Ignite Creation Date:
2024-05-05 @ 6:32 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00493727
Status:
COMPLETED
Last Update Posted:
2008-05-19
First Post:
2007-06-27
Brief Title:
Use of Mucomyst to Ameliorate Oxidant Stress in Diabetics With Proteinuria
Sponsor:
US Department of Veterans Affairs
Organization:
VA Office of Research and Development
Study Overview
Official Title:
Use of Mucomyst NAC to Ameliorate Oxidant Stress in Diabetic Patients as Measurable by Surrogate Serum Markers
Status:
COMPLETED
Status Verified Date:
2008-05
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:
The study will look at the effect of 30 days of treatment of 15 diabetics with proteinuria with N-acetylcysteine Mucomyst at a dose of 1 gm twice a day by mouth The primary outcome that will be measured is change in the oxidant stress as measurable by changes in the serum level of isoprostane Glutathione peroxidase aconitase and Total oxidant stress Secondary outcomes measured will be changes in proteinuria and kidney function as measured by spot urine prcr and estimated GFR by MDRD formula
Detailed Description:
Mucomyst Acetylcysteine for amelioration of diabetic nephropathy
Hypothesis
Treatment with Mucomyst over several months will reduce the oxidant stress and thereby reduce the proteinuria and the progression of renal failure in patients with diabetic nephropathy
Rationale
Mucomyst or Acetylcysteine has now been found to be beneficial in ameliorating radio-contrast induced acute renal failure in several different studies ref 1 The beneficial effects of Mucomyst is most likely due to its antioxidative properties Oxidative stress plays a major role in diabetic complication especially in diabetic nephropathy
In a recent in vitro study Acetylcysteine ameliorated the deleterious effects of albumin on cultured renal proximal tubular epithelial cells Murine proximal tubular cells were treated with albumin 30 mgml medium for various lengths of time The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells The activation of STATs was mediated mostly by Jak2 and required no protein synthesis In addition activation of Stat1 occurred even after neutralization of IFN- The activation of STATs was inhibited by N-acetyl-L-cysteine a precursor of glutathione and a reactive oxygen species ROS scavenger and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading suggesting that albumin per se could generate ROS in proximal tubular cells The activation of STATs occurred by way of the ROS generating system and especially through the membrane-bound NADPH oxidase system Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS Hence not only the ROS generating system but also the ROS scavenging system may contribute to the induction of ROS by albumin
N-acetylcysteine also may attenuate the course of hepatorenal syndrome a renal vasoconstrictive response of indeterminate nature that develops during advanced liver failure This effect shown in experimental settings 9 and in a preliminary clinical report 10 could imply a better preservation of liver function However direct renal protective mechanisms may play a role also considering the ubiquitous distribution of acylases that catalyze the deacetylation of NAC 11 Indeed recent studies suggest that NAC may increase intracellular glutathione and ameliorate renal ischemia-reflow injury 12-14 inferior vena cava-occlusion 15 or kidney damage from cis-platinum 16 cyclosporine 17 and other nephrotoxic insults 18 19 NAC has been reported recently to prevent radiocontrast nephropathy in high-risk patients 20 These studies conducted in a clinical trial without preliminary experiments in animals underscore the safety of oral NAC administration
As stated above the mechanism of NAC-related organ protection is primarily attributed to scavenging oxygen free radicals either directly or through increasing intracellular glutathione concentration 3 4 Indeed decreased malonaldehyde production indicates an attenuation of membrane damage from oxygen-free radicals 3 but other protective mechanisms may play a role as well 21 Improved local microcirculation may be a major potential NAC-related organ-protective mechanism NAC was reported to augment papillary flow 22 and was found to improve renal vasodilation in response to acetylcholine 15 Thus perhaps some of the protective effects of NAC can be attributed to improved glomerular hemodynamics or to the prevention of hypoxic tubular damage via restoration of altered renal microcirculation
NAC ameliorates renal vasoconstriction an effect that seems to be mediated by mechanisms other than prostaglandins and nitric oxide
NAC had been safely used in a large group of ESRD patients for over one year 600 mg bid by mouth in a prospective randomized trial The group treated with NAC had reduction in composite cardiovascular endpoints 18 vs 47 Ref Circulation2003107 992 Tepel et al
Similarly in a RCt of Alzheimer patients NAC treatment for 6 months showed benefit in cognitive tasks in the treatment group Ref Neurology2001 23 57 Adair et al
Intravenous injection of NAC prior to dialysis increased the dialysis clearance of homocysteine and improved endothelial function in a group of ESRD patient Ref Circulation 2003 109 369 Scholze et al
NAC treatment was also found to have potentiating effect of the antihypertensive effects of ACE inhibitors in hypertensive patients Blood pressure 2002 11235 Barrios et al
In another RCT in an aging population chronic treatment with NAC was seen to cause significant decrease in plasma TNF-alpha and improved the muscle strength Ref J Mol MED 2003 81 118 Hauer et al
Protocol
All patients with diabetes and proteinuria at any level will be eligible for the study Patients who are on dialysis and who have known allergy to Mucomyst will be excluded
Patients will get Mucomyst 1000 mg by mouth twice a day for 30 days Urine and serum will be collected at the beginning at 15 and 30 days after starting Mucomyst and 30 days after stopping Mucomyst Portions of the blood and urine will be frozen and mailed to a special lab to measure the chemicals that determine the level of oxidative stress The particular chemicals that will be tested for are isoprostane in urine and isoprostane aconitase glutathione peroxidase and total serum antioxidant stress in the blood The special tests will be done by Dr Valyathans lab Locally we will test blood and urine for proteinuria and kidney Fx
Data collection
Demographic information
Wt BP at every visit
Med list rechecked at every visit
At every visit
