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1.
J Pharmacol Exp Ther ; 372(1): 21-29, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31628204

RESUMEN

During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. SIGNIFICANCE STATEMENT: Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.


Asunto(s)
Citocromo P-450 CYP2A6/antagonistas & inhibidores , Inhibidores Enzimáticos/uso terapéutico , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Tiofenos/uso terapéutico , Tabaquismo/tratamiento farmacológico , Animales , Citocromo P-450 CYP2A6/metabolismo , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Femenino , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Nicotina/metabolismo , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Agentes para el Cese del Hábito de Fumar/efectos adversos , Agentes para el Cese del Hábito de Fumar/farmacología , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Tiofenos/farmacología
2.
Compr Psychiatry ; 95: 152125, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31669972

RESUMEN

BACKGROUND: The effects of the combination therapy of varenicline and bupropion in smoking cessation are still controversial. METHODS: Databases including PubMed, EMBASE, Cochrane Library and Web of Science were scanned without time and language limitation. Subgroup analysis was performed to assess the effect of combination therapy in smokers with different level of nicotine dependence and cigarette consumption. RESULTS: Four randomized controlled trials involving a total of 1230 smokers were included. Compared with varenicline monotherapy, combination treatment with varenicline and bupropion could significantly improve the abstinence rate at the end of treatment (RR 1.153, 95% CI 1.019 to 1.305, P=0.024). The benefit existed at 6months follow-up (RR 1.231, 95% CI 1.017 to 1.490, P=0.033), disappeared at 12months follow-up (RR 1.130, 95% CI 0.894 to 1.428, P=0.305), and mainly concentrated in highly dependent smokers (RR 1.631, 95% CI 1.290 to 2.061, P<0.001) and heavy smokers (RR 1.515, 95% CI 1.226 to 1.873, P<0.001) rather than individuals with low nicotine dependence (RR 0.989, 95% CI 0.815 to 1.199, P=0.907) or low cigarette consumption (RR 0.985, 95% CI 0.800 to 1.212, P=0.252). For safety outcomes, the combination treatment was associated with more anxiety (RR 1.717, 95% CI 1.176 to 2.505, P=0.005) and insomnia (RR 1.268, 95% CI 1.076 to 1.494, P=0.005) symptoms compared with varenicline monotherapy. CONCLUSION: Compared with varenicline monotherapy, combination treatment with varenicline and bupropion can significantly improve the abstinence rate at the end of treatment and 6months follow-up, mainly in highly dependent smokers and heavy smokers.


Asunto(s)
Bupropión/uso terapéutico , Cese del Hábito de Fumar/métodos , Fumar/tratamiento farmacológico , Vareniclina/uso terapéutico , Adulto , Quimioterapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agonistas Nicotínicos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Tabaquismo/tratamiento farmacológico
3.
Nicotine Tob Res ; 21(11): 1496-1505, 2019 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-31665746

RESUMEN

INTRODUCTION: Many smokers do not achieve abstinence using current smoking cessation options. This randomized controlled trial (RCT) investigated a novel nutritional supplement to assist with quitting smoking. METHODS: Following a baseline phase where cigarettes per day and nicotine dependence were measured, participants (n = 107) were randomized to placebo (n = 50) or micronutrient conditions (n = 57). A 4-week pre-quit phase permitted titration up to 12 capsules/day. During the quit phase (12 weeks), participants were registered with a public Quitline while consuming micronutrients or placebo. Carbon monoxide levels were measured to confirm smoking cessation. RESULTS: Forty-five (42%) participants completed the trial. Treatment and placebo groups did not differ on the primary outcome of continuous abstinence at 12 weeks using intention-to-treat analysis; however, 28% of the micronutrient-treated group had quit versus 18% for placebo (odds ratio [OR] = 1.78, 95% confidence interval [CI] = 0.71 to 4.48), with number needed to treat = 10. Comparison of cigarette consumption (cigarettes per day) between micronutrient and placebo groups showed that those taking micronutrients reported reduced consumption throughout the trial, notably at pre-quit weeks 1 and 4, and at quit phase week 4. There were no serious adverse events, blinding was successful, and there were no substantive group differences in side effects or dropout rate. CONCLUSION: This is the first RCT investigating the impact of micronutrients on smoking reduction, finding that micronutrients reduced harm through reduction in number of cigarettes smoked relative to placebo. The small sample and high dropout rate limit confidence in the conclusions and generalizability of the study; however, assessed by number needed to treat, micronutrients are comparable to other smoking cessation treatments but with fewer side effects. Future research using larger and longer trials including cost-effectiveness and biomarker measures is encouraged. IMPLICATIONS: Micronutrients are being increasingly studied for the treatment of psychiatric conditions, but direct application of micronutrients as a treatment for addictions is novel. There is extensive evidence that micronutrients alleviate stress. Given that tobacco smoking is often used to cope with stress, taking micronutrients may moderate the stress of withdrawal and increase the chance of a successful quit attempt. This study is the first known RCT to investigate the use of micronutrients to support smoking cessation. Treatments that are safe, effective, relatively inexpensive, and readily available are needed and micronutrient supplements offer one such possible alternative.


