtained encrypted data from the Norwegian Prescription Database of everyone who received drugs for alcohol use disorder in the period 2004-2016. The drugs included were disulfiram, acamprosate, naltrexone 50 mg and nalmefene. RESULTS: The annual prescription prevalence rate increased from 0.85 to 1.13 per 1000 during the observation period. Half of all patients only received prescribed drugs once, and Disulfiram was the most commonly prescribed drug. There was a slight increase in the prevalence rate in age groups up to and including 55 years, and a significant increase for the over-55s. CONCLUSION: There was a slight increase in the prescription prevalence rate during the observation period. Disulfiram was the most commonly prescribed drug. The prescription increase was greatest among women and in the group of over-55s.


Assuntos
Acamprosato/administração & dosagem , Dissuasores de Álcool/administração & dosagem , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Dissulfiram/administração & dosagem , Uso de Medicamentos , Naltrexona/análogos & derivados , Acamprosato/uso terapêutico , Adulto , Dissuasores de Álcool/uso terapêutico , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Dissulfiram/uso terapêutico , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/uso terapêutico , Noruega/epidemiologia , Sistema de Registros
4.
Neuropsychopharmacology ; 43(9): 1915-1923, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29907878

RESUMO

Forced abstinence from chronic two bottle-choice ethanol drinking produces the development of negative affective states in female C57BL/6J mice. We previously reported that this disrupted behavior is acutely reversed by administration of ketamine 30 min-prior to testing. Here we assessed whether ketamine can be used as an inoculant against the development of abstinence- dependent affective disturbances. In parallel, we examined the impact of ketamine administration on long-term potentiation (LTP) in the bed nucleus of the stria terminalis (BNST), a region implicated in affective disturbances. We administered ketamine (3 mg/kg i.p.) to female C57BL/6J mice with a history of chronic ethanol drinking at either the onset, two, or 6 days- post-abstinence and observed its impact on affective behavior in the elevated plus maze (EPM), the Novelty Suppressed Feeding Test (NSFT), and the Forced Swim Test (FST). In addition, we assessed BNST synaptic plasticity with field potential electrophysiology two to 3 weeks into abstinence. We found that early abstinence was associated with disrupted behavior on the EPM. Ketamine administered at the onset of forced abstinence prevented both the deficit in early EPM behavior, and the delayed deficits in NSFT and FST. However, ketamine administered either two or 6 days post-abstinence failed to prevent the abstinence-induced affective disturbances. To begin to explore potential alterations in neural circuit activity that accompanies these actions of ketamine, we assessed the impact of ketamine administration at the onset of forced abstinence and measured LTP induction in the BNST. We find that early ketamine administration persistently increased the capacity for LTP within the BNST. These findings suggest a critical period at the onset of forced abstinence in which ketamine inoculation can prevent the development of affective disturbances, in part by enhancing plasticity within the BNST.


Assuntos
Transtornos Relacionados ao Uso de Álcool/complicações , Ketamina/farmacologia , Transtornos do Humor/tratamento farmacológico , Psicotrópicos/farmacologia , Núcleos Septais/efeitos dos fármacos , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Afeto/efeitos dos fármacos , Afeto/fisiologia , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Modelos Animais de Doenças , Feminino , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Transtornos do Humor/etiologia , Transtornos do Humor/fisiopatologia , Núcleos Septais/fisiopatologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Síndrome de Abstinência a Substâncias/psicologia , Técnicas de Cultura de Tecidos
5.
Med Clin North Am ; 102(4): 683-696, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29933823

RESUMO

Despite the availability of effective medications and psychosocial interventions for the management of a substance use disorder, some individuals repeatedly fail the most aggressive treatment regimens. For such individuals, alternative treatment options exist seeking to mitigate the negative consequences of the use of harmful substances. Participation in a managed alcohol program, or the use of sustained-release oral morphine or injectable opioid agonist treatment or the creation of safe injecting facilities, are examples of such nonstandard approaches. This article reviews the available evidence of these treatment modalities.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Morfina/uso terapêutico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/terapia , Analgésicos Opioides/administração & dosagem , Preparações de Ação Retardada , Heroína/uso terapêutico , Humanos , Morfina/administração & dosagem , Morfina/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/terapia , Habitação Popular/organização & administração , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença
6.
Handb Exp Pharmacol ; 248: 113-156, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29736774

