Advertisement
Mayo Clinic Proceedings Home

Effect of Glutathione Infusion on Leg Arterial Circulation, Cutaneous Microcirculation, and Pain-Free Walking Distance in Patients With Peripheral Obstructive Arterial Disease: A Randomized, Double-Blind, Placebo-Controlled Trial

      Objective

      To assess the effects of glutathione on pain-free walking distance (PFWD) and hemodynamic parameters in patients with peripheral artery disease.

      Patients and Methods

      Forty patients with Fontaine stage II peripheral artery disease who were seen between September 2000 and March 2001 at the vascular laboratory and ward of the Division of Vascular Medicine and Rehabilitation at Verona University were studied in a double-blind, placebo-controlled trial. The patients were randomly assigned (20 per group) to treatment with intravenous glutathione twice a day or saline solution twice a day for 5 days. Treatments were administered in a double-blind manner. The 2 groups of patients underwent measurement of PFWD by strain-gauge plethysmography and laser Doppler flowmetry (with postischemic test) of the symptomatic leg at rest and after treadmill test. All measurements and tests were repeated 12 hours after the last infusion.

      Results

      Between the 2 groups, hemodynamic tests showed no differences in baseline values and at rest after treatment. At rest, no differences were observed between basal and posttreatment values; findings in the saline group were similar during tests before and after the infusion period. In the glutathione group, we observed increases in PFWD (196±15 vs 143±11 m; P<.04), macrocirculatory flow after treadmill test with plethysmography at the end of treatment (9.3±2 vs 2.8±0.5 mL per 100 mL/min; P<.002), and postischemic hyperemia with laser Doppler flowmetry, registered as perfusion units (PU), at the end of infusions (14.4±3.2 vs 6.18±1.5 PU; P<.005), with a greater area under the curve after treatment (705±103 vs 508±45 PU/s; P<.001) and reduced time to flow motion (32±4 vs 48±11 seconds; P<.05).

      Conclusion

      In patients with peripheral artery disease, glutathione prolongs PFWD and shows an improvement of macrocirculatory and microcirculatory parameters.
      PFWD (pain-free walking distance), PU (perfusion units)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      REFERENCES

