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PubMed1983

Biotransformation of drugs in rats treated with a synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP).

Natural immunoadjuvant mixtures like BCG and FCA are known to produce gross alterations of drug-metabolizing systems in the rat. Since it has been shown that the smallest structure of various bacterial peptidoglycans, possessing adjuvant activity, is muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), the possibility has been tested whether this substance is involved in production of the observed metabolic changes. Synthetic compound was applied subcutaneously for the period of 21 days, and the in vitro activity of 7-ethoxycoumarin-O-de-ethylase, aminopyrine-N-demethylase, together with the microsomal content of cytochrome P-450 and b5, and the in vivo acetylation of sulphadimidine, were investigated. No effect of MDP on any of these tests was noted in both the Lewis arthritic strain and the AVN disease-free strain. It is suggested that MDP is metabolically inactive and that the defects in metabolism of drugs, following bacterial-adjuvant treatment, are likely to be due to some additional cell-wall components, other than peptidoglycans. Furthermore, our data support the view of no relationship between the development of metabolic changes and the established arthritic lesions in rats.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

The fate of nor-muramyl dipeptide (3H-labelled) after local administration in incomplete Freund's adjuvant in the guinea pig.

The fate of 3H-nor-muramyl dipeptide has been investigated after administration with bovine serum albumin (BSA) in Freund's incomplete adjuvant in the guinea pig footpad. Emulsions of two different stiffnesses , both of which were capable of inducing delayed-type hypersensitivity to BSA, were compared. Both emulsions produced stable depots of intact nor-MDP at the injection site. At early times retention of nor-MDP was greater with the stiffer emulsion and circulating levels of nor-MDP were greater with the looser emulsion; at 24 h there were no differences between the two. Distribution of nor-MDP to the draining lymph nodes was highly variable and no difference was apparent between the two emulsions. Levels of radioactivity in more distant lymph nodes were minimal, and in other tissues no radioactivity was detected. Thus it has not been possible to clarify the role of nor-MDP in this system in terms of its distribution through the local lymphatics, however, some information has emerged about the stability and integrity of nor-MDP in local adjuvant formulation.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Muramyl dipeptide protects decomplemented mice from surgically-induced infection.

Muramyl dipeptide (MDP) is a natural product of bacterial cell-wall breakdown, which can now be produced synthetically; it is the smallest component of the mycobacterial cell wall capable of reproducing the adjuvant activities of Freund's complete adjuvant. We tested the well-documented, protective effect of MDP to increase survival in a murine model simulating surgically-induced bacteremia. The protocol involved the bacterial innoculation of control and decomplemented mice in the presence and the absence of pretreatment with MDP. Bacteremia in both the control and decomplemented groups pretreated with MDP was decreased statistically at 24 h (P less than 0.01) as compared to controls. Likewise, survival was increased significantly at 24 h (P less than 0.05), 48 h (P less than 0.001), and 72 h (P less than 0.001) using the same group comparisons. We conclude, therefore, that MDP maintains its protective effect in the absence of complement, supporting the view that the mechanism of action of MDP is complement independent.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Stimulatory effects of muramyl dipeptide and its butyl ester derivative on the proliferation and activation of macrophages in vitro.

Muramyl dipeptide (MDP) and the butyl ester derivative, N-acetylmuramyl-L-alanyl-D-glutamine-alpha-n-butyl ester (MDP[Gln]OnBu), were shown to induce the in vitro proliferation of oil-induced guinea pig peritoneal exudate cells (PEC). Both agents induced 10-20 fold increases in tritiated thymidine incorporation in PEC cultures. The maximal effects occurred in 72 h cultures stimulated with either 0.1 microgram MDP or 10 micrograms MDP[Gln]OnBu. The mitogenic effects of MDP appeared to be mediated by a macrophage product detected in the supernatants of MDP-stimulated cultures. Supernatants of MDP- or MDP[Gln]OnBu-stimulated PEC cultures were also inhibitory to normal fibroblast growth and cytotoxic to L929 tumor cells. These results indicated that these agents may stimulate macrophages by modulating secretory functions. In addition, either peptidoglycan was capable of activating bactericidal activity in in vitro macrophage cultures. Initial studies of possible mechanisms of action revealed an early increase in the level of cyclic GMP. The possible role of cyclic GMP in mediating the stimulation of macrophage secretory processes is discussed.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

The effects of immunomodulating peptidoglycan monomer and muramyl dipeptide on hepatic microsomal UDP-glucuronyltransferase and beta-glucuronidase.