RESUMO

In the brain, fast inhibitory neurotransmission is mediated primarily by the ionotropic subtype of the gamma-aminobutyric acid (GABA) receptor subtype A (GABAAR). It is well established that the brain's GABAAR system mediates many aspects of neurobehavioral responses to alcohol (ethanol; EtOH). Accordingly, in both preclinical studies and some clinical scenarios, pharmacologically targeting the GABAAR system can alter neurobehavioral responses to acute and chronic EtOH consumption. However, many of the well-established interactions of EtOH and the GABAAR system have been identified at concentrations of EtOH ([EtOH]) that would only occur during abusive consumption of EtOH (≥40 mM), and there are still inadequate treatment options for prevention of or recovery from alcohol use disorder (AUD, including abuse and dependence). Accordingly, there is a general acknowledgement that more research is needed to identify and characterize: (1) neurobehavioral targets of lower [EtOH] and (2) associated brain structures that would involve such targets in a manner that may influence the development and maintenance of AUDs.Nearly 15 years ago it was discovered that the GABAAR system of the cerebellum is highly sensitive to EtOH, responding to concentrations as low as 10 mM (as would occur in the blood of a typical adult human after consuming 1-2 standard units of EtOH). This high sensitivity to EtOH, which likely mediates the well-known motor impairing effects of EtOH, combined with recent advances in our understanding of the role of the cerebellum in non-motor, cognitive/emotive/reward processes has renewed interest in this system in the specific context of AUD. In this chapter we will describe recent advances in our understanding of cerebellar processing, actions of EtOH on the cerebellar GABAAR system, and the potential relationship of such actions to the development of AUD. We will finish with speculation about how cerebellar specific GABAAR ligands might be effective pharmacological agents for treating aspects of AUD.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Cerebelo/fisiologia , Antagonistas de Receptores de GABA-A/farmacologia , Etanol , Humanos , Receptores de GABA-A , Ácido gama-Aminobutírico
7.
Neuropharmacology ; 138: 10-19, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29775679

RESUMO

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode KV7 channels influence alcohol intake and dependence. KV7 channels are a class of slowly activating voltage-dependent K+ channels that regulate neuronal excitability. Studies indicate that the KV7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and KV7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA KV7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective KV7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that KV7.4 channels are a critical mediator of excessive alcohol drinking.


Assuntos
Transtornos Relacionados ao Uso de Álcool/metabolismo , Canais de Potássio KCNQ/metabolismo , Área Tegmentar Ventral/metabolismo , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Animais , Dopamina/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Feminino , Predisposição Genética para Doença , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos Wistar , Área Tegmentar Ventral/efeitos dos fármacos
8.
Neuropharmacology ; 137: 194-201, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-29758386

RESUMO

We have previously demonstrated that the neurokinin-1 receptor (NK1R) is upregulated in the central nucleus of the amygdala of alcohol preferring (P) rats and that this receptor mediates escalated alcohol consumption in this strain. However, it is unclear if non-genetic models of escalated consumption are also mediated by NK1R signaling, and if so, what brain regions govern this effect. In the experiments presented here, we use two methods of inducing escalated alcohol intake in outbred Wistar rats: yohimbine pretreatment and intermittent alcohol access (Monday, Wednesday, and Friday availability; 20% alcohol). We found that escalated alcohol consumption induced by both yohimbine injection and intermittent access is attenuated by systemic administration of the NK1R antagonist L822429. Also, when compared to continuous alcohol access or access to water alone, NK1R expression was increased in the nucleus accumbens (NAC) and dorsal striatum, but not the amygdala. Escalated consumption induced by intermittent access was attenuated when the NK1R antagonist L822429 was infused directly into the dorsal striatum, but not when infused into the NAC. Taken together, these results suggest that NK1R upregulation contributes to escalated alcohol consumption that is induced by genetic selection, yohimbine injection, and intermittent access. However there is a dissociation between the regions involved in these behaviors with amygdalar upregulation contributing to genetic predisposition to escalated consumption and striatal upregulation driving escalation that is induced by environmental exposures.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Transtornos Relacionados ao Uso de Álcool/metabolismo , Receptores da Neurocinina-1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Dissuasores de Álcool/farmacologia , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Animais não Endogâmicos , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Piperidinas/farmacologia , Ratos Wistar , Ioimbina/farmacologia
9.
ACS Chem Neurosci ; 9(7): 1616-1624, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29708326

RESUMO

Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as "Lilu" and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3'- O-ß-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5- O-ß-d-diglucopyranoside (5), oxyresveratrol- 4'- O-ß-d-glucopyranoside (6), oxyresveratrol-3- O-ß-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development.