Asunto(s)
Minerales/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Cese del Hábito de Fumar , Tabaquismo/tratamiento farmacológico , Vitaminas/uso terapéutico , Administración Oral , Adolescente , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Minerales/administración & dosificación , Agonistas Nicotínicos/administración & dosificación , Resultado del Tratamiento , Vitaminas/administración & dosificación , Adulto Joven
4.
Ther Adv Respir Dis ; 13: 1753466619875925, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31533544

RESUMEN

Smoking causes various diseases and is a major public health threat worldwide. Therefore, promoting smoking cessation is the most important intervention contributing to maintaining the health of smokers and nonsmokers and saving enormous financial expense. We reviewed existing and emerging smoking-cessation pharmacotherapies from the Cochrane Database of Systemic Reviews, PubMed, Ovid, and ClinicalTrials.gov databases. A literature review revealed that bupropion may be appropriate for patients interested in reducing smoking who dislike, or who have failed, nicotine-replacement therapy (NRT). Additionally, varenicline and NRT are efficacious first-line smoking cessation treatments and should be given to all individuals unless contraindicated. The reviews of this paper are available via the supplementary material section.


Asunto(s)
Bupropión/uso terapéutico , Fumar Cigarrillos/prevención & control , Agonistas Nicotínicos/uso terapéutico , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco , Tabaquismo/tratamiento farmacológico , Vareniclina/uso terapéutico , Bupropión/efectos adversos , Fumar Cigarrillos/efectos adversos , Humanos , Agonistas Nicotínicos/efectos adversos , Recurrencia , Agentes para el Cese del Hábito de Fumar/efectos adversos , Tabaquismo/diagnóstico , Resultado del Tratamiento , Vareniclina/efectos adversos
5.
Eur J Pharmacol ; 861: 172592, 2019 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-31421087

RESUMEN

Neurobehavioral bases of tobacco addiction and nicotine reinforcement are complex, involving more than only nicotinic cholinergic or dopaminergic systems. Memantine is an NMDA glutamate antagonist used to improve cognitive function in people with Alzheimer's disease. Glutamate may be an important component of the reinforcing effects of nicotine, so memantine was evaluated as a potential smoking cessation aid. Two studies were conducted with adult female rats, one testing acute effects of memantine over a range of doses for changing nicotine self-administration and the other testing the chronic effects of memantine to reduce nicotine self-administration. Acute memantine injections slightly, but significantly, increased nicotine self-administration in a dose-related manner. In contrast, chronic memantine treatment significantly reduced nicotine self-administration. During the first day of memantine administration in the chronic study, nicotine self-administration was significantly elevated replicating the acute study. Starting in the second week of treatment there was a significant reduction of nicotine self-administration relative to controls. This was seen because memantine treatment prevented the increase in nicotine self-administration shown by controls. There even continued to be a memantine-induced lowered nicotine self-administration during the week after the cessation of memantine treatment. Memantine or other drugs affecting NMDA glutamate receptors may be useful aids to smoking cessation. Full efficacy for reducing nicotine self-administration was seen as the NMDA drug treatment is given chronically. Importantly, the effect persisted even after treatment is ended, indicating the high potential for NMDA glutamate receptors to impact nicotine addiction.


Asunto(s)
Memantina/farmacología , Nicotina/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Femenino , Memantina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Autoadministración , Factores de Tiempo , Tabaquismo/tratamiento farmacológico
6.
Cochrane Database Syst Rev ; 8: CD009164, 2019 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-31425618

RESUMEN

BACKGROUND: Pharmacological treatments for tobacco dependence, such as nicotine replacement therapy (NRT), have been shown to be safe and effective interventions for smoking cessation. Higher levels of adherence to these medications increase the likelihood of sustained smoking cessation, but many smokers use them at a lower dose and for less time than is optimal. It is important to determine the effectiveness of interventions designed specifically to increase medication adherence. Such interventions may address motivation to use medication, such as influencing beliefs about the value of taking medications, or provide support to overcome problems with maintaining adherence. OBJECTIVES: To assess the effectiveness of interventions aiming to increase adherence to medications for smoking cessation on medication adherence and smoking abstinence compared with a control group typically receiving standard care. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialized Register, and clinical trial registries (ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform) to the 3 September 2018. We also conducted forward and backward citation searches. SELECTION CRITERIA: Randomised, cluster-randomised or quasi-randomised studies in which adults using active pharmacological treatment for smoking cessation were allocated to an intervention arm where there was a principal focus on increasing adherence to medications for tobacco dependence, or a control arm providing standard care. Dependent on setting, standard care may have comprised minimal support or varying degrees of behavioural support. Included studies used a measure that allowed assessment of the degree of medication adherence. DATA COLLECTION AND ANALYSIS: Two authors independently screened studies for eligibility, extracted data for included studies and assessed risk of bias. For continuous outcome measures, we calculated effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we calculated effect sizes as risk ratios (RRs). In meta-analyses for adherence outcomes, we combined dichotomous and continuous data using the generic inverse variance method and reported pooled effect sizes as SMDs; for abstinence outcomes, we reported and pooled dichotomous outcomes. We obtained pooled effect sizes with 95% confidence intervals (CIs) using random-effects models. We conducted subgroup analyses to assess whether the primary focus of the adherence treatment ('practicalities' versus 'perceptions' versus both), the delivery approach (participant versus clinician-centred) or the medication type were associated with effectiveness. MAIN RESULTS: We identified two new studies, giving a total of 10 studies, involving 3655 participants. The medication adherence interventions studied were all provided in addition to standard behavioural support.They typically provided further information on the rationale for, and emphasised the importance of, adherence to medication or supported the development of strategies to overcome problems with maintaining adherence (or both). Seven studies targeted adherence to NRT, two to bupropion and one to varenicline. Most studies were judged to be at high or unclear risk of bias, with four of these studies judged at high risk of attrition or detection bias. Only one study was judged to be at low risk of bias.Meta-analysis of all 10 included studies (12 comparisons) provided moderate-certainty evidence that adherence interventions led to small improvements in adherence (i.e. the mean amount of medication consumed; SMD 0.10, 95% CI 0.03 to 0.18; I² = 6%; n = 3655), limited by risk of bias. Subgroup analyses for the primary outcome identified no significant subgroup effects, with effect sizes for subgroups imprecisely estimated. However, there was a very weak indication that interventions focused on the 'practicalities' of adhering to treatment (i.e. capabilities, resources, levels of support or skills) may be effective (SMD 0.21, 95% CI 0.03 to 0.38; I² = 39%; n = 1752), whereas interventions focused on treatment 'perceptions' (i.e. beliefs, cognitions, concerns and preferences; SMD 0.10, 95% CI -0.03 to 0.24; I² = 0%; n = 839) or on both (SMD 0.04, 95% CI -0.08 to 0.16; I² = 0%; n = 1064), may not be effective. Participant-centred interventions may be effective (SMD 0.12, 95% CI 0.02 to 0.23; I² = 20%; n = 2791), whereas those that are clinician-centred may not (SMD 0.09, 95% CI -0.05 to 0.23; I² = 0%; n = 864).Five studies assessed short-term smoking abstinence (five comparisons), while an overlapping set of five studies (seven comparisons) assessed long-term smoking abstinence of six months or more. Meta-analyses resulted in low-certainty evidence that adherence interventions may slightly increase short-term smoking cessation rates (RR 1.08, 95% CI 0.96 to 1.21; I² = 0%; n = 1795) and long-term smoking cessation rates (RR 1.16, 95% CI 0.96 to 1.40; I² = 48%; n = 3593). In both cases, the evidence was limited by risk of bias and imprecision, with CIs encompassing minimal harm as well as moderate benefit, and a high likelihood that further evidence will change the estimate of the effect. There was no evidence that interventions to increase adherence to medication led to any adverse events. Studies did not report on factors plausibly associated with increases in adherence, such as self-efficacy, understanding of and attitudes toward treatment, and motivation and intentions to quit. AUTHORS' CONCLUSIONS: In people who are stopping smoking and receiving behavioural support, there is moderate-certainty evidence that enhanced behavioural support focusing on adherence to smoking cessation medications can modestly improve adherence. There is only low-certainty evidence that this may slightly improve the likelihood of cessation in the shorter or longer-term. Interventions to increase adherence can aim to address the practicalities of taking medication, change perceptions about medication, such as reasons to take it or concerns about doing so, or both. However, there is currently insufficient evidence to confirm which approach is more effective. There is no evidence on whether such interventions are effective for people who are stopping smoking without standard behavioural support.