The effects of immunomodulating peptidoglycans, peptidoglycan monomer (PGM) and muramyl dipeptide (MDP), on hepatic microsomal UDP-glucuronyltransferase (uridine diphosphoglucuronate glucuronosyl transferase, EC 2.4.1.17) and beta-glucuronidase (beta-D-glucuronide glucuronohydrolase, EC 3.2.1.31) were tested in female C57Bl mice. 4-Methylumbelliferone and p-nitrophenol were used as representative substrates for one functional form of UDP-glucuronyltransferase (GT1) and testosterone for the second functional form (GT2) of the enzyme. Both PGM and MDP were found to transiently inhibit the activity of UDP-glucuronyltransferase. There was no significant difference in the magnitude of inhibition of the two functionally different enzyme forms. The activity of microsomal beta-glucuronidase was tested using 4-methylumbelliferyl glucuronide and p-nitrophenyl glucuronide as substrates. Time dependent transient inhibition of beta-glucuronidase activity was observed with both peptidoglycans. In addition, the effect of MDP on cytochrome P-450 was tested, since we have shown previously that PGM affected this system. MDP decreased the content of cytochrome P-450 and inhibited the activity of related enzymes.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1987

Comparative interaction of free and liposome-encapsulated nor-muramyl dipeptide or muramyl tripeptide phosphatidylethanolamine (3H-labelled) with human blood monocytes.

The purpose of this study was to analyse on biochemical and functional levels the interaction of free and liposome-encapsulated nor-muramyl dipeptide (nor-MDP) or muramyl tripeptide phosphatidylethanolamine (MTP-PE) with human peripheral blood monocytes. The activation of tumoricidal properties in monocytes by free MTP-PE required approximately 40-fold less material than free nor-MDP. Encapsulation of either MTP-PE or nor-MDP within multilamellar liposomes (MLV) increased the efficiency of the immunomodulators for activation of monocytes. The initial interaction of free 3H-nor-MDP or 3H-MTP-PE with monocytes was influenced by lipophilic derivatization, but neither derivatives exhibited characteristics of specific binding to the monocyte surface. The encapsulation of 3H-nor-MDP or 3H-MTP-PE within MLV increased uptake of both compounds by monocytes. The metabolic fate of MLV-entrapped 3H-nor-MDP was unaltered, but liposome encapsulation retarded the metabolism of 3H-MTP-PE. Collectively, the data suggest that the activation of monocytes by muramyl peptides results from an intracellular interaction which can be modulated by both lipophilic derivatization and/or liposome-encapsulation of this immunomodulator.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

Immunopharmacological activities of chemically synthesized lipid A-subunit analogue GLA-27 combined with muramyl dipeptide via spacers of different carbon chain length.

A lipid A-subunit analogue GLA-27, a 4-O-phosphono-D-glucosamine derivative carrying 3-O-tetradecanoyl and N-3-tetradecanoyloxytetradecanoyl groups, exhibited significant biological activities but no detectable pyrogenicity or local Shwarzman activity. In order to synthesize compounds combining GLA-27 with muramyl dipeptide (MDP), the OH group at the C6 position of GLA-27 was first succinylated. A compound which combined a succinylated GLA-27 (GLA-101) with 1-deoxy N-acetyl-muramyl-L-alanyl-D-isoglutamine methyl ester (1-deoxy MDP) via spacers of different carbon chain lengths of 5, 11 and 15, termed GLA-105, GLA-106 and GLA-107, respectively, and their biological activities were investigated. Intraperitoneal administration of combined preparations with spacers, GLA-105 and GLA-107, induced much higher phagocytic activity in peritoneal macrophages than GLA-27, GLA-101 and 1-deoxy MDP. The activity of GLA-106 did not increase by the combination. In induction of natural killer (NK) activity in peritoneal cells, GLA-105 and GLA-107 were significantly more active than 1-deoxy MDP but only comparable with GLA-27. GLA-101 showed stronger NK activity than GLA-27. The activity of GLA-106 was stronger than 1-deoxy MDP but weaker than GLA-27, GLA-105 and GLA-107. Mitogenic, interferon-inducing and tumor necrosis factor-inducing activities decreased by combining GLA-101 with 1-deoxy MDP. GLA-101, GLA-105 and GLA-107 strongly inhibited the formation of lesions on the tail of mice infected with Vaccinia virus. The activity was almost equivalent to that of GLA-27.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1988

The stimulatory effect of muramyl dipeptide (MDP) on the proliferation processes in parenchymal organs of rats.