Assuntos
Depressores do Sistema Nervoso Central/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Etanol/efeitos adversos , Substâncias Protetoras/farmacologia , Estilbenos/farmacologia , Veratrum , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Transtornos Relacionados ao Uso de Álcool/patologia , Animais , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Masculino , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Fototerapia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/isolamento & purificação , Distribuição Aleatória , Estilbenos/química , Estilbenos/isolamento & purificação
10.
Neuropsychopharmacology ; 43(9): 1867-1875, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29728649

RESUMO

Repeated cycles of intoxication and withdrawal enhance the negative reinforcing properties of alcohol and lead to neuroadaptations that underlie withdrawal symptoms driving alcohol dependence. Pharmacotherapies that target these neuroadaptations may help break the cycle of dependence. The sigma-1 receptor (σ1R) subtype has attracted interest as a possible modulator of the rewarding and reinforcing effects of alcohol. However, whether the sigma-2 receptor, recently cloned and identified as transmembrane protein 97 (σ2R/TMEM97), plays a role in alcohol-related behaviors is currently unknown. Using a Caenorhabditis elegans model, we identified two novel, selective σ2R/Tmem97 modulators that reduce alcohol withdrawal behavior via an ortholog of σ2R/TMEM97. We then show that one of these compounds blunted withdrawal-induced excessive alcohol drinking in a well-established rodent model of alcohol dependence. These discoveries provide the first evidence that σ2R/TMEM97 is involved in alcohol withdrawal behaviors and that this receptor is a potential new target for treating alcohol use disorder.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Fármacos do Sistema Nervoso Central/farmacologia , Receptores sigma/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Álcool/metabolismo , Animais , Caenorhabditis elegans , Fármacos do Sistema Nervoso Central/química , Depressores do Sistema Nervoso Central/administração & dosagem , Relação Dose-Resposta a Droga , Descoberta de Drogas , Etanol/administração & dosagem , Ratos , Receptores sigma/genética , Síndrome de Abstinência a Substâncias/metabolismo
11.
Curr Drug Metab ; 19(13): 1056-1064, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29219048

RESUMO

BACKGROUND: Gamma-hydroxybutyrate (GHB or sodium oxybate) is both an exogenous and endogenous molecule with neuromodulator properties. In the United States, GHB is an approved drug for the treatment of narcolepsy and narcolepsy with cataplexy in adults. In some European Union countries, sodium oxybate is applied for the treatment of opioid and alcohol withdrawal. OBJECTIVE: The aim of the present review was to describe the state of art of the pre-clinical research and the clinical evidence related to GHB used alone or in combination with other treatments in alcohol withdrawal syndrome and alcohol abstinence maintenance. METHOD: Internationally published pre-clinical findings and clinical studies investigating the effects of GHB on alcohol withdrawal syndrome and alcohol abstinence maintenance were collected and described considering seven clinical studies involving GHB in the treatment of alcohol withdrawal abstinence and five clinical studies involving GHB in the treatment of alcohol abstinence maintenance. Furthermore, GHB pharmacology and characteristics of abuse were briefly detailed. RESULTS: Clinical evidence indicates that GHB is effective in reducing symptoms of alcohol withdrawal syndrome and produces beneficial effects comparable to those of benzodiazepines or chlometiazole. GHB proved effective in increasing alcohol abstinence maintenance and in reducing alcohol craving, but it did not show any influence in relapses of heavy drinkers when given alone. Conversely, it seems to be effective in reducing relapses in alcohol dependent patients when given in combination with naltrexone and escitalopram. CONCLUSION: Despite this bunch of evidence, studies are still limited and investigations including a larger number of patients are needed. In addition, some safety concerns, such as insufficiency against hallucinations in alcohol withdrawal and potential development of GHB dependence have to be more investigated.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Fármacos do Sistema Nervoso Central/uso terapêutico , Oxibato de Sódio/uso terapêutico , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Abstinência de Álcool , Fármacos do Sistema Nervoso Central/farmacologia , Humanos , Oxibato de Sódio/farmacologia
12.
J Subst Abuse Treat ; 85: 109-115, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29150316

RESUMO

Extended-release naltrexone (XRNTX) is an effective treatment for alcohol use disorder (AUD). We sought to evaluate the feasibility, acceptability, and preliminary effectiveness and cost-effectiveness of XRNTX delivered as a stand-alone service to persons with severe AUD who are high utilizers of multiple urgent and emergency medical services (HUMS). Of 15 HUMS persons with severe AUD selected based on chart review, 11 agreed to participate. Participants received a mean of 4.5 injections (range 2-7). Modest benefits from XRNTX were observed in terms of patients' Urge-to-Drink Score and the costs of emergency medical services utilized. Though limited by a small sample size, costs including client utilization and study related expenses during the post-enrollment period were less than client utilization costs in the pre-enrollment period. We also observed non-significant improvements in the number of drinking days, but no change in quality of life as measured by the EQ-5D. Eighty-eight percent of participants perceived XRNTX as helping with their drinking. Findings need to be replicated in a larger study, however if replicated, the cost savings could be substantial.


