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Luis Almeida

Publications and source records attributed to Luis Almeida.

13 recordsLinked to original sources
PubMed2007

Eslicarbazepine acetate (BIA 2-093).

Eslicarbazepine acetate (ESL) [(S)-(--)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder. ESL shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. In pharmacokinetic studies in humans, ESL was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), which is responsible for pharmacological activity. ESL has been tested in patients with refractory partial-onset seizures and was found to be efficacious and well tolerated. Monotherapy studies in adult epileptic patients and add-on studies in epileptic children are in the planning process. The efficacy and safety data appear to be very promising considering the refractory nature of the epileptic population enrolled in studies to date. Results of ongoing phase III studies in adult epileptic patients are expected to be available in 2007 and are required to define the position of ESL in the therapy of patients with epilepsy.

Animals↗
PubMed2005

Effect of food on the pharmacokinetic profile of eslicarbazepine acetate (BIA 2-093).

OBJECTIVE: To investigate the effect of food on the pharmacokinetics of eslicarbazepine acetate (BIA 2-093), a new voltage-gated sodium channel antagonist. MATERIAL AND METHODS: Single-centre, open-label, randomised, two-way crossover study in 12 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 14 days or more. In each of the study periods subjects were administered a single dose of eslicarbazepine acetate 800 mg following either a standard high-fat content meal or 10 hours of fasting. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (C(max)) in fed (test) and fasting (reference) conditions were, respectively, 12.8 +/- 1.8 microg/mL and 11.3 +/- 1.9 microg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC(infinity)) were, respectively, 242.5 +/- 32.1 microg.h/mL and 243.6 +/- 31.1 microg.h/mL (arithmetic mean +/- SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference C(max )geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC(infinity) ratio, the PE and 90% CI were 1.00 and 0.95, 1.04, respectively. Bioavailability of eslicarbazepine acetate administered in fed and fasting conditions was similar and bioequivalence is accepted for both AUC(infinity) and C(max) because the 90% CI lies within the acceptance range of 0.80-1.25. No statistically significant differences were found in time of occurrence of C(max). CONCLUSION: The presence of food had no significant effect on the pharmacokinetics of eslicarbazepine acetate and therefore this new voltage-gated sodium channel antagonist may be administered without regard to meals.

Adult↗
PubMed2005

Eslicarbazepine acetate (BIA 2-093) : relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200mg and 800mg tablet formulations.

PURPOSE: To investigate the bioavailability and bioequivalence of three different formulations of eslicarbazepine acetate (BIA 2-093): 50 mg/mL oral suspension (test 1), 200mg tablets (test 2) and 800mg tablets (reference). DESIGN, SUBJECTS AND METHODS: Single-centre, open-label, randomised, three-way crossover study in 18 healthy subjects. The study consisted of three consecutive periods separated by a washout period of 7 days or more. Each subject received a single dose of eslicarbazepine acetate 800mg on three different occasions: 16mL of oral 50 mg/mL suspension, four 200mg tablets or one 800mg tablet. RESULTS: Eslicarbazepine acetate was rapidly and extensively metabolised to BIA 2-005. Maximum BIA 2-005 plasma concentrations (Cmax) and area under the plasma concentration-time curve from time 0 to infinity (AUCinfinity) were, respectively (arithmetic mean +/- SD), 18.0 +/- 4.6 microg/mL and 325.7 +/- 64.9 microg x h/mL for test 1, 16.0 +/- 4.0 microg/mL and 304.2 +/- 66.0 microg x h/mL for test 2, and 17.0 +/- 4.1 microg/mL and 301.1 +/- 60.0 microg x h/mL for the reference formulation. Point estimate (PE) and 90% confidence intervals (CIs) for AUCinfinity test 1/reference geometric mean ratio were 1.09 and 1.01, 1.15; for Cmax ratio, PE and 90% CI were 1.07 and 0.97, 1.15. When test 2 and the reference formulations were compared, the PE and 90% CI were 0.99 and 0.94, 1.07 for the AUCinfinity ratio, and 0.94 and 0.86, 1.02 for the Cmax ratio. Bioequivalence of test versus reference formulations is thus accepted for both AUCinfinity and Cmax because the 90% CIs lie within the acceptance range of 0.80-1.25. CONCLUSION: The pharmacokinetic profiles of eslicarbazepine acetate oral 50 mg/mL suspension, 200mg tablet and 800mg tablet formulations were essentially similar, and the formulations can be considered bioequivalent.

