MXPA94007703A - Method for the treatment of the septicoutilizando timosina alf shock - Google Patents

Abstract

The present invention relates to the use of thymosin alfa-1 for the manufacture of a medicament for the treatment of septic shock induced by endotoxin

Description

METHOD FOR TREATMENT OF THE PUTREFACTIVE SHOCK USING TIMOSINE t CAUSAHIENT The George Washington University Medical Center NATIONALITY United States DOMICILE 2300 Eye Street, N.W., Washington, D.C. 20037, United States of America INVENTORS Alian L. Goldstein and Mírela O. Fagarasen. NATIONALITY American and Romanian, respectively DOMICILE 6407 Bradle? Blvd., Bethesda, Mar? Land, United States of America and 950 25th Street, N.W. Apartment 608 North, Washington, D.C. 20037, United States of America, respectively This application is a continuation-in-part of U.S. patent application, Serial No. 08 / 132,859, filed on October 7, 1993, in process.

Field of the Invention The present invention relates to a method for the treatment of putrefactive shock in mammals.

BACKGROUND OF THE INVENTION Thymosin aj ("Tc-i") is a peptide originally derived from the thymus gland, which has been reported to contain 28 amino acids. The information on the amino acid sequence of Ta is described in U.S. Pat. No. 4,079,127, incorporated herein by reference. Insightful studies of Ta toxicity in mice, monkeys and dogs showed no adverse effects at doses up to 0.25 mg / kg / day for 14 days. Studies of chronic toxicity of Taj in mice and monkeys showed no adverse effects at doses of up to 1 mg / kg / day for 26 weeks. Ta, is a modulator of the immune system that has so far been reported as useful, among other things, in the treatment of lung cancer, Hepatitis B and Hepatitis C. The putrefactive shock is a condition in which the infection is widely disseminated In many areas of the body, the infection is usually spread through the blood from one tissue to another and causing extensive damage. Putrefactive shock can occur with numerous medical conditions, including (1) peritonitis caused by the spread of infection from the uterine and fallopian tubes; (2) peritonitis resulting from rupture of the bowel, sometimes caused by intestinal disease or intestinal ulcers; (3) generalized infection resulting from the spread of a simple infection; (4) gangrenous generalized infection resulting specifically from fluid bacilli of gangrene; and (5) dispersion of infection within the blood from the kidney or urinary tract. The putrefactive shock is of a critical concern from a clinical point of view because, among other reasons, this condition frequently leads to death. Although the putrefactive shock is somehow a common clinical phenomenon, the mechanisms involved as well as the pathological changes remain poorly understood. For example, despite the treatment of the bacterial infection, many patients deteriorate further, which may be due to the clinical sequelae of hypotension with low systemic vascular resistance, renal failure, major respiratory pain syndrome, severe coagulopathy and severe ethabolic dysfunction. Thus, there is an urgent need in the art for effective methods of treatment of putrefactive shock.

Summary of the Invention According to the present invention, a method of treatment of putrefactive shock in mammals includes the administration to said mammals of an amount of Ta, effective to treat putrefactive shock.

