Glutathione,
Whey Protein Clinical
Trials
► 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
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Clinical trials of Glutathione and Whey protein
in Sports Nutrition
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Clinical
trial of Whey Protein in Stress-related Cognitive Decline
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Clinical
trials of Whey Protein in Bone Formation
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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 undenatured 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 undenatured whey, 9 placebo)
were analyzed. Both peak power and 30-s work capacity increased
significantly in the undenatured whey 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.
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