CZ30194A3 - The use of peptidoglycan monomer (pgm), n-acyl derivatives and complexes with metal thereof when preparing medicaments for correction immuno=suppressive and hepato-suppressive states of organism - Google Patents

Abstract

The invention relates to the use of the peptidoglycan monomer (PGM), its N-acyl derivatives of formula (I), and its metal complexes of formulae (Ia) or (Ib) in the preparation of medicaments for the correction of the immunosuppressive and hepatosuppressive effects of anaesthetics and operative stress in surgical treatment or in other immunosuppressive, immunodeficient, and hepatosuppressive states, to achieve a swift and safe recovery of the patients.

Description

(57) The present invention relates to the use of a peptidoglycan monomer (PGM) and its N-acyl derivatives of the general formula I, in which R represents a hydrogen atom, Ac represents a straight chain alkylcarboxylic acid group of 2 to 18 carbon atoms, branched chain alkylcarboxylic acid of 5 up to 18 carbon atoms, unsaturated alkenylcarboxylic acids having 12 to 18 carbon atoms or aromatic carboxylic acids having 7 to 12 carbon atoms and X represents a hydrogen atom, an alkali or alkaline earth metal atom or a quaternary ammonium salt of an organic base, and their divalent metal complexes of formula (Ia) or (Ib) in combination with other conventional non-toxic, physiologically acceptable substances in the preparation of medicaments for correcting immunosuppressive hepatosuppressive conditions of organisms caused by anesthetics and / or surgical stress in surgery or other immunosuppressive, immunodeficiency and hepatosuppressive conditions e achieved rapid and safe recovery of patients.

A3 21 (51) 301-94 (13)

A 61 K 37/02

CHjOII CHjOII / Z IVII'11

CJfo CONJQ Clh CHj

I I 'I

CnjCHCO.NÍICÍíCO-NHCilCíijCUjCO.MíCHCO.SJICHCO.NílCHCOOX

2) .1

R-IISCHCHONIIj

N · Cle · N · Ac · Mur

D · Ala »ΙΊ-Ale« Ο

N-Ac-Cu-N-Ac-Mur

Ajpni

Ο.ΛΙι ». »'ΛΙη »Q

Me 2a De 2b Nl 2c Of 2d Cd (IA)

Mi 3a Cu 3b n _R

JhN

112N-II

HER

I D · Al * D · ΛΙλ · O

N 'Ac G1' N 'A' Mur 'ib

Use of peptidoglycan monomer (PGM), its N-acyl derivatives and its metal complexes in the preparation of drugs for the correction of immunosuppressive and hepatosuppressive conditions of the organism

Technical field

The present invention relates to the use of the peptidoglycan monomer (PGM), its N-acyl derivatives and its metal complexes in the preparation of medicaments for correcting the immunosuppressive and hepatosuppressive effects of anesthetics and surgical stress in surgery or other immunosuppressive, immunodeficiency and hepatosuppressive conditions. and safe patient recovery.

