Pedro Silveira

Effect of Food on the Pharmacokinetic Profile of Eslicarbazepine Acetate (BIA 2-093)

AbstractObjective: 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 800mg 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 (Cmax) in fed (test) and fasting (reference) conditions were, respectively, 12.8 ± 1.8 μg/mL and 11.3 ± 1.9 μg/mL, and the areas under the plasma concentration time curve from 0 to infinity (AUC∞) were, respectively, 242.5 ± 32.1 μg · h/mL and 243.6 ± 31.1 μg · h/mL (arithmetic mean ± SD). The point estimate (PE) and 90% confidence interval (90% CI) of the test/reference Cmax geometric mean ratio were 1.14 and 1.04, 1.25, respectively; for the AUC∞ 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∞ and Cmax 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 Cmax. 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.

Bioavailability and bioequivalence of two enteric-coated formulations of omeprazole in fasting and fed conditions

AbstractObjective: To investigate the relative bioavailability and bioequivalence, in fasting and fed conditions, of repeated doses of two omeprazole enteric-coated formulations in healthy volunteers. Material and methods: Open label, single-centre study consisting of two consecutive randomised, two-way crossover trials (a fasting trial and a fed trial). Each trial consisted of two 7-day treatment periods in which subjects received one daily dose of the test (Ompranyt®) or reference (Mopral®) formulations. At day 7 and day 14 (fasting trial), products were administered in fasting conditions and blood samples were taken for omeprazole plasma assay over 12 hours. At day 21 and day 28 (fed trial), products were administered after a standard high-calorie and high-fat meal and 12-hour blood samples taken. Omeprazole plasma concentrations were quantified by a validated method using a reverse-phase high performance liquid chromatography with UV detection (HPLC-UV). Results: Twenty-four subjects were enrolled and 23 completed the study. Under fasting conditions, the mean ± SD maximum omeprazole plasma concentration (Cmax) was 797 ± 471 μg/L for Ompranyt® and 747 ± 313 μg/L for Mopral® with a point estimate (PE) of 1.01 and a 90% confidence interval (CI) of 0.88, 1.16. The mean ± SD area under the plasma concentration curve from administration to last observed concentration (AUC0–12) was 1932 ± 1611 μg · h/L and 1765 ± 1327 μg · h/L for Ompranyt® and Mopral®, respectively (PE = 1.09; 90% CI 0.95, 1.25). In the presence of food, the Cmax was 331 ± 227 μg/L and 275 ± 162 μg/L (PE = 1.21; 90% CI 0.92, 1.59) and AUC0–12 was 1250 ± 966 μg · h/L and 1087 ± 861 μg · h/L (PE = 1.16; 90% CI 0.92, 1.47) for Ompranyt® and Mopral®, respectively. Bioequivalence of the formulations in the fasting condition was demonstrated both for AUC0–12 and for Cmax because the 90% CI lay within the acceptance range of 0.80–1.25. In contrast with the fasting condition, there were significant reductions in rate (Cmax) and extent (AUC0–12) of systemic exposure when test and reference formulations were administered with food. The food effect was more marked with Mopral® than with Ompranyt®, and the bioequivalence criterion was not fulfilled because the 90% CI fell out of the acceptance range of 0.80, 1.25, for both Cmax and AUC0–12. The two formulations were similarly well tolerated. Conclusion: Bioequivalence of Ompranyt® (test formulation) and Mopral® (reference) formulations was demonstrated after repeated dosing in the fasting condition. Following a high-calorie and high-fat meal, there was a significant reduction in rate and extent of systemic exposure for both products, with Ompranyt® being less affected than Mopral® by the presence of food.

Intramuscular Etofenamate versus Diclofenac in the Relief of Renal Colic A Randomised, Single-Blind, Comparative Study

AbstractObjective: To compare the efficacy and adverse effects of intramuscular etofenamate and intramuscular diclofenac in the relief of acute renal colic. Patients and methods: A multicentre, randomised, single-blind study was performed in 119 patients admitted to the emergency room for renal colic. Patients were assigned to treatment with either etofenamate l000mg or diclofenac 75mg, both administered intramuscularly. Pain was self-assessed using a 4-point verbal rating scale (VRS) and a visual analogue scale (VAS) just before drug administration and 30, 60, 120 and 240 min later. Results: The two groups were similar with regard to baseline characteristics. The percentages of patients who reported an improvement in the VRS at 60 min post-administration (primary variable) were 84.5% with etofenamate and 83.3% with diclofenac (p = 0.73). At the other timepoints (30, 120 and 240 min), the proportions of patients improved were, respectively, 69.5%, 82.6% and 79.3% in the etofenamate group, and 75.0%, 81.7% and 80.0% in the diclofenac group. The VAS score showed a statistically significant improvement in both groups, but no differences between groups were found.Analgesic rescue medication was required by 11 (18.6%) patients in the etofenamate group and by 12 (20.0%) patients in the diclofenac group. Mild to moderate adverse events were reported by 3.4% of patients receiving etofenamate and by 5.0% of patients receiving diclofenac. Conclusion: Etofenamate and diclofenac were similarly effective and tolerated in the relief of acute renal colic.

