Ignite Creation Date:
2024-05-06 @ 2:47 AM
Last Modification Date:
2024-10-26 @ 11:23 AM
Study NCT ID:
NCT02125045
Status:
COMPLETED
Last Update Posted:
2014-05-08
First Post:
2013-11-26
Brief Title:
Sublingual L-GSH Supplementation in Male Subjects With Smoking Habit andor Hypertension
Sponsor:
Niguarda Hospital
Organization:
Niguarda Hospital
Study Overview
Official Title:
Medium Term Effect of Sublingual L-glutathione L-GSH Supplementation on Flow Mediated Dilation and Oxidative Stress Markers in Male Subjects With Smoking Habit andor Arterial Hypertension
Status:
COMPLETED
Status Verified Date:
2014-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 andor 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 PHT Srl 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 andor 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 andor hypertension defined as arterial blood pressure 140 andor 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
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 andor 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 PHT Srl 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 andor 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 andor hypertension defined as arterial blood pressure 140 andor 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 Parkinsons and Alzheimers 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 andor 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 PHT Srl 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 andor 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 cigarettedie andor arterial hypertension PAS140 mmHg andor PAD90 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 11 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
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 Parkinsons and Alzheimers 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 andor 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 PHT Srl 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 andor 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 cigarettedie andor arterial hypertension PAS140 mmHg andor PAD90 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 11 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None