► Clinical trials of Glutathione and Whey protein in HIV-AIDS

► Clinical trials of Glutathione and Whey protein in Cancer

► Clinical trial of Whey protein in Chronic Hepatitis B and C

► Clinical trials of Glutathione and Whey protein in Sports Nutrition

► Clinical trial of Whey Protein in Stress-related Cognitive Decline

► Clinical trials of Whey Protein in Bone Formation

► Clinical trials of Glutathione in Male Infertility

Clinical Trials with Glutathione, Whey Protein in HIV-AIDS

Disturbed glutathione metabolism and decreased antioxidant levels in human immunodeficiency virus-infected patients during highly active antiretroviral therapy - potential immunomodulatory effects of antioxidants
Aukrust P, Muller F, Svardal AM, Ueland T, Berge RK, Froland SS. [J Infect Dis. 2003 Jul 15;188(2):232-8. Epub 2003 Jun 09.]
We examined the effect of highly active antiretroviral therapy (HAART) on plasma levels of several antioxidants and intracellular glutathione-redox status in CD4+ T cells, in 20 HIV-infected patients. HAART was accompanied by both an improvement of glutathione-redox status and an increase in levels of antioxidant vitamins, without full normalization. Glutathione supplementation in vitro increases T cell proliferation and suppresses the spontaneous release of tumor necrosis factor-alpha from peripheral blood mononuclear cells, in HIV-infected patients receiving HAART. Our findings suggest that therapeutic intervention aimed at normalization of oxidative disturbances in HIV infection could be of interest, in addition to HAART.

Bioactive, Cysteine-Rich Dietary Supplement Alleviates Gastrointestinal Side-Effects with Associated Weight Gain and Marked Improvement in HAART Adherence in AIDS Patients
A recent open label trial was conducted by Louisa Pacheco, M.D. and her colleagues on the therapeutic use of un-denatured whey protein with HIV/AIDS patients at the Tidewater AIDS Crisis Task Force in Norfolk, Virginia. Patients taking the nutraceutical achieved significant reduction in gastrointestinal side effects (diarrhea, nausea, vomiting, impaired appetite), as well as improved energy levels. Additionally, they were able to adhere to their HAART medications as prescribed, which they had previously been unable to do. In fact, patients using the nutraceutical became 100% adherent to HAART by the end of the 8- week trial. Non-participating patients experienced an average weight loss of 8.5 lbs and remained non-adherent with anti-retroviral therapy. Summary & Conclusions: This immune-enhancing GRAS nutraceutical can be used beneficially in AIDS patients to promote weight gain, improve their health status and tolerance for taking HAART. Thus, including it as part of an AIDS patient’s therapeutic regimen may improve three major conditions - immune deficiency, weight loss, and adherence to HAART.

Oral supplementation with whey proteins increases plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Schlaak JF, Buhl R. [Eur J Clin Invest. 2001 Feb;31(2):171-8.] Ddifferent strategies to supplement cysteine supply have been suggested to increase glutathione levels in HIV-infected individuals. The aim of this study was to evaluate the effect of oral supplementation with two different cysteine-rich whey protein formulas on plasma GSH levels and parameters of oxidative stress and immune status in HIV-infected patients. In glutathione-deficient patients with advanced HIV-infection, short-term oral supplementation with whey proteins increases plasma glutathione levels. A long-term clinical trial is clearly warranted to see if this "biochemical efficacy" of whey proteins translates into a more favourable course of the disease.

Effects of long-term supplementation with whey proteins on plasma glutathione levels of HIV-infected patients
Micke P, Beeh KM, Buhl R. [Eur J Nutr 2002 Feb;41(1):12-8] HIV infection is characterized by an enhanced oxidant burden and a systemic deficiency of the tripeptide glutathione (GSH), a major antioxidant. Whey proteins are rich in cysteine as well as in GSH precursor peptides. In order to evaluate the effects of whey supplementation on plasma GSH levels, HIV-infected patients were treated with whey proteins for a period of six months. Supplementation with whey proteins persistently increased plasma glutathione levels in patients with advanced HIV-infection. The treatment was well tolerated. A larger long-term trial is clearly warranted to evaluate whether this positive influence on the glutathione metabolism translates into a more favorable course of the disease.