BACKGROUND OF THE INVENTION

Numerous publications of clinical and experimental research over the past decade have shown that surgical stress and / or anesthesia administered in surgery leads to transient immunosuppression, which may pose a risk to the patient's life due to increased susceptibility to infections, spread of tumor metastases, slowed wound healing, etc. pathogenesis-generated immunosuppression contribute together to anesthesia with its toxic effects, surgical stress and changes in the neuro-endocrino-immune relationship resulting from transient paralysis of the central nervous system under anesthesia (Watkins J. (1980): Br. J. Hosp. Med. 23 , 5835-590, Udovic-Sirola M. et al (1989) in Immune Consequences of Trauma, Shock and Sepsis, pp 411-417), while some effects are due to changes in liver-level metabolism that occur after administration of anesthesia and surgical stress. The hepetotoxic effect of anesthesia can be explained by the fact that most halogenated narcotics are metabolized in the liver, which may provide toxic intermediates such as trifluoroacetyl halides or free radicals (Satoh H. et al. (1985): J. Pharm. Exp. Therap. 233 857.). In predisposed persons, this may lead to the development of autoimmune hepatitis (Vergani D. et al. (1980): N. Engl. J. Med. 303, 66.). It should be emphasized that this immunosuppressive and hepatotoxic effect is not limited to patients who are operated under endotracheal anesthesia, but may also include a medical staff operating in the operating room. Chronic halothane exposure appears to result in 1.3 to 2.0 more frequent cancer development in female subjects (Baden YM et al. (1986) in Anesthesia, Miller RD (ed.), NY, p. 730). ). In view of the serious consequences that may arise after postoperative immunosuppression and prolonged exposure to anesthetic agents, the high number of therapeutic trials for preventive action is not surprising. Thus, the use of: immunoglobulin (Nitsche D. et al. (1988): International Congress on Iramune Consequences of Trauma, Shock and Sepsis; OP 52), synthetic hormones (Faist E. et al. (1987): Int. J. Clin Pharm Res 7: 83-87, Waymack JP et al (1985) Arch Surg 120: 43 Faist E. (1989) Immune Consequences of Trauma, Shock and Sepsis, page 509 to 517), transfer factors and interferons (Josten Ch. et al. (1988) lst International Congress on Immune Consequences of Trauma, Shock and Sepsis, OP 43; Livingston DH et al. (1989) in Immune Consequences of Trauma, Shock and Sepsis, pp. 551-555), H-2 receptor blockers (Nielsen HJ et al. (1988): International Congress on Immune Consequences of Trauma, Shock and Sepsis, OP 49), monoclonal antibodies against endotoxins (Sagawa T (1989) in Immune Consequences of Trauma, Shock and Sepsis, pp. 495-507), vasoactive agents (Schontharting M. et al. (1988): lst. International Congress on Immune Consequences of Trauma, Shock and Sepsis, OP 57), antagonists of platelet activating factors (Fletcher J.R. et al. (1988): lst International Congress on Immune Cosequences of Trauma, Shock and Sepsis, OP 56) and various immunomodulators (Schopf RE et al. (1988): lst International Congress on Immune Consequences of Trauma, Shock and Sepsis; Tsang KP et al (1986): Int J. Immunopharmacol, £ 437, Hadden JW et al (1989) at the International Congress on Immune Consequences of Trauma, Shock and Sepsis, pp. 509-517.).

The biologically active substance peptidoglycan monomer (PGM) is available by biosynthesis (according to Yugoslavian patent 35040) and has been isolated as a chemically defined compound (according to Klaic B .: Carbohydr. Res. (1982) 110, 320; Yugoslav patent 40472; Austrian patent 362740) . Later, its N-acyl derivatives (Yugoslav patent application P-626/89, European patent application 390093) and its metal complexes were prepared (Yugoslav patent application P-1982/86, European patent application 268271). The isolated substances are well soluble in water and in physiological solutions, are non-toxic and pyrogen-free. They have immunostimulatory, antimetastatic and antitumor activity.

SUMMARY OF THE INVENTION

The present invention provides novel use of the peptidoglycan monomer (PGM), and its N-acyl derivatives of general formula I Cu CH ₂ ON ₂ ON

OH

NHAc

CIH CONlb CH ₃ CH ₃

I I II

Cn ₃ CHCO-NHCHCO-NHCHCH ₂ CH ₂ CO-MJCHCO-NHCHCO-NHCHCOOX (CH ₂ ) ₃ k-ynchconii ₂ (I) wherein R represents a hydrogen atom, Ac represents a straight chain alkyl carboxylic acid group having 2 to 18 carbon atoms , C 5 -C 18 branched chain alkylcarboxylic acids, C 12 -C 18 unsaturated alkenyl carboxylic acids or C 7 -C 12 aromatic carboxylic acids and X represents a hydrogen atom, an alkali metal or alkaline earth metal atom or a quaternary ammonium salt of an organic bases, and complexes thereof with divalent metals of formula Ia or 1b

N. Ac - Gle · N - Ac · Mur

D - Ala - D - Ala - O

A ₂ P ^m

H-N-i-H

MeMe

2a Co 2b Ni 2c Zn 2d Cd pressure)

N - Ac - Glc - N - Ac · Mur

A ₂ pm

And ₂ pm: h ₂ N—! H

H ₂ N r - - H

D - Ala D - Ala

Me

3a Cu

3b n _R [M. Ac-Glc-N · Ac · Mup in the presence of drugs for the correction of humoral-type and cell-mediated immunosuppressive conditions induced by administration of anesthetics and / or surgical stress in surgery, other immunosuppressive and immunodeficiency conditions induced by sepsis, burns, physical exhaustion, paraneoplastic syndrome and similar and for correcting the hepatosuppressive state of the organism, stopping changes in hepatic nucleic acids, particularly hepatic proteins, induced by anesthesia and / or surgical stress, as well as other conditions related to immunosuppression and / or hepatic disorders, poisoning, hepatitis, etc.

