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The Effects of L-Arginine on Symptomatic Patients with Nonreconstructable Vascular Disease
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The Effects of L-Arginine on Symptomatic Patients with Nonreconstructable Vascular Disease
- Dennis E. Weiland, MD
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Abstract: A persistent dilemma exists about how to treat pain and ulceration in patients with vascular disease whose stenosis or occlusion cannot be reconstructed by angioplasty, stenting, or bypass. These patients are prone to infection, amputation, and narcotic addiction. Therefore, to prevent these complications, the blood supply to the extremity must be increased by medication that produces vasodilatation. L-arginine fits this description, as it is a precursor to nitric oxide and a potent vasodilator. L-arginine is now readily available in 2 different products (RESOURCE® Arginaid® EXTRA, Novartis Medical Nutrition, Fremont, Mich, and JUVEN®, Ross Products, Columbus, Ohio). In this study, 6 patients with nonreconstructable vascular disease were given L-arginine (RESOURCE Arginaid EXTRA), 2 packs daily, for a 2-week period. In all cases, the reported pain was reduced and the ulcers either healed or reduced in size. Those patients with renal compromise showed no elevation in creatinine or blood/urea/nitrogen. The results of this anecdotal study would encourage the trial use of L-arginine in this select group of patients.
Pain, infections, and ulcerations that will not heal are common complications in patients with severe peripheral vascular disease. If the vascular stenosis or occlusion can be dilated or bypassed, these symptoms often disappear. However, if the arteries cannot be dilated or bypassed, treatments must be medical. Few drugs are available for this use, and often, antiplatelet medications are prescribed to improve circulation and prevent clotting. These drugs may produce various bleeding complications and are variably effective.1,2
L-arginine has been investigated as part of the continued search for less toxic drugs that produce vasodilatation. Since L-arginine is a semi-essential amino acid and is a precursor to nitric oxide, administration of larger amounts may produce systemic vasodilatation and relieve the ischemic vascular symptoms. This thesis is supported by Boger et al3 and Gryglewski et al4 who showed that daily infusions of L-arginine (12.6 g) for 7 days increased blood flow and transcutaneous oxygen saturation, improved walking distance, lessened the recovery time from pain, and reduced both platelet aggregation and euglobulin clot lysis time.3,4
L-arginine exhibits other vascular benefits including inhibiting the development of atherosclerosis,5 improving brachial artery flow-mediated vasodilatation in hypercholesterolemic young adults (19–40 years),6 reducing monocyte adhesiveness, and reducing platelet hyperaggregability.7 In patients with stable angina, oral L-arginine reduced myocardial ischemia and improved maximal work loads.8
Materials and Methods Six patients with pain, ulcers, or both and nonreconstructable peripheral vascular disease were placed on L-arginine (RESOURCE® Arginaid® EXTRA, Novartis Medical Nutrition, Fremont, Mich), 1 pack twice daily, for 2 weeks. Transcutaneous oxygen levels (TCOM) were measured on the first 3 patients before and after the institution of L-arginine. Conventional wound care therapy was continued during the 2-week course of L-arginine therapy. Photos of the wounds were taken before and after therapy.
Results Case 1. An 82-year-old man with diabetes developed an ulcer on his left 1st metatarsophalangeal joint from wearing a new pair of shoes. Cultures showed Staphylococcus epidermidis, Stenotrophomonas, and gamma, nonhemolytic Streptococcus. The patient failed to respond to topical and systemic antibiotics. Angiograms showed no possibility of angioplasty or bypass. The patient was placed on 2 weeks of L-arginine and showed complete healing of the wound in 8 weeks (Figure 1).
Case 2. An 81-year-old black woman with diabetes presented with a persistent ulceration on her right leg. The ulcer had initially responded to hyperbaric oxygen therapy and topical and systemic antibiotics but recurred. The patient was started on L-arginine. During a 2-month period, the patient’s pain improved and the wound healed (Figure 2).
Case 3. An 87-year-old white man with diabetes presented with bilateral heel ulcers. The left heel ulcer healed, but the ulcer on the right heel persisted. The patient had severe peripheral vascular disease and failed to respond to topical antibiotics. At his last visit on 12/13/05, the ulcer showed only minimal improvement, but the pain had decreased (Figure 3).
Case 4. A 69-year-old man developed severe pain in his legs from multiple emboli following placement of cardiac stents. The emboli produced multiple cyanotic sites in the feet. One cyanotic site on the little toe produced tissue necrosis and a nonhealing ulcer. The wounds failed to respond to topical antibiotics. The patient was placed on L-arginine, and the wounds healed in 2 weeks. The wounds remained healed 1 month follow-up (Figure 4).
Case 5. An 83-year-old man presented with multiple ulcerations of both feet. The patient had severe peripheral vascular disease and cardiomyopathy. The wounds failed to respond to silver-containing topical antibiotics. The patient was belatedly started on L-arginine and continued this treatment for several weeks. His ulcers improved and finally healed with continued L-arginine. The cardiomyopathy may have contributed to the slowed response (Figure 5 and 6).
Case 6. A 70-year-old woman presented with severe rest pain and leg weakness from peripheral vascular disease. The patient had superficial ulcers covered with eschar and was disabled from pain and weakness. After 2 weeks of L-arginine treatment, her pain and cyanosis remarkably improved. The superficial ulcers showed signs of healing, and the ischemic discoloration in the legs improved (Figure 7).
