DESIGN REVISION BY: AVIS BETANCOURT 8/6/2012

L-GlutamateL-Glutamate

L-CysteineL-Cysteine› the rate-limiting substratethe rate-limiting substrate› cystine (cysteine=cysteine) is an ideal form cystine (cysteine=cysteine) is an ideal form

of cysteine for glutathione synthesis of cysteine for glutathione synthesis

GlycineGlycine

DNADNA synthesis and repair synthesis and repair ProteinProtein synthesis synthesis ProstaglandinProstaglandin synthesis synthesis Amino acidAmino acid transport transport

MetabolismMetabolism of toxins and carcinogens of toxins and carcinogens Immune systemImmune system enhancement enhancement PreventionPrevention of oxidative cell damage of oxidative cell damage EnzymeEnzyme activation activation

› Lomaestro, B. Ann Pharmacother, 1995 Dec;(12):1263 -Lomaestro, B. Ann Pharmacother, 1995 Dec;(12):1263 -73.73.

““Objective: Objective: To perform a meta-analysis To perform a meta-analysis addressing whether enteral nutrition with addressing whether enteral nutrition with immune-enhancing feeds benefit critically ill immune-enhancing feeds benefit critically ill patients after trauma, sepsis, or major surgery.”patients after trauma, sepsis, or major surgery.”

““Main outcome measures were mortality, Main outcome measures were mortality, infection,ventilator days, intensive care unit infection,ventilator days, intensive care unit stay, hospital stay, diarrhea days, calorie intake stay, hospital stay, diarrhea days, calorie intake and nitrogen intake.”and nitrogen intake.”

› Beale, R., Crit. Care Med. 1999, Dec.;27(12):2799-805.Beale, R., Crit. Care Med. 1999, Dec.;27(12):2799-805.

BENEFITS:BENEFITS:› Infection: a significant reduction in the Infection: a significant reduction in the

relative risk of acquiring infection. relative risk of acquiring infection. › Ventilator Days: a significant reduction Ventilator Days: a significant reduction

overall.overall.› Hospital Length of StayHospital Length of Stay: : the reduction in the reduction in

hospital LOS was significant.hospital LOS was significant. SAFETY:SAFETY:

› No increase in side effects of feeding was No increase in side effects of feeding was reported in patients receiving reported in patients receiving immunonutrition.immunonutrition.

““Glutathione Levels in Antigen-presenting Glutathione Levels in Antigen-presenting Cells Modulate Th1 Versus Th2 Response Cells Modulate Th1 Versus Th2 Response PatternsPatterns.” (Title of Article).” (Title of Article)› ““...the ...the Th1 patternTh1 pattern is characterized by interleukin is characterized by interleukin

12 (IL-12) and interferon 12 (IL-12) and interferon (IFN- (IFN-) production and ) production and the up-regulation cell-mediated, e.g.,the up-regulation cell-mediated, e.g.,delayed delayed hypersensitvityhypersensitvity, (DTH) responses.”, (DTH) responses.”

› ““The The Th2 responseTh2 response pattern is characterized by IL- pattern is characterized by IL-4 and IL-10 production and up-regulation of a 4 and IL-10 production and up-regulation of a variety of variety of antibody responsesantibody responses.” .”

Peterson, J., Proc. Natl. Acad. Sci. U S A 1998, Peterson, J., Proc. Natl. Acad. Sci. U S A 1998, Mar. 17;95(6): 3071-3076.Mar. 17;95(6): 3071-3076.

““Antigen-presenting cells (APC) -- macrophages, Antigen-presenting cells (APC) -- macrophages, dendritic cells, and B cells -- are central to the dendritic cells, and B cells -- are central to the development of either Th1 or Th2 immunity development of either Th1 or Th2 immunity because because antigen presentation and antigen presentation and recognition are required to initiate recognition are required to initiate responsesresponses.”.”

