Amílcar Falcão

Intranasal drug delivery: how, why and what for?

Over the recent decades the interest in intranasal delivery as a non-invasive route for drugs is increased.Since the nasal mucosa offers numerous benefits as a target tissue for drug delivery, a wide variety of therapeutic compounds may be administered intranasally for topic, systemic and central nervous system action. We have, herein, outlined the relevant aspects of nasal anatomy, physiology and histology, and the biological, physicochemical and pharmaceutical factors that must be considered during the process of discovery and development of nasal drugs as well as in their incorporation into appropriate nasal pharmaceutical formulations.

Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers

This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8-1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (C(max)) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration-time curve (AUC(0-tau)) was 3.1, 11.2, 33.0 and 78.9 ng.h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1-3 h following single-doses and 2-5 h following repeated dosing. Trough (C(min)) concentrations were < or = 1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.

Blood–brain barrier models and their relevance for a successful development of CNS drug delivery systems: A review

During the research and development of new drugs directed at the central nervous system, there is a considerable attrition rate caused by their hampered access to the brain by the blood-brain barrier. Throughout the years, several in vitro models have been developed in an attempt to mimic critical functionalities of the blood-brain barrier and reliably predict the permeability of drug candidates. However, the current challenge lies in developing a model that retains fundamental blood-brain barrier characteristics and simultaneously remains compatible with the high throughput demands of pharmaceutical industries. This review firstly describes the roles of all elements of the neurovascular unit and their influence on drug brain penetration. In vitro models, including non-cell based and cell-based models, and in vivo models are herein presented, with a particular emphasis on their methodological aspects. Lastly, their contribution to the improvement of brain drug delivery strategies and drug transport across the blood-brain barrier is also discussed.

Liquid chromatographic methods for the quantification of catecholamines and their metabolites in several biological samples—A review

The measurement of catecholamines and their metabolites in biological samples remains a current analytical challenge, in spite of the great diversity of methodologies that have been developed throughout the years. High-performance liquid chromatography is the standard method for their separation and quantification in biological samples, either coupled with electrochemical, fluorescence, chemiluminescence or mass spectrometry detection. This review summarizes the most important physicochemical properties of catecholamines, the wide panoply of sample preparation techniques and the main issues to consider during the development of chromatographic methods. The major difficulties encountered during the optimization of these procedures are related with the high tendency of catecholamines to oxidize and the very low quantities at which they exist in biological matrices. Herein, the most important aspects that ought to be considered during collection, treatment and storage of fluid and tissue samples intended for catecholamine analysis are underlined, the chromatographic conditions are compared and the technical advantages and limitations of each detection system are discussed.

THE MAXIMAL ELECTROSHOCK SEIZURE (MES) MODEL IN THE PRECLINICAL ASSESSMENT OF POTENTIAL NEW ANTIEPILEPTIC DRUGS

The choice of appropriate animal models for the initial in vivo testing of potential anticonvulsant compounds is one of the most important steps in the successful search for new antiepileptic drugs. The purpose of this paper is to describe the most important aspects to take into account when performing the maximal electroshock seizure (MES) test in the routine laboratory screening of new antiepileptics: the conventional and threshold MES test experimental procedures, the factors affecting experimental data (laboratory conditions, administration vehicles and drug formulations, time after drug administration, and stimulus duration and site of stimulation) and the assessment of anticonvulsant activity are discussed.

Pharmacokinetics of Trans‐resveratrol Following Repeated Administration in Healthy Elderly and Young Subjects

From the Department of Research and Development, S Mamede do Coronado, Portugal (Dr Nunes, Dr Almeida, Mr Rocha, Mr Fernandes-Lopes, Ms Loureiro, Dr Wright, Dr Vaz-da-Silva, Dr Soares-da-Silva); Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal (Dr Almeida, Dr Vaz-da-Silva, Dr Soares-da-Silva); Department of Health Sciences, University of Aveiro, Portugal (Dr Almeida); and 4Health Consulting, BIOCANT, Cantanhede, Portugal (Dr Falcao). Submitted for publication February 27, 2009; revised version accepted May 10, 2009. Address for correspondence: Patricio Soares-da-Silva, MD, PhD, Department of Research & Development, BIAL, A Av da Siderurgia Nacional, 4745-457 S Mamede do Coronado, Portugal; e-mail: psoares.silva@bial.com.DOI: 10.1177/0091270009339191

