4 results on '"Vaz Da Silva M"'
Search Results
2. Pharmacokinetic-pharmacodynamic interaction between nebicapone and controlled-release levodopa/benserazide: a single-center, Phase I, double-blind, randomized, placebo-controlled, four-way crossover study in healthy subjects.
- Author
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Nunes T, Machado R, Rocha JF, Fernandes-Lopes C, Costa R, Torrão L, Loureiro AI, Falcão A, Vaz-da-Silva M, Wright L, Almeida L, and Soares-da-Silva P
- Abstract
BACKGROUND: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. OBJECTIVES: The primary objective of this study was to investigate the effect of nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3-O-methylated metabolite (3-O-methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. METHODS: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of > or = 5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. RESULTS: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m2) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C(max) increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of nebicapone 50, 100, and 200 mg, respectively. After administration of nebicapone 50, 100, and 200 mg, 3-OMD C(max) decreased 44%, 57%, and 58%, and 3-OMD AUC(0-infinity) decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC(0-t), increased with all doses of nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by nebicapone occurred at approximately 1.5 hours postdose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity; T(max) of nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. CONCLUSIONS: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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3. Etamicastat, a novel dopamine β-hydroxylase inhibitor: tolerability, pharmacokinetics, and pharmacodynamics in patients with hypertension.
- Author
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Almeida L, Nunes T, Costa R, Rocha JF, Vaz-da-Silva M, and Soares-da-Silva P
- Subjects
- Adolescent, Adult, Aged, Antihypertensive Agents administration & dosage, Arylamine N-Acetyltransferase genetics, Arylamine N-Acetyltransferase metabolism, Benzopyrans administration & dosage, Blood Pressure Monitoring, Ambulatory, Dose-Response Relationship, Drug, Double-Blind Method, Heart Rate drug effects, Humans, Hypertension physiopathology, Imidazoles administration & dosage, Isoenzymes genetics, Isoenzymes metabolism, Male, Middle Aged, Phenotype, Young Adult, Antihypertensive Agents adverse effects, Antihypertensive Agents pharmacokinetics, Benzopyrans adverse effects, Benzopyrans pharmacokinetics, Blood Pressure drug effects, Dopamine beta-Hydroxylase antagonists & inhibitors, Hypertension drug therapy, Imidazoles adverse effects, Imidazoles pharmacokinetics
- Abstract
Background: Etamicastat is a dopamine β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure., Objective: This study assessed the tolerability, pharmacokinetics, and pharmacodynamics of etamicastat in patients with arterial hypertension., Methods: This randomized, double-blind, placebo-controlled study was conducted in male patients aged between 18 and 65 years with mild to moderate hypertension. Participants received once-daily doses of etamicastat 50, 100, or 200 mg or placebo for 10 days. Antihypertensive effect was assessed by 24-hour ambulatory blood pressure monitoring (ABPM)., Results: The study enrolled 23 male volunteers, with ages between 49 and 64 years. There were no serious adverse events reported. All adverse events were mild to moderate in intensity and resolved without sequelae. Etamicastat Tmax was 1 hour postdose, and mean t½ was 19 to 28 hours following repeated administration. Etamicastat underwent N-acetylation by N-acetyltransferase 2 (NAT2), forming the metabolite BIA 5-961. Following repeated administration, mean etamicastat AUC was 2- to 3-fold greater in poor acetylators than in rapid acetylators. Approximately 50% of the etamicastat dose was recovered in urine-30% as unchanged etamicastat and 20% as BIA 5-961. Dose-dependent decreases in systolic and diastolic blood pressure were observed after 10 days of treatment. The mean (95% CI) decreases versus placebo in nighttime SBP were statistically significant with all 3 etamicastat doses (50 mg, -11.66 mm Hg [-21.57 to -1.76; P < 0.05]; 100 mg, -14.92 mm Hg [-24.98 to -4.87; P < 0.01]; and 200 mg, -13.62 mm Hg [-22.29 to -3.95; P < 0.01])., Conclusions: Etamicastat was well tolerated and showed a pharmacokinetic profile consistent with a once-daily regimen. NAT2 phenotype markedly affected the pharmacokinetics. The antihypertensive effect of etamicastat, assessed by 24-hour ABPM, was dose dependent up to 100 mg. The assessment of etamicastat as a novel antihypertensive therapy requires further study in broader populations. EudraCT trial registration 2008-002789-09., (© 2013 Elsevier HS Journals, Inc. All rights reserved.)
- Published
- 2013
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4. Pharmacokinetics and tolerability of etamicastat following single and repeated administration in elderly versus young healthy male subjects: an open-label, single-center, parallel-group study.