““......GSH depletionGSH depletion inhibits Th1-associated inhibits Th1-associated cytokine production and/or cytokine production and/or favors Th2-favors Th2-associated responsesassociated responses.”.”› Peterson, J., Proc. Natl. Acad. Sci. U S A 1998, Mar. Peterson, J., Proc. Natl. Acad. Sci. U S A 1998, Mar.

17;95(6): 3071-3076.17;95(6): 3071-3076.

““Therefore, low intracellular glutathione levels in Therefore, low intracellular glutathione levels in antigen-presenting cells correlate with defective antigen-presenting cells correlate with defective processing of antigen with disulfide bonds, processing of antigen with disulfide bonds, indicating that this thiol may be a indicating that this thiol may be a criticalcritical factor in factor in regulating productive antigen processing.”regulating productive antigen processing.”› Short, S., Eur. J. Immunol. 1996, Dec;26(12):3015-3020.Short, S., Eur. J. Immunol. 1996, Dec;26(12):3015-3020.

Most antigens are proteins with disulfide bonds. Most antigens are proteins with disulfide bonds. GSH reduces disulfide bonds. Low GSH prevents GSH reduces disulfide bonds. Low GSH prevents disulfide bond reduction.disulfide bond reduction.

1. RSSR’ + GSH 1. RSSR’ + GSH RSH + GSSR’ RSH + GSSR’ 2. GSSR’ + GSH 2. GSSR’ + GSH GSSG + R’SH GSSG + R’SH

““Lymphocyte proliferation in response to mitogenic lectins is Lymphocyte proliferation in response to mitogenic lectins is directly dependent upon glutathione (GSH) availability.”directly dependent upon glutathione (GSH) availability.”

““...the restoration of lymphocyte proliferation by exogenous GSH ...the restoration of lymphocyte proliferation by exogenous GSH is more closely linked to effects on intracellular rather than is more closely linked to effects on intracellular rather than extracellular GSH.”extracellular GSH.”

““These studies confirm the importance of intracellular GSH in These studies confirm the importance of intracellular GSH in lymphocyte proliferation.”lymphocyte proliferation.”› Hamilos, D., Immunopharmacology, 1989, 18;223-235.Hamilos, D., Immunopharmacology, 1989, 18;223-235.

Glutathione levels in antigen-presenting cells Glutathione levels in antigen-presenting cells modulate Th1 versus Th2 response patterns.modulate Th1 versus Th2 response patterns.

Antigen presentation and recognition are Antigen presentation and recognition are required to initiate immune responses.required to initiate immune responses.

Key events that determine whether IFN-Key events that determine whether IFN- is is produced occur almost immediately.produced occur almost immediately.

IFN-IFN- production predominates when GSH production predominates when GSH levels are high.levels are high.

GSH depletion may play a GSH depletion may play a keykey role in role in exacerbating HIV and other infectious exacerbating HIV and other infectious diseases in which Th2 predominance is an diseases in which Th2 predominance is an important aspect of the disease pathology.important aspect of the disease pathology.

““Glutathione Deficiency is Associated with Glutathione Deficiency is Associated with Impaired Survival in HIV DiseaseImpaired Survival in HIV Disease.” (Title of .” (Title of Article from Stanford)Article from Stanford)

““The crucial connection revealed here between The crucial connection revealed here between GSH deficiency and survival in HIV disease was GSH deficiency and survival in HIV disease was foreshadowed by several studies.”foreshadowed by several studies.”

Survival in all HIV+: Survival in all HIV+: GSBGSB 0.91 = 90%, GSB 0.91 = 90%, GSB 0.91 = 32%.0.91 = 32%.

Survival in CD4 Survival in CD4 200: 200: GSBGSB 1.05 = 87%, GSB 1.05 = 87%, GSB 1.05 = 17%.1.05 = 17%.› Herzenberg, L, Proc. Natl. Acad. Sci. U S A 1997, Mar. Herzenberg, L, Proc. Natl. Acad. Sci. U S A 1997, Mar.