Asunto(s)
Cumplimiento de la Medicación/estadística & datos numéricos , Agonistas Nicotínicos/uso terapéutico , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco , Tabaquismo/tratamiento farmacológico , Benzazepinas/uso terapéutico , Bupropión/uso terapéutico , Quimioterapia Combinada/métodos , Humanos , Nortriptilina/uso terapéutico , Quinoxalinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Prevención del Hábito de Fumar
7.
Mar Drugs ; 17(9)2019 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-31443523

RESUMEN

Abstract: α-Conotoxin TxIB is a specific antagonist of α6/α3ß2ß3(α6ß2*) nicotinic acetylcholine receptor (nAChR) with an IC50 of 28 nM. Previous studies have shown that α6ß2* nAChRs are abundantly expressed in midbrain dopaminergic neurons and play an important role in mediating the mechanism of nicotine and other drugs reward effect. It provided important targets for the development of anti-addiction drugs. The present study evaluated the pharmacological activity of TxIB in vivo with conditioned place preference (CPP) model, which were induced by subcutaneous injection (s.c.) of nicotine (NIC, 0.5 mg/kg). α-Conotoxin TxIB inhibited the expression and reinstatement of CPP in mice dose-dependently, but had no significant effect on locomotor activity. The concentrations of dopamine (DA), γ-aminobutyric acid (GABA) and noradrenaline (NE) in different brain regions were measured by enzyme-linked immunosorbent assay (ELISA). We found that TxIB could inhibit the concentrations of DA, GABA and NE in different brain regions (such as nucleus accumbens (NAc), hippocampus (HIP) and prefrontal cortex (PFC)) in NIC-induced mice. The concentrations of DA and NE were decreased in ventral tegmental area (VTA), while GABA had little change. The current work described the inhibition activity of TxIB in NIC-induced CPP, suggesting that α6ß2* nAChR-targeted compound may be a promising drug for nicotine addiction treatment.


Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Conotoxinas/farmacología , Antagonistas Nicotínicos/farmacología , Receptores Nicotínicos/metabolismo , Tabaquismo/tratamiento farmacológico , Animales , Técnicas de Observación Conductual , Conducta Animal/efectos de los fármacos , Conotoxinas/uso terapéutico , Modelos Animales de Enfermedad , Dopamina/análisis , Dopamina/metabolismo , Humanos , Inyecciones Subcutáneas , Ligandos , Masculino , Ratones , Nicotina/administración & dosificación , Nicotina/efectos adversos , Antagonistas Nicotínicos/uso terapéutico , Norepinefrina/análisis , Norepinefrina/metabolismo , Recompensa , Área Tegmental Ventral/química , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismo , Ácido gamma-Aminobutírico/análisis , Ácido gamma-Aminobutírico/metabolismo
8.
Brasília; CONITEC; jul. 2019. tab.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1024743