CTN (Canadian HIV Trials Network) Trial Results - Whey protein supplementation CTN043: Whey Protein Supplementation in HIV-Infected Children: A Pilot Study
This study assessed the value of whey protein, a milk supplement, to prevent severe weight loss in children with AIDS. This was an open label, pilot study (both investigators and volunteers knew which treatment was being given), with only one study group. Participants received daily oral supplementation of whey protein, given as a powder at a starting dose based on 20% of the total daily protein requirement, and increased by increments of five percent every month during four months to reach 35% of the total protein intake at the end of the six-month study. Study Population: Fourteen children were enrolled in four centres. Essential requirements for study entry included wasting syndrome (severe weight loss) within the six months preceding entry into the study. Of 14 participants enrolled, 11 were evaluated. The age of the participants ranged from eight months to 15 years. None of the children experienced any toxicity (side effects) such as diarrhea, vomiting or milk intolerance. All of them gained weight, between 3.2% and 18% from their starting weight. Eight demonstrated improvements in growth parameters, such as in tricep skinfolds, with mid-arm muscle circumference increasing from +1.2% to +25% independently of energy intake. No changes were found in CD4 cell count, but two children experienced a significant increase in CD8 cell count. Whey protein is very well-tolerated in children with AIDS, and it was shown to improve nutrition and growth in a subgroup of patients.
 

Whey Protein for Wasting: CTN079: Multicentre, Double-blind, Randomized Control Study of Whey Protein Concentrate HMS-90 vs Casein in Patients with AIDS and Wasting Syndrome
One study of this all-natural product concluded that this "whey protein concentrate" a derivative of cows milk, is completely safe for people who have been diagnosed as lactose-intolerant. This analysis has lead to the funding of phase 3, clinical trial on adult AIDS patients with wasting syndrome. About the study: Treating AIDS-related wasting syndrome with a whey protein concentrate (WPC) may combat the negative effect of oxidative stress, improve T-cell function and T-cell survival, as well as aid in the control of HIV replication. The study's primary objectives are to determine the effect of WPC on nutrition in patients with AIDS-related wasting syndrome, and to determine the glutathione-changing activity of WPC in people with AIDS-related wasting syndrome.
 

Whey proteins as a food supplement in HIV-seropositive individuals
Bounous G, Baruchel S, Falutz J, Gold P. Department of Surgery, Montreal General Hospital, Quebec. [Clin Invest Med 1993 Jun;16(3):204-9] On the basis of numerous animal experiments, a pilot study was undertaken to evaluate the effect of undenatured, biologically active, dietary whey protein in 3 HIV-seropositive individuals over a period of 3 months. Whey protein concentrate was prepared so that the most thermosensitive proteins, such as serum albumin which contains 6 glutamylcysteine groups, would be in undenatured form. Whey protein powder dissolved in a drink of the patient's choice was drunk cold in quantities that were increased progressively from 8.4 to 39.2 g per day. Patients took whey proteins without adverse side effects. In the 3 patients whose body weight had been stable in the preceding 2 months, weight gain increased progressively between 2 and 7 kg, with 2 of the patients reaching ideal body weight. Serum proteins, including albumin, remained unchanged and within normal range, indicating that protein replenishment per se was not likely the cause of increased body weight. The glutathione content of the blood mononuclear cells was, as expected, below normal values in all patients at the beginning of the study. Over the 3-month period, glutathione levels increased in all 3 cases. In conclusion, these preliminary data indicate that, in patients who maintain an adequate total caloric intake, the addition of "bioactive" whey protein concentrate as a significant portion of total protein intake increases body weight and shows elevation of glutathione (GSH) content of mononuclear cells toward normal levels. This pilot study will serve as a basis for a much larger clinical trial.
 

