Twenty-one HIV-infected patients (median age, 40 years) with toxic neuropathy induced by antiretroviral drugs received 1,500 mg of acetyl-L-carnitine (ALC) twice a day for a median duration of 14 months (range, 5-33 months). After six months of treatment, histological evidence of nerve regeneration was seen; these improvements continued (epidermis and dermis) or stabilized (sweat glands) after 24 months of treatment. The neuropathy improved in 76% of the patients and remained stable in an additional 19%.

Comment: Nucleoside analogue reverse transcriptase inhibitors (NRTI) such as stavudine, zalcitabine, and didanosine, which are used to treat HIV infection, disrupt neuronal mitochondrial DNA synthesis, impairing energy metabolism and resulting in a toxic neuropathy that causes significant morbidity. Serum ALC levels are decreased in patients with neuropathy associated with NRTI therapy. The results of the present study suggest that ALC treatment can improve symptoms and promote peripheral nerve regeneration in HIV-infected patients with drug-induced neuropathy.

Hart AM, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS. 2004;18:1549-1560.

Twenty-five HIV-infected patients being treated with a reverse-transcriptase inhibitor were randomly assigned to receive, in double-blind fashion, 100 mg of coenzyme Q10 (CoQ10) or placebo twice a day for three months. Nine (69%) of 13 patients receiving CoQ10, as compared with 1 (8%) of 12 receiving placebo, reported an improvement in general well-being (p < 0.01). However, CoQ10 treatment appeared to cause an increase in pain in patients with peripheral neuropathy, which then returned to the baseline level of severity when CoQ10 was discontinued.

Comment: Blood CoQ10 levels have been found to be low in patients with AIDS, and CoQ10 deficiency may result in impaired immune function. In an uncontrolled trial, supplementation with 200 mg/day of CoQ10 improved symptoms and reduced the frequency of opportunistic infections. However, the results of the present study suggest that HIV-infected patients with drug-induced neuropathy may have an adverse reaction to CoQ10. Patients who experience an increase in neuropathic pain after taking CoQ10 should consider discontinuing it or reducing the dose.

Rabing Christensen E, et al. Mitochondrial DNA levels in fat and blood cells from patients with lipodystrophy or peripheral neuropathy and the effect of 90 days of high-dose coenzyme Q treatment: a randomized, double-blind, placebo-controlled pilot study. Clin Infect Dis. 2004;39:1371-1379.

Thirty-eight patients (median age, 36 years) with AIDS-associated diarrhea and/or wasting were randomly assigned to receive, in double-blind fashion, one of the following treatments daily for seven days: 1) 46 g of glycine (control), 2) 30 g of glutamine plus 15 g of glycine, 3) 4 g of alanyl-glutamine plus 42 g of glycine, or 4) 44 g of alanyl-glutamine (which is equimolar to 30 g of glutamine). All regimens were isonitrogenous. Nineteen of 20 patients receiving glutamine or high-dose alanyl-glutamine improved, as compared with 38% of controls (p < 0.003). Low-dose alanyl-glutamine was also effective, but less so than high-dose alanyl-glutamine. Blood levels of antiretroviral drugs, which were universally low at baseline, increased in patients receiving high-dose alanyl-glutamine or glutamine by 113% (p = 0.02) and 14% (p = 0.01), respectively.

Comment: Glutamine plays an important role in both gastrointestinal function and immune function. The results of the present study indicate that glutamine is an effective treatment for AIDS-associated diarrhea and also increases antiretroviral drug levels to some extent. The mechanism of the increase in drug levels is probably related to an improvement in malabsorption. In previous studies of AIDS patients, supplementation with 30 g/day or more of glutamine was not associated with any serious adverse effects.

Alanyl-glutamine is a dipeptide that releases glutamine after being hydrolyzed in vivo. The fact that this peptide increased antiretroviral drug levels to a greater extent than did glutamine suggests that alanyl-glutamine is more effective than glutamine at reversing gastrointestinal pathology. However, the study lasted only seven days, and it is possible that the benefits of glutamine would have "caught up" to those of the dipeptide in a longer study. Alanyl-glutamine does not appear to be readily available at the present time, whereas glutamine is widely available and relatively inexpensive.

Bushen OY, et al. Diarrhea and reduced levels of antiretroviral drugs: improvement with glutamine or alanyl-glutamine in a randomized controlled trial in northeast Brazil. Clin Infect Dis. 2004;38:1764-1770.