Collection of blood for different measures of oxidant stress serum will be frozen to be sent to Dr Vallyathans lab later
Blood for renal function test
Spot urine proteincr quantitative proteinuria and also for measuring isoprostane
Outcome
The primary outcome will be the reduction in the measured oxidant stress markers in the serum such as isoprostane glutathione peroxidase aconitase and total oxidant stress Secondary outcome will be reduction in proteinuria and the change in kidney function during treatment with Mucomyst
Hypothesis
Treatment with Mucomyst over several months will reduce the oxidant stress and thereby reduce the proteinuria and the progression of renal failure in patients with diabetic nephropathy
Rationale
Mucomyst or Acetylcysteine has now been found to be beneficial in ameliorating radio-contrast induced acute renal failure in several different studies ref 1 The beneficial effects of Mucomyst is most likely due to its antioxidative properties Oxidative stress plays a major role in diabetic complication especially in diabetic nephropathy
In a recent in vitro study Acetylcysteine ameliorated the deleterious effects of albumin on cultured renal proximal tubular epithelial cells Murine proximal tubular cells were treated with albumin 30 mgml medium for various lengths of time The results showed that albumin could activate Stat1 and Stat5 within 15 min in proximal tubular cells The activation of STATs was mediated mostly by Jak2 and required no protein synthesis In addition activation of Stat1 occurred even after neutralization of IFN- The activation of STATs was inhibited by N-acetyl-L-cysteine a precursor of glutathione and a reactive oxygen species ROS scavenger and fluorescence-activated cell sorter analysis showed upregulation of intracellular ROS after albumin overloading suggesting that albumin per se could generate ROS in proximal tubular cells The activation of STATs occurred by way of the ROS generating system and especially through the membrane-bound NADPH oxidase system Reduced activities of glutathione peroxidase and catalase could also be responsible for the accumulation of intracellular ROS Hence not only the ROS generating system but also the ROS scavenging system may contribute to the induction of ROS by albumin
N-acetylcysteine also may attenuate the course of hepatorenal syndrome a renal vasoconstrictive response of indeterminate nature that develops during advanced liver failure This effect shown in experimental settings 9 and in a preliminary clinical report 10 could imply a better preservation of liver function However direct renal protective mechanisms may play a role also considering the ubiquitous distribution of acylases that catalyze the deacetylation of NAC 11 Indeed recent studies suggest that NAC may increase intracellular glutathione and ameliorate renal ischemia-reflow injury 12-14 inferior vena cava-occlusion 15 or kidney damage from cis-platinum 16 cyclosporine 17 and other nephrotoxic insults 18 19 NAC has been reported recently to prevent radiocontrast nephropathy in high-risk patients 20 These studies conducted in a clinical trial without preliminary experiments in animals underscore the safety of oral NAC administration
As stated above the mechanism of NAC-related organ protection is primarily attributed to scavenging oxygen free radicals either directly or through increasing intracellular glutathione concentration 3 4 Indeed decreased malonaldehyde production indicates an attenuation of membrane damage from oxygen-free radicals 3 but other protective mechanisms may play a role as well 21 Improved local microcirculation may be a major potential NAC-related organ-protective mechanism NAC was reported to augment papillary flow 22 and was found to improve renal vasodilation in response to acetylcholine 15 Thus perhaps some of the protective effects of NAC can be attributed to improved glomerular hemodynamics or to the prevention of hypoxic tubular damage via restoration of altered renal microcirculation
NAC ameliorates renal vasoconstriction an effect that seems to be mediated by mechanisms other than prostaglandins and nitric oxide
NAC had been safely used in a large group of ESRD patients for over one year 600 mg bid by mouth in a prospective randomized trial The group treated with NAC had reduction in composite cardiovascular endpoints 18 vs 47 Ref Circulation2003107 992 Tepel et al
Similarly in a RCt of Alzheimer patients NAC treatment for 6 months showed benefit in cognitive tasks in the treatment group Ref Neurology2001 23 57 Adair et al
Intravenous injection of NAC prior to dialysis increased the dialysis clearance of homocysteine and improved endothelial function in a group of ESRD patient Ref Circulation 2003 109 369 Scholze et al
NAC treatment was also found to have potentiating effect of the antihypertensive effects of ACE inhibitors in hypertensive patients Blood pressure 2002 11235 Barrios et al
In another RCT in an aging population chronic treatment with NAC was seen to cause significant decrease in plasma TNF-alpha and improved the muscle strength Ref J Mol MED 2003 81 118 Hauer et al
Protocol
All patients with diabetes and proteinuria at any level will be eligible for the study Patients who are on dialysis and who have known allergy to Mucomyst will be excluded
Patients will get Mucomyst 1000 mg by mouth twice a day for 30 days Urine and serum will be collected at the beginning at 15 and 30 days after starting Mucomyst and 30 days after stopping Mucomyst Portions of the blood and urine will be frozen and mailed to a special lab to measure the chemicals that determine the level of oxidative stress The particular chemicals that will be tested for are isoprostane in urine and isoprostane aconitase glutathione peroxidase and total serum antioxidant stress in the blood The special tests will be done by Dr Valyathans lab Locally we will test blood and urine for proteinuria and kidney Fx
Data collection
Demographic information
Wt BP at every visit
Med list rechecked at every visit
At every visit
Collection of blood for different measures of oxidant stress serum will be frozen to be sent to Dr Vallyathans lab later
Blood for renal function test
Spot urine proteincr quantitative proteinuria and also for measuring isoprostane
Outcome
The primary outcome will be the reduction in the measured oxidant stress markers in the serum such as isoprostane glutathione peroxidase aconitase and total oxidant stress Secondary outcome will be reduction in proteinuria and the change in kidney function during treatment with Mucomyst
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