Glutathione deficiency is associated with impaired survival in HIV disease
Herzenberg LA, De Rosa SC, Dubs JG, Roederer M, Anderson MT, Ela SW, Deresinski SC, Herzenberg LA. Department of Genetics, Stanford University Medical School, CA 94305-5125, USA. In vitro studies showing that low GSH levels both promote HIV expression and impair T cell function suggested a link between GSH depletion and HIV disease progression. Clinical studies presented here directly demonstrate that low GSH levels predict poor survival in otherwise indistinguishable HIV-infected subjects. Specifically, we show that GSH deficiency in CD4 T cells from such subjects is associated with markedly decreased survival 2-3 years after baseline data collection. This finding, supported by evidence demonstrating that oral administration of the GSH prodrug N-acetylcysteine replenishes GSH in these subjects and suggesting that N-acetylcysteine administration can improve their survival, establishes GSH deficiency as a key determinant of survival in HIV disease. Further, it argues strongly that the unnecessary or excessive use of acetaminophen, alcohol, or other drugs known to deplete GSH should be avoided by HIV-infected individuals.
 

Stanford NAC Study: Glutathione Level Predicts Survival
Author: John S. James [AIDS Treatment News; Issue: 266 03/07/97] A small randomized controlled trial of oral N-acetylcysteine(NAC) was run in San Francisco in 1993 and 1994. A report from this study was published in the PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, USA; it was also presented at a major immunology conference in San Francisco on February 22, receiving television and newspaper coverage. The basic findings were: (1) For persons with a CD4 count under 200, an abnormally low level of glutathione -- inside CD4 T-cells in the blood --was remarkably predictive of poor survival. (Glutathione is the major defense of those cells against oxidative stress.) Persons with a CD4 count under 200, who also had very low glutathione levels, had an estimated three-year survival a slow as 20 percent -- compared to 60 to 80 percent survival for those with CD4 below 200 but with adequate glutathione levels. (2) Oral NAC helped to replenish low glutathione in blood cells. Followup studies two to three years later showed that persons who were given or chose to take NAC during the trial had considerably better survival than similar subjects who did not take NAC.

N- acetylcysteine replenishes glutathione in HIV infection
De Rosa SC, Zaretsky MD, Dubs JG, and others. [Eur J Clin Invest 2000 Oct;30(10):915-29.] Glutathione (GSH) deficiency is common in HIV-infected individuals and is associated with impaired T cell function and impaired survival. N-acetylcysteine (NAC) is used to replenish GSH that has been depleted by acetaminophen overdose. Studies here test oral administration of NAC for safe and effective GSH replenishment in HIV infection. Whole blood GSH levels in NAC arm subjects significantly increased, bringing GSH levels in NAC-treated subjects to 89% of uninfected controls. NAC treatment for 8 weeks safely replenishes whole blood GSH and T cell GSH in HIV-infected individuals. Thus, NAC offers useful adjunct therapy to increase protection against oxidative stress, improve immune system function and increase detoxification of acetaminophen and other drugs. These findings suggest that NAC therapy could be valuable in other clinical situations in which GSH deficiency or oxidative stress plays a role in disease pathology.
 

Clinical Trials with Glutathione, Whey Protein in Cancer

Multi-Center Cancer Study Accepted for Peer Review Publication September, 2000 (WPC as a Cystine Donor)

The use of a whey protein concentrate in the treatment of patients with metastatic carcinoma: a phase I-II clinical study Kennedy RS, Konok GP, Bounous G, Baruchel S, Lee TD. [Anticancer Res. 1995 Nov-Dec;15(6B):2643-9.] Glutathione (GSH) concentration is high in most tumour cells and this may be an important factor in resistance to chemotherapy.........experiments have shown a differential response of tumour versus normal cells to various cysteine delivery systems.........at concentrations that induce GSH synthesis in normal human cells, a specially prepared whey protein concentrate, caused GSH depletion and inhibition of proliferation in human breast cancer cells. On the basis of this information five patients with metastatic carcinoma of the breast, one of the pancreas and one of the liver were fed 30 grams of this whey protein concentrate daily for six months.......The results indicate that whey protein concentrate might deplete tumour cells of GSH and render them more vulnerable to chemotherapy.

Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomised trial
Smyth JF, Bowman A, Perren T, Wilkinson P, Prescott RJ, Quinn KJ, Tedeschi M. ICRF Medical Oncology Unit, Western General Hospital, Edinburgh, UK. [Ann Oncol 1997 Jun;8(6):569-73]
Early clinical trials have suggested that glutathione (GSH) offers protection from the toxic effects of cisplatin. PATIENTS AND One hundred fifty-one patients with ovarian cancer (stage I-IV) were evaluated in a clinical trial of cisplatin (CDDP) +/- glutathione (GSH). The objective was to determine whether GSH would enhance the feasibility of giving six cycles of CDDP at 100 mg/m2 without dose reduction due to toxicity. The results demonstrate that adding GSH to CDDP allows more cycles of CDDP treatment to be administered because less toxicity is observed and the patient's quality of life is improved.

German study finds whey protein supplement boosts antioxidants
[Treatmentupdate 2001 May;13(1):2]
 

Clinical Trial in Chronic Hepatitis B & C

Nutritional therapy of chronic hepatitis by whey protein (non-heated)
Watanabe A, Okada K, Shimizu Y, Wakabayashi H, Higuchi K, Niiya K, Kuwabara Y, Yasuyama T, Ito H, Tsukishiro T, Kondoh Y, Emi N, Kohri H. [J Med 2000;31(5-6):283-302] In an open study the clinical efficacy of milk serum (whey) protein (cysteine content: 7.6-fold higher than that of casein) isolated from fresh milk and purified without heating was evaluated in 25 patients with chronic hepatitis B or C.These findings suggest that long-term supplementation with undenatured whey protein alone may be effective for improving liver dysfunctions in patients with chronic hepatitis B.
 

Clinical Trial in Sports Nutrition

Effect of supplementation with a cysteine donor on muscular performance
Lands LC, Grey VL, Smountas AA. [J Appl Physiol. 1999 Oct;87(4):1381-5. ] Division of Respiratory Medicine, McGill University Health Centre-Montreal Children's Hospital, Montreal, Quebec, Canada H3H 1P3. Oxidative stress contributes to muscular fatigue. GSH is the major intracellular antioxidant, the biosynthesis of which is dependent on cysteine availability. We hypothesized that supplementation with a whey-based cysteine donor designed to augment intracellular GSH would enhance performance. Follow-up data on 18 subjects (9 Immunocal, 9 placebo) were analyzed. Both peak power and 30-s work capacity increased significantly in the Immunocal group, with no change in the placebo group. Lymphocyte GSH also increased significantly in the whey protein group, with no change in the placebo group. This is the first study to demonstrate that prolonged supplementation with a product designed to augment antioxidant defenses resulted in improved volitional performance.

The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue mass and muscle strength
Burke DG, Chilibeck PD, Davidson KS, Candow DG, Farthing J, Smith-Palmer [1: Int J Sport Nutr Exerc Metab 2001 Sep;11(3):349-64]
Our purpose was to assess muscular adaptations during 6 weeks of resistance training in 36 males randomly assigned to supplementation with whey protein (W), whey protein and creatine monohydrate (WC), or placebo (P). Lean tissue mass increased to a greater extent with training in WC compared to the other groups, and in the W compared to the P group. Bench press strength increased to a greater extent for WC compared to W and P. Knee extension peak torque increased with training for WC and W, but not for P. Males that supplemented with whey protein while resistance training demonstrated greater improvement in knee extension peak torque and lean tissue mass than males engaged in training alone. Males that supplemented with a combination of whey protein and creatine had greater increases in lean tissue mass and bench press than those who supplemented with only whey protein or placebo.
 

Clinical Trial in Stress-related Cognitive Decline

Whey protein rich in alpha-lactalbumin increases the ratio of plasma tryptophan to the sum of the other large neutral amino acids and improves cognitive performance in stress-vulnerable subjects
Markus CR, Olivier B, de Haan EH. [Am J Clin Nutr. 2002 Jun;75(6):1051-6.]
The negative effect of chronic stress on performance may be mediated by reduced brain serotonin function. The uptake of the serotonin precursor tryptophan into the brain depends on nutrients that influence the availability of tryptophan by changing the ratio of plasma tryptophan to the sum of the other large neutral amino acids (Trp-LNAA ratio). A diet-induced increase in tryptophan may increase brain serotonergic activity levels and improve cognitive performance, particularly in high stress-vulnerable subjects. We tested whether alpha-lactalbumin, a whey protein with a high tryptophan content, would increase the plasma Trp-LNAA ratio and improve cognitive performance in high stress- vulnerable subjects. A significantly greater increase in the plasma Trp-LNAA ratio after consumption of the alpha-lactalbumin diet than after the control diet was observed; memory scanning improved significantly only in the high stress-vulnerable subjects. The results suggest that dietary protein rich in alpha-lactalbumin improves cognitive performance in stress-vulnerable subjects via increased brain tryptophan and serotonin activities.
 

