Search

Hypoxemia can be life-threatening, both acutely and chronically. Because hypoxemia causes vascular dysregulation that further restricts oxygen availability to tissue, it can be pharmacologically addressed. We hypothesized that theophylline can be safely combined with the [[beta].sub.2]-adrenergic vasodilator bambuterol to improve oxygen availability in hypoxemic patients. Ergogenicity and hemodynamic effects of bambuterol and theophylline were measured in rats under hypobaric and normobaric hypoxia (12% [O.sub.2]). Feasibility in humans was assessed using randomized, double-blind testing of the influence of combined slow-release theophylline (300 mg) and bambuterol (20 mg) on adverse events (AEs), plasma [K.sup.+], pulse, blood pressure, and drug interaction. Both drugs and their combination significantly improved hypoxic endurance in rats. In humans, common AEs were low [K.sup.+] ( Key words: hypoxemia, hypoxia, combination therapy, xanthine drugs, beta-adrenergic receptor agonist, drug safety, bioequivalence, human study, animal study. L'hypoxemie peut menacer le pronostic vital, tant par son exposition aigue que chronique. Comme l'hypoxemie cause un dereglement vasculaire qui entraine des restrictions supplementaires de la disponibilite de l'oxygene pour les tissus, il est possible d'approcher le probleme a l'aide de methodes pharmacologiques. Nous avons pose l'hypothese selon laquelle la theophylline peutetre associee sans risque au bambuterol, un vasodilatateur [beta]2-adrenergique, pour ameliorer la disponibilite de l'oxygene chez les patients hypoxemiques. Nous avons mesure l'ergogenicite et les effets hemodynamiques du bambuterol et de la theophylline chez des rats en conditions d'hypoxie hypobare et normobare ([O.sub.2] a 12 %). Nous avons evalue la faisabilite chez l'homme a l'aide d'une etude a double insu avec repartition aleatoire portant sur l'influence de l'association de la theophylline a liberation lente (300 mg) avec du bambuterol (20 mg) sur les evenements indesirables (EI), la kaliemie, le pouls, la tension arterielle et l'interaction entre les medicaments. Les deux medicaments ainsi que leur association ont permis d'ameliorer l'endurance des rats a l'hypoxie. Chez l'humain, les EI les plus frequents etaient l'hypokaliemie ( Mots-cles : hypoxemie, hypoxie, traitement d'association, xanthines, agoniste des recepteurs beta adrenergiques, innocuite des medicaments, bioequivalence, etude chez l'homme, etude chez les animaux., Introduction Lack of oxygen in the blood, hypoxemia, can be caused by various conditions, such as environmental shortage of oxygen ('thin air' at high altitude), obstruction of air flow (chronic [...]

MW01‐6‐189WH (MW189) is a novel central nervous system–penetrant small‐molecule drug candidate that selectively attenuates stressor‐induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first‐in‐human, randomized, double‐blind, placebo‐controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug‐related treatment‐emergent adverse event was infusion‐site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose‐proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low‐dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF‐α and higher levels of the anti‐inflammatory cytokine IL‐10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury. [ABSTRACT FROM AUTHOR]

We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo‐controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia‐induced headaches. Aminophylline, ambrisentan, and their combination all significantly (P < 0.05 vs. placebo) improved submaximal hypoxic exercise performance (19.5, 20.6, and 19.1% >placebo). Single‐dose ambrisentan increased blood oxygenation in resting, hypoxic subjects. We conclude that combined aminophylline and ambrisentan offer promise to safely increase exercise capacity in hypoxemic humans without relying on increasing blood oxygen availability. [ABSTRACT FROM AUTHOR]