RESUMEN

INTRODUÇÃO: O tabagismo é fator causal para doenças incapacitantes e fatais, como câncer, doenças cardiovasculares e respiratórias crônicas. Atualmente, o modelo de tratamento adotado no SUS tem como base a abordagem cognitivo-comportamental e apoio farmacoterápico, quando necessário, com reposição de nicotina e cloridrato de bupropiona. TECNOLOGIA: Tartarato de Vareniclina (Champix®). PERGUNTA: O tratamento com vareniclina é mais eficaz, seguro e custo-efetivo para a cessação do tabagismo do que as terapias farmacológicas atualmente disponíveis no SUS? EVIDÊNCIAS CIENTÍFICAS: A vareniclina (período habitual de tratamento de 12 semanas) demonstrou eficácia quando comparada ao grupo placebo, para a cessação do tabagismo - 6 meses ou mais (RR 2,24; IC95% 2,06 - 2,43). Quando comparada com bupropiona, a vareniclina mostrou-se mais eficaz tanto na abstinência aos 6 meses (RR 1,39; IC95% 1,25 ­ 1,54), como na abstinência às 52 semanas (RR 1,52; IC95% 1,22 ­ 1,88), ambas com tratamento usual (12 semanas). Na comparação com TRN isolada, a vareniclina também mostrou uma eficácia maior para abstinência aos 6 meses (RR 1,25; IC95% 1,14 ­ 1,37), ambas com tratamento usual (12 semanas). Contudo, quanto se compara a vareniclina com a combinação de TRN (CTRN), não foi verificada diferença entre os tratamentos (OR 1,06; IC95% 0,75-1,48). Resultado similar foi verificado em um ECR que avaliou a comparação direta entre a CTRN e vareniclina, a taxa de cessação do tabagismo após seis meses foi estatisticamente semelhante entre os grupos, correspondendo a 26,8% e 23,6%, respectivamente. Os eventos adversos moderados significativamente mais frequentes para vareniclina foram: náusea, insônia, sonhos anormais e dor de cabeça. Depressão e ideação suicida não apresentaram associação com o uso de vareniclina. Por fim, observou-se um risco aumentado de 25% de eventos adversos sérios para a utilização de vareniclina em comparação ao placebo (RR 1,25; IC25% 1,04 - 1,49). AVALIAÇÃO ECONÔMICA: O tratamento com vareniclina não se mostrou mais custo-efetivo que o tratamento com CTRN, sendo a vareniclina uma alternativa dominada pela CTRN, com mesma efetividade e custo médio por paciente superior. Os resultados para a simulação probabilística (Monte Carlo de 1ª e 2ª ordem) com 10.000 simulações de 3.000 pacientes foram similares e a razão de custo-efetividade incremental da CTRN quando comparada à alternativa não dominada de monoterapia com bupropiona foi de R$ 2.106,32/QALY. A CTRN apresentou razão de custoefetividade incremental favorável inclusive em limiares de disposição a pagar restritos, apresentando 100% de probabilidade de ser custo-efetiva no limiar de 0,5 PIB perca pita. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Ambas as tecnologias mostraram grande variação dentro dos diversos cenários simulados em comparação à TRN isolada e à bupropiona. O impacto orçamentário da vareniclina variou entre R$ 14.155.153,65 a R$ 208.083.216,00, e o da CTRN (forma lenta e rápida de liberação de nicotina) variou entre R$ 9.574.166,25 a R$ 290.210.250,00. Tal variação mostra a necessidade de se avaliar as incertezas relacionados ao uso dos medicamentos, como a quantidade média consumida, a estrutura do sistema de saúde, a proporção de pacientes que teriam acesso a prescrição médica e o orçamento disponível, de forma a obter o menor impacto orçamentário com a estratégia mais custo-efetiva. RECOMENDAÇÃO PRELIMINAR: O Plenário, na reunião da CONITEC realizada em 08 de maio de 2019, considerou que o modelo de tratamento para a cessação do tabagismo adotado no Brasil já preconiza e disponibiliza a utilização de farmacoterapia adjuvante pelo SUS (TRN e Cloridrato de Bupropiona). Não há evidência científica, até o momento, da superioridade da vareniclina para a cessação do tabagismo, quando comparada com a combinação de duas TRN (forma lenta e rápida de liberação de nicotina) e a avaliação econômica mostrou a vareniclina como opção dominada em relação à combinação de TRN. Portanto, emitiu-se recomendação preliminar pela não incorporação no SUS da vareniclina (Champix®) para o tratamento do tabagismo. CONSULTA PÚBLICA: Foram recebidas 8 contribuições técnico-científicas e 39 contribuições de experiência ou opinião, a maioria discordante com a recomendação preliminar da CONITEC. Não foram apresentados dados de eficácia, segurança, custo-efetividade e impacto orçamentário, relacionados a comparação da vareniclina com a CTRN, para contra argumentar os dados apresentados nesse relatório. A CONITEC entendeu que não houve argumentação que justificasse a alteração da sua recomendação inicial. RECOMENDAÇÃO FINAL: Os membros da CONITEC em 03/07/2019 deliberaram por recomendar a não incorporação no SUS da vareniclina (Champix®) para dependência à nicotina. Foi assinado o Registro de Deliberação nº 468/2019. DECISÃO: Não incorporar a vareniclina para a cessação do tabagismo, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 41, publicada no Diário Oficial da União nº 61, seção 1, página 148, em 25 de julho de 2019.