The hitherto unknown activity of PGM, its N-acyl derivatives and their divalent metal salts is illustrated in a model of experimentally induced postoperative immunosuppression.

Considering that most surgical operations are performed under general endotracheal anesthesia maintained by the administration of halogenated anesthetics, an experimental model has been designed to induce immunosuppression similarly to humans by applying halothane anesthesia with or without surgical stress. For this reason, BALB / c mice 2.5 to 3 months old are placed in hermetically sealed 11 metabolic cages containing soda lime (a mixture of calcium oxide and sodium hydroxide) to which air is supplied (by a respirator for small animals) with an addition of 0.5 to 3 1% halothane (flow rate 350 ml / min). This anesthesia is maintained for 1 hour. Animals from the control group were subjected to the same procedure except that no halothane was added to the air. A subgroup of mice was only anesthetized with halothane, the subgroup was further subjected to surgical stress in the form of laparotomy (abdominal wall intersection). This operation prevented the animals from being subjected to halothane anesthesia and was performed under brief ether anesthesia. To achieve the same condition for control of this group, the laparotomy + halothane control groups were subjected to brief ether anesthesia immediately prior to the halothane anesthesia. In the humoral and cell-mediated immunity control, the animals were then immunized with: a) sheep erythrocytes (OE) and on the fourth day after sensitization the spleen plaque count was analyzed, b) allogeneic tumor cells, sarcoma I growth (from A / J mice) and time rejection and c) by parental splenocytes for analysis of local donor cell response (BALB / c) to (BALB / cx CBA1F1 hybrid as recipient. Each group included 5-8 animals. Statistical analysis was performed by Student's t-test.

The results show that halothane anesthesia in itself showed an immunosuppressive effect on humoral and cell-mediated immunity (Fig. 1) and that surgical stress caused by laparotomy enhanced this immunosuppression. In mice that are sensitized with sheep erythrocytes, halothane anesthesia alone blocked plaque formation (PFC) in the spleen by 48.5% (p <0.001) and lapa6 rotomy by a further 27% (Fig. 1A); inhibition of cell-mediated immunity was demonstrated by prolonging the time with allogeneic tumor from day 11 to day 14 (anesthesia alone) and from day 14 to day 16 (anesthesia + surgical stress; p <0.05) (Fig. 1B). Inhibition of cell-mediated immunity by halothane anesthesia alone was confirmed in a model of local donor cell response to recipient cells (GVHR - graft versus host) where donor anesthesia induced a significant reduction in hamstring lymph node size response on day 7 post parental lymphocyte injection (from normal) 8.3 ± 1.5 mg to 4.0 ± 1.0; p <0.05).

Halothane-induced diminution of the humoral immune response was accompanied by hypoplasia (imperfect development) of bone marrow and spleen, a decrease in the proportion of CD4 and CD8 ⁺ cells and an increase in the number of non-phenotype cells (Fig. 2).

The simultaneous determination of hepatic proteins and nucleic acids in OE-sensitized and halothane-anesthetized mice showed some hepatosuppressive activity of anesthesia and its significant effect on reducing the amount and concentration of hepatic proteins, DNA and RNA (Fig. 3). The experimental model was followed by mimicking most of the symptoms that may occur after surgery in an anesthetized patient and which cause:

1. immunosuppression (a) of the humoral type, and

b) cell-mediated type,

2. hepatosuppressive effect.

In this state of immuno and hepatosuppression, we further tested the effects of PGM and its analogues and compared their effects on intact mice. The results obtained show that PGM and its analogs are highly effective in correcting such postoperative immunosuppression, while their effects are much weaker in intact organisms.

Medicinal product: PGM and its N-acyl derivatives and complexes with bivalent metals or mixtures thereof can be administered intravenously, intraperitoneally, intramuscularly and subcutaneously in the formulation

Dalšími other non-toxic, physiologically acceptable substances known to those skilled in the art. The unit dose size and form depend on the body weight and the individual condition of the body. PGM and its N-acyl derivatives and divalent metal complexes can be administered at a dose of 5 to 50 mg per kg body weight.