Description of the Preferred Forms of Realization. It has been surprisingly discovered that Thymosin a, (Ta,) is effective in the treatment or prevention of putrefactive shock of sepsis in mammals. This discovery was surprising because the Thymosin was expected to have no activity with respect to the putrefactive shock when initially tested. The terms "Tymosine aj" and "Ta," refer to peptides that possess the amino acid sequence described in US Pat. No. 4,079,137, supra. The putrefactive shock in mammals occurs associated with a series of events in the body of the mammal referred to as the "cascade sepsis". Cascade sepsis typically begins with bacterial infection of the mammalian host resulting in the release of bacterial toxins, introduction of endotoxins, activation of host defensive systems, ie, plasma protein systems as well as cellular defense systems including endothelial cells, macrophages, monocytes and neutrophils, with release of proinflammatory mediators including cytokines, lipid metabolites, proteases, toxic oxygen products, nitric oxide and adhesion proteins. According to one aspect of the present invention, effective amounts of Ta are administered to a subject to reduce the levels of free radicals in the blood of the subject and thereby treat or prevent the putrefactive shock in the subject or obstruct the progress of cascade sepsis in the subject. It has been found that Ta reduces the levels of free radicals in the blood almost as much as SOD (super oxide dismutase), an enzyme that eliminates free radicals. When an effective amount of Ta is administered to a mammal, to prevent putrefactive shock or to treat putrefactive shock, the levels of pathological mediators of bacteria-induced lethality decrease in the mammalian blood. It has been found that Ta, obstructs cascade sepsis in mammals. During sepsis, the lipid peroxidation in blood is increased (nMol of malonildialdehyde), but return to normal or almost normal with the administration of Ta. Sepsis also reduces levels of circulating glutathione in the blood. However, the administration of Ta returns to normal or almost normal levels of circulating glutathine. As noted above, administration of Ta during sepsis decreases blood levels of hydroperoxide and glutathione levels in blood. Administration of Ta, during sepsis also decreases cGMP levels of the cerebellum, and decreases blood levels of arachidonic acid metabolites, such as TXJS2 and 6-keto-PGF, a, PAF and cytokines such as IL-la and TNF-a. While not wishing to be bound by any particular theory, it is believed that the reduction in blood levels of pathological mediators of lethality induced by bacteria in mammals decreases the amount of infection in the mammal, which, in turn, helps to obstruct the sepsis in cascade, and to avoid and treat the putrefactive shock. Therefore, in accordance with the present invention, methods are provided for treating and preventing putrefactive shock in mammals. The methods of the present invention include administration to mammals of Ta, in effective amounts to prevent putrefactive shock, treat putrefactive shock and effective amounts of Ta, to obstruct the advancement of cascade sepsis. According to preferred embodiments of the present invention, effective amounts of Ta are administered to subjects to treat or prevent putrefactive shock in the subjects, or to obstruct the advancement of cascade sepsis in the subjects. In these embodiments, the subjects are preferably human. In accordance with preferred embodiments of the present invention, compositions containing Ta, can be formulated in a conventional manner for administration by a suitable route. Suitable routes of administration include, but are not limited to, oral, rectal, nasal, topical, vaginal and parenteral (including subcutaneous, intramuscular, intravenous and intradermal). Particularly preferred embodiments use oral or parenteral administration, with parenteral administration being a more preferred embodiment. It will be appreciated that the preferred route may vary with the condition, age and species of the recipient. While not essential, in preferred embodiments, Ta is administered as part of a pharmaceutical formulation. The formulations of the present invention comprise Ta, together with one or more pharmaceutically acceptable carriers and optionally with other therapeutic ingredients. The ported (s) is (are) "acceptable" (s) in the sense of being compatible with other ingredients of the formulation and not deleterious to the recipient thereof. The formulations include those suitable for oral administration, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal). The formulations can conveniently be presented in unit dosage form, for example, prolonged-release tablets and capsules, and can be prepared by any suitable pharmaceutical methods. Such methods include, but are not limited to, the step of bringing the Ta into association with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the Ta, with liquid carriers or finely divided carriers, or both, and subsequently, if necessary, shaping the product. Formulations of the present invention, suitable for oral administration, can be presented as discrete units such as capsules, seals or tablets, each containing a predetermined amount of Ta, such as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, etc. A tablet can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine Ta, in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, dispersing agent or active surface agent. The molded tablets can be made by molding in a suitable machine a mixture of a compound in powder form and moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide controlled or slow release of the active ingredient. Formulations suitable for topical administration include rhombs comprising Ta, in a flavored base, usually sucrose and acacia or tragacanth; tablets comprising Ta, in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouth rinses comprising Ta, to be administered in a suitable liquid carrier. Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels and pastes comprising Ta, and a pharmaceutically acceptable carrier, or may use a transdermal patch containing the ingredient to be administered. Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate. Suitable formulations for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of from about 20 to about 500 microns, which is administered in the form in which the powder is taken, for example, by rapid inhalation through the nasal passage from a powder container held near the nose. Suitable formulations wherein the carrier is a liquid, for administration, such as, for example, a nasal spray or as nasal drops, include aqueous or oily solutions of the active ingredient.