Administration, Oral↗
PubMed2004

Platelet hyperactivation in maintained growth hormone-deficient childhood patients after therapy withdrawal as a putative earlier marker of increased cardiovascular risk.

GH deficiency (GHD) is associated with a higher risk of vascular disease, whose pathophysiological mechanisms remains not yet fully elucidated. This study aimed to assess the main cardiovascular risk indexes, plasma catecholamines content, and the platelet function in childhood-onset GHD patients. Some of the main clinical examinations related with cardiovascular risk, plasma catecholamines content, as well as platelet intracellular free calcium concentration ([Ca(2+)](i)), whole-blood aggregation, and morphology were evaluated in childhood-onset GHD patients treated with GH for a variable period and off GH therapy for at least 2 yr before entry into study and in sex-, age-, and body mass index-matched control groups. Among the patients, group 1 (GHD-1) has recovered GH levels after withdrawal, whereas group 2 (GHD-2) has remained GH deficient. Minor differences on the cardiovascular risk indexes were observed between the groups. Plasma catecholamine concentrations in the GHD groups did not statistically differ from the control group, but higher adrenaline content was observed in the GHD-2 group when compared with the GHD-1 one. Basal and thrombin-evoked [Ca(2+)](i) and platelet aggregation were identical between the GHD-1 group and the matched control. However, the GHD-2 group has increased thrombin-evoked [Ca(2+)](i) (297.0 +/- 15.7 Deltanmol/liter; P < 0.01), collagen, and ADP-induced platelet aggregation (33.3 +/- 4.3 and 12.5 +/- 2.1 Omega, respectively; P < 0.05) vs. the control-2 group (Delta[Ca(2+)](i): 102.1 +/- 13.6 Deltanmol/liter; aggregation: 19.6 +/- 2.9 and 6.2 +/- 0.8 Omega). The platelet hyperreactivity state in the GHD-2 was reinforced by morphologic studies of electron microscopy. In conclusion, there were minor differences between the GHD-1 group and the controls, which might be due to the recovery of GH levels after therapy withdrawal. However, the maintained GHD group, despite minor cardiovascular risk index differences, has increased [Ca(2+)](i) and aggregation, which could indicate a hyperactivation state that might be viewed as an earlier marker of cardiovascular disturbances.

Adult↗
PubMed2004

Safety, tolerability, and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic, in a rising multiple-dose study in young healthy humans.