4;94(5): 1967-1972.4;94(5): 1967-1972.

““Type 1 and Type 2 Cytokines in HIV Infection -- Type 1 and Type 2 Cytokines in HIV Infection -- a Possible Role in Apoptosis and Disease a Possible Role in Apoptosis and Disease Progression.Progression.” (Title of Article)” (Title of Article)

““...a strong type 1/weak type 2 cytokine ...a strong type 1/weak type 2 cytokine production profile was observed in HIV-production profile was observed in HIV-seropositive patients with delayed or absent seropositive patients with delayed or absent disease progression, whereas progression of HIV disease progression, whereas progression of HIV infection was characterized by a weak type infection was characterized by a weak type 1/strong type 2 cytokine production profile.”1/strong type 2 cytokine production profile.”› Clerici, M., Ann. Med. 1997, Jun.;29(3):185-188. Clerici, M., Ann. Med. 1997, Jun.;29(3):185-188.

Glutathione Deficiency is Associated with Glutathione Deficiency is Associated with Impaired Survival in HIV Disease.Impaired Survival in HIV Disease.

Survival in all HIV+:Survival in all HIV+: GSBGSB 0.91 = 90%, 0.91 = 90%, GSBGSB 0.91 = 32%. 0.91 = 32%.

Survival in CD4Survival in CD4 200: 200: GSBGSB 1.05 = 87%, 1.05 = 87%, GSBGSB 1.05 = 17%. 1.05 = 17%.

Antiretroviral therapies will not Antiretroviral therapies will not successfully eradicate HIV and HIV-successfully eradicate HIV and HIV-seropositive patients will not be ultimately seropositive patients will not be ultimately cured unless therapies aimed at restoring cured unless therapies aimed at restoring the immune system are associated with the the immune system are associated with the antiretroviral drugs currently employed.antiretroviral drugs currently employed.

““We describe a case of a patient who had We describe a case of a patient who had obstructive lung disease responsive to obstructive lung disease responsive to corticosteroids, and low whole blood GSH levels.”corticosteroids, and low whole blood GSH levels.”

““After 1 month of supplementation with a whey-After 1 month of supplementation with a whey-based oral supplement designed to provide GSH based oral supplement designed to provide GSH precursors, whole blood precursors, whole blood GSH levels and GSH levels and pulmonary function increased significantly pulmonary function increased significantly and dramaticallyand dramatically.”.”

› Lands, L., J. Appl. Physio. 1999, Oct.;87(4):1381-5.Lands, L., J. Appl. Physio. 1999, Oct.;87(4):1381-5.

Relationship to Relationship to Immunocal® intake:Immunocal® intake:

› Time 6 on Time 6 on Immunocal® 1 month.Immunocal® 1 month.

› Time 7 off Time 7 off Immunocal®.Immunocal®.

› Time 8 back on Time 8 back on Immunocal®.Immunocal®.

Immunocal® significantly Immunocal® significantly and dramatically and dramatically increased pulmonary increased pulmonary function.function.

Contains highly concentrated amounts of cystine (cysteine = cysteine) because of a new Pasteurization technique which preserves the disulfide bond between the two cysteines.

The naturally occurring constituent heat labile proteins found in “Mother’s Milk” that imparts immune enhancement.

Dose: 10 - 40 grams per day for adults and ½ gram/Kg for infants and young children up to 40 Kg.

High dose to reverse cachexia: up to 120 grams has been reported (anecdotal) to increase total body weight 15% in two weeks in a near death AIDS patient with cachexia.

Hepatic Nitrogen Metabolism: Cysteine from muscle catabolism arrives in the liver in the form of cystine. Enteral feeding of cystine takes advantage of this well-developed metabolic pathway that is also utilized when digesting breast milk which has well documented and indisputable immune enhancing properties.