Formulations suitable for vaginal administration may be presented as tampons, creams, gels, pastes, foams or atomized formulations containing, in addition to the appropriate carriers. Formulations suitable for parenteral administration include sterile aqueous and non-aqueous injectable solutions, which may optionally contain anti-oxidants, regulators, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in multi-dose or single-dose containers, for example, sealed vials and flasks, and can be stored under dry and frozen (lyophilized) conditions that require only the addition of the sterile liquid carrier, for example water for injections, immediately before use. The extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the type previously described. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other suitable agents that are related to the type of formulation in question, for example, those suitable for oral administration may include flavoring agents. A dose for administration of the compositions in the present invention is an amount of Ta, effective to treat putrefactive shock or to prevent putrefactive shock, which may be in the range of from about 0.4 mg to about 4 mg for a container human when administered by subcutaneous injection, preferably from about 1 to about 4 mg. A dose may be administered to the patient daily, one or more times per day of administration, for example, two or three times per day, and doses may be administered one or more days per week, for example, two, three, four, five, six or seven days a week. The invention is applicable to Ta, natural (ie occurring naturally), as well as Ta, synthetic and Ta, recombinant having the amino acid sequence of Ta, natural, amino acid sequence substantially similar to it, or a abbreviated sequence form thereof, and its biologically active analogs (including mutains) that dye replaced, deleted, elongated, replaced or modified sequences of some other form, and which possess bioactivity substantially similar to that of Ta ,. According to one embodiment of the present invention, Ta can be administered in combination with a therapeutically effective amount of other substances useful for treating putrefactive shock, such as, for example, antibiotics or antibodies (polyclonal or monoclonal) directed to antigens. located on endotoxins. Of course, the acceptable dose range of the other substances will depend on their properties (ie, the range of acceptable dose will depend on which other substance is being administered). Ta, and another substance useful in the prevention or treatment of putrefactive shock may be administered "in combination" which, as defined herein, includes various schemes designed to administer Ta, and the other substance to the subject, whether the other substance and Ta, whether or not administered separately or together, such that the desired dosages of Ta, and the other substance are present in the subject at the same time. Any suitable scheme can be used to administer Ta, and other substances useful in the prevention or treatment of putrefactive shock "in combination" according to the present invention. Appropriate doses of Ta, alone or Ta, in combination with another substance useful to treat or prevent putrefactive shock and that can be administered go from 1 to 3 times or more per day. The precise dose administered will depend on the age, condition and other factors of the recipient. The following examples are for illustrative purposes only and should not be construed in a limiting sense.

Example 1 Ta, synthetic was provided by Alpha 1 Biomedicals Inc. (Two Democracy Center, 6903 Rockledge Drive, Ste. 1200, Bethesda, Maryland 20817) Ta, was prepared by peptide synthesis in solid phase. Swiss Webster mice 4-6 weeks old (20-25 g) were divided into two groups: endotoxic mice (in acute treatment of endotoxin 60 mg / kg ip) and endotoxic mice treated with 3 subcutaneous injections of 100 μg of Ta, (5 minutes, 2 and 4 hours after administration of endotoxin), or a single subcutaneous injection of 100 μg Ta, immediately after administration of endotoxin, as indicated below. The results presented in Tables I and II indicate that Ta, administered 3 times after the administration of endotoxin, increased the survival rate of mice treated with 100% endotoxin. The results presented in Tables III-VII show effects of Ta, respectively on levels of alonildi aldehyde in the blood of the mice, glutathione levels, cGMP levels of the cerebellum, TNF-a levels of the blood serum, and levels of IL-la and TNF-a in blood serum.