This was a double-blind, randomized, placebo-controlled study to investigate rising oral doses of BIA 2-093 (S-(-)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide), a putative new antiepileptic drug. Within each of 4 dosage groups of 8 healthy male adult subjects, 2 subjects were randomized to receive placebo, and the remaining 6 subjects were randomized to receive BIA 2-093 (200 mg bid, 400 mg qd, 800 mg qd, and 1200 mg qd) for 8 days. Concentrations of BIA 2-093 in plasma or urine were generally not measurable. Median maximum plasma concentrations of the major metabolite (licarbazepine, (+/-)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide) were attained (t(max)) at 2 to 3 h postdose; thereafter, plasma concentrations declined with a mean apparent terminal half-life of 9 to 13 h following repeated dosing. The extent of systemic exposure to licarbazepine increased in an approximately dose-proportional manner following single and repeated administration. Licarbazepine accumulated in plasma following repeated administration of BIA 2-093; the mean extent of accumulation (R(O), calculated from AUC(0-tau) (day 8)/AUC(0-tau) (day 1)) was 3.0 after repeated, twice-daily dosing and 1.4 to 1.7 after once-daily dosing. Steady-state plasma licarbazepine concentrations were attained at 4 to 5 days of once- or twice-daily dosing, consistent with an effective half-life on the order of 20 to 24 h. The mean renal clearance of licarbazepine from plasma was approximately 20 to 30 mL/min, which is low compared with the glomerular filtration rate. The total amount of licarbazepine recovered in urine was approximately 20% within 12 h postdose and 40% within 24 h postdose. All adverse events were mild in severity, except for 1 case of somnolence of moderate severity, which occurred in a subject receiving 1200 mg BIA 2-093. The incidence of adverse events was similar between all treatment groups, including placebo. There were no serious adverse events. In conclusion, BIA 2-093 was well tolerated and appeared to be rapidly and extensively metabolized to licarbazepine following single and repeated administration to healthy young subjects.

Adolescent↗
PubMed2003

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/benserazide.

BIA 3-202 is a novel catechol-O-methyltransferase (COMT) inhibitor being developed for use as a levodopa-sparing agent in Parkinson's disease. This study investigated the effect of four single oral doses of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg) compared with placebo on plasma concentrations of levodopa and its metabolite 3- O-methyl-levodopa (3-OMD) and on inhibition of erythrocyte COMT in healthy subjects receiving 100 mg of levodopa and 25 mg of benserazide (Madopar 125). This was a single-centre, double-blind, placebo-controlled, randomised, crossover study with five single-dose treatment periods. The washout period between doses was 2 weeks. On each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Madopar 125. Tolerability was assessed by recording adverse events, vital signs, continuous electrocardiogram and clinical laboratory parameters. In the study, 18 subjects (12 male and 6 female) participated. The drug combination was well tolerated. All doses of BIA 3-202 significantly increased the area under the concentration-time curve (AUC) versus placebo, ranging from 39% (95% confidence intervals, 1.06-1.69) with 50 mg to 80% (95% confidence intervals, 1.42-2.22) with 400 mg. No significant change in mean maximum plasma concentrations (C(max)) of levodopa was found. Mean C(max) and AUC of 3-OMD significantly decreased for all doses tested. BIA 3-202 caused a rapid and reversible inhibition of S-COMT activity, ranging from 57% (50 mg) to 84% (400 mg). In conclusion, the novel COMT inhibitor BIA 3-202 was well tolerated and significantly increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard release levodopa/benserazide.

Acetophenones↗
PubMed2003

Drosophila morphogenesis: the Newtonian revolution.

Recent quantitative modeling of dorsal closure in the fruitfly Drosophila has revealed how multiple forces drive sealing of the two symmetrical epithelial sheets. A predictive model based on the new data allows gene function to be linked to the forces that drive tissue movement.

Animals↗
PubMed2003

Pharmacokinetic and pharmacodynamic profiles of BIA 3-202, a novel catechol-O-methyltransferase (COMT) inhibitor, during multiple-dose administration to healthy subjects.