The invention is further illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Correction of humoral-type immunosuppression in anesthetized and operated animals by PGM (Ia)

Since we found that major suppression of homoral immunity occurs in halothane-anesthetized and laparotomized mice (Fig. 1), we tested the prevention of immunosuppression by application of PGM. For this reason, mice received a single intraperitoneal injection of PGM dissolved in 0.05 ml of physiological saline immediately after laparotomy and OE-sensitization and immediately before halothane anesthesia. The results presented in Table 1 demonstrate that PGM (10 mg / kg) in anaesthetized mice increased the plaque generation for 94.3% (PFC / 10 ^6), while mice who received the halothane anesthesia and were also subjected to operational stress, PFC formation was even stimulated up to 206.4% relative to the control injected with saline only.

Table 1

Humoral immunity of anesthetized and laparotomized mice treated with PGM

halothane remedy halothane-induced immuno- group PFC / 10 suppression PFC / spleen PFC / 10 under the influence of PGM PFC / spleen laparotomy + SRBC + PGM 10mg / kg 300.6 ± 42.7 ** 62968.3 ± 16551.1 * 206% 124,80% laparotomy + SRBC + physiol. solution 98 ± 22.5 2800.2 ± 7997.5 SRBC + PGM 10 mg / kg 260.8 ± 20.9 50007.8 ± 4043.9 94.30 % 64.70% OE + fysiol.r. 134.2 ± 31.4 30363,5Í10194,7

JU JL 4g

Statistically significant relative to control (p <0.01; p <0.001)

Table 2 shows that the best correction of halothane immunosuppression is achieved with a low dose of PGM. Simultaneous research into the effect of PGM in non-aesthetized mice showed that the effect was only seen in immunosuppressive mice. The increase in plaque formation in anesthetized mice treated with PGM was accompanied by an increase in the number of bone marrow cells and peripheral leukocytosis.

Table 2 (first part)

Humoral immunity in anesthetized and non-anesthetized mice after treatment with PGM

group without halothane PFC / 10 PFC / spleen OE + PGM 100 mg / kg OE + fysiol. solution 225 + 6.9 60339 + 5112.6 OE + PGM 50 mg / kg 385.6 + 36.1 * 111608.4 + 11079.3 * OE + fysiol. solution 498.7 + 47.1 178282.3 + 25557.8 OE + PGM 10 mg / kg 465.6 + 25.7 87670.5 + 5552.2 * OE + fysiol. solution 598.1 + 36.9 159847,7110628,2

Table 2 (second part, completion)

group with halothane halothane remedy induced immunosuppression by PGM PFC / 10 PFC / spleen pfc / 11: PFC / spleen OE + PGM 100 mg / kg 39.6 ± 6.0 * 8129.4 ± 845.8 * -67% -72,80% OE + fysiol. solution 120 ± 14 29888 ± 6031.5 OE + PGM 50 mg / kg 159.3 ± 39.5 ** 36085.2 ± 10629.6 * -9% -32,40% OE + fysiol. solution 175 ± 12 53356.9 ± 1864.6 OE + PGM 10 mg / kg 651.2 ± 85.4 * 106092 + 4812.9 * 66.20 % 32.10% OE + fysiol. solution 391.8 ± 7.1 80301.8 ± 6369.5

Statistically significant relative to control (** p <0.01; * p <0.001)

Example 2

Correction of humoral-type immunosuppression by the action of PGM-bivalent metal complexes

The PGM-Zn complex dissolved in physiological saline is injected at the same dose as in the previous example (10 mg / kg) to anesthetized and non-anesthetized OE-treated mice. This experiment is repeated three times. All investigations with PGM-Zn showed improved immunocorrection activity compared to PGM and increased plaque formation in anesthetized mice by 73.5%, 73.1%, and 101.4%, respectively, relative to the control that received saline alone.

These effects are accompanied by multiplication of spleen and bone marrow cells.

Table 3

Humoral immunity in anesthetized mice treated with PGM and its derivatives

group number of animals with halothane PFC / 10 ⁶ correction (%) PGM-10mg / kg 6 860 + 66.1 29.50 PGM-Zn 5 1152 ± 41.1 73.50 L-PGM-Na 6 932.5 ± 78.1 40.40 fysiol. mol. 5 664 ± 51.9 control PGM-10mg / kg 5 295 ± 42.3 21.90 PGM-Zn 5 419 ± 41.0 73.10 L-PGM-Na 5 508 ± 3.9 109.90 fysiol. mol. 5 242 ± 11.1 control PGM-10mg / kg 5 1782Í200 68.40 PGM-Zn 6 2131Í164 101.40 L-PGM-Na 6 2338Í184 120.90 fysiol. rozpk • 6 1058.3 ± 135 control

Example 3

Correction of humoral-type immunosuppression with N-acyl derivatives of PGM

Sodium N-lauroyl-PGM (PGM-L-Na) is dissolved in physiological saline. This solution is injected into anesthetized and sensitized mice. This will double the stimulation of plaque formation in the spleen (multiplication of 109.9% and 120.9%) relative to the control given only saline. This effect was not present in non-anesthetized mice.