TABLE Survival of Swiss Webster Mice After Doses of Lethal Endotoxin and Ta, Number of Live Mice EXPERIMENTAL GROUPS 0 Hours 24 Hours 48 hours 72 Hours Endotoxin 60 mg / kg 7 1 1 1 Endotoxin 60 mg / kg '7 7 7 7 + Ta, 100 μq 3X TABLE II Protective Effect of Ta, on the Survival of Mice Treated with Lethal Doses of Endotoxin Number of Live Mice EXPERIMENTAL GROUPS 0 24 48 72 7 14 hr hr hr days days Endotoxin 60 mg / kg 8 0 Endotoxin 60 mg / kg 8 8 8 8 8 8 + Ta, 100 μg 3X TABLE III Effects of Ta, on changes in blood hydroperoxide levels after treatment of mice with lethal doses of endotoxin EXPERIMENTAL GROUPS Malonildialdehyde levels in blood (nMol MDA) Control 17.5 ± 1.20 Endotoxin 60 mg / kg 38.2 ± 2.90 Endotoxin 60 mg / kg 16.9 ± 1.36 + Ta, 100 μg 3X * Whole blood samples (0.5 ml) were obtained by mixing of tails 1 hour after administering endotoxin.

TABLE IV Effects of Ta glutathione levels in mice treated with lethal doses of endotoxin RBC GSH EXPERIMENTAL GROUPS (μmoles / ml cells) Control 1.25 ± 0.09 Endotoxin 60 mg / kg 0.61 ± 0.05 Endotoxin 60 mg / kg 1.12 ± 0.12 + Ta, 100 μg / mouse lx * Total erythrocyte glutation, 98% of which is in the reduced form (GSH), was determined by the "cyclic method" enzymatic.

TABLE V Effects of Ta on cerebrospinal cGMP levels in mice treated with lethal doses of endotoxin EXPERIMENTAL GROUPS Cyclic GMP of the cerebellum cortex (pmol per mg / protein) Control 10.1 ± 0.20 Endotoxin 60 mg / kg 30.7 ± 4.10 i.p. Endotoxin 60 mg / kg 14.6 ± 1.20 i.p. + Ta, 100 μg lx TABLE VI Levels of TNF-α in mice treated with lethal doses of endotoxin EXPERIMENTAL GROUPS TNF-a (pg / ml) 1 hr 3 hr 5 hr Endotoxin 60 mg / kg 1098 ± 106 783 ± 38 623 ± 51 Endotoxin 60 mg / kg 638 ± 57 426 ± 37 297 ± 27 + Ta, 100 μg lx TABLE VII Levels * of TNF-α and IL-la in mice protected against lethality induced by endotoxin, by pre-treatment with SOD and Ta, Pre-treatment TNF-a (pg / ml) IL-la (pg / ml) None 4462 ± 123 1137 ± 123 SOD (3.3 X 104 μ / kg) 63 ± 5.1 53 ± 3.1 Ta, 100 μg / mouse lx 285 ± 23.6 109 ± 71 * Mice were pre-treated with SOD (Super Oxide Dismatase), 30 minutes before the administration of endotoxin. Blood for determination of TNFa and levels of IL-la was collected 1 hour after administration of endotoxin. Example 2 Using the same materials and methods as in Example 1, the time and dose dependence of the protective effect of a subcutaneous injection of Ta on endotoxin lethality were studied. The results are presented in Table VIII. As can be seen in Table VIII, Ta, had a protective effect on the toxicity of endotoxin when it was given immediately after, 2 and 4 hours after the endotoxin treatment or when it was provided 2, 4 and 6 hours after the treatment of endotoxin The effective protective dose was 100 μ of Ta, administered three times.

TABLE VIII Survival of Swiss Webster Mice following the Lethal Dose of Endotoxin and Ta, Number of Live Mice Experimental Groups 0 hr 24 hr 48 hr 72 hr 96 hr 120 hr Endotoxin 60 mg / kg 8 4 4 4 4 4 Endotoxin 60 mg / kg 8 8 8 8 8 8 + Ta, 100 μg 3x; Ta, was administered immediately after, 2 and 4 hr after the endotoxin. Endotoxin 60 mg / kg + Ta, 100 μg 3x; Ta, was administered 2, 4 and 6 hr after the endotoxin. Endotoxin 60 mg / kg + Ta, 10 μg 3x; Ta, was administered immediately after, 2 and 4 hr after the endotoxin.