Discussion The early and prolonged response to the short-term administration of L-arginine was surprising and gratifying. These patients had little hope of achieving relief from conventional therapy yet received comfort from a product that is natural and relatively inexpensive.
Many cardiovascular benefits may be achieved with L-arginine treatment. Smoking produces increased adhesiveness of the monocytes to the endothelial wall and produces endothelial vasodilator dysfunction. This is reversed by L-arginine.9 In patients with angina and normal coronary angiograms (Syndrome X), the endothelial vasodilator dysfunction of the microvasculature found in these patients is reversed by a single intravenous infusion of L-arginine.10 It also reverses the coronary endothelial dysfunction associated with aging.11 Myocardial ischemia and improvement of the maximal work load is attained with L-arginine in patients with stable angina.8
There is a dark side to the use of L-arginine in vascular disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase (eNOS). In a study by Vallance et al,12 patients with renal failure showed high levels of ADMA that produced vasoconstriction of vascular rings, and this was reversible by L-arginine. Levels of ADMA are associated with disease severity in patients with peripheral arterial disease. As such, ADMA may lead to the development of atherosclerosis.3 In ischemia-reperfusion injury, eNOS is transformed into a generator of superoxide radicals that are harmful to tissues. Interestingly, this is reversed by the administration of L-arginine.13 In a recent article, Schulman et al14 described the use of L-arginine in a randomized series of patients with myocardial infarction for 6 months. The L-arginine arm of the study was stopped because 6 of the participants (8.6%) died. One patient died of myocardial rupture following a second myocardial infarction; 2 others were found dead at home (cause of death unclear); 2 died of sepsis; and another died 3 weeks following cessation of L-arginine. The use of L-arginine in this acute clinical setting is not advised; however, in other clinical settings, it appears to be beneficial and has minimal or no adverse effects.
Conclusions L-arginine appears to exert its cardiovascular effects by conversion to nitric oxide via eNOS. By restoring the endothelium-derived NO production, disorders with reduced eNOS benefit from the administration of L-arginine. By this mechanism, exogenous L-arginine appears to benefit those with nonreconstructable vascular disease.
Endogenous ADMA found in some of these disorders benefits from the exogenous administration of L-arginine. As more studies develop, the mechanisms for the production of nitric oxide and its antagonists will play a greater role in the understanding of other disease states.15 For example, elevated ADMA levels are found in preecampsia.16 This understanding will undoubtedly lead to more effective treatments.
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References
1. Jackson MR, Clagett GP. Antithrombotic therapy in peripheral arterial occlusive disease. Chest. 2001;119(1 Suppl):283S–299S.
2. Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344(21):1608–1621.
3. Boger RH, Bode-Boger SM, Thiele W, et al. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation. 1997;95(8):2068–2074.
4. Gryglewski RJ, Grodzinska L, Kostka-Trabka E, et al. Treatment with L-arginine is likely to stimulate generation of nitric oxide in patients with peripheral arterial obstructive disease. Wien Klin Wochenschr. 1996;108(4):111–116.
5. Boger RH, Bode-Boger SM, Brandes RP, et al. Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin. Circulation. 1997;96(4):1282–1290.
6. Clarkson P, Adams MR, Powe AJ, et al. Oral L-arginine improves endothelium-dependent dilation of hypercholesterolemic young adults. J Clin Invest. 1996;97(8):1989–1994.
7. McVeigh GE, Lemay L, Morgan D, Cohn JN. Effects of long-term cigarette smoking on endothelium-dependent responses in humans. Am J Cardiol. 1996;78(6):668–672.
8. Lekakis JP, Papamichael CM, Argios N, et al. Peripheral vascular endothelial dysfunction in patients with microvascular angina pectoris. J Am Coll Cardiol. 1997;29:175A.
9. Adams MR, Jessup W, Celermajer DS. Cigarette smoking is associated with increased human monocyte adhesion to endothelial cells: reversibility with oral L-arginine but not vitamin C. J Am Coll Cardiol. 1997;29(3):491–497.
10. Ceremuzynski L, Chamiec T, Herbaczynska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997;80(3):331–333.
11. Chauhan A, More RS, Mullins PA, et al. Aging-associated endothelial dysfunction in humans is reversed by L-arginine. J Am Coll Cardiol. 1996;28(7):1796–1804.
12. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339(8793):572–575.
13. Huk I, Nanobashvili J, Neumayer C, et al. L-arginine treatment alters the kinetics of nitric oxide and superoxide release and reduces ischemia/reperfusion injury in skeletal muscle. Circulation. 1997;96(2):667–675.
14. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295(1):58–64.
15. Maxwell AJ, Cooke JP. Cardiovascular effects of L-arginine. Curr Opin Nephrol Hypertens. 1998;7(1):63–70.
16. King RG, Di Iulio JL, Gude NM, Brennecke SP. Effect of asymmetric dimethyl arginine on nitric oxide synthase activity in normal and pre-eclamptic placentae. Reprod Fertil Dev. 1995;7(6):1581–1584.
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| Wounds - ISSN: 1044-7946 - Volume 18 - Issue 8 - August 2006 - Pages: 238 - 244 | |
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The following is a collection of publications from Healthpoint intended to facilitate expeditious, cost-effective wound care management. There will be nine publications total. |
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