Lavagem broncoalveolar: metodologia e aplicação clínica

RESUMO A lavagem broncoalveolar e um metodo largamente utilizado no estudo da patologia pulmonar. Nas doencas intersticiais, a analise da lavagem broncoalveolar fornece, com frequencia, informacoes relevantes para o diagnostico, orientacao terapeutica, prognostico e interpretacao etiopatogenica das mesmas. Os autores abordam a tecnica e metodologia do processamento da lavagem broncoalveolar, as suas principais indicacoes clinicas e os achados mais caracteristicos em diferentes patologias pulmonares.

Estudo nacional de qualidade de vida na asma - Aplicação do Asthma Quality of LIfe Questionnaire de Marks (AQLQ-M) na população portuguesa

The Portuguese version of the Marks Asthma Quality of Life Questionnaire (AQLQ-M) has already proven to have good diagnostic properties, and is suitable for use with Portuguese asthma patients. The last forty years have seen a worldwide rise in the rate, morbidity, mortality and economic burden associated with asthma and the disease continues to be underdiagnosed and undertreated. In this study the AQLQ-M was administered to 826 asthmatic patients from continental Portugal (97.9% Caucasian, mean age 40.5 years, 30.2% male, 69.8% female), followedup by pulmonologists and allergologists. Patients were classified in line with the Global Initiative for Asthma (GINA) severity categories: 40.5% intermittent asthma, 26.9% mild persistent, 21.4% moderate persistent, 11.2% severe persistent. AQLQ-M scores maintained significant relationships with asthma severity, symptoms and lung function. Most of the patients were not managed and 74.6% were observed in an emergency room during last year. Women reported poorer QoL than men in all the questionnaire’s subscales. Surprisingly, smokers presented better QoL than non-smokers. The results of this study evidence that the Portuguese version of the AQLQ-M is a useful instrument for measuring health-related quality of life in adults with asthma. Rev Port Pneumol 2008; XIV (4): 459-486

Psychomotor Effects of Mexazolam vs Placebo in Healthy Volunteers

ObjectiveMexazolam is an oxazolo-benzodiazepine demonstrating chemical similarities to oxazolam and cloxazolam. This trial aimed to assess the effect of mexazolam on psychomotor performance.DesignThe study was a double-blind, single-dose, randomised, two-way crossover, placebo-controlled trial.Study participants33 healthy male and female adult volunteers.Main outcome measuresPsychomotor performance was evaluated through the Leeds Psychomotor Test Battery [critical flicker fusion (CFF) threshold and choice reaction time with its three components (recognition reaction time — RRT, motor reaction time — MRT, and total reaction time — TRT)] and, in an exploratory way, a car-driving simulation (CDS). After performing a baseline test set, each volunteer received, in a randomised fashion, either a single oral dose of mexazolam 1mg or placebo and, 3 hours later, the test set was repeated. After a washout of at least 10 days, the procedures were repeated in a crossover way. Tolerability was assessed through the reporting of adverse events.ResultsA total of 33 healthy subjects were enrolled. In the Leeds Psychomotor Test Battery, no statistically significant differences were found between post-versus pre-placebo results, post-versus pre-mexazolam results, and placebo versus mexazolam results (post-administration: CFF: p = 0.480, RRT: p = 0.195, MRT: p = 0.470, TRT: p = 0.169). In the CDS, there were no statistical differences between placebo and mexazolam scores [pre-administration: total time score (TTS): p = 0.519, best lap time (BLT): p = 0.499; post-administration: TTS: p = 0.940, RRT: p = 0.995]. There was a statistically significant improvement between post- and pre-placebo scores (TTS: p = 0.032, BLT: p = 0.023) and between post- and pre-mexazolam scores (TTS: p = 0.016, BLT: p = 0.030), indicating a learning effect induced by the repetition of the tests. A total of three volunteers reported a total of three adverse events: somnolence, which occurred following mexazolam administration, and headache and flu-like syndrome, which occurred after placebo administration.ConclusionsMexazolam does not have psychomotor performance-impairing effects at therapeutic doses. Reduced effects on psychomotor performance in anxious patients may lead to better compliance and to specific indications for this benzodiazepine.