Example 4

Correction of cell-mediated immunosuppression by PGM complexes with divalent metals and PGM N-acyl derivatives

PGM and its analogs were tested for total GVHR. In this test, they were administered immediately after parental splenocyte injection into the soft part of the hind leg of the F1 hybrids or immediately prior to halothane anesthesia. PGM-Zn was found to enhance the knee lymph node size response on day 7 after injection, while PGM-L-Na significantly increased the number of large lymph nodes in the local lymph node on day 10 post-injection (evaluated by cell flow counter).

Table 4 GVHR + halothane

lymph gland weight differences Day 5 7 .den 10.den PGM 2.2 ± 1.4 5.2 ± 0.8 3 ± 1.3 L-PGM-Na 2,5 ± 1 4.3 ± 1.7 2.5 ± 0.7 PGM-Zn 6.2 ± 1.4 fysiol.roztok 1.5 ± 0.2 4 ± 1 1.8 ± 1.4

cell differences in lymph gland (in millions)

Day 5 7 .den 10.den PGM 5.66 3 6.2 L-PGM-Na 7.66 1.84 3.57 PGM-Zn 2.9 fysiol.roztok 2.38 3.6 number of large cells (in thousands) Day 5 7 .den 10.den PGM 6,034 8,032 7.82 L-PGM-Na 6,038 6,462 17,494 PGM-Zn 4,677 fysiol.roztok 5,337 5,391

Example 5

Correction of hepatosuppressive effects during halothane anesthesia by PGM

Since we found that halothane anesthesia in OE-sensitized mice caused a reduction in the number of hepatic proteins and nucleic acids (Figure 2), we sought to determine if PGM application affected those changes that accompanied humoral-type immunosuppression. The results presented in Table 5 show that a small dose of PGM induces a significant increase in all liver parameters (DNA, RNA and proteins) of interest. Simultaneous testing of the effect of PGM on intact mice showed that the stimulatory effects of PGM were present only in anesthetized animals, i.e. mice with suppressed liver activity.

Table 5 (first part)

Hepatotropic effect of PGM in anesthetized and non-anesthetized mice

group mg / 100b.hm DNA mg / g mg / 100b.hm RNA mg / g halotant PGM 100 mg / kg 10.09 * ± 2 1.59 * ± 0.45 15.36 * ± 4.7 2.5 * ± 0.93 halothane + PGM 50 mg / kg 6.17 ± 0.6 1.2 ± 0.09 10.11 + 3.04 1.95 ± 0.45 halothane + PGM 10 mg / kg 8.74 * ± 2.72 1.64 * ± 0.46 16.73 * ± 4.99 3.15 * ± 0.82 halothane + physiological solution* 6.88 ± 1.01 1.24 ± 0.22 9.34 ± 1.78 1.67 ± 0.38 0 + PGM 50 mg / kg 8.17 ± 2.47 1.74 ± 0.67 12.83 ± 2.12 2.57 ± 0.59 0 + PGM 10 mg / kg 7.14 ± 1.55 1.48 ± 0.35 12.25 ± 1.69 2.54 ± 0.38 0 + physiol. solution** 7.91 ± 0.97 1.60 ± 0.45 II, 74 ± 2.08 2.21 ± 0.46

Table 5 (second part, completion)

group proteins mg / 100b.hm. mg / g halothane + PGM 100 mg / kg 492.5 ± 69.2 78.4 ± 12.9 halothane + PGM 50 mg / kg 379.3 ± 57.3 78.4 ± 12 halothane + PGM 10 mg / kg 605.5 * ± 134.7 113.9 * ± 22.3 halotant physiological solution* 463.5 ± 88.2 83.7 ± 15.4 0 + PGM 50 mg / kg 491.8 ± 92.1 95.9 ± 10.4 0 + PGM 10 mg / kg 414.6 ** + 20.6 85.9 + 3.9 0 + physiol. solution 529.9 ± 69.7 110.7 ± 26.8

Statistically significant between groups carrying the same index p <0.05.