Antigen Presenting Cells: Prefer cystine for GSH synthesis which is required to initiate the immune response then feed lymphocytes cysteine as an immunoregulatory signal.

Astrocytes: Prefer cystine for GSH synthesis and feed cysteine to neurons to protect against neurodegenerative diseases.

“Role of Cysteine and Glutathione in HIV Infection and Other Diseases Associated with Muscle Wasting and Immunological Dysfunction.” (Title of Article)

“Evidence suggests that 1) the cystine level is regulated primarily by the normal postabsorptive skeletal muscle protein catabolism, 2) the cystine level itself is a physiological regulator of nitrogen balance and body cell mass...”› Dröge, W., FASEB J. 1997, Nov;11(13):1077-89.

AIDS, sepsis, major injury, trauma, AIDS, sepsis, major injury, trauma, cancer, chronic fatigue syndrome, cancer, chronic fatigue syndrome, Crohn’s disease, ulcerative colitis, and Crohn’s disease, ulcerative colitis, and athletic over-training are associated with:athletic over-training are associated with:› low cystine,low cystine,› low glutamine, low glutamine, › elevated glutamate,elevated glutamate,› increased urea production, andincreased urea production, and› reduced natural killer (NK) cell activity.reduced natural killer (NK) cell activity.

This diagram demonstrates This diagram demonstrates the relationship between the relationship between cystine and nitrogen cystine and nitrogen balance to be as follows:balance to be as follows:

Cystine.Cystine. Protons (HProtons (H++).). Bicarbonate (HCOBicarbonate (HCO22

--).). Carbamoylphosphate.Carbamoylphosphate. Ammonium ion (NH4Ammonium ion (NH4++) is ) is

saved. saved. This results in positive This results in positive

nitrogen balance with nitrogen balance with maintenance or increase in maintenance or increase in weight.weight.

This diagram demonstrates This diagram demonstrates the relationship between the relationship between cystine and nitrogen cystine and nitrogen balance to be as follows:balance to be as follows:

Cystine.Cystine. Protons (HProtons (H++).). Bicarbonate (HCOBicarbonate (HCO22

--) .) . Carbamoylphosphate.Carbamoylphosphate. Ammonium ion (NH4Ammonium ion (NH4++) is ) is

saved.saved.

This results in negative This results in negative nitrogen balance with nitrogen balance with decrease in weight and decrease in weight and possible cachexia.possible cachexia.

Cystine (cysteine=cysteine) is the preferred form of cysteine for macrophages and astrocytes.› “Macrophages consume cystine...”

Gmunder, H., Macrophages Regulate Intracellular Glutathione Levels of Lymphocytes. Cell. Immunol., 1990, Aug.; 129(1): 32-46.

› “These results demonstrate that astroglial cells prefer cystine...” Kranich, O., Glia, 1998, Jan.;22(1): 11-8.

Enterocyte nutrient transport is one way: from the gut to the cell to the capillary.

Enterocytes cannot transport nutrients from the blood vessel.

Enterocytes starve as the rest of the body is fed by way of the vasculature.

Enterocytes pull away from each other as a consequence of gut atrophy.

Bacteria slip between the atrophying enterocytes.Bacteria slip between the atrophying enterocytes. Bacteria enter lymph nodes and then gain access to Bacteria enter lymph nodes and then gain access to

thoracic duct.thoracic duct. The thoracic duct emtpies into the blood flowing The thoracic duct emtpies into the blood flowing

toward the right heart and into the pulmonary toward the right heart and into the pulmonary circulation.circulation.

Atrophic gut cannot generate sufficient amounts of Atrophic gut cannot generate sufficient amounts of secretory IgA.secretory IgA.

The lungs are also compromised and pneumonitis The lungs are also compromised and pneumonitis frequently occurs due to constant seeding and lack of frequently occurs due to constant seeding and lack of IgA.IgA.