Relative Bioavailability of Two Enteric-Coated Formulations of Omeprazole following Repeated Doses in Healthy Volunteers

ObjectiveThis study aimed to investigate the relative bioavailability and bioequivalence of two omeprazole enteric-coated formulations following repeated doses (steady state) in healthy male and female adult volunteers.Design and Study ParticipantsThe study formulation (Ompranyt® 20mg capsules, Bial-Industrial Farmaceutica SA, Spain) was compared with an omeprazole reference formulation (Mopral® 20mg capsules, Laboratório Astra, Spain). 24 participants were randomised using a two-way, crossover design to receive either one capsule/day of Ompranyt® or one capsule/day of Mopral® during two sequential periods of five consecutive days each. The participants were administered the drugs in the fasting state. Omeprazole concentrations in plasma samples were quantified by a validated method using a reversed-phase high performance liquid chromatography with UV detection (HPLC-UV). The validation method is described.SettingThe study was conducted at the Human Pharmacology Unit, Department of Research & Development, Laboratorios Bial (S. Mamede do Coronado, Portugal).ResultsThe arithmetic mean ± SD values of the area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞) were 1474 ± 1417 μg/L·h for Ompranyt® and 1490 ± 1276 μg/L·h for Mopral®. The geometric means ratio (Ompranyt®/Mopral®) was 0.99, with 90% confidence intervals (CI) of 0.97–1.03. The estimated maximum plasma concentration (Cmax) was 630.1 ± 516.7 μg/L for Ompranyt® and 736.7 ± 443.3 μg/L for Mopral®, with a geometric means ratio (Ompranyt®/Mopral®) of 0.96 (90% CI: 0.94-0.99). Bioequivalence of these two formulations was accepted based on the two one-sided ANOVA for AUC0-∞ as well as for Cmax. In both cases, the 90% CI lies within the acceptance range of 0.80–1.25.ConclusionBioequivalence of Ompranyt® and Mopral® was demonstrated after repeated drug administration in fasting conditions, and both products were similarly well tolerated. Therefore, both formulations are expected to be equivalent in a clinical setting.

Effects of enalapril and imidapril in the capsaicin cough challenge test and spirometry parameters in healthy volunteers

Background: Angiotensin-converting enzyme inhibitors are highly effective, welltolerated drugs, but are associated with respiratory adverse effects such as cough and wheezing. Objectives: In this double-blind, randomized, two-way crossover study, the effects of two angiotensin-converting enzyme inhibitors, enalapril and imidapril, in the capsaicin cough challenge test and spirometry parameters were investigated. Methods: The study involved two sequential 21-day periods separated by a 7-day washout period. In each period, volunteers received a once-daily oral dose of placebo during the first 7 days, imidapril 5 mg or enalapril 10 mg from days 8 to 14, and imidapril 10 mg or enalapril 20 mg from days 15 to 21. Cough challenge was performed at baseline and at the end of each week of treatment. Spirometry was performed before and immediately after the capsaicin challenge. Fourteen healthy subjects were enrolled, but one was withdrawn while taking enalapril due to dry cough. Results: Neither enalapril nor imidapril significantly altered the capsaicin cough threshold. A small but significant reduction in forced expiratory volume in 1 sec and forced vital capacity was demonstrated after treatment with enalapril (p = 0.017 and p = 0.018, respectively), but not with imidapril. Capsaicin cough challenge was not associated with bronchospasm. Conclusion: Studies in asthmatics are needed to assess the clinical relevance of these data.

Hemotórax e hemopneumotórax espontâneos: causas raras de internamento

RESUMO Os autores fazem a revisao e descricao sumaria dos 5 casos de hemotorax e hemopneumotorax espontâneos internados no servico de Pneumologia do H.S.Joao entre 1983 e 1995, comentando as situacoes em que foi possivel identificar patologia subjacente com eles relacionada. Foram diagnosticados 1 caso de neuroepitelioma periferico,1 caso de aderencias pleurais e 1 caso de bolhas subpleurais. Os restantes 2 casos foram considerados idiopaticos. Todos foram submetidos a drenagem toracica e apenas 1 doente necessitou de transfusao. O “follow-up” variou entre 6 meses e 3 anos, nao se tendo observado recidiva de hemotorax em nenbum caso. Nao se verificaram sequelas e todos os doentes se mantem assintomatieos apos a resolucao do hemopneumotorax.

National study of asthma quality of life--application of the Asthma Quality of Life Questionnaire (AQLQ-M) by Marks in the Portuguese population.

The Portuguese version of the Marks Asthma Quality of Life Questionnaire (AQLQ-M) has already proven to have good diagnostic properties, and is suitable for use with Portuguese asthma patients. The last forty years have seen a worldwide rise in the rate, morbidity, mortality and economic burden associated with asthma and the disease continues to be underdiagnosed and undertreated. In this study the AQLQ-M was administered to 826 asthmatic patients from continental Portugal (97.9% Caucasian, mean age 40.5 years, 30.2% male, 69.8% female), followed up by pulmonologists and allergologists. Patients were classified in line with the Global Initiative for Asthma (GINA) severity categories: 40.5% intermittent asthma, 26.9% mild persistent, 21.4% moderate persistent, 11.2% severe persistent. AQLQ-M scores maintained significant relationships with asthma severity, symptoms and lung function. Most of the patients were not managed and 74.6% were observed in an emergency room during last year. Women reported poorer QoL than men in all the questionnaires subscales. Surprisingly, smokers presented better QoL than non-smokers. The results of this study evidence that the Portuguese version of the AQLQ-M is a useful instrument for measuring health-related quality of life in adults with asthma.