Assuntos
Dissuasores de Álcool/administração & dosagem , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Naltrexona/administração & dosagem , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Análise Custo-Benefício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Qualidade de Vida
13.
Drug Alcohol Depend ; 181: 77-84, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29035708

RESUMO

OBJECTIVE: Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. METHOD: In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. RESULTS: We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. CONCLUSION: This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Modelos Animais de Doenças , Descoberta de Drogas/estatística & dados numéricos , Uso Off-Label/estatística & dados numéricos , Animais , Bases de Dados Factuais , Humanos , Roedores
14.
Brain Res ; 1676: 83-90, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28912059

RESUMO

Excessive ethanol (EtOH) intake, especially to prenatal exposure, can significantly affect cognitive function and cause permanent learning and memory injures in children. As a result, how to protect children from EtOH neurotoxicity has gained increasing attention in recent years. Piracetam (Pir) is a nootropic drug derived from c-aminobutyric acid and can manage cognition impairments in multiple neurological disorders. Studies have shown that Pir can exert therapeutic effects on EtOH-induced memory impairments, but the underlying mechanism is still unknown. In this study, we found that Pir inhibited ethanol-induced memory deficit by mediating multiple pathways. Treatment with EtOH could cause cognitive deficit in juvenile rats, and triggered the alteration of synaptic plasticity. Administration with Pir significantly increased long-term potentiation and protected hippocampus neurons from EtOH neurotoxicity. Pir intervention ameliorated EtOH-induced cell apoptosis and inhibited the activation of Caspase-3 in vitro, suggesting that Pir protected neurons by anti-apoptotic effects. Pir could decrease the expression of LC3-II and Beclin-1 induced by EtOH, and increase the phosphorylation of mTOR and reduce the phosphorylation of Akt, which suggested that the protective effect of Pir was involved in regulation of autophagic process and mTOR/Akt pathways. In conclusion, we speculate that Pir reduces EtOH-induced neuronal damage by regulation of apoptotic action and autophagic action, and our research offers preclinical evidence for the application of Pir in ethanol toxicity.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Piracetam/farmacologia , Transtornos Relacionados ao Uso de Álcool/patologia , Transtornos Relacionados ao Uso de Álcool/fisiopatologia , Transtornos Relacionados ao Uso de Álcool/psicologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Etanol/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Hipocampo/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/fisiologia , Distribuição Aleatória , Ratos Sprague-Dawley , Técnicas de Cultura de Tecidos
15.
Drug Metab Pers Ther ; 32(3): 129-136, 2017 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-28787271

RESUMO

BACKGROUND: Haloperidol is used for the treatment of alcohol use disorders in patients with signs of alcohol-related psychosis. Haloperidol therapy poses a high risk of adverse drug reactions (ADR). Contradictory data, which include the effects of genetic polymorphisms in genes encoding the elements of haloperidol biotransformation system on haloperidol metabolism rate and plasma drug concentration ratio, are described in patients with different genotypes. The primary objective of this study was to investigate the effects of CYP2D6 and CYP3A5 genetic polymorphisms on haloperidol equilibrium concentration in patients with alcohol use disorder. METHODS: The study included 69 male patients with alcohol use disorder. Genotyping was performed using the allele-specific real-time PCR. CYP2D6 and CYP3A were phenotyped with HPLC-MS using the concentration of endogenous substrate of the enzyme and its urinary metabolites [6-hydroxy-1,2,3,4-tetrahydro-ß-carboline(6-HO-THBC) to pinoline ratio for CYP2D6 and 6-ß-hydroxycortisol to cortisol ratio for CYP3A]. The equilibrium plasma concentration was determined using LC-MS-MS. RESULTS: Results indicated that both C/D indexes and equilibrium concentration levels depend on CYP2D6 genetic polymorphism, but only in patients receiving haloperidol intramuscular injections [0.26 (0.09; 0.48) vs. 0.54 (0.44; 0.74), p=0.037]. CONCLUSIONS: The study demonstrates that CYP2D6 genetic polymorphism (1846G>A) can affect haloperidol concentration levels in patients with alcohol use disorder.