Clinical Trial in Bone Formation
 

Milk basic protein promotes bone formation and suppresses bone resorption in healthy adult men
Toba Y, Takada Y, Matsuoka Y, Morita Y, Motouri M, Hirai T, Suguri T, Aoe S, Kawakami H, Kumegawa M, Takeuchi A, Itabashi A. [Biosci Biotechnol Biochem. 2001 Jun;65(6):1353-7.] In the previous in vitro and in vivo studies, we have shown that milk whey protein, especially its basic protein fraction (milk basic protein [MBP]), promoted bone formation and suppressed bone resorption. This present study examines the effect of MBP on the biochemical markers of bone metabolism in healthy adult men. The results suggest that MBP promoted bone formation and suppressed bone resorption, while maintaining the balance of bone remodeling.

Controlled trial of the effects of milk basic protein (MBP) supplementation on bone metabolism in healthy adult women
Aoe S, Toba Y, Yamamura J, Kawakami H, Yahiro M, Kumegawa M, Itabashi A, Takada Y. [Biosci Biotechnol Biochem. 2001 Apr;65(4):913-8.] Recent in vitro and in vivo studies showed that milk whey protein, especially its basic protein fraction, contains several components capable of both promoting bone formation and inhibiting bone resorption. The object of this study was to examine the effects of MBP on bone metabolism of healthy adult women. A daily MBP supplementation of 40 mg in healthy adult women can significantly increase their BMD independent of dietary intake of minerals and vitamins. This increase in BMD might be primarily mediated through inhibition of osteoclast-mediated bone resorption by the MBP supplementation.
 

Clinical trials of Glutathione in Male Infertility

Glutathione therapy for male infertility
Lenzi A, Lombardo F, Gandini L, Culasso F, Dondero F. [Arch Androl 1992 Jul-Aug;29(1):65-8] Eleven infertile men were treated with glutathione (600 mg/day IM) for 2 months. The patients were suffering from dyspermia associated with various andrological pathologies. Standard semen and computer analyses of sperm motility were carried out before treatment and after 30 and 60 days of therapy. Glutathione exerted significant effect on sperm motility patterns. Glutathione appears to have a therapeutic effect on some andrological pathologies causing male infertility.

Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility
Lenzi A, Culasso F, Gandini L, Lombardo F, Dondero F. [Hum Reprod 1993 Oct;8(10):1657-62] Glutathione therapy was used for 2 months in a placebo-controlled double-blind cross-over trial of 20 infertile patients with dyspermia associated with unilateral varicocele (VAR) or germ-free genital tract inflammation (INF). Glutathione therapy demonstrated a statistically significant positive effect on sperm motility, in particular on the percentage of forward motility, the kinetic parameters of the computerized analysis and on sperm morphology. The findings of this study indicate that glutathione therapy could represent a possible therapeutical tool for both of the selected andrological pathologies.

Glutathione treatment of dyspermia: effect on the lipoperoxidation process
Lenzi A, Picardo M, Gandini L, Lombardo F, Terminali O, Passi S, Dondero F. [Hum Reprod 1994 Nov;9(11):2044-50] We recently introduced reduced glutathione into the therapeutic protocols in some selected cases of dyspermia. This therapy improved semen quality both in a pilot follow-up study and in a double-blind cross-over trial. This improvement was seen in patients with varicocele and germ-free genital tract inflammation, two pathologies in which production of reactive oxygen species or other toxic compounds could have a pathogenic role. The results showed an improvement in both sperm parameters and cell membrane characteristics. This study suggests that biochemical modifications in membrane constitution could explain the seminal results of glutathione therapy. On the other hand, it seems likely that only subjects with systemic membrane disturbances associated with andrological pathologies express this membrane damage in spermatozoa, resulting in dyspermia. This sperm alteration can be partially reversed by glutathione therapy if the structural cell membrane damage is not too severe.