Asunto(s)
Humanos , Tabaquismo/tratamiento farmacológico , Cese del Hábito de Fumar/métodos , Vareniclina/uso terapéutico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
9.
MedEdPORTAL ; 15: 10812, 2019 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-31139731

RESUMEN

Introduction: Though the prevalence of smoking has decreased, it remains the second leading risk for early death and disability worldwide. At the primary care level, the combined use of behavioral interventions and pharmacotherapy has been shown to be more effective in reduction of smoking. Among behavioral interventions, cognitive behavioral therapy (CBT) provides a useful framework for helping patients quit smoking. Methods: This 90-minute workshop was led by two facilitators, a general internist who practices as a primary care physician and a clinical psychologist with content expertise in CBT. This pairing provided complementary perspectives to allow for learner engagement. To evaluate the workshop, we used a pre-/postsurvey that was administered at the beginning and the end of the workshop. Participants were asked how often they incorporated (presurvey) and intended to incorporate (postsurvey) CBT as part of smoking cessation counseling in their clinical practices. Results: There was a statistically significant change in learners' perceived usefulness of CBT for smoking cessation from pre- to postworkshop. Discussion: Our workshop is a unique contribution to the literature. Limitations of our study include not knowing the long-term effect of knowledge acquisition or decay. Our future direction will be to produce training that applies CBT to other common chronic diseases that have a huge behavioral component in primary care, such as insomnia, chronic pain, and obesity.


Asunto(s)
Terapia Cognitivo-Conductual , Internado y Residencia , Atención Primaria de Salud , Cese del Hábito de Fumar , Tabaquismo/tratamiento farmacológico , Adulto , Femenino , Humanos , Masculino
10.
Drug Alcohol Depend ; 200: 26-33, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31082665

RESUMEN

BACKGROUND: People living with HIV/AIDS (PLWH) smoke tobacco at higher rates and have more difficulty quitting than the general population, which contributes to significant life-years lost. The effectiveness of varenicline, one of the most effective tobacco dependence treatments, is understudied in HIV. We evaluated the safety and efficacy of varenicline for smoking cessation among PLWH. METHODS: This was a single-site randomized, double-blind, placebo-controlled, phase 3 clinical trial (NCT01710137). PLWH on antiretroviral therapy (ART) who were treatment-seeking daily smokers were randomized (1:1) to 12 weeks of varenicline (n = 89) or placebo (n = 90). All participants were offered six smoking cessation behavioral counseling sessions. The primary outcome was 7-day point prevalence abstinence, confirmed with breath carbon monoxide, at Weeks 12 and 24. Continuous abstinence and time to relapse were secondary outcomes. Safety measures were treatment-related side effects, adverse events, blood pressure, viral load, and ART adherence. RESULTS: Of the 179 smokers, 81% were African American, and 68% were male. Varenicline increased cessation at Week 12 (28.1% vs. 12.1%; OR = 4.54, 95% CI:1.83-11.25, P = .001). Continuous abstinence from Week 9 to 12 was higher for varenicline vs. placebo (23.6% vs. 10%; OR = 4.65, 95% CI:1.71-12.67, P = .003); at Week 24, there was no effect of varenicline for point prevalence (14.6% vs. 10%), continuous abstinence (10.1% vs. 6.7%), or time to relapse (Ps > .05). There were no differences between varenicline and placebo on safety measures (Ps > .05). CONCLUSIONS: Varenicline is safe and efficacious for short-term smoking cessation among PLWH and should be used to reduce tobacco-related life-years lost in this population.


Asunto(s)
Infecciones por VIH/tratamiento farmacológico , Fumadores , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Cese del Hábito de Fumar/métodos , Tabaquismo/tratamiento farmacológico , Vareniclina/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Femenino , Infecciones por VIH/epidemiología , Infecciones por VIH/psicología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Fumadores/psicología , Cese del Hábito de Fumar/psicología , Agentes para el Cese del Hábito de Fumar/efectos adversos , Tabaquismo/epidemiología , Tabaquismo/psicología , Resultado del Tratamiento , Vareniclina/efectos adversos , Adulto Joven
11.
Obes Rev ; 20(6): 895-905, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30816006

RESUMEN

Smoking cessation is a public health priority to reduce smoking-related morbidity and mortality. However, weight gain is a known primary reason for not trying to quit smoking. The aim of the current study was to investigate differences in weight gain associated with different pharmacological smoking cessation interventions. Randomized controlled trials (RCTs) that reported weight gain related to pharmacologic treatments for smoking cessation were analysed using network meta-analysis with a random effects model. Thirty-one RCTs with 5650 participants were included. Ten drugs and 22 regimens were identified. Nicotine patches plus fluoxetine, topiramate with/without nicotine patches, nicotine patches plus methylphenidate, nicotine spray/gum/lozenges, high-dose nicotine patches (42 mg/21 mg), naltrexone with/without nicotine patches, or bupropion with/without nicotine patches were associated with less weight gain than the placebo/control arm. Nicotine patches plus fluoxetine were associated with the least weight gain of all smoking cessation treatments. In addition, the nicotine patch plus topiramate and nicotine inhaler was associated with the best success rate and the least dropout rate, respectively. Overall, the nicotine patch 14 mg plus fluoxetine 40 mg, nicotine patch 14 mg plus fluoxetine 20 mg, and topiramate 200 mg would be the three best pharmacologic treatments based upon both weight gain effect and success rate.


