Sublingual L-GSH Supplementation in Male Subjects With Smoking Habit and/or Hypertension
Condition: Health Subjects With Cardiovascular Risk Factors
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      The strategies to prevent cardiovascular diseases play a prominent role in the guidelines of
      different scientific societies. Risk factors lead to several biological reactions within the
      cell in terms of pathophysiology, and thus of response to the homeostasis alteration. It is
      known that both smoking habit and hypertension alters endothelial functions through direct
      oxidative damage to endothelial cells, decrease in nitric oxide availability, and affects the
      mobilization of endothelial progenitor cells from the bone marrow.

      Several studies have identified this response in the activation of mechanism that prevent the
      formation of oxidizing species, detoxifying any dangerous products. The antioxidant systems
      are, thus, the main endogenous defense against free radicals, and glutathione seems to play
      an important role in this mechanism. Reduced glutathione (GSH), formed by cysteine, glycine
      and glutamate, enters into the detoxification processes of endogenous products, such as
      peroxides which are the final pathway of many reactions caused by cardiovascular risk
      factors. It also acts on the 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. A reduced bioavailability of GSH has been associated with neurodegenerative
      diseases such as Parkinson's and Alzheimer's or with increased risk of cardiovascular events.

      The imbalance in the GSH homeostasis and aminothiols redox state is also involved in
      mechanisms that cause both chronic obstructive pulmonary and lung diseases and cystic
      fibrosis. Low levels of GSH have been found in individuals with HIV and are associated to
      reduced patients survival.

      On the basis of previous data, it is conceivable that supplementation of GSH, whose
      concentrations decrease merely with age, may improve the endogenous antioxidant defense and
      may contribute to decrease of oxidants tissue damage, a typical characteristic of many acute
      and chronic diseases.

      Several authors studied the effect of GSH oral administration in acute and in medium-long
      term treatment in healthy volunteers or in patients affected by different diseases.
      Unfortunately, they did not find any beneficial effect in terms of oxidative stress reduction
      and/or disease improvement. GSH was also administered intravenous, intramuscular or
      intrabronchial without positive results.

      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. Preliminary data obtained at the
      Institute of Clinical Physiology Institute of Milan in a small sample of healthy volunteers
      have shown that sublingual administration (100 mg) of a new preparation of L-glutathione
      (OXITION, PH&T S.r.l.) is able to increase over 4 h, plasma and erythrocyte GSH
      concentrations with an average of 70% compared to the endogenous physiological levels. This
      increase is not detectable after oral intake of the same molecule due to the gastrointestinal
      barrier. The primary objective of this study is to determine whether medium-term sublingual
      administration of reduced L-GSH for 4 weeks to male subjects with risk factor smoking habit
      and/or arterial hypertension results in improved endothelial function, as assessed by
      arterial FMD, when compared to placebo. A favourable response to study compound will result
      in a greater endothelium-dependent vasodilatory ability as assessed by the ratio between peak
      flow after reactive hyperaemia and basal flow. Secondary study objective is to determine
      differences between L-GSH supplementation and placebo in terms of oxidative stress markers.

      Sixteen male healthy subjects will be randomized to sequential allocation to reduced L-GSH or
      placebo, according to the following inclusion criteria: age from 40 to 60 years, without any
      signs or symptoms of cardio-cerebro-vascular event at the enrolment, with smoking habit (>10
      cigarette/die) and/or arterial hypertension (PAS≥140 mmHg and/or PAD≥90 mmHg or in
      anti-hypertensive treatment). Consenting subjects will be enrolled and sequentially assigned
      to study treatment following a double-blind, cross over, randomized and controlled
      experimental design (L-GSH versus placebo) with a 3-week wash-out period between the two
      treatments. Each intervention will last 4 weeks. Baseline evaluation includes interview for
      history and nutritional characterization, blood pressure and heart rate assessment, blood
      sampling for routine haematological analysis [serum fasting glucose (GLU), total cholesterol
      (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C), triglycerides (TG), creatinine
      (CREA), urea, gamma-glutamyl-transpeptidase (GGT), aspartate-amino transferase (AST)
      alanine-amino transferase (ALT)], and specific biochemical determination of endogenous redox
      status (total and reduced plasma aminothiols, total and reduced blood glutathione by HPLC)
      and oxidative stress mediators [plasma nitrotyrosine (NT), plasma malondialdehyde (MDA) and
      plasma 8-hydroxy-2'-deoxyguanosine (8-OHdG) by ELISA Kits]. FMD will be measured by a non
      invasive plethysmographic method (Endo-PAT2000) based on the registration of pulsatile blood
      volume in the fingertips of both hands.

      After baseline assessment, patients will be randomized through a computer based procedure to
      active treatment or placebo in a 1:1 ratio. Study drug will be dispensed. At the 4-week
      follow-up, vital signs assessment, blood sampling for routine and specific biochemical
      determination, and FMD test will be again performed.
    

Intervention name(s): L-GSH; Placebo
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Reduced glutathione is formed by cysteine, glycine and glutamate. It enters into the detoxification processes of endogenous products, such as peroxides which are the final pathway of many reactions caused by cardiovascular risk factors. It also acts on the exogenous compounds, such as pollutants, heavy metals and some drugs.; Placebo will be prepared using the same excipients of the dietary supplement without active substance.
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: GSH; cardiovascular risk factors; endothelial dysfunction; oxidative stress