Aims Reduced nitric oxide (NO) availability may adversely affect renal perfusion and glomerular filtration. magnitude was within the physiological range. RPF and GFR recovered partly 2 hours after end of VAS203\infusion and was normal at beginning of the second infusion period. Compared to placebo, preglomerular resistance (.0001), and to lesser extent postglomerular resistance ( .0001) increased, resulting in a decrease of intraglomerular pressure (.01). No treatment related effect on markers of early kidney injury, and on renal function (for all .20) have been observed. Conclusions Our phase\I\study in healthy humans indicates that VAS203 R112 (10?mg/kg body weight) reduces renal perfusion and glomerular function within the physiological range mainly due to vasoconstriction at the preglomerular site. synthesized iNOS, the cofactor antagonist is incorporated directly into the high affinity cofactor binding site, resulting in more effective inhibition of iNOS.7, 9, 10 These properties of antipterins suggest that VAS203 might be more suitable as a therapeutic agent. In an experimental animal model of TBI, VAS203 application led to an improved neurological outcome after experimental TBI.11 In accordance, an explorative phase IIa (the NOSynthase inhibition in TRAumatic brain injury [NOSTRA]) trial comprising 32 patients with moderate and severe TBI revealed an improved functional outcome in VAS203\treated patients.12 In both the first\in\man study and the NOSTRA trial, VAS203 did not cause major safety hepatic, haematological or cardiac toxic effects, but led to acute kidney injury (AKI) in a dose\dependent manner in few subjects.12 This finding has not been foreseen from animal studies. The potential benefit of VAS203 is related to its selective inhibition of newly synthesized iNOS in TBI, but may also inhibit iNOS in other organs such as the kidney. In renal cells constitutional nNOS, eNOS and also iNOS are indicated in the healthy state and thus the kidneys are most vulnerable to iNOS inhibition.13 The aim of this phase\I\study was to characterize in detail the pharmacological effects of VAS203 on renal haemodynamics in healthy individuals. 2.?METHODS 2.1. Study cohort and design This randomized, double\blind, mix\over, solitary\centre study was conducted under the legal sponsorship of the Medical Faculty of Friedrich\Alexander University or college Erlangen\Nrnberg, Germany, between August 2015 and May 2016. The study was planned for 16 healthy male participants, who have been recruited in the area of ErlangenCNrnberg, Germany; qualified subjects were enrolled consecutively. Main inclusion criteria were male aged between 18 and 45?years having a body weight between 60 and 100?kg. Main exclusion criteria were a R112 CockcroftCGault creatinine clearance 90?mL/min, and any clinically significant diseases. Written educated consent was acquired prior to study inclusion. Participants underwent a screening phase 3C7?days before start of treatment to ensure that they were healthy. Participants were randomized pairwise into 2 organizations receiving 1st VAS203 and placebo, respectively. During the treatment phase, the subjects were hospitalized in the study centre for 2?days (1 night time) for each infusion period. In addition, renal function was identified 48?hours after start of infusion. After a 21C35\day time wash\out period (based on the pharmacokinetic profile of VA203), participants returned for Rabbit Polyclonal to HSL (phospho-Ser855/554) second treatment phase period (mix\over). It was prespecified, that after the 1st (i.e. 1 VAS203 and 1 placebo) experienced received the first infusion and has shown no indicators of AKI for 48?hours after start of infusion, the second infusion period can be started after fulfilling the respective wash\out period. In addition to this 1st R112 blinded security interim analysis as well as after conductance of 6 full cross\over subjects (with both infusion periods), a second interim blinded security analysis and statement was communicated to the legal German expert (Bundesinstitut fr Arzneimittel und Medizinprodukte). Blinded study medication (intravenous infusions) were provided by the local Pharmacy of the University or college Hospital Erlangen. The study protocol was authorized by the Local Ethics Committee (University or college of ErlangenCNrnberg) and the study was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice recommendations. The study was authorized at www.clinicaltrials.gov (ID: “type”:”clinical-trial”,”attrs”:”text”:”NCT02992236″,”term_id”:”NCT02992236″NCT02992236). The monetary supporter Vasopharm GmbH, Wrzburg, Germany, did not contribute to study conduction or data collection. 2.2. Assessment of renal haemodynamics Renal haemodynamics were measured using the constant\infusion inputCclearance technique with sodium p\aminohippurate (PAH; Clinalfa, Basel, Switzerland) and inulin (Inutest, Fresenius, Linz, Austria).