RESUMO
Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is understudied, we evaluated the potential antinociceptive effect of the reversible MAO-A inhibitors moclobemide and 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in a mouse neuropathic pain model induced by chronic constriction injury (CCI) of the sciatic nerve. Neuropathic mice showed a decreased mechanical paw withdrawal threshold (PWT) 7 days after lesion compared with the baseline PWT, characterizing the development of hyperalgesia. Moclobemide (100-300 µmol/kg, s.c.) and 2-DMPI (30-300 µmol/kg, s.c.) treatments were able to reverse the CCI-induced hyperalgesia, with 50% inhibitory dose (ID50) values of 39 (18-84) and 11 (4-33) µmol/kg, and maximum inhibition (Imax) values of 88±14 and 98±15%, respectively, at the 300 µmol/kg dose. In addition, we observed a significant increase in the MAO-A activity in the lumbar spinal cord of CCI-submitted mice compared with sham-operated animals. Furthermore, the antihyperalgesic effects of both 2-DMPI and moclobemide were largely reversed by intrathecal injection of the 5-HT3 receptor antagonist ondansetron (10 µg/site). These results suggest a possible involvement of MAO-A in the mechanisms of neuropathic pain and a potential utility of the reversible inhibitors of MAO-A in the development of new therapeutic approaches to treat it.
Assuntos
Analgésicos/uso terapêutico , Anisóis/uso terapêutico , Imidazolinas/uso terapêutico , Moclobemida/uso terapêutico , Monoaminoxidase/metabolismo , Neuralgia/tratamento farmacológico , Analgésicos/farmacologia , Análise de Variância , Animais , Anisóis/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Imidazolinas/farmacologia , Masculino , Camundongos , Moclobemida/farmacologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Pregabalina , Teste de Desempenho do Rota-Rod , Fatores de Tempo , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêuticoRESUMO
As vulvovaginites constituem causa frequente de queixa pré-natal. Entre as mais comuns, destacam-se a candidíase, a vaginose bacteriana e a tricomoníase. Permanece polêmico se o rastreamento e o tratamento dessas afecções seriam medidas eficazes contra o parto prematuro. Esta revisão teve como objetivo avaliar as principais opções terapêuticas dessas vulvovaginites durante a gestação, com base nas melhores evidências científicas disponíveis. A literatura recomenda, para tratamento durante a gravidez, o uso tópico de imidazólicos durante sete dias nos casos de candidíase. O metronidazol é boa opção para o tratamento da vaginose bacteriana (via oral ou vaginal por sete dias) e também para os casos de tricomoníase (via oral, dose única e tratamento do parceiro). Nas gestações de alto risco para o parto pré-termo, sobretudo no segundo trimestre, o uso do metronidazol merece cautela, visto poder aumentar este risco
The vulvovaginitis is frequent cause of complaints prenatal. Among the most common, stand out as candidiasis, bacterial vaginosis and trichomoniasis. It remains controversial whether screening and treatment of these conditions would be effective against premature birth. This review aimed to evaluate the main therapeutic options for these vulvovaginitis during pregnancy based on the best available scientific evidence. The literature recommends for treatment during pregnancy, topical imidazole for seven days in cases of candidiasis. Metronidazole is a good choice for the treatment of bacterial vaginosis (orally or vaginally for seven days) and also in case of trichomoniasis (orally, single dose and partners treatment). In pregnancies at high risk for preterm delivery, especially in the second quarter, the use of metronidazole merits caution, since it may increase this risk
Assuntos
Humanos , Feminino , Gravidez , Candidíase Vulvovaginal/terapia , Complicações Infecciosas na Gravidez/microbiologia , Vaginite por Trichomonas/terapia , Vaginose Bacteriana/terapia , Clindamicina/uso terapêutico , Fluconazol/uso terapêutico , Imidazolinas/uso terapêutico , Macrolídeos/uso terapêutico , Metronidazol/uso terapêutico , Trabalho de Parto Prematuro/prevenção & controleRESUMO
Monoamine oxidase (MAO) inhibitors were the first antidepressant drugs to be prescribed and are still used today with great success, especially in patients resistant to other antidepressants. In this study, we evaluated the MAO inhibitory properties and the potential antidepressant action of 2-(3,4-dimethoxy-phenyl)-4,5-dihydro-1H-imidazole (2-DMPI) in mice. We found that 2-DMPI inhibited both MAO isoforms (K(i) values were 1.53 (1.3-1.8) µM and 46.67 (31.8-68.4) µM for MAO-A and MAO-B, respectively) with 30-fold higher selectivity toward MAO-A. In relation to the nature of MAO-A inhibition, 2-DMPI showed to be a mixed and reversible inhibitor. The treatment with 2-DMPI (100-1000 µmol/kg, s.c.) caused a significant decrease in immobility time in the tail suspension test (TST) without affecting locomotor activity, motor coordination or anxiety-related activities. Conversely, moclobemide (1000 µmol/kg, s.c.) caused a significant increase in immobility time in the TST, which appeared to be mediated by a nonspecific effect on motor coordination function. 2-DMPI (300 µmol/kg, s.c.) decreased serotonin turnover in the cerebral cortex, hippocampus and striatum, whereas dopamine turnover was diminished only in the striatum, and norepinephrine turnover was not changed. The antidepressant-like effect of 2-DMPI was inhibited by the pretreatment of mice with methysergide (2 mg/kg, s.c., a non-selective serotonin receptor antagonist), WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) or haloperidol (0.05 mg/kg, i.p., a non-selective dopamine receptor antagonist). These results suggest that 2-DMPI is a prototype reversible and preferential MAO-A inhibitor with potential antidepressant activity, due to its modulatory effect on serotonergic and dopaminergic systems.
Assuntos
Anisóis/farmacologia , Antidepressivos/farmacologia , Monoaminas Biogênicas/metabolismo , Depressão/metabolismo , Imidazolinas/farmacologia , Isoenzimas/antagonistas & inibidores , Inibidores da Monoaminoxidase/farmacologia , Animais , Anisóis/antagonistas & inibidores , Anisóis/uso terapêutico , Antidepressivos/antagonistas & inibidores , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Interações Medicamentosas , Haloperidol/farmacologia , Imidazolinas/antagonistas & inibidores , Imidazolinas/uso terapêutico , Cinética , Masculino , Metisergida/farmacologia , Camundongos , Moclobemida/farmacologia , Inibidores da Monoaminoxidase/uso terapêutico , Piperazinas/farmacologia , Piridinas/farmacologiaRESUMO
Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease characterized mainly by pulmonary airflow limitation that is not fully reversible. New different pharmacological approaches to decrease inflammation of the airways and consequently disease progression and increase airway obstruction reversibility have been developed. In the present article, we review the new patents on phosphoinositide 3 kinase and NFκb inhibitors for future therapies.