When the assumption of homoscedasticity is not met for analytical data, a simple and effective way to counteract the greater influence of the greater concentrations on the fitted regression line is to use weighted least squares linear regression (WLSLR). The purpose of the present paper is to stress the relevance of weighting schemes for linear regression analysis and to show how this approach can be useful in the bioanalytical field. The steps to be taken in the study of the linear calibration approach are described. The application of weighting schemes was shown by using a high-performance liquid chromatography method for the determination of lamotrigine in biological fluids as a practical example. By using the WLSLR, the accuracy of the analytical method was improved at the lower end of the calibration curve. Bioanalytical methods data analysis was improved by using the WLSLR procedure.

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.

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This systematic review was not funded. The authors declare that they have no conflicts of interest. Concept and study design were created by Pousinho, Morgado, and Alves. Pousinho took the lead in data collection, along with Alves, and data interpretation was performed by Pousinho, Falcão, and Alves. The manuscript was primarily written by Pousinho, along with Alves, and revised by Alves, Morgado, and Falcão.

Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the k(off) value of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.

AIMSThe aim of this study was to assess the tolerability, pharmacokinetics and inhibitory effect on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity following repeated doses of opicapone. METHODSThis randomized, placebo-controlled, double-blind study enrolled healthy male subjects who received either once daily placebo or opicapone 5, 10, 20 or 30 mg for 8 days. RESULTSOpicapone was well tolerated. Its systemic exposure increased in an approximately dose-proportional manner with an apparent terminal half-life of 1.0 to 1.4 h. Sulphation was the main metabolic pathway. Opicapone metabolites recovered in urine accounted for less than 3% of the amount of opicapone administered suggesting that bile is likely the main route of excretion. Maximum S-COMT inhibition (Emax) ranged from 69.9% to 98.0% following the last dose of opicapone. The opicapone-induced S-COMT inhibition showed a half-life in excess of 100 h, which was dose-independent and much longer than plasma drug exposure. Such a half-life translates into a putative underlying rate constant that is comparable with the estimated dissociation rate constant of the COMT-opicapone complex. CONCLUSIONDespite its short elimination half-life, opicapone markedly and sustainably inhibited erythrocyte S-COMT activity making it suitable for a once daily regimen. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Currently available catechol-O-methyltransferase (COMT) inhibitors used as adjunctive therapy in levodopa-treated Parkinson's disease patients have clinical limitations. Due to liver toxicity, the use of tolcapone requires liver function monitoring. Entacapone is considered to be safe, but its efficacy is limited and it requires frequent dosing. Opicapone is a novel third generation COMT inhibitor designed to provide high COMT inhibitory potency and avoid cell toxicity. WHAT THIS STUDY ADDS• Based on the observation that the duration of COMT inhibition after opicapone administration is dose-independent and that it reflects an underlying kinetic process that is consistent with the dissociation rate constant of the COMT-opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible COMT-opicapone complex. The results clearly suggest that opicapone has a unique pharmacodynamic profile adequate for a once daily regimen, which in the treatment of Parkinson's disease patients could represent an advantage over entacapone and tolcapone.

Dendritic cells (DCs) are considered a very promising arm to activate the immune system in immunotherapeutic strategies against cancer. DCs are the most powerful antigen-presenting cells (APCs), being highly efficient at generating robust immune responses. They are also considered the center of the immune system, since they provide a crucial link between both innate and adaptive immune responses. Thus, DC-based cancer immunotherapy aims to take advantage of these unique characteristics of DCs to better fight cancer. During the last decade, they have been the subject of numerous studies intending to develop immunotherapeutic strategies against cancer through vaccination. For this purpose, it is essential to gain a better insight into DC immunobiology, regulation of innate and adaptive immune systems, and tumor microenvironment, as well as applying the latest advances in science in order to boost their enormous anti-tumor immunotherapeutic potential. In this review, we will hold focus on DC immunobiology (from their origin, location, and special properties and distinct subsets to the innate and adaptive immunity), on the new concept of cancer immunoediting, and on the knowledge given by clinical trials using DC vaccines. Finally, future perspectives for this emerging field are highlighted.

This study aimed to compare three different extracts of Saco sweet cherry, namely the non-colored fraction, colored fraction, and total extract concerning phenolic composition, antioxidant and antidiabetic potential, and erythrocytes’ protection and effects on Caco-2 cells. Twenty-two phenolic compounds were identified using high-performance liquid chromatography with diode-array detection. Hydroxycinnamic acids were the most predominant in both the non-colored fraction and total extract, while cyanidin-3-O-rutinoside was the main anthocyanin found in the colored fraction. The total extract was the most effective against 1,1-diphenyl-2-picrylhydrazyl, nitric oxide, and superoxide radicals, and in the inhibition of α-glucosidase enzyme. The colored fraction revealed the best activity against hemoglobin oxidation and hemolysis. Regarding to Caco-2 cells, the colored extract exhibited the highest cytotoxic effects, while the total extract was the most efficient in protecting these cells against oxidative damage induced by tert-butyl hydroperoxide.