Example 6

Hepatotropic effects of PGM, PGM complexes with divalent metals and PGM N-acyl derivatives in anesthetized and operated mice

The effects of PGM and its analogs were tested in anesthetized and operated mice. PGM was found to cause an increase in DNA, RNA, and protein content in the liver of the animals. The effects of N-acyl derivatives on proteins in the liver were equally intense, while PGM-Zn stimulated the association of hepatic proteins, even more intensively than PGM alone.

Table 6 (Part One)

Hepatotropic effect of PGM and its analogues in mice undergoing anesthesia and surgery

group DNA mg / 100b.hm. mg / g surgery + halothane + PGM *** 10 mg / kg 16.76 ** 12.23 2.98 ** 10.29 surgery! halotan! PGM-Zn 10 mg / kg 11,3914,16 2,0310,81 surgery! halotan! L-PGM-Na 10 mg / kg 13,3711,89 2,3910,44 surgery + halotam physiological solution** 12,6412,63 2,2410,59 surgery! physiological solution* 15,4412,57 2,6510,36

Table 6 (Part Two)

group RNA mg / 100b.hm. mg / g surgery + halothane + PGM *** 10 mg / kg 23.82 * ** ** ± 0.8 4.26 * ± 0.23 surgery + halothane + PGM-Zn 10 mg / kg 16.45 ± 6.24 2.93 ± 1.22 surgery + halothane + L-PGM-Na 10 mg / kg 22.57 ± 4.31 4.03 ± 0.81 surgery + halotant physiological solution** 18.14 * ± 2.84 3.20 ± 0.66 surgery + physiological solution* 22.51 ± 0.92 3.88 ± 0.02

Table 6 (Part Three, Completion) Protein mg / 100b.hm. mg / g surgery!

halotam

PGM *** (10 mg / kg) surgery + halotam PGM-Zn (10 mg / kg) surgery! halotam L-PGM-Na (10 mg / kg) surgery!

halotam saline ** surgery!

saline *

540.2 * 181.8

667.8 **** 136.9

616 **** 164.3

456.7158

434,218.2

96.1 **** '*** 110.5

118 *, ****** 15.1

109.5 **** 14.3

80.2110.2

7514,2

Statistically significant between groups carrying the same index p <0.05.

Claims (6)

PATENT CLAIMS Use of a peptidoglycan monomer (PGM) and its N-acyl derivatives of the general formula I (<»2) 3 R-HNCHCONII2 (I) wherein R is hydrogen, Ac is a straight chain alkyl group of 2 to 18 carbon atoms, a branched chain alkylcarboxylic acid of 5 to 18 carbon atoms, an unsaturated alkenylcarboxylic acid of 12 to 18 carbon atoms or a C7-C12 aromatic carboxylic acid and X is a hydrogen atom, an alkali metal or alkaline earth metal atom or a quaternary ammonium salt of an organic base, and its divalent metal complexes of formula Ia or Ib N · Ac - Gle · N · Ac - Mur D-Ala-D-Ala-O, 2Pm H _: N - I - H (1a) Me 2a Co 2b Ni 2c Zn 2d Cd Ν - Ac · Gle - Ν - Ac - Mur characterized in that it is used in combination with other conventional non-toxic, physiologically acceptable substances in the preparation of medicaments for the correction of immunosuppressive and hepatosuppressive states of the organism. Use according to claim 1, characterized in that the immunosuppressive conditions include a humoral type and a cell-mediated type induced by administration of various anesthetics and / or surgical stress in surgery, and other immunosuppressive and immunodeficiency conditions induced by sepsis, burns, physical exhaustion, paraneoplastic syndrome. etc. Use according to claim 1, characterized in that the hepatosuppressive state of the organism comprises changes in hepatic nucleic acids, in particular hepatic proteins, induced by anesthesia and / or surgical stress, as well as other conditions related to immunosuppression and / or hepatic disorders, poisoning, hepatitis, etc. Use according to claim 1, characterized in that medicaments are prepared for intravenous, intraperitoneal, intramuscular and subcutaneous administration. Use according to claim 1, characterized in that the weight of the dose and the formulation depends on the body weight and the individual condition of the organism. Use according to claim 1, characterized in that PGM, its N-acyl derivatives and complexes with divalent metals are administered in a dose of 5 to 50 mg / kg body weight.