Effect of Repeated Dosing of Naproxcinod on Renal Hemodynamic and on Sodium Balance in Healthy Volunteers Before and After a Single Dose of Furosemide

Inclusion criteria

• Healthy, non smoker male subjects aged 18 and 35 years (inclusive), at the Screening visit.
• Body Mass Index (BMI) strictly between 18 and 30 kg/m² (inclusive) with body weight≥ 50 kg at the Screening visit.
• Normal physical examination at the Screening visit.
• Normal ECG (12-lead) at the Screening visit, as judged by the Investigator.
• At Screening and run-in period visits , Systolic Blood Pressure (SBP) between 100 and 139 mmHg (inclusive) and Diastolic Blood Pressure (DBP) between 50 and 89 mmHg (inclusive).
• At Screening and run-in period visits, HR between 45 and 90 bpm (inclusive).
• Subjects must be able to understand the written information sheet and informed consent and comply with all study requirements.
• Subjects must provide a written, dated and signed informed consent prior to any study procedure.

Exclusion criteria

• A history of hypersensitivity reactions (such as asthma, rhinitis, or urticaria) to aspirin, naproxen or any other NSAIDs; or hypersensitivity or contraindications to organic nitrate drugs or hypersensitivity to furosemide or to sinistrine or PAH.
• Family history of hypertension which may disqualify the subject, as judged by the investigator..
• History of any clinically relevant gastrointestinal (such as gastritis or gastric ulcer), respiratory, psychiatric, neurologic, kidney, liver, cardiac disease, bleeding disorder, other disease/condition or abnormal physical finding which may interfere with the study objectives. The investigator may disqualify any subject for a sound medical or psychiatric reason.
• History or presence of ASAT >40UI/L, ALAT >40UI/L, serum bilirubin 3 times above the Upper Limit of Normal range at the Screening visit.
• Creatinine clearance inferior/equal to 80 ml/min as calculated with the Cockcroft-Gault formula (Appendix 5 of the protocol) at the Screening visit.
• Plasmatic potassium <3.5 mmole/L at the Screening visit.
• Seropositivity for HBs, HBc, HIV 1 or HIV 2 at the Screening visit.
• Donations of blood, plasma or platelets within 3 months prior to the Screening visit or donation planned during the 3 months following Day 8.
• Any clinically significant abnormal laboratory values at the Screening visit.
• At the Screening visit, after 1 minute in a standing position, a drop of more than 20 mmHg in SBP or 10 mmHg in DBP or a clinical manifestation of postural hypotension.
• Chronic use of any drugs (prescription or OTC) within 4 weeks prior to Visit 2 (single use of medication such as paracetamol for headache will be tolerated at the lowest possible dose).
• Intake of any Nitric Oxide Synthase Inhibitor within 1 month before Screening visit.
• History of drug addiction or alcohol abuse as defined by DSM IVR, diagnostic criteria for drug and alcohol abuse or drug addiction.
• Positive drug screening (opiates, cannabinoids, cocaine, benzodiazepines, amphetamines, barbiturates) at the Screening visit.
• Current participation or participation within 60 days prior to the Screening visit, in another investigational study, including the present study or any previous enrolment in a naproxcinod study.
• In custody due to an administrative or a legal decision, or under tutelage, or being admitted to a sanitary or social institution.
• Any direct or indirect involvement with the study conduct or staff at site or any family link with study site staff.