Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVES: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870. METHODS: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned. RESULTS: Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred. CONCLUSION: HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

Coumarin analogue 3-methyl-7H-furo[3,2-g]chromen-7-one as a possible antiparkinsonian agent / El análogo de cumarina 3-metil-7H-furo[3,2-g]cromen-7-ona, un posible agente antiparkinsoniano

Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.

Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.

Orientaçöes básicas para os enfermeiros na ministraçäo de psicofármacos / Basic orientations to nurses for psichopharmaco ministration

Com este trabalho os autores querem contribuir para que o enfermeiro tenha mais uma referência norteadora de sua açäo ao sentir o paciente que faz uso de psicofármacos. Säo descritos os grupos farmacológicos e destacadas as consideraçöes sobre o emprego dos mesmos.

Transtornos relacionados ao estresse: aspectos diagnósticos e opçöes terapêuticas / Stress related disorders: diagnostic features and treatment options

Os transtornos relacionados ao estresse pós-traumático - transtorno de estresse pós-traumático e transtorno agudo de estresse - têm recebido cada vez maior atençäo de clínicos e pesquisadores. Um quadro típico de sintomas surge após um indivíduo ver, estar envolvido, ou apenas ouvir sobre um evento extremamente estressor. As principais características clínicas säo a recordaçäo aflitiva do trauma, um padräo de evitaçäo de estímulos relacionados ao trauma e distanciamento afetivo, e uma constante hiperestimulaçäo autonômica. O tratamento envolve psicoterapia cognitivo-comportamental e o uso de psicofármacos

Moclobemida no tratamento da fobia social / Moclobemida in the treatment of social phobia

A Fobia Social tem apresentado características que a tornam uma entidade peculiar dentro dos quadros ansiosos. Sua melhora com o tratamento farmacológico com antidepressivos vem se firmado dentro das diversas terapias utilizzadas para combatÛ-la. Baseado em estudos iniciais do uso de IMAO no tratamento da Fobia Social, este trabalho foi desenvolvido com a nova geraçÒo de IMAO com a finalidade de evitar os efeitos colaterais dos IMAOs clássicos e a restriçÒo dietÚtica. Foi usada a moclobemida, um inibidor reversÝvel e especÝfico da monoaminooxidase A. É um estudo aberto, nÒo comparativo, onde sÒo avaliados 20 casos de Fobia Social, de acordo com os critérios da DSM-III-R e CID-10. Os pacientes foram examinados semanalmente por um período de 2 meses e submetidos Ós escalas de ansiedade de HAMILTON, de Fobia Social de LIEBOWITZ e CGI de evoluçÒo, como métodos auxiliares de avaliaçÒo. Nenhum paciente foi submetido concomitantemente a tratamento psicoterápico. SÒo discutidos os resultados, assim como os dados demogrßficos, características clínicas, comorbidade e efeitos colaterais.

Effects of central epinephrine synthesis inhibition on stress-induced prolactin secretion in male rats

1. The present study was designed to examine the role of central epinephrine pathways in the control of stress-induced prolactin secretion in male adulto Wistar rats. 2. Intracerebroventricular adminsitration of two epinephrine synthesis inhibitors, SKF64139 (5 and 10 µg/rat) and LY 134046 (10 and 20 µg/rat), 6 h before the onset of immobilization stress blocked prolactin secretion in a dose-dependent manner. Prolactin values before stress were about 4.0 ng/ml and increased to almost 50 ng/ml in the control group. SKF 64139 injection in the higher dose (10 µg/rat) induced a complete blockade of the stress-induced prolactin release, whereas partial blockade was observed after the higher dose (20 µg/rat) of LY 134046. 3.Salbutamol pretreatment (10 µg/rat) completely restored stress-induced prolactin secretion in animals receiving a central injection of both epinephrine synthesis inhibitors under the same conditions as described above. 4. It is suggested that epinephrine pathways in the brain play an important role in the control of prolactin release occuring during immobilization stress

Antidepresivos inhibidores de la monoaminooxidasa / Antidepressive agents inhibitors of monoaminooxidase

Se realizó una revisión de la literatura disponible sobre la situación actual de los antidepresivos inhibidores de la monoamino-oxidasa, IMAO. Se buscaba obtener parámetros útiles en el desarrollo de un criterio en el sentido de si tienen o no utilidad actualmente. Después de una breve relación Histórica se entra a discutir el tipo de padecimientos en que los IMAO han resultado tradicionalmente beneficiosos. Se mencionan estudios comparativos y se puntualizan efectos colaterales y reacciones a otras drogas. Se concluye que los IMAO son medicamentos que conservan su indicación en desórdenes severos de ansiedad y fobia así como en aquellos casos en que fracasen otros antidepresivos