Assuntos
Antipsicóticos/uso terapêutico , Citocromo P-450 CYP2D6/genética , Haloperidol/uso terapêutico , Psicoses Alcoólicas/tratamento farmacológico , Adulto , Transtornos Relacionados ao Uso de Álcool/complicações , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Citocromo P-450 CYP3A/genética , Genótipo , Haloperidol/efeitos adversos , Haloperidol/farmacocinética , Humanos , Injeções Intramusculares , Isoenzimas , Masculino , Espectrometria de Massas/métodos , Polimorfismo Genético , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas em Tandem/métodos
19.
Adv Ther ; 34(7): 1636-1649, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28540656

RESUMO

INTRODUCTION: Nalmefene is the first drug to be approved for reducing alcohol consumption in alcohol use disorder (AUD) patients at high drinking risk. In real-world settings, there is a high prevalence of concurrent psychiatric disorders in AUD subjects, with associated increased morbidity and worse prognosis. This study evaluated the use of nalmefene in AUD patients with stabilized psychiatric comorbidity previously treated unsuccessfully for alcohol dependence, and assessed craving reduction and safety. METHODS: Sixty-five AUD outpatients treated with as-needed 18 mg nalmefene for 24 weeks were included. Primary outcome measures were: changes in heavy drinking days (HDDs) and total alcohol consumption (TAC, g/day). Secondary outcome measures were: changes in drinking risk level and craving (obsessive-compulsive drinking scale and visual analogue scale for craving). RESULTS: Forty-two AUD subjects (64.6%) had one or more stabilized psychiatric comorbidity. There was a significant reduction in HDDs, TAC and craving measures (p < 0.001), with no differences between subjects with and without psychiatric comorbidity. Nalmefene was safe and well tolerated in all patients. CONCLUSION: As-needed nalmefene reduced drinking and craving in AUD subjects with and without psychiatric comorbidity. These findings suggest that nalmefene is a valid therapeutic option in real-world clinical settings, where comorbid conditions are common, and has the potential to engage AUD patients who may otherwise not have sought help. FUNDING: Lundbeck Italia S.P.A.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Transtornos Mentais/tratamento farmacológico , Naltrexona/análogos & derivados , Antagonistas de Entorpecentes/uso terapêutico , Adulto , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/uso terapêutico
20.
Alcohol Clin Exp Res ; 41(3): 466-472, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28247556

RESUMO

Several clinical trials have evaluated naltrexone as a treatment for alcohol use disorders (AUDs), but few have focused on women. The aim of this review was to systematically review and summarize the evidence regarding the impact of naltrexone compared to placebo for attenuating alcohol consumption in women with an AUD. A systematic review was conducted using PubMed, Cochrane, Web of Science, CINAHL, and Alcohol Studies Database to identify relevant peer-reviewed randomized controlled trials (RCTs) published between January 1990 and August 2016. Seven published trials have evaluated the impact of naltrexone on drinking outcomes in women distinct from men; 903 alcohol-dependent or heavy drinking women were randomized to receive once daily oral or depot (injectable) naltrexone or placebo with/without behavioral intervention. Two studies examining the quantity of drinks per day observed trends toward reduction in drinking quantity among women who received naltrexone versus placebo. The 4 studies examining the frequency of drinking had mixed results, with 1 study showing a trend that favored naltrexone, 2 showing a trend that favored placebo, and 1 that showed no difference. Two of the 3 studies examining time to relapse observed trends that tended to favor naltrexone for time to any drinking and time to heavy drinking among women who received naltrexone versus placebo. While the growing body of evidence suggests a variety of approaches to treat AUD, the impact of naltrexone to combat AUD in women is understudied. Taken together, the results suggest that naltrexone may lead to modest reductions in quantity of drinking and time to relapse, but not on the frequency of drinking in women. Future research should incorporate sophisticated study designs that examine gender differences and treatment effectiveness among those diagnosed with an AUD and present data separately for men and women.


Assuntos
Consumo de Bebidas Alcoólicas/prevenção & controle , Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Relacionados ao Uso de Álcool/diagnóstico , Transtornos Relacionados ao Uso de Álcool/epidemiologia , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Prevenção Secundária/métodos , Resultado do Tratamento
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