The tolerability, pharmacodynamics, and pharmacokinetics of BIA 3-202 (50 mg, 100 mg, and 200 mg twice daily and 200 mg thrice daily), a novel catechol-O-methyltransferase (COMT) inhibitor, were investigated in healthy volunteers. BIA 3-202 was administered to four sequential groups of 8 healthy male subjects under a double-blind, randomized, placebo-controlled design. Within each group, 2 subjects were randomized to treatment with placebo. Treatment duration was 9 days: single dose on the first and last days and twice or thrice daily on days 3 to 8. BIA 3-202 was well tolerated at all dose regimens tested. Median maximum plasma BIA 3-202 concentrations were attained at 0.5 to 2.5 hours postdose. Thereafter, concentrations declined with a t1/2 of approximately 2 to 4 hours. The increase in the extent of systemic exposure, as measured by AUC0-tau, was approximately proportional to the administered dose. Steady state of plasma BIA 3-202 concentrations occurred by day 4 in all dose groups. Less than 1% of the total dose administered was excreted in urine up to 48 hours postdose. BIA 3-202 markedly reduced soluble COMT (S-COMT) activity in erythrocytes, with maximum inhibition occurring at 1 to 2 hours postdose; enzyme activity returned to baseline levels by approximately 8 hours. Inhibition of S-COMT activity appeared to increase with increasing doses of BIA 3-202 on both day 1 and day 9. In conclusion, BIA 3-202 was well tolerated in all the oral multiple-dose regimens tested. BIA 3-202 was shown to inhibit S-COMT activity in erythrocytes, and its pharmacokinetics appeared to be linear (i.e., dose independent and time invariant).

Acetophenones↗
PubMed2003

Pharmacokinetics and pharmacodynamics of BIA 3-202, a novel COMT inhibitor, during first administration to humans.

OBJECTIVE: To determine the tolerability, pharmacodynamics and pharmacokinetics of single oral doses of BIA 3-202, a novel catechol-O-methyltransferase (COMT) inhibitor, in healthy male volunteers. METHODS: Single increasing oral doses of BIA 3-202 (10, 30, 50, 100, 200, 400 and 800mg) were administered under fasting conditions to seven sequential groups of nine subjects, under a double-blind, randomised, placebo-controlled design. In an additional group of eight subjects (group 8), a single dose of BIA 3-202 400mg was administered on two occasions, once under fasting conditions and once with a high-fat meal, under an open-label, two-way crossover design. RESULTS: BIA 3-202 was well tolerated at all doses tested. Most adverse events were mild in severity and their incidence was similar between BIA 3-202 and placebo. Maximum plasma concentrations (C(max)) of BIA 3-202 were attained at 0.5-2.5h (t(max)) and thereafter declined with an apparent terminal half-life (t(1/2)) of 1.5-5h. Over the dose range of 10-800mg, there was an approximately dose-proportional increase in the area under the plasma concentration-time curve (AUC) values of BIA 3-202: for a dose level increase in the ratio 3.0:1.7:2.0:2.0:2.0:2.0, AUC increased in the ratio 3.1:1.7:1.9:2.2:2.1:1.7. Plasma concentrations of the O-methylated derivative, BIA 3-270, increased markedly less than predicted from a proportional relationship: for a dose level increase in the ratio 1:80, AUC(0-t )increased in the ratio 1:5. In most subjects, the t(max) of BIA 3-270 was attained at the last sampling time and, therefore, t(1/2 )could not be estimated. Urine assays showed that less than 1% of the total dose administered was excreted in urine as BIA 3-202. Urine concentrations of BIA 3-270 were below the limit of quantification. In group 8, the rate and extent of systemic availability (t(max), AUC and C(max)) of BIA 3-202 and BIA 3-270 after a high-fat meal were similar to those under fasting conditions. Inhibition of COMT activity in erythrocytes reached maximum levels at 2-2.5h post dose, with sustained inhibition up to approximately 4-6 hours, returning to baseline by about 16 hours. CONCLUSION: BIA 3-202 was well tolerated at single 10-800mg oral doses and presented dose-proportional kinetics. It effectively inhibited COMT activity and the presence of food did not affect its pharmacokinetics or COMT inhibitory activity. The results provide a basis for further clinical studies with BIA 3-202.

Acetophenones↗
PubMed2003

Safety, tolerability and pharmacokinetic profile of BIA 2-093, a novel putative antiepileptic agent, during first administration to humans.

OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of BIA 2-093 [S-(-)-10-acetoxy-10,11-dihydro-5H-dibenzo/b,f/aze- pine-5-carboxamide] in healthy male volunteers. DESIGN: This was a double-blind, randomised, placebo-controlled, single ascending dose study performed with BIA 2-093, a new putative antiepileptic drug. PARTICIPANTS AND METHODS: Groups of eight healthy male subjects (two randomised to receive placebo and the remaining six to receive BIA 2-093) received single oral doses of BIA 2-093 of 20, 50, 100, 200, 400, 600, 900 and 1200 mg. A total of 64 healthy male volunteers aged 18-35 years participated in the study. RESULTS: The incidence of adverse events, which were mild in severity, was similar between all treatment groups, including the placebo group. There were no serious adverse events during this study. No clinically significant abnormalities in laboratory safety tests, vital signs, weight, physical examination or ECG were reported. BIA 2-093 appeared to be rapidly and extensively metabolised to BIA 2-005 [RS(+/-)-10,11-dihydro-10-hydroxy-5H-dibenzo/b,f/azepine-5-carboxamide], the major metabolite, and oxcarbazepine (the minor metabolite), following single oral doses of BIA 2-093 of 20-1200 mg. Plasma BIA 2-093 concentrations were generally below the limit of quantification of the assay. Maximum plasma concentrations (C(max)) of BIA 2-005 and oxcarbazepine were reached, respectively, at 0.75-4h and 6h postdose, after which they declined with an approximate mean apparent terminal half-life of 8-17h and 7-12h, respectively. The increase in systemic exposure to BIA 2-005 was approximately proportional to the administered dose for C(max) and greater than dose proportional for the area under the concentration-time curve. Renal clearance of BIA 2-005 (20 mL/min) appeared to be constant over the dose range studied, indicating that the dose-dependent urinary recovery was due either to increased formation of BIA 2-005 with increasing dose level or to decreased non-renal elimination of the metabolite. CONCLUSIONS: BIA 2-093 undergoes extensive metabolism to BIA 2-005 and was well tolerated at oral doses of 20-1200 mg.The results provide a basis for further clinical trials with BIA 2-093.

Administration, Oral↗
PubMedDate not supplied

Pharmacokinetic-pharmacodynamic interaction between BIA 3-202, a novel COMT inhibitor, and levodopa/carbidopa.

This study investigated the tolerability and the pharmacokinetic and pharmacodynamic interactions between single oral administration of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg), a novel catechol-O-methyltransferase (COMT) inhibitor, and standard carbidopa/levodopa 25 mg/100 mg (Sinemet 25/100) in healthy adult volunteers. This was a single-center, double-blind, placebo-controlled, randomized, crossover study with 5 single-dose treatment periods with a washout period of 2 weeks between doses. During each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Sinemet 25/100. Tolerability was assessed by recording adverse events, vital signs, continuous EKG, and clinical laboratory parameters. Pharmacokinetic parameters of levodopa and 3-O-methyl-levodopa (3-OMD) were determined. The activity of soluble COMT in erythrocytes was also measured. Eighteen subjects (10 men and 8 women) participated in the study. The drug combination was well tolerated, with the adverse events reported being transient and generally mild in severity. Mean levodopa Cmax values were attained at 0.8 to 1.8 hours postdose. Thereafter, plasma levodopa levels declined with a mean t1/2 that increased in a manner that depended on the dose of BIA 3-202. The increase in systemic exposure to levodopa (AUC0-infinity) occurred at all doses of BIA 3-202, attaining its maximum at 200 mg BIA 3-202 (95% conficence interval, 1.43-1.73). The mean Cmax and AUC0-infinity values of 3-OMD decreased dose proportionally in BIA 3-202-treated subjects, with differences being statistically significant for all the doses tested. Maximum COMT inhibition occurred between 0.8 and 2.0 hours postdose, and ranged from 56 (50 mg) to 85% (400 mg). Time to return to baseline COMT activity ranged from 6 (50 mg) to 18 hours (400 mg), following the same dose-dependent tendency. In conclusion, the novel COMT inhibitor BIA 3-202 increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard levodopa/carbidopa.

Acetophenones↗