Asunto(s)
Cese del Hábito de Fumar/métodos , Tabaquismo/tratamiento farmacológico , Aumento de Peso/efectos de los fármacos , Humanos , Resultado del Tratamiento
13.
Pharm Biol ; 57(1): 8-12, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30707857

RESUMEN

CONTEXT: Nicotine, a bioactive component of tobacco, is highly addictive. Numerous therapies have been developed for smoking cessation, and all have met with limited success. Our laboratory has previously shown that an extract of Passiflora incarnata Linn. (Passifloraceae) antagonized the expression of nicotine locomotor sensitization in rats. OBJECTIVE: This study examined the ability of vitexin, a flavonoid found in P. incarnata, to ameliorate the signs of nicotine sensitization in rats. MATERIALS AND METHODS: Male Wistar rats were administered 0.4 mg/kg nicotine or vehicle (n = 16-18 per group) once a day for four consecutive days. Nicotine administration produces sensitization of locomotor activity. On the fifth day, locomotor activity was monitored as rats from each treatment group were administered either 30 or 60 mg/kg vitexin or its vehicle (n = 4-6 per group) 30 min before a challenge dose of 0.4 mg/kg nicotine. RESULTS: The challenge dose of nicotine resulted in locomotor activity in rats sensitized to nicotine for 4 days that was approximately twice that measured in rats treated with vehicle during the sensitization phase. Rats sensitized to nicotine and then treated with 60 mg/kg vitexin prior to the nicotine challenge exhibited a level of locomotor activity equivalent to the vehicle-treated controls. DISCUSSION: Vitexin antagonized the expression of nicotine locomotor sensitization in rats as the whole extract did in the previous study. CONCLUSION: Vitexin should be examined in future studies to evaluate its potential for treating nicotine addiction in humans.


Asunto(s)
Apigenina/farmacología , Nicotina/farmacología , Cese del Hábito de Fumar/métodos , Animales , Locomoción/efectos de los fármacos , Masculino , Antagonistas Nicotínicos/farmacología , Passiflora/química , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Tabaquismo/tratamiento farmacológico
14.
Psychopharmacology (Berl) ; 236(6): 1887-1900, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30758525

RESUMEN

RATIONALE AND OBJECTIVES: Simultaneous alcohol and nicotine consumption occurs in the majority of individuals with alcohol use disorder (AUD) and nicotine dependence. Varenicline (Var) is used to assist in the cessation of nicotine use, while naltrexone (Nal) is the standard treatment for AUD. Despite evidence that ethanol (EtOH) and nicotine (NIC) co-use produces unique neuroadaptations, preclinical research has focused on the effects of pharmacotherapeutics on a single reinforcer. The current experiments examined the effects of Var and Nal on EtOH, NIC, or EtOH+NIC intake. METHODS: Animals were randomly assigned to one of four drinking conditions of 24-h access to a three-bottle choice paradigm, one of which always contained water. Drinking conditions were water only, 0.07 and 0.14 mg/mL NIC (NIC only), 15% and 30% EtOH (EtOH only), or 15% and 30% EtOH with 0.14 mg/mL NIC (EtOH+NIC). The effects of Var (0, 1, or 2 mg/kg) or Nal (0, 1, or 10 mg/kg) injections on maintenance and relapse consumption were determined during four consecutive days. RESULTS: Var reduced maintenance and relapse NIC intake but had no effect on EtOH or EtOH+NIC drinking. Conversely, Nal reduced EtOH maintenance and relapse drinking, but had no effect on NIC or EtOH+NIC drinking. DISCUSSION: The results indicate the standard pharmacological treatments for nicotine dependence and AUD were effective at reducing consumption of the targeted reinforcer but neither reduced EtOH+NIC co-use/abuse. These findings suggest that co-abuse may promote unique neuroadaptations that require models of polysubstance abuse to develop pharmacotherapeutics to treat AUD and nicotine dependence.


Asunto(s)
Consumo de Bebidas Alcohólicas/tratamiento farmacológico , Etanol/administración & dosificación , Naltrexona/administración & dosificación , Nicotina/administración & dosificación , Tabaquismo/tratamiento farmacológico , Vareniclina/administración & dosificación , Disuasivos de Alcohol/administración & dosificación , Consumo de Bebidas Alcohólicas/genética , Consumo de Bebidas Alcohólicas/psicología , Animales , Femenino , Inyecciones Subcutáneas , Distribución Aleatoria , Ratas , Autoadministración , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Tabaquismo/genética , Tabaquismo/psicología
15.
Biomed Pharmacother ; 112: 108630, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30797147

RESUMEN

5-HT3R antagonists such as ondansetron, granisetron and tropisetron have been clinically used to treat nausea and vomiting in chemotherapy patients. However, current study and research revealed novel potentials of these ligands in other diseases like inflammation, Alzheimer's, and drug abuse. Towards utilising these drugs as anti-smoking agents to treat nicotine dependence problem, there are conflicting reports regarding the potential of these ligands in modulating the effects of nicotine in both human and animal behavioural studies. This is complicated by the heterogeneity of 5-HT3R itself, cross regulation between nicotinic acetylcholinergic receptor (nAChR) and distinct pharmacological profiles of 5-HT3R antagonists. This review gathered existing studies conducted investigating the potential of "-setron" class of 5-HT3R antagonists in modulating nicotine effects. We proposed that the mechanism where 5-HT3R antagonists mediate the effects of nicotine could be attributed by both direct at 5-HT3R and indirect mechanism in nicotine addiction downstream regulation. The indirect mechanism mediated by the 5-HT3R antagonist could be through α7 nAChR, 5-HT1B receptor (5-HT1BR), 5-HT1C receptor (5-HT1CR), calcineurin activity, p38 MAPK level, PPAR-γ and NF-κß. Our review suggested that future studies should focus on newer 5-HT3R antagonist with superior pharmacological profile or the one with multitarget action rather than high selectivity at single receptor.


