Treatment of Chagas disease with nifurtimox requires age-and body weight-adjusted dosing, resulting in complex dosing instructions. Appropriate formulations are needed for precise and compliant dosing, especially in pediatric patients. We characterized the biopharmaceutical features of a standard nifurtimox 120-mg tablet and a 30-mg tablet developed to improve dose accuracy. Two open-label, randomized crossover studies were conducted in adult outpatients with Chagas disease.One study investigated whether 4 × 30-mg tablets and 1 × 120-mg tablet were bioequivalent and whether tablets can be administered as an aqueous slurry without affecting bioavailability. The second study investigated the effect of a high-calorie/high-fat diet versus fasting on the absorption of nifurtimox after a single 4 × 30-mg dose. Interventions were equivalent if the 90% confidence interval (CI) of their least-squares (LS) mean ratios for both AUC 0-tlast and C max were in the range of 80%-125%. The 4 × 30-mg and 1 × 120-mg tablet doses were bioequivalent (AUC 0-tlast : LS mean ratio, 104.7%; 90%CI, 99.1%-110.7%; C max : LS mean ratio, 101.7%; 90%CI, 89.4%-115.6%; n = 24). Exposure when giving the 4 × 30-mg dose as a slurry or as tablets was comparable, with an AUC 0-tlast ratio of 93.2% (84.2%-103.1%; n = 12) and a slightly decreased C max ratio for the slurry of 76.5% (68.8%-85.1%). Food improved the bioavailability of nifurtimox substantially (AUC 0-tlast ratio fed/fasted , 172%; 90%CI, 154%-192%; C max ratio fed/fasted , 168%; 90%CI, 150%-187%). The data indicate that the 30-and 120-mg tablets are suitable for dosing adult and pediatric patients accurately; nifurtimox should be administered under fed conditions.

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The effects of the chronic in vivo inhibition of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine methyl ester (L-NAME) on vascular contractility were studied in the rat perfused mesenteric bed. The chronic treatment with L-NAME during 4 weeks induced a rise in systolic blood pressure (basal: 115.1 +/- 6.5 mmHg; chronic L-NAME treatment: 171.7 +/- 7.7 mmHg, n = 16, P < 0.05). After the chronic NOS inhibition, the potentiation of the maximal vasoconstrictor responses to noradrenaline, phenylephrine and KCl was to the same extent as that observed after the in vitro exposure to 100 microM L-NAME. No further potentiation of the contractile responses was achieved when the mesenteric beds isolated from L-NAME treated rats were incubated in vitro with 100 microM L-NAME. The endothelium removal but not the inhibition of prostanoid synthesis with either 10 microM indomethacin or 10 microM 17-octadecynoic acid potentiated the contractions to noradrenaline and to KCl both under control conditions as well as after the chronic in vivo administration of L-NAME. These observations taken together suggest that after chronic L-NAME maximum inhibition of nitric oxide synthase was achieved and no compensatory mechanisms able to counterbalance the increase in contractile responses were developed. Further studies are necessary to elucidate the nature of the factors, other than nitric oxide, that contribute to the potentiation of contractile responses observed when the endothelium is removed after L-NAME treatment.

Background In view of the emergence of SARS-CoV-2 immune escape variants and evidence of waning immunity, new immunisation strategies and variant-adapted vaccines are needed. Based on preclinical proof of concept studies and requirement of variant-adapted and booster vaccines, the Gamma Variant RBD-based ARVAC-CG vaccine was selected for a first clinical trial in humans. Methods Eighty participants (healthy adults, 18-55 years-old) were sequentially assigned to receive two (28 days apart) intramuscular doses of 25-lower case Greek mug (n=60) or 50-lower case Greek mug (n=20) of a Gamma RBD-based subunit vaccine adjuvanted with aluminium hydroxide. The primary endpoint was safety. The secondary objective was to describe the neutralising antibody response against the SARS-CoV-2 Ancestral strain and several variants of concern (Gamma, Delta, Omicron BA.1 and Omicron BA.5) measured by a live virus-based neutralisation assay. Cellular immune responses were studied as an exploratory objective by an enzyme-linked immunospot (ELISpot) assay. This trial is registered in ClinicalTrials.gov (NCT05656508). Findings The interim results from the ongoing phase 1 study are described. ARVAC-CG exhibited a satisfactory safety profile, a robust and broad booster response of neutralising antibodies against the Ancestral strain of SARS-CoV-2, the Gamma variant, and other VOCs (Delta, Omicron BA.1 and Omicron BA.5) and a booster effect on T cell immunity. Interpretation ARVAC-CG is safe and highly immunogenic when used as booster in individuals previously immunised with different COVID-19 vaccine platforms. These results warrant further clinical evaluation of this vaccine candidate for boosting other COVID-19 vaccines.

The aim of the present work was to evaluate, in the rat isolated mesenteric bed, whether increasing age is associated with alterations in the ATP sensitive K § channels functionality. Moreover, studies were performed in order to evaluate the effects of aging on the synthesis of vascular prostanoids as well as on its possible contribution to the pressor responses of this vascular bed. Male Wistar rats of 3 month (adults) and 24 month (aged) were used. Although no differences were found among adult and aged rats in pressor responses to 2-30 nmol noradrenaline and to 40-160 nmol KCl, the relaxant responses to the K + channel opener, 10 -e M cromakalim, were significantly diminished in the aged group compared to the adults, On the other hand, whereas PGF2a and 6-keto PGFla production was not modified with age, the thromboxane B 2 and prostaglandin E 2 production in the mesenteric bed from 24 month old rats was significantly increased compared to the adult group, Furthermore, the cyclooxigenase synthesis inhibitor, 10 .5 M indomethacin reduced the pressor responses induced by noradrenaline in the mesenteric beds from adults but not from aged rats, It is concluded that there is an age related reduction in the functionality of the ATP sensitive K § channels in the rat mesenteric bed, In addition, aging produces an increase in the release of vasoconstrictor as well as of vasodilator prostanoids, whose contribution to noradrenaline induced pressor responses appears to be less relevant in the older animals,