- Author
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Nunes T, Rocha JF, Vaz-da-Silva M, Falcão A, Almeida L, and Soares-da-Silva P
- Subjects
- Adolescent, Adult, Age Factors, Aged, Area Under Curve, Arylamine N-Acetyltransferase genetics, Benzopyrans administration & dosage, Benzopyrans adverse effects, Drug Administration Schedule, Enzyme Inhibitors administration & dosage, Enzyme Inhibitors adverse effects, Genotype, Humans, Imidazoles administration & dosage, Imidazoles adverse effects, Isoenzymes genetics, Male, Time Factors, Young Adult, Benzopyrans pharmacokinetics, Dopamine beta-Hydroxylase antagonists & inhibitors, Enzyme Inhibitors pharmacokinetics, Imidazoles pharmacokinetics
- Abstract
Background: Etamicastat is a new dopamine-β-hydroxylase (DβH) inhibitor currently in clinical development for the treatment of hypertension and heart failure., Objectives: To evaluate the pharmacokinetics and tolerability of etamicastat after single and repeated administration in elderly subjects (aged ≥65 years) relative to young adult healthy controls (aged 18-45 years)., Methods: This was a single-center, open-label, parallel-group study in young male adults (n = 13; mean [SD] age 32.6 [16.4] years; range, 18-44 years; weight 79.0 [16.4] kg; systolic blood pressure 117 [12] mm Hg and diastolic blood pressure 61 [7] mm Hg) and 12 elderly male volunteers (n = 12; age 69.3 [3.3] years; weight 69.2 [9.5] kg; systolic blood pressure 115 [13] mm Hg and diastolic blood pressure 64 [4] mm Hg), conducted in 2 consecutive periods. All subjects were white, except for 1 black elderly subject. In Phase A, subjects received a single dose of 100 mg etamicastat. In Phase B, subjects received 100 mg/d etamicastat for 7 days. The pharmacokinetic parameters of etamicastat and its acetylated metabolite BIA 5-961 were calculated after the single dose of Phase A and the last dose of Phase B. Subjects' N-acetyltransferase type 1 (NAT1) and type 2 (NAT2) genotyping was performed and acetylator status inferred., Results: After a single dose of etamicastat 100 mg, mean (SD) plasma C(max) and plasma AUC(0-∞) were, respectively, 1.3 (0.5) ng/mL/kg and 12.4 (7.8) ng × h/mL/kg in elderly subjects, and 1.3 (0.4) ng/mL/kg and 10.0 (6.6) ng × h/mL/kg in young subjects. At steady-state, C(max) and AUC(0-24) were 1.8 (0.5) ng/mL/kg and 15.0 (6.4) ng × h/mL/kg in elderly subjects, and 1.5 (0.7) ng/mL/kg and 12.5 (6.5) ng × h/mL/kg in young subjects. Elderly/young geometric mean ratios and 90% CIs were, respectively, 0.944 (0.788-1.131) and 1.164 (0.730-1.855) for etamicastat C(max) and AUC(0-∞) after a single dose, and 1.225 (0.960-1.563) and 1.171 (0.850-1.612) for etamicastat C(max) and AUC(0-24) at steady state. Etamicastat steady-state plasma concentrations were reached after 3 to 4 days of dosing. The mean etamicastat accumulation ratio was 1.7 in both age groups. Following etamicastat single dose, mean (SD) BIA 5-961 C(max) and AUC(0-∞) were, respectively, 3.5 (2.1) ng/mL/kg and 28.4 (14.7) ng × h/mL/kg in elderly subjects, and 2.5 (1.5) ng/mL/kg and 16.5 (9.7) in young subjects. At steady state, BIA 5-961, C(max), and AUC(0-24) were 4.3 (2.6) ng/mL/kg and 34.6 (17.6) ng × h/mL/kg in elderly subjects, and 3.1 (2.0) ng/mL/kg and 22.2 (11.8) ng × h/mL/kg in young subjects. Large interindividual variability dependent on the NAT2 acetylator status was found in the pharmacokinetic parameters of etamicastat and BIA 5-961. Systemic exposure to etamicastat was higher and systemic exposure to BIA 5-961 was lower in NAT2 poor metabolizers compared with rapid metabolizers. No effect on heart rate and blood pressure was found in the young group. In the elderly, a decrease of supine blood pressure was observed. Postural changes in blood pressure were unaffected. Four adverse events (AEs) were reported by each group: nasopharyngeal pain, sciatica, asthenia, and back pain the elderly group, and headache (2 cases), insomnia, and myopericarditis by the young group. Myopericarditis led to study discontinuation for this subject and was considered to be of probable viral etiology. All other AEs were mild to moderate in intensity., Conclusion: The pharmacokinetic profile of etamicastat was not significantly different in these small groups of healthy young versus elderly adult male volunteers., (Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.)
- Published
- 2011
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