Example 3 Using the same methods and materials as in Examples 1 and 2, the effect that Ta has on the levels of IL-la, TNFal, PAG, Tx /? 2 and 6-keto-PGF was studied. of blood, which are pathological mediators of endotoxin-induced lethality. The results are presented in Tables IX-XIV.

As can be seen in Tables IX-XIV, Ta, decreases the serum levels of IL-la, TNFal as well as the plasma levels of PAG, Tx / 32 and 6-keto-PGF, after the administration of a lethal dose of endotoxin intraperitonally. TABLE IX EXPERIMENTAL GROUPS (Serum levels) IL-la p / ml 1 hr 3 hr Endotoxin 60 mg / kg 492 ± 45.2 550 ± 37.1 Endotoxin 60 mg / kg + 83 ± 7.1 165 ± 13.7 Ta, 100 μg administered immediately after TABLE X EXPERIMENTAL GROUPS (Plasma levels) PAF ps / ml 0.5 hr 1 hr 2 hr 3 hr Endotoxin 60 mg / kg 78 ± 6 279 ± 17 127 ± 13 55 ± 3 Endotoxin 60 mg / kg + 48 ± 3 136 ± 9 68 ± 4 32 ± 2 Ta, 100 μg administered immediately after TABLE XI EXPERIMENTAL GROUPS (Plasma levels) T? ß? (pa / ml) 0.5 hr 1 hr 2 hr 3 hr Endotoxin 60 mg / kg 1442 ± 103 2937 ± 258 912 ± 105 695 ± 65 Endotoxin 60 mg / kg + 910 ± 85 1921 ± 185 530 ± 47 391 ± 260 Ta, 100 μg administered immediately after TABLE XII EXPERIMENTAL GROUPS (Plasma levels) 6-keto-PGF la (pa / ml) 0.5 hr 1 hr 2 hr 3 hr Endotoxin 60 mg / kg 341 ± 31 1141 ± 112 897 ± 75 811 ± 7 Endotoxin 60 mg / kg + 224 ± 19 745 ± 62 341 ± 33 205 ± 19 Ta, 100 μg administered immediately after TABLE XIII EXPERIMENTAL GROUPS (Serum Levels) PAF (pa / ml) 1 hr 3 hr 5 hr Endotoxin 60 mg / kg 938 662 567 Endotoxin 60 mg / kg + 783 508 429 Ta, 100 μg administered immediately after TABLE XIV EXPERIMENTAL GROUPS (Serum levels) TNF-a (pa / ml) 1 hr 3 hr 5 hr Endotoxin 60 mg / kg 938 662 567 Endotoxin 60 mg / kg + 783 508 429 Ta, 100 μg administered immediately after Example 4 Using a putrefactive shock model in rats (Sprague-Dawley, males, 200-225 g each), the effect of a subcutaneous injection of Thymosin to, alone and in combination with antibiotics was studied. Peritonitis was induced in rats in the following manner. An incision of 1 cm was made inside the peritoneal, which exposed the caecum. A strong ligature was placed around the caecum with 4-0 distal suture at the small intestine insertion, forming an area of devitalized tissue while maintaining the continuity of the intestine. A 16-gauge needle was punctured into the anti-mesenteric surface of the caecum and a small amount of fecal contents was expressed through the wound. The caecum was relocated within the peritoneal cavity, and the anterior peritoneal wall and skin were closed with surgical staples. Each animal was given a normal saline bolus (15 ml / kg) for hydration and allowed to recover throughout the night. The results presented in Table XV show that the Ta increased the survival of the rats.

TABLE XV Survival of Sprague-Dawley rats immediately after putrefactive shock, antibiotics and thymosin a. EXPERIMENTAL GROUPS 0 hr 24 hr 48 hr 72 hr Rats with peritonitis + 10 antibiotics * Rats with peritonitis + 10 antibiotics * + Thymosin at g / rat x 3 ** * gentamicin sulfate, 1 mg / rat ** at 0 hr, 2 hr and 4 hr post induction of peritonitis Results presented in Tables XVI to XIX show the effects of Ta, respectively on rat cytokine levels, blood malonyldialdehyde levels, glutathione levels and metabolic levels of arachidonic acid.