Three patients who presented with severe poison ivy were treated with oral prednisone plus 50 mg/day of DHEA, tapered to 25 mg/day after 1-3 doses. Most lesions resolved within 1-4 days. Based on the patients' past experiences with poison ivy, the response to DHEA plus prednisone appeared to be substantially better than what would have been expected with prednisone alone.

Comment: Systemic glucocorticoids such as prednisone are often used to treat severe episodes of poison ivy dermatitis. Glucocorticoid treatment suppresses adrenal secretion of DHEA, a hormone that modulates immune function in a number of different ways. The results of the present study suggest that short-term treatment with DHEA enhances the beneficial effect of glucocorticoids in patients with severe poison ivy. Additional studies are needed to confirm these preliminary findings. As the poison ivy season is now upon us, readers are urged to administer DHEA to patients who require glucocorticoids for severe poison ivy dermatitis, and to report their findings in a letter to the Townsend Letter.

Geracioti TD Jr. DHEA supplementation of systemic glucocorticoids for treatment of poison ivy dermatitis. Int J Dermatol 2005;44:974-976.

One hundred-fifty-three patients (mean age, 60.3 years) who had had a first acute myocardial infarction three to 21 days previously were randomly assigned to receive, in double-blind fashion, L-arginine or placebo for 6 months. The dose of L-arginine was 1 g three times a day for the first week, 2 g three times a day for the second week, and 3 g three times a day thereafter. Six participants (8.6%) in the L-arginine group died during the study period, vs. none in the placebo group (p = 0.01). Because of safety concerns, the study was terminated prematurely.

Comment: As a precursor to nitric oxide, L-arginine functions as a vasodilator and improves endothelial function, effects that might be beneficial for patients with heart disease. In previous studies, L-arginine supplementation increased exercise tolerance and improved quality of life in patients with congestive heart failure and in those with angina pectoris. It is surprising, therefore, that the present study showed an increase in mortality from L-arginine supplementation in patients with a recent myocardial infarction.

The results of this study might be explained by a fundamental, though often overlooked, principle of nutrition: that nutrients function in the body as a team and that administration of large doses of a single nutrient will in some instances cause biochemical imbalances, with potential adverse effects. I have pointed out previously that supplementation with high doses of pure alpha-tocopherol (vitamin E) depletes another important cardioprotective component of the "vitamin E complex" (gamma-tocopherol), and that a deficiency of gamma-tocopherol might explain why treatment with high-dose alpha-tocopherol increased the risk of developing heart failure in one study. If that is the case, then "mixed tocopherols" (the form in which vitamin E occurs in food) would be expected to be both safer and more effective than alpha-tocopherol for the prevention and treatment of cardiovascular disease.

A similar mechanism might be in operation with respect to L-arginine. While nitric oxide produced from L-arginine has a number of beneficial effects on the cardiovascular system, it is also a highly unstable molecule that promotes the formation of reactive oxidants such as peroxynitrite. Peroxynitrite and other nitric oxide-derived oxidants appear to be inflammatory mediators that promote the development of atherosclerosis. Interestingly, the compound that has been shown most clearly to scavenge reactive nitrogen compounds is gamma-tocopherol. Moreover, in the process of quenching nitric oxide-derived oxidants, gamma-tocopherol is converted to 5-nitro-gamma-tocopherol, an apparently inactive metabolite.

Thus, as with high-dose alpha-tocopherol, high-dose L-arginine might deplete gamma-tocopherol, potentially reversing the beneficial cardiovascular effects of L-arginine. Based on the results of the present study, it is probably not a good idea to recommend large doses of L-arginine for people who have had a recent myocardial infarction. If L-arginine is being used to treat angina or heart failure, it should be administered as part of a comprehensive nutritional program, including supplementation with mixed tocopherols.

Schulman SP, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006;295:58-64.

One hundred-eighty-two patients with idiopathic pulmonary fibrosis were randomly assigned to receive, in double-blind fashion, N- acetylcysteine (NAC), 600 mg 3 times a day, or placebo for 1 year, in addition to standard therapy with prednisone plus azathioprine. After 12 months, compared with placebo, NAC decreased the mean loss of vital capacity by 9% (p = 0.02) and of carbon monoxide diffusing capacity by 24% (p = 0.003). Mortality was 9% in the NAC group and 11% in the placebo group (p = 0.69). There were no significant differences in type or severity of adverse events between groups, except for a significantly lower rate of myelotoxic medication side effects in the group taking NAC (p = 0.03).