        • Enstrom JE
        • Kanim LE
        • Klein MA
        Vitamin C intake and mortality among a sample of the United States population.
        Epidemiology. 1992; 3: 194-202
        • Stephens NG
        • Parsons A
        • Schofield PM
        • Kelly F
        • Cheeseman K
        • Mitchinson MJ
        Randomised controlled trial of vitamin E in patients with coronary artery disease: Cambridge Heart Antioxidant Study.
        Lancet. 1996; 347: 781-786
        • Gokce N
        • Keaney Jr, JF
        • Frei B
        • et al.
        Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease.
        Circulation. 1999; 99: 3234-3240
        • Haeger K
        Long-time treatment of intermittent claudication with vitamin E.
        Am J Clin Nutr. 1974; 27: 1179-1181
        • Panza JA
        • Casino PR
        • Kilcoyne CM
        • Quyyumi AA
        Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension.
        Circulation. 1993; 87: 1468-1474
        • Anderson TJ
        • Uehata A
        • Gerhard MD
        • et al.
        Close relation of endothelial function in the human coronary and peripheral circulations.
        J Am Coll Cardiol. 1995; 26: 1235-1241
        • Yeung AC
        • Vekshtein VI
        • Krantz DS
        • et al.
        The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress.
        N Engl J Med. 1991; 325: 1551-1556
        • Gryglewski RJ
        • Palmer RM
        • Moncada S
        Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor.
        Nature. 1986; 320: 454-456
        • Liao JK
        • Shin WS
        • Lee WY
        • Clark SL
        Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase.
        J Biol Chem. 1995; 270: 319-324
        • Handin RI
        • Karabin R
        • Boxer GJ
        Enhancement of platelet function by superoxide anion.
        J Clin Invest. 1977; 59: 959-965
        • van Marwijk Kooy M
        • Akkerman JW
        • van Asbeck S
        • Borghuis L
        • van Prooijen HC
        UVB radiation exposes fibrinogen binding sites on platelets by activating protein kinase C via reactive oxygen species.
        Br J Haematol. 1993; 83: 253-258
        • Chiu JJ
        • Wung BS
        • Shyy JY
        • Hsieh HJ
        • Wang DL
        Reactive oxygen species are involved in shear stress-induced intercellular adhesion molecule-1 expression in endothelial cells.
        J Arterioscler Thromb Vasc Biol. 1997; 17: 3570-3577
        • Medford RM
        • Erickson S
        • Chappel D
        • Offermann MK
        • Nerem R
        • Alexander RW
        Laminar shear stress and redox sensitive regulation of human vascular endothelial cell VCAM-1 gene expression [abstract].
        Circulation. 1994; 90 (Abstract 0438.): I-83
        • Laurindo FR
        • Pedro Mde A
        • Barbeiro HV
        • et al.
        Vascular free radical release: ex vivo and in vivo evidence for a flow-dependent endothelial mechanism.
        Circ Res. 1994; 74: 700-709
        • Hsieh HJ
        • Cheng CC
        • Wu ST
        • Chiu JJ
        • Wung BS
        • Wang DL
        Increase of reactive oxygen species (ROS) in endothelial cells by shear flow and involvement of ROS in shear-induced c-fos expression.
        J Cell Physiol. 1998; 175: 156-162
        • Ronson RS
        • Nakamura M
        • Vinten-Johansen J
        The cardiovascular effects and implications of peroxynitrite.
        Cardiovasc Res. 1999; 44: 47-59
        • Meister A
        Glutathione-ascorbic acid antioxidant system in animals.
        J Biol Chem. 1994; 269: 9397-9400
        • Ghigo D
        • Alessio P
        • Foco A
        • et al.
        Nitric oxide synthesis is impaired in glutathione-depleted human umbilical vein endothelial cells.
        Am J Physiol. 1993; 265: C728-C732
        • Celermajer DS
        • Sorensen K
        • Ryalls M
        • et al.
        Impaired endothelial function occurs in the systemic arteries of children with homozygous homocystinuria but not in their heterozygous parents.
        J Am Coll Cardiol. 1993; 22: 854-858
        • Ludmer PL
        • Selwyn AP
        • Shook TL
        • et al.
        Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.
        N Engl J Med. 1986; 315: 1046-1051
        • Vita JA
        • Frei B
        • Holbrook M
        • Gokce N
        • Leaf C
        • Keaney Jr, JF
        L-2-Oxothiazolidine-4-carboxylic acid reverses endothelial dysfunction in patients with coronary artery disease.
        J Clin Invest. 1998; 101: 1408-1414
        • Freedman JE
        • Frei B
        • Welch GN
        • Loscalzo J
        Glutathione peroxidase potentiates the inhibition of platelet function by S-nitro-sothiols.
        J Clin Invest. 1995; 96: 394-400
        • Kugiyama K
        • Ohgushi M
        • Motoyama T
        • et al.
        Intracoronary infusion of reduced glutathione improves endothelial vasomotor response to acetylcholine in human coronary circulation.
        Circulation. 1998; 97: 2299-2301
        • Dahllof AG
        • Bjorntorp P
        • Holm J
        • Schersten T
        Metabolic activity of skeletal muscle in patients with peripheral arterial insufficiency.
        Eur J Clin Invest. 1974; 4: 9-15
        • Corsi C
        • Pollastri M
        • Marrapodi E
        • Leanza D
        • Giordano S
        • D'Iddio S
        L-propionyl carnitine effect on postexercise and postischemic hyperemia in patients affected by peripheral vascular disease.
        Angiology. 1995; 46: 705-713
        • Kohler M
        Evaluation of compensation of chronic arterial occlusions [in German].
        Vasa. 1973; 2: 4-11
        • TransAtlantic Inter-Society Consensus (TASC)
        Management of peripheral arterial disease (PAD).
        Int Angiol. 2000; 19: 73
      1. Kappert A. Angiologia, fisiopatologia e clinica. In: Lehrbuch und Atlas der Angiologie. 12th ed (Italian edition). 1991: 77-78.

        • del Guercio R
        • Leonardo G
        • Arpaia MR
        Evaluation of postischemic hyperemia on the skin using laser Doppler velocimetry: study on patient s with claudication intermittens.
        Microvasc Res. 1986; 32: 289-299
        • Kvernebo K
        • Slasgsvold CE
        • Stranden E
        Laser Doppler flowmetry in evaluation of skin post-ischaemic reactive hyperaemia: a study in healthy volunteers and atherosclerotic patients.
        J Cardiovasc Surg (Torino). 1989; 30: 70-75
        • Seifert H
        • Jager K
        • Bollinger A
        Analysis of flow motion by the laser Doppler technique in patients with peripheral arterial occlusive disease.
        Int J Microcirc Clin Exp. 1988; 7: 223-236
        • Heidrich H
        • Allenberg J
        • Cachovan M
        • German Society of Angiology
        • et al.
        Guidelines for therapeutic studies on peripheral arterial occlusive disease in Fontaine stages II-IV [in German] [published correction appears in Vasa. 1993;22:190].
        Vasa. 1992; 21: 333-343
        • Shoemaker JK
        • Halliwill JR
        • Hughson RL
        • Joyner MJ
        Contributions of acetylcholine and nitric oxide to forearm blood flow at exercise onset and recovery.
        Am J Physiol. 1997; 273: H2388-H2395
        • Prasad A
        • Andrews NP
        • Padder FA
        • Husain M
        • Quyyumi AA
        Glutathione reverses endothelial dysfunction and improves nitric oxide bioavailability.
        J Am Coll Cardiol. 1999; 34: 507-514
        • Wilkin JK
        Periodic cutaneous blood flow during postocclusive reactive hyperemia.
        Am J Physiol. 1986; 250: H765-H768
        • Colantuoni A
        • Bertuglia S
        • Intaglietta M
        Microvascular vasomotion: origin of laser Doppler flux motion.
        Int J Microcirc Clin Exp. 1994; 14: 151-158