TABLE XVI Effect of Ta, on Cytokine Levels in a Putrefactive Shock Model in Rat EXPERIMENTAL GROUPS TNFa (pa / ml) IL-la (pg / ml) Undetectable undetectable control Rats with putrefactive shock 2658 ± 197 1387 ± 123 Rats with putrefactive shock + 1231 ± 129 689 ± 53 Ta, l mg / rat x 3 as previously TABLE XVII Effect of Ta, on lipid peroxidation in a rat putrefactive shock model Malonildialdehyde blood levels EXPERIMENTAL GROUPS (nMol of MDA) Control 15.3 ± 1.3 18.6 ± 1.1 Rats with putrefactive shock 49.1 ± 3.5 46.3 ± 3.8 Rats with putrefactive shock + 17.1 ± 1.6 21.9 ± 2.3 Ta, 1 mg / rat x 3 as previously TABLE XVIII Effect of Ta, on glutathione levels in a rotten putrefactive shock model RBC GSH EXPERIMENTAL GROUPS (itmoles / ml cells) Control 1.38 ± 0.1 1.46 ± 0.13 Rats with putrefactive shock 0.43 ± 0.05 0.29 ± 0.04 Rats with putrefactive shock + 1.29 ± 0.07 1.20 ± 0.085 Ta, 1 mg / rat x 3 as previously TABLE XIX Effect of Ta on metabolite levels of arachidonic acid in a rat putrefactive shock model EXPERIMENTAL GROUPS 6-cet? -PGF (Pa / ml) T X fl, (Pa / ml) Control 58 ± 3.5 89 ± 7.6 Rats with putrefactive shock 1828 ± 145.3 3622 ± 295 Rats with putrefactive shock + 1132 ± 96 2353 ± 197 Ta, 1 mg / rat x 3 as above The results presented in Tables XX and XXI show that Ta increases the survival rate of rats with putrefactive shock. TABLE XX Number of Live Rats EXPERIMENTAL GROUPS 0 hr 24 hr 48 hr 72 hr Rats with putrefactive shock 10 2 2 0 Rats with putrefactive shock + 10 9 9 5 Ta, 1 mg / rat x 3 as above TABLE XXI Number of Live Rats EXPERIMENTAL GROUPS 0 hr 24 hr 48 hr 72 hr Rats with putrefactive shock 10 1 0 0 Rats with putrefactive shock + 10 8 7 3 Ta, 1 mg / rat x 3 as above While the invention has been described and illustrated in detail and in reference to certain preferred embodiments, those skilled in the art will appreciate that various modifications, changes, Omissions and substitutions can be made without departing from the spirit of the invention.

Claims (36)

Novelty of the Invention Having described the present invention is considered as a novelty and, therefore, the ownership of what is contained in the following claims is claimed:

1. A method for obstructing the advancement of a cascade sepsis in a mammal in which a cascade sepsis is occurring, which comprises administering to said mammal an obstructive amount of cascade sepsis, thymosin a, (Ta ,).

2. The method of claim 1, wherein said mammal is human.

3. The method of claim 2, wherein the Ta is administered at a dose of from about 0.4 to about 4 mg.

4. The method of claim 2, wherein the Ta is administered at a dose of from about 1 to about 4 mg.

5. The method of claim 3, wherein the Ta is administered parenterally.

6. The method of claim 5, wherein the Ta is administered intravenously.

The method of claim 1, wherein Ta, is Ta, synthetic.

The method of claim 1, wherein said amount of Ta is sufficient to reduce in said mammal at least one member selected from the group consisting of cGMP levels of the cerebellum, levels of malonyldialdehyde in blood, blood glutathione levels, blood PAF levels, Txfl2 levels in blood, levels of 6-keto-PGF, a blood, levels of IL-la in blood and levels of TNFa in blood.

9. A method for preventing putrefactive shock in a mammal after the introduction of endotoxin into said mammal, comprising administering to said mammal an effective amount of Ta, to prevent putrefactive shock, wherein the putrefactive shock is prevented in said mammal. mammal for at least 72 hours after the administration of said Ta.