Asunto(s)
Palonosetrón/farmacología , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas del Receptor de Serotonina 5-HT3/farmacología , Tabaquismo/tratamiento farmacológico , Humanos , Palonosetrón/uso terapéutico , Receptores de Serotonina 5-HT3/genética , Antagonistas del Receptor de Serotonina 5-HT3/uso terapéutico , Tabaquismo/genética , Tabaquismo/metabolismo
16.
Artículo en Inglés | MEDLINE | ID: mdl-30605063

RESUMEN

BACKGROUND: The morbidity and mortality associated with tobacco smoking is well established. Nicotine is the addictive component of tobacco. Nicotine, through the non-neuronal α7nicotinic receptor, induces cell proliferation, neo-angiogenesis, epithelial to mesenchymal transition, and inhibits drug-induced apoptosis. OBJECTIVE: To understand the genetic, molecular and cellular biology of addiction, chronic obstructive pulmonary disease and lung cancer. METHODS: The search for papers to be included in the review was performed during the months of July- September 2018 in the following databases: PubMed (http://www.ncbi.nlm.nih.gov), Scopus (http://www.scopus.com), EMBASE (http://www.elsevier.com/online-tools/embase), and ISI Web of Knowledge (http://apps.webofknowledge.com/). The following searching terms: "nicotine", "nicotinic receptor", and "addiction" or "COPD" or "lung cancer" were used. Patents were retrieved in clinicaltrials.gov (https://clinicaltrials.gov/). All papers written in English were evaluated. The reference list of retrieved articles was also reviewed to identify other eligible studies that were not indexed by the above-mentioned databases. New experimental data on the ability of nicotine to promote transformation of human bronchial epithelial cells, exposed for one hour to Benzo[a]pyrene-7,8-diol-9-10-epoxide, are reported. RESULTS: Nicotinic receptors variants and nicotinic receptors upregulation are involved in addiction, chronic obstructive pulmonary disease and/or lung cancer. Nicotine through α7nicotinic receptor upregulation induces complete bronchial epithelial cells transformation. CONCLUSION: Genetic studies highlight the involvement of nicotinic receptors variants in addiction, chronic obstructive pulmonary disease and/or lung cancer. A future important step will be to translate these genetic findings to clinical practice. Interventions able to help smoking cessation in nicotine dependence subjects, under patent, are reported.


Asunto(s)
Neoplasias Pulmonares/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Agentes para el Cese del Hábito de Fumar/metabolismo , Fumar Tabaco/metabolismo , Tabaquismo/metabolismo , Animales , Humanos , Neoplasias Pulmonares/inducido químicamente , Neoplasias Pulmonares/tratamiento farmacológico , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/uso terapéutico , Patentes como Asunto , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Receptores Nicotínicos/metabolismo , Factores de Riesgo , Cese del Hábito de Fumar/métodos , Agentes para el Cese del Hábito de Fumar/farmacología , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Fumar Tabaco/tratamiento farmacológico , Tabaquismo/tratamiento farmacológico
17.
Brain Behav Immun ; 75: 228-239, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30391635

RESUMEN

Nicotine withdrawal is associated with cognitive deficits including attention, working memory, and episodic memory impairments. These cognitive deficits are a hallmark of nicotine abstinence which could be targeted in order to prevent smoking relapse. The underlying mechanisms, however, are poorly understood. In this study, memory impairment was observed in mice 4 days after the precipitation of nicotine withdrawal by the nicotinic antagonist mecamylamine. The presence of cognitive deficits correlated with microglial activation in the hippocampus and the prefrontal cortex. Moreover, an increased expression of neuroinflammatory markers including IL1ß, TNFα and IFNγ was found in both memory-related brain regions. Notably, flow cytometric analysis also revealed an enhancement of TNFα and IFNγ plasmatic levels at the same time point during nicotine withdrawal. Impaired neurogenesis, as shown by reduction in the expression of the endogenous cell proliferation marker Ki67 and the early neuron marker doublecortin, was also associated with nicotine abstinence. Treatment with the non-psychoactive cannabinoid cannabidiol abolished memory impairment of nicotine withdrawal and microglia reactivity, reduced the expression of IL1ß and IFNγ in the hippocampus and the prefrontal cortex, respectively, and normalized Ki67 levels. The nonsteroidal anti-inflammatory drug indomethacin also prevented cognitive deficits and microglial reactivity during withdrawal. These data underline the usefulness of anti-inflammatory agents to improve cognitive performance during early nicotine abstinence.


Asunto(s)
Antiinflamatorios/uso terapéutico , Cognición/fisiología , Tabaquismo/tratamiento farmacológico , Animales , Atención , Encéfalo/metabolismo , Cannabidiol/farmacología , Trastornos del Conocimiento/complicaciones , Disfunción Cognitiva/complicaciones , Disfunción Cognitiva/etiología , Hipocampo/metabolismo , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Memoria a Corto Plazo/fisiología , Ratones , Ratones Endogámicos C57BL , Microglía/metabolismo , Nicotina/metabolismo , Agonistas Nicotínicos/farmacología , Corteza Prefrontal/metabolismo , Fumar , Cese del Hábito de Fumar/métodos , Tabaquismo/inmunología
18.
Telemed J E Health ; 25(5): 425-431, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30048208

RESUMEN

Introduction: While smoking remains one of the leading causes of death in Mexico, uptake of evidence-based cessation therapy remains low. Widespread use of mobile devices and internet in Mexico has created new avenues for providing access to cessation treatment. Methods: We assessed the feasibility and acceptability of "Vive Sin Tabaco… ¡Decídete!" (English: Live without Tobacco…. Decide!), a web-based, informed decision-making tool designed to help Mexican smokers develop a quit plan and take advantage of cessation resources. We invited 164 smokers in two primary care clinics. Measures included physical, situational, and psychological nicotine dependence, interest in using pharmacotherapy and counseling, smoking status at 3 months, and satisfaction with the program. Results: Most participants were light smokers and reported low-to-moderate nicotine dependence. Immediately after using ¡Vive Sin Tabaco… ¡Decídete!, the majority were interested in quitting, set a quit date, and reported interest in using pharmacotherapy and cessation counseling. Follow-up rate at 3 months was 81.5%; seven-day point prevalence abstinence was 19.1% using intention-to-treat analysis. Conclusion: Integration of e-Health tools in primary healthcare settings has the potential to improve knowledge about cessation treatments among smokers and integrate smoking cessation into routine of care.