Comment: Idiopathic pulmonary fibrosis is a chronic progressive disorder that has a poor prognosis. Previous studies have shown that glutathione levels are depleted in lung tissue of patients with this condition, and that treatment with NAC increased glutathione levels and had a favorable effect on lung function. The American Thoracic Society–European Respiratory Society recommends therapy with prednisone and a cytotoxic agent, such as azathioprine, for idiopathic pulmonary fibrosis. However, there is little evidence that these agents alter the natural history of the disease. The results of the present study by suggest either that NAC is beneficial for patients with idiopathic pulmonary fibrosis or that the combination of prednisone and azathioprine is toxic to these patients. If the latter is true, then the beneficial effects of NAC in this study might be due to prevention of prednisone and azathioprine toxicity. Azathioprine is known to deplete liver tissue of glutathione, an effect that might be prevented by NAC.

Additional research is needed to determine whether or not one would need to poison the patients with non-evidence-based conventional therapy before they could benefic from NAC.

Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen HM, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-2242.

Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2285-2287.

Thirty-five healthy adults who were homozygous for the methylenetetrahydrofolate reductase (MTHFR) TT genotype, 26 heterozygotes (CT), and 28 with the wild-type genotype (CC) were randomly assigned to receive, in double-blind fashion, 1.6 mg/day of riboflavin or placebo for 12 weeks. In the TT group, riboflavin supplementation decreased the mean homocysteine concentration by 22% (from 16.1 micromol/L at baseline to 12.5 micromol/L; p = 0.003 compared with baseline; p = 0.007 compared with the 6% increase over baseline in the placebo group). In the subgroup of TT subjects with lower riboflavin status at baseline (n = 16), the mean homocysteine concentration decreased by 40% with riboflavin supplementation (from 22.0 to 13.2 micromol/L; p = 0.010). Homocysteine levels did not change in the CC or CT groups, even though those groups had been pre-selected for suboptimal riboflavin status.

Comment: MTHFR is an enzyme that catalyzes the conversion of homocysteine to methionine. Individuals homozygous for the MTHFR 677C  T polymorphism require higher-than-normal amounts of folic acid in order to maintain low plasma homocysteine levels. They also have reduced activity of the MTHFR enzyme as a result of inappropriate loss of the flavin adenine dinucleotide (FAD) cofactor, of which riboflavin is a component. In the present study, riboflavin supplementation decreased homocysteine concentrations substantially in people with the MTHFR 677 TT genotype, particularly those with initially low riboflavin status. The authors of this report suggested that these findings might explain why this common polymorphism carries an increased risk of coronary heart disease in Europe but not in North America, where riboflavin fortification has existed for more than 50 years. Since nearly 20% of the population is homozygous for this polymorphism, homocysteine-lowering therapy should include not only folic acid, vitamin B6, and vitamin B12, but also riboflavin.

McNulty H, et al. Riboflavin lowers homocysteine in individuals homozygous for the MTHFR 677C  T polymorphism. Circulation. 2006;113:74-80.

Sixteen inpatients (37-92 years) with a stage 2, 3, or 4 pressure ulcer were randomly assigned to receive a standard hospital diet (n = 6); a standard diet plus a protein/energy supplement (n = 5); or a standard diet plus a protein/energy supplement providing additional arginine (9 g/day), vitamin C (500 mg/day) and zinc (30 mg/day) (n = 5) for three weeks. Only patients receiving additional arginine, vitamin C, and zinc demonstrated clinically significant ulcer healing (mean improvement, 73%), and the degree of improvement was significantly greater after three weeks in that group than in the other two groups (p < 0.05).

Comment: While malnutrition is common in patients with chronic pressure ulcers, studies evaluating the effects of individual nutrients (such as vitamin C or zinc) have produced equivocal results. In the present study, a clear beneficial effect was observed with a supplement that included three nutrients that play a role in wound healing. Other nutrients that are important for wound healing include protein, B vitamins, copper, and vitamin A.

Desneves KJ, et al. Treatment with supplementary arginine, vitamin C and zinc in patients with pressure ulcers: a randomised controlled trial. Clin Nutr. 2005;24:979-987.