10. The method of claim 9, wherein the putrefactive shock is prevented in said mammal for at least 120 hours after the administration of said Ta ,.

The method of claim 9, wherein the putrefactive shock is prevented in said mammal for at least 14 days after the administration of said Ta.

The method of claim 9, wherein said mammal is human.

The method of claim 12, wherein the Ta is administered at a dose of from about 0.4 to about 4 mg.

The method of claim 12, wherein the Ta is administered at a dose of from about 1 to about 4 mg.

15. The method of claim 13, wherein the Ta is administered parenterally.

16. The method of claim 15, wherein the Ta is administered intravenously.

17. The method of claim 9, wherein Ta, is Ta, synthetic.

18. The method of claim 9, wherein said amount of Ta is sufficient to reduce in said mammal at least one member selected from the group consisting of cGMP levels of the cerebellum, levels of malonyldialdehyde in blood, blood glutathione levels, blood PAF levels, Txfl2 levels in blood, levels of 6-keto-PGF, a blood, levels of IL-la in blood and levels of TNFa in blood.

19. A method for treating putrefactive shock in a mammal, which comprises administering to said mammal an effective amount of Ta, to treat putrefactive shock.

20. The method of claim 19, wherein said mammal is human.

21. The method of claim 20, wherein the Ta is administered at a dose of from about 0.4 to about 4 mg.

22. The method of claim 20, wherein the Ta is administered at a dose of from about 1 to about 4 mg.

23. The method of claim 22, wherein the Ta is administered parenterally.

24. The method of claim 23, wherein the Ta is administered intravenously.

25. The method of claim 19, wherein Ta, is Ta, synthetic.

26. The method of claim 19, wherein said amount of Ta is sufficient to reduce in said mammal at least one member selected from the group consisting of cGMP levels of the cerebellum, levels of malonyldialdehyde in blood, blood glutathione levels, blood PAF levels, blood levels of Txfl2 in blood, levels of 6-keto-PGF, a in blood, levels of IL-la in blood and levels of TNFa in blood.

27. A pharmaceutical unit dose containing an amount of Ta, selected from the group consisting of an effective amount of Ta, to obstruct cascade sepsis in a mammal, an effective amount of Ta, to prevent cascade sepsis in a mammal and an effective amount of Ta, to treat cascade sepsis in a mammal, wherein said Ta, is provided in a carrier that is pharmaceutically acceptable for the administration of a mammal.

28. The pharmaceutical unit dose of claim 27, containing from about 0.4 to about 4 mg of Ta ,.

29. The pharmaceutical unit dose of claim 27, containing from about 1 to about 4 mg of Ta ,.

30. The pharmaceutical unit dose of claim 28, which is in a form for parenteral administration, wherein the carrier is a sterile liquid carrier suitable for parenteral administration.

31. The pharmaceutical unit dose of claim 30, which is in a form for intravenous administration.

32. The pharmaceutical unit dose of claim 31, wherein the Ta is dissolved in a sterile isotonic saline solution.

33. The pharmaceutical unit dose of claim 27, wherein the Ta is present in said pharmaceutical unit dose in an amount sufficient to reduce in said mammal at least one member selected from the group consisting of cGMP levels of the cerebellum, malonyldialdehyde levels in blood, blood glutathione levels, blood PAF levels, blood Txfl2 levels, 6-keto-PGF levels, a blood levels, IL-la levels in blood and levels of TNFa in blood.

34. The method of claim 1, wherein said administration of Ta reduces the levels of free radicals in blood in said mammal.

35. The method of claim 9, wherein said administration of Ta reduces the levels of free radicals in blood in said mammal.

36. The method of claim 19, wherein said administration of Ta reduces the levels of free radicals in blood in said mammal. In testimony of which I sign the present descriptive memory and claims in Mexico City, D. F. on the fifth day of the month of October of 1994. By The George Washington University Medical Center HR: emy Ing. Hugo Rodríguez Mejía A p o d a r o d Extract of the Description A method to treat putrefactive shock in a mammal, including the administration of an effective amount of Ta, to treat putrefactive shock to the mammal.