Asunto(s)
Computadoras de Mano , Técnicas de Apoyo para la Decisión , Cese del Hábito de Fumar/métodos , Telemedicina/métodos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Consejo/métodos , Toma de Decisiones , Estudios de Factibilidad , Femenino , Humanos , Masculino , México , Persona de Mediana Edad , Atención Primaria de Salud , Agentes para el Cese del Hábito de Fumar/uso terapéutico , Tabaquismo/tratamiento farmacológico , Tabaquismo/epidemiología , Adulto Joven
19.
Addiction ; 114(3): 515-522, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30370685

RESUMEN

BACKGROUND AND AIMS: Nicotine replacement therapy (NRT) may be more effective in aiding smoking cessation if higher doses of nicotine from it can be tolerated. We examined the responses to, and 4-week abstinence rates observed, when titrating the dose of transdermal nicotine patch up to 84 mg/day over 4 weeks prior to a target quit date and titrating down again over 4 weeks afterwards. DESIGN: Clinical cohort study. SETTING: Tobacco dependence clinic, Mar del Plata, Argentina. PARTICIPANTS: Fifty smokers seeking help with stopping smoking. INTERVENTION: Participants started on one 21-mg/24-hour patch 4 weeks prior to their target quit day (TQD). The dose was increased weekly by adding a 21-mg patch unless participants reported adverse effects and/or did not wish to increase the dose. The dose was reduced by 21 mg/day each week from 1 week post-TQD, until it reverted to the standard dose (21 mg/day) at 4 weeks post-TQD. Participants received weekly behavioural support and could also use oral NRT from the TQD. Participants were advised to smoke ad libitum during the pre-quit period. MEASUREMENTS: Proportion of participants progressing through each stage of dosing, adherence, adverse effects, changes in cigarette consumption, smoke intake and enjoyment of smoking during the pre-quit period; withdrawal symptoms; carbon monoxide-validated abstinence during 4 weeks post-TQD. FINDINGS: Of the 50 participants, 72.0% (n = 36) progressed to the 84-mg nicotine dose and 94.0% (n = 47) completed the trial. Adverse effects consisted primarily of nausea and were mild and well tolerated. Cigarette consumption, smoke intake and enjoyment of smoking declined significantly during the pre-quit period. Forty-one (82%) participants achieved 4 weeks validated abstinence. Abstainers experienced no detectable cigarette withdrawal symptoms. CONCLUSIONS: Most smokers seeking help with stopping appear to be able to tolerate doses of transdermal nicotine patch up to 84 mg/day during a 4-week pre-quit up-titration period with minimal side effects.


Asunto(s)
Nicotina/administración & dosificación , Agentes para el Cese del Hábito de Fumar/administración & dosificación , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco , Tabaquismo/tratamiento farmacológico , Adulto , Estudios de Factibilidad , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad
20.
Pharmacol Biochem Behav ; 176: 16-22, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30419272

RESUMEN

Tobacco addiction each year causes millions of deaths worldwide. Brain nicotinic acetylcholine receptors have been shown to be central to tobacco addiction. Nicotine replacement therapy aids tobacco cessation, but the success rate is still far too low. This may in part be due to the fact that neurons with nicotinic receptors are not the only neural systems involved in tobacco addiction. Interacting neural systems also play important roles in tobacco addiction. Nicotine increases the release of a variety of neurotransmitters, including dopamine and serotonin. Dopamine, in particular dopamine D1 receptors, has been shown to be involved in the reinforcing action of nicotine. Serotonin through its actions on 5-HT2C receptors has been shown to play a key role in modulating the reinforcement of addictive drugs, including nicotine and alcohol. Combination of treatments could provide greater treatment efficacy. These studies were conducted to evaluate combination therapies utilizing nicotine replacement therapy in conjunction with either a dopamine D1 receptor antagonist SCH-23390 or a serotonin 5-HT2C receptor agonist, lorcaserin. Female Sprague-Dawley rats were given access to self-administer nicotine via IV infusions. Osmotic pumps were implanted to reproduce the kinetic of chronic nicotine patch therapy. SCH-23390 (0.02 mg/kg) or lorcaserin (0.6 mg/kg) were administered prior to nicotine self-administration sessions. Reproducing earlier findings SCH-23390, lorcaserin and nicotine replacement therapy were effective at reducing IV nicotine self-administration. 5HT2C agonist treatment had additive effects with chronic nicotine infusion for significantly lowering nicotine self-administration. This study demonstrates the feasibility of combination of chronic nicotine with therapies targeting non-nicotinic receptors as treatment options for tobacco addiction.


Asunto(s)
Benzazepinas/farmacología , Benzazepinas/uso terapéutico , Nicotina/administración & dosificación , Receptores de Dopamina D1/antagonistas & inhibidores , Agonistas del Receptor de Serotonina 5-HT2/uso terapéutico , Tabaquismo/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Benzazepinas/administración & dosificación , Quimioterapia Combinada , Femenino , Bombas de Infusión Implantables , Nicotina/farmacología , Ratas , Ratas Sprague-Dawley , Autoadministración , Agonistas del Receptor de Serotonina 5-HT2/administración & dosificación , Cese del Hábito de Fumar/métodos , Dispositivos para Dejar de Fumar Tabaco
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