Glutathione

Abstract

The use of glutathione to treat or prophylax smallpox infection, to treat or prophylax chemical warfare agents, or to treat or prophylax radiation injury to humans due to release of radioactive elements is proposed. The preferred formulation is an oral dosage form, with reduced glutathione stabilized by ascorbic acid in at least equimolar concentration. The formulation may be in unit dosage form or in bulk.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application claims benefit of priority under 35 U.S.C. §119(e) from U.S. Provisional Patent Application No. 62 / 182,229, filed Jun. 19, 2015, the entirety of which are each expressly incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to the use of glutathione for treatment and / or prophylaxis of various conditions.BACKGROUND OF THE INVENTION[0003]The ubiquitous tripeptide L-glutathione (GSH) (gamma-glutamyl-cysteinyl-glycine), is a well known biological antioxidant, and in fact is believed to be the primary intracellular antioxidant for higher organisms. When oxidized, it forms a dimer (GSSG), which may be recycled in organs having glutathione reductase. Glutathione may be transported through membranes by the sodium-dependent glutamate pump. Tanuguchi, N., et al. Eds., Glutathione Centennial, Academic Press, New York (1989), expressly incorporated herein by reference.[0004]Glutathione (L-g...

AI Technical Summary

Benefits of technology

[0235]These disadvantageous effects of over expressed IL-4 in acute viral infections can occur without bioengineering. Insufficient intracellular glutathione concentrations resulting from aging (26, 46), diabetes (27, 28), prior exposures to chemical toxins (29, 31, 52), or during the course of serious infections (15-17, 21, 53), as outlined previously, will skew immune response patterns to Th2 pathways (13, 18-23) and result in disadvantageous up-regulation and increased expression of IL-4.

[0236]Among the IL-4 disadvantages during an acute viral infection, described under Property One and Property Two, is the up-regulation of the cyclooxygenases (COX-2), and the lipoxygenases (5-, 12-, 15-), resulting in excess formation of lipid hydroperoxides (LOOH's) and the simultaneous down-regulation of the protective enzymes that disassemble LOOH's (GSH peroxidases and GSH S-transferases) (82). Schnurr and colleagues (82) in 1999 included human peripheral monocytes in their studies of this inverse regulation by IL-4. Further, To find out whether these regulatory processes also occur in vivo, arachidonic acid oxygenase and phospholipid hydroperoxide glutathione peroxidase activity was assayed in various tissues of transgenic mice that systemically overexpress interleukin 4. In lung, spleen, kidney and heart, an increased arachidonic acid oxygenase activity was detected when transgenic mice were compared with inbred controls. The phospholipid hydroperoxide glutathione peroxidase activity was impaired in lung, liver, and spleen of the transgenic animals (82).

[0237]Sandstrom and co-workers (81) demonstrated 15-HPETE, derived from 15-lipoxygenase activity, and several other hydroperoxy fatty acids were lethal to a T cell line that is chronically HIV infected (8E5) because of a “marked reduction in glutathione peroxidase activity inherent in the 8E5 T cell line (81).

[0238]IL-4, therefore, when overexpressed by viral engineering, or insufficient glutathione concentrations that skew T helper response patterns to Th2, can result in lethal accumulations of hydroperoxyls by up-regulating 12- and 15-lipoxygenases to produce increased quantities of 12- and 15-HPETE's. These can not be reduced to the less toxic 12- and 15-HETE's because the relevant GSH peroxidases have been down-regulated by IL-4 (82).

[0239]In addition, in the course of acute inflammation and NFκB activation, Cox-2 is induced (47). Kim et al (47) demonstrated, however, that the induction of Cox-2 could be inhibited, in their model systems, by glutathione, N-acetyl cysteine, and pyrrolidine dithiocarbamate (PDTC) (47).

[0240]Glutathione therapy that effectively replenishes and maintains intracellular concentrations should be able to down regulate IL-4 produced as a result of overly favored Th2 response patterns (13, 18-23), and also correct the GSH insufficiencies that may lead to Th2 cytokines in people over 45 (26), in diabetics (27, 28), in the chemically exposed (29, 31, 52), and in those with serious, overwhelming infections (15-17, 21, 53). The results of GSH therapy could include down regulation of 12- and 15-lipoxygenases, up-regulation of GSH peroxidases, and down regulation of the NFκB cascades that include the induction of Cox-2. These favorable biochemical results would help lead to the prevention and reduction of cyto- and tissue toxicities associated with smallpox infections.

Problems solved by technology

Otherwise these cause tissue-disrupting excesses of reactive intermediates from lipid hydroperoxides (alkoxy radicals, LO., and hydroxyls, .OH).

Images