RESUMEN
BACKGROUND: Neisseria meningitidis serogroup B is a well-recognized cause of bacterial meningitis and sepsis for which no broadly protective vaccine exists. Whole genome sequencing was used to identify three antigens: factor H binding protein (fHbp), Neisserial adhesin A (NadA), and Neisseria heparin binding antigen (NHBA) for an investigational vaccine candidate (rMenB). This was the first trial of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB), containing rMenB and outer membrane vesicles (OMV) from the New Zealand epidemic strain in humans. RESULTS: Seventy adults enrolled and received study vaccine. All vaccines were generally well tolerated. Immune responses were observed to multiple serogroup B strains following all investigational vaccines, suggesting the potential for broad coverage against this serogroup. Immunogenicity was enhanced by the addition of OMV; the 4CMenB displayed the optimal profile for further investigation. METHODS: In a phase I, observer blind, randomized trial, healthy adults (18-40 years of age) were randomized 2:2:1 to receive 3 doses of 4CMenB, rMenB with OMV from the Norwegian outbreak strain, or rMenB alone. Pre- and postvaccination sera were evaluated in a serum bactericidal assay using human complement (hSBA) against a panel of 15 serogroup B strains, with titers ≥ 4 considered protective. Solicited injection site and systemic reactions were evaluated for 7 days following each vaccination and adverse events were reported throughout the study. CONCLUSION: In this trial, 4CMenB displayed a favorable profile for further clinical development. 4CMenB demonstrated immunogenicity against multiple heterologous serogroup B strains. All vaccines were generally well tolerated in this study.
Asunto(s)
Vacunas Meningococicas/inmunología , Neisseria meningitidis Serogrupo B/inmunología , Adolescente , Adulto , Proteínas de la Membrana Bacteriana Externa/inmunología , Femenino , Humanos , Masculino , Estudios ProspectivosRESUMEN
Fluoxetine hydrochloride (CAS 59333-67-4) is a selective serotonin reuptake inhibitor (SSRI) widely used as antidepressant drug. The aim of the present trial was to assess the bioequivalence of a new formulation of the drug (test formulation) as compared to a reference product from the Swiss market. Both drugs were available as 20 mg dispersible tablets. The trial was performed according to a two-period, two-sequence, balanced, randomised, single-dose design with a wash-out phase of at least 56 days. The two formulations were tested in 30 male healthy volunteers. A specific highly sensitive bioassay in tandem mass spectrometry allowed to set the limit of quantification to 100 pg/ml for fluoxetine and norfluoxetine. Average t(max) was 5.4 h for fluoxetine and 71-80 h for norfluoxetine. The peak concentration was on average 14 ng/ml for fluoxetine and 10.5 ng/ml for norfluoxetine. Half-life was on average 48-50 h for fluoxetine and 130-138 h for norfluoxetine. AUC infinity for fluoxetine and norfluoxetine were on average 790 and 2800 ng x ml(-1) x h, respectively. All these figures demonstrate that plasma concentration-time profiles of fluoxetine and norfluoxetine are quite different. Applied statistical tests, suggested by operating guidelines, demonstrated bioequivalence of the test formulation and the reference formulation. The conclusion on bioequivalence was based on both fluoxetine and norfluoxetine results. 90 % confidence Intervals for Cmax, AUCt and AUC infinity (fluoxetine and norfluoxetine) were within the acceptance range (0.80-1.25) and t(max), processed with a non-parametric test, did not show any statistically significant difference between test and reference formulation. Safety and tolerability proved to be similarly good with both test and reference formulation. In conclusion, the present trial has demonstrated bioequivalence of the test and the reference formulation, both consisting of fluoxetine hydrochloride dispersible tablets.