Effect of renal impairment on the pharmacokinetics of eslicarbazepine acetate

OBJECTIVE Antiepileptic drugs are often used in patients with some degree of renal impairment. The objective of this study was to evaluate the effect of renal function on the pharmacokinetics of eslicarbazepine acetate (ESL, formerly known as BIA 2-093), a new antiepileptic drug under clinical development. METHODS ESL pharmacokinetics following 800 mg single dose was characterized in subjects with normal renal function (n=8, control group), and in patients with mild renal impairment (n=8), moderate renal impairment (n=8), severe renal impairment (n=8), and end-stage renal disease requiring hemodialysis (n=8). RESULTS ESL suffered extensive first-pass hydrolysis to eslicarbazepine (S-licarbazepine), the main active metabolite. While eslicarbazepine Cmax did not significantly differ between the different groups, the extent of systemic exposure, assessed by AUC, increased when renal function decreased. Eslicarbazepine CL/F and CLR were, respectively, 3.40 l/h and 1.04 l/h (17.3 ml/min) in the control group, and 2.10 l/h (35.0 ml/min) and 0.61 l/h (10.2 ml/min) in the mild, 1.60 l/h (26.7 ml/min) and 0.22 l/h (3.7 ml/min) in the moderate, and 1.33 l/h (21.2 ml/min) and 0.09 l/h (1.5 ml/min) in the severe renal impairment groups. Although the total amount of eslicarbazepine recovered in urine until 72 h post-dose was similar in the control and mild renal impairment groups, a decrease was found in the moderate and severe renal impairment groups. Major metabolites recovered in urine were eslicarbazepine and its glucuronide form. Clearance of minor metabolites (R-licarbazepine, oxcarbazepine and their glucuronides) was also dependent on renal function. In patients with end-stage renal disease, dialysis was effective in removing the ESL metabolites from the circulation. CONCLUSIONS ESL metabolites are excreted primarily by renal route and their clearance is dependent on renal function. ESL dosage adjustment may be necessary in patients with a creatinine clearance <60 ml/min.

Efficacy and safety of eslicarbazepine acetate as add‐on treatment in patients with focal‐onset seizures: Integrated analysis of pooled data from double‐blind phase III clinical studies

Purpose: To evaluate the efficacy and safety profile of eslicarbazepine acetate (ESL) added to stable antiepileptic therapy in adults with partial‐onset seizures.

Effect of food on the pharmacokinetic profile of trans-resveratrol.

OBJECTIVE It has been postulated that trans-resveratrol may act as an antioxidant, cardioprotective, neuroprotective and cancer chemopreventive agent. The objective of this study was to investigate the effect of food on the bioavailability of trans-resveratrol following oral administration. MATERIAL AND METHODS Single-centre, open-label, randomized, 2-way crossover study on 24 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 7 days or more. On each of the study periods subjects were administered a single-dose of 400 mg of trans-resveratrol following either a standard high fat content meal or 8 hs of fasting. RESULTS There was a large interindividual variability in the trans-resveratrol pharmacokinetic parameters. Mean +/- SD maximum plasma concentration (Cmax) was 42.2 +/- 36.6 ng/ml in fed and 47.3 +/- 30.0 ng/ml in fasting conditions. Median time to Cmax (tmax) was 2.0 h in fed and 0.5 h in fasting (p < 0.0001). The fed/fasting geometric mean ratio (GMR) and 90% confidence interval (90% CI) were 79.4 and 53.8, 117.0% for Cmax, and 106.0 and 86.8, 128.0% for the area under the plasma concentration-time curve (AUC0- yen). The 90% CI for the GMR of AUC0- yen and Cmax fall outside the usual bioequivalence acceptance range of 80, 125%, but that of AUC0- yen was close to the bioequivalence standard. CONCLUSION The rate of absorption of trans-resveratrol following an oral 400 mg single-dose was significantly delayed by the presence of food, as reflected by Cmax and tmax. However, the extent of absorption, as reflected by AUC- yen, was not affected in a relevant way.

Pharmacokinetics, Efficacy, and Tolerability of Eslicarbazepine Acetate in Children and Adolescents With Epilepsy

This study investigates the pharmacokinetics of eslicarbazepine acetate (ESL), a new voltage‐gated sodium channel blocker, in epileptic children aged 2 to 7 years (n = 11) and 7 to 11 years (n = 8) and adolescents aged 12 to 17 years (n = 10). The study explores ESL efficacy and tolerability. Patients were treated with ESL once‐daily doses of 5 mg/kg/day on weeks 1 to 4, 15 mg/kg/day on weeks 5 to 8, and 30 mg/kg/day (or 1800 mg/day, whichever was less) on weeks 9 to 12. At the end of each 4‐week period, a 24‐hour pharmacokinetic profiling was performed. Similar to adults, ESL was rapidly metabolized to eslicarbazepine. In all age groups, eslicarbazepine peak concentrations were reached 0.5 hour to 3 hours after ESL dosing, and Cmax and AUC0–24 were dose proportional. Eslicarbazepine Cmax was similar between age groups following administration of identical ESL dose/kg, but AUC0–24 depended on age due to a faster plasma clearance of eslicarbazepine in younger children compared with adolescents. R‐licarbazepine and oxcarbazepine were minor metabolites. A dose‐dependent decrease in seizure frequency was observed in children aged 2 to 7 years and adolescents aged 12 to 17 years but not in children aged 7 to 11 years. One patient in each group became seizure free. ESL was generally well tolerated.