Medium Term Effect of Sublingual L-glutathione (L-GSH) Supplementation on Flow Mediated Dilation and Oxidative Stress Markers in Male Subjects With Smoking Habit and/or Arterial Hypertension

Background. The antioxidant systems are the main endogenous defense against free radicals, and glutathione seems to play an important role in this mechanism. Reduced glutathione enters into the detoxification processes of endogenous products, such as hydro- and lipoperoxides and exogenous compounds such as pollutants, heavy metals and some drugs. Changes in GSH homeostasis have been implicated in the etiology and progression of several diseases. Supplementation of GSH may improve the endogenous antioxidant defense and may contribute to decrease of oxidants tissue damage a pathophysiologic mechanism of many acute and chronic diseases.

However, the efficacy of GSH treatment seems to be closely related to the degree of its absorption and to the increase of its concentrations in plasma and cells. Previous studies of oral GSH administration in healthy volunteers or in patients failed to find any effect in terms of oxidative stress reduction and/or disease improvement because the GSH is quickly catabolized by gastrointestinal tract. We have recently observed (preliminary data) that a new sublingual formulation of L-GSH (OXITION), produced by PH&T S.r.l., is able to increase erythrocyte and plasma GSH levels in healthy volunteers bypassing gastrointestinal barrier.

Objectives. The primary study objective is to determine whether medium term (4 weeks) of sublingual L-GSH supplementation to a population with smoking habit and/or arterial hypertension may result in improved endothelial function as assessed by the flow mediated dilation (FMD) technique versus placebo. FMD is a surrogate end point validated in the literature as prognostic predictor for major cardiovascular events in patients with endothelial dysfunction. Secondary study objectives are to determine differences between the 2 treatment in terms of oxidative stress markers.

Methods. This is a phase 3, double-blind, randomized, placebo-controlled, cross-over study performed in only one centre. Sixteen male subjects, aged ≥ 40 and ≤ 60 years, with smoking habit and/or hypertension defined as arterial blood pressure ≥ 140 and/or 90 mmHg or in anti-hypertensive treatment, will be enrolled and randomized to receive sublingual L-GSH (100 mg twice a day) or placebo according to a double-blind cross-over design for 4 weeks with a 3-week wash-out period between the two treatments. Baseline and at the end of each treatment period, FMD assessment and blood samples collection for routine (creatinine, urea, AST, ALT GGT, total cholesterol, HDL, LDL, triglycerides, fasting glucose) and specific (aminothiols, nitrotyrosine, malondialdehyde, 8-hydroxy-deoxyguanine) biochemical determination will be performed.