Asunto(s)
Fluoxetina/administración & dosificación , Fluoxetina/farmacocinética , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Química Farmacéutica , Estudios Cruzados , Método Doble Ciego , Fluoxetina/efectos adversos , Fluoxetina/análogos & derivados , Semivida , Humanos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Equivalencia TerapéuticaRESUMEN
OBJECTIVE: This paper describes the pharmacokinetics and the pharmacodynamics, in terms of monoamino oxidase type B (MAO-B) inhibition, in male healthy volunteers of orally administered safinamide, a new neuroprotectant that in experimental models has demonstrated strong anticonvulsant and antiparkinson activities. METHODS: Four clinical trials covering the dose range of 25-10,000 microg/kg were carried out to describe pharmacokinetics, pharmacodynamics and tolerability of safinamide, administered in single or repeated dose regimen to steady state, including a food interaction trial. All the above trials were carried out after the Ethics Committee's approval and signature of the consent form by the volunteers. In single dose trials blood sampling covered a 24 h-period in pharmacodynamic trials, 48 h-period in pharmacokinetic trials. In the case of repeated dose regimen to steady state a pre-dose sample was drawn on the first six study days, whereas the curve was explored on the 7th study day, prolonging blood sampling over a 48 h-period after the last dosing. Safinamide level was determined in plasma by a very sensitive and specific LC-MS-MS method, with a low limit of quantification of 0.5 ng/ml of plasma. Pharmacokinetic analysis was carried out with non-compartmental method and, in one case, also with the two-compartmental method. Monoamine oxidase activity of both types A and B (MAO-A and MAO-B) was determined in plasma at different times (MAO-B) and correlated to safinamide levels, or in urine (MAO-A). RESULTS: Pharmacokinetics of safinamide proved to be linearly and proportionally related to the administered doses. The absorption of safinamide was rapid with peak plasma concentrations ranging from 2 to 4 h. Food prolonged the rate and did not affect the extent of absorption of safinamide. In repeat dose regimen once daily, the steady state was reached on the 5th study day with a marginal accumulation factor of 1.5-1.7. The drug was cleared with a t(1/2) of about 22 h. Safinamide reversibly inhibited MAO-B enzyme. Full inhibition was observed with single doses >/= 600 microg/kg, and a relevant, dose dependent, progressive inhibition was encountered with doses starting from 25 microg/kg. Even at the highest single dose of 10 mg/kg no evidence of MAO-A inhibition was observed. CONCLUSION: Enteral absorption of the drug is linear and proportional to the doses administered. The drug is cleared from the body with a t(1/2) of approximately equal to 22 h, without producing any clinically relevant accumulation at steady state. The MAO-B inhibitory activity, without affecting MAO-A, is useful to prevent a dopamine bioinactivation in patients suffering from Parkinson's disease. Safinamide tolerability in the four clinical trials proved to be good.
Asunto(s)
Alanina/análogos & derivados , Alanina/farmacocinética , Anticonvulsivantes/farmacocinética , Antiparkinsonianos/farmacocinética , Bencilaminas/farmacocinética , Fármacos Neuroprotectores/farmacocinética , Adolescente , Adulto , Alanina/administración & dosificación , Alanina/farmacología , Anticonvulsivantes/administración & dosificación , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Área Bajo la Curva , Bencilaminas/administración & dosificación , Bencilaminas/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Dieta , Grasas de la Dieta/farmacología , Relación Dosis-Respuesta a Droga , Electrocardiografía/efectos de los fármacos , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Monoaminooxidasa/sangre , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/administración & dosificación , Fármacos Neuroprotectores/farmacología , Reproducibilidad de los Resultados , TelemetríaRESUMEN
Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout. ACE activity in serum and zofenopril, zofenoprilat, enalapril and enalaprilat plasma concentrations were determined during and on the last day of the two study periods. Both zofenopril and enalapril were extensively converted through hydrolysis to their active metabolites zofenoprilat and enalaprilat, respectively. Zofenopril exhibited a complete and a more rapid hydrolysis rate compared to enalapril, which is reflected by the higher metabolite to parent drug ratio of Cmax and AUCss, tau showed by this compound. Even though only two dose levels were investigated in this trial, the pharmacokinetics of both drugs seem to be linear. In line with previous trials, both compounds at both dose levels investigated produced complete or almost complete inhibition of ACE activity in serum, for a period lasting 6-8 h after administration, the inhibition being still relevant 24 h thereafter. The tolerability of the two drugs at both dose levels proved to be very good as demonstrated by subjective and objective symptoms, by the absence of relevant adverse events, and by laboratory biochemical parameters and vital signs evaluated before and after the trial. Blood pressure showed a fairly decreasing trend with both the drugs, systolic and diastolic blood pressure values being however within normal range in all the subjects. In no case symptoms of hypotension were experienced. In conclusion, zofenopril calcium and enalapril maleate show very good tolerability and appear to exert similar activity on serum ACE. The main difference in the pharmacokinetics of the two compounds is the conversion from pro-drug to the active metabolite which is faster with zofenopril.