The administration of muramyl dipeptide (MDP) in a single dose of 2 mg/kg increased markedly the utilization of 3H-thymidine for the synthesis of DNA thymine in liver, kidney and thymus, while no effect has been observed in spleen. Higher doses of MDP (5 mg and 10 mg) did not further increase the effect, but, on the contrary, in some tissues such as thymus, the effect was abolished. The repeated administration of 1 mg/kg of MDP for 7 days, contrary to single administration, had no effects. The measurement of proliferation activity in the experiment where DNA in the organs has been previously labeled with 3H-thymidine, has shown that the repeated administration of MDP (1 mg/kg) led to a more rapid decay in specific activity of DNA thymine in liver, kidney and thymus, but no effect was seen in spleen. The activities of thymidine kinase in the cytosole fraction of thymus and spleen after a single administration of MDP (1 mg/kg), are influenced in different ways. While in thymus the enzyme activity increased between 16 and 24 h, not being markedly changed in the early intervals, in spleen a significant decrease in phosphorylation of 14C-thymidine can be observed as early as 2 h after administration, and the decrease persists up to 48 h.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

Interleukin-1-induced sleep and febrile responses differentially altered by a muramyl dipeptide derivative.

Muramyl dipeptide (N-acetylmuramyl-L-alanyl-D-isoglutamine; AcMur-L-Ala-D-iGln; MDP) is a somnogenic, pyrogenic, and immunoadjuvant component of bacterial cell wall peptidoglycan. It enhances the production of the cytokine interleukin 1 (IL-1) in vivo and in vitro; IL-1 itself is somnogenic and pyrogenic. The pyrogenic effects of IL-1 may be separated from its somnogenicity by the use of antipyretics. A methyl ester derivative of MDP (murametide; AcMur-L-Ala-D-Gln-alpha-methyl ester) blocks IL-1-induced fever, but induces IL-1 production/release. Therefore, the effects of murametide on IL-1-induced sleep and fever responses were determined. Rabbits were pretreated with intravenous injections of murametide 0, 30 or 60 min before intravenous injection of a pyrogenic/somnogenic dose of recombinant IL-1 beta (rIL-1 beta). Murametide alone produced no effects on sleep or brain temperatures. Murametide given simultaneously with rIL-1 beta potentiated increases of brain temperatures, whereas when there was a 60 min delay between the injection of murametide and rIL-1 beta, responses were similar to those induced by rIL-1 beta alone. Murametide given 30 min before rIL-1 beta, blocked the expected IL-1-induced fevers but not the rIL-1 beta-mediated increases of slow-wave sleep and decreases of rapid-eye-movements sleep. These results reinforce the conclusion that, in part, independent brain mechanisms are involved in the somnogenic and pyrogenic actions of IL-1.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1989

The adjuvant effect of a muramyl dipeptide (MDP) analog on temperature-sensitive Salmonella mutant vaccine.

Adjuvant effect of a synthetic muramyl dipeptide analog, MDP-Lys (L18), MurNAc-L-Ala-D-glu[Lys(CO-(CH2)16-CH3)-OH]NH2 on a live Salmonella enteritidis vaccine, a temperature-sensitive mutant Ts-O strain that was obtained from the virulent S. enteritidis No.11 strain and could not grow at 37 degrees C, but could multiply at 25 degrees C as fast as the parent strain, was examined. Although the Ts-O organisms were avirulent and could hardly multiply in vivo when the organisms were injected into C57BL/6 mice and its mutant beige strain, which has a malfunction of phagocytic cells, injection of these mice with Ts-O endowed them with some protective immunity against infection by the virulent No.11 strain. When MDP-Lys(L18) was injected with Ts-O vaccine, the protection and the bactericidal capacity in the peritoneal cavities and spleens of these mice were augmented. MDP-Lys(L18) was still effective when it was injected at 48 h before or after the inoculation of Ts-O vaccine. Its effect was also observed against infection by the virulent S. cholerae-suis Hokkaido strain, a strain that does not share common O-antigenic determinants with the S. enteritidis No.11 or Ts-O strain. In addition, the mice that were inoculated simultaneously with Ts-O organisms and MDP-Lys(L18) were examined 10 days later for their footpad delayed type hypersensitivity reactions against Ts-O antigen. Mice inoculated with MDP-Lys(L18) and Ts-O showed augmented footpad swelling in comparison with the controls. These findings indicate that MDP-Lys(L18) is capable of augmenting the cellular immunity by live vaccine.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Effect of methyl esterification of isoglutamine residue in 6-O-acylated muramyl dipeptides on expression of immunopharmacological activities.

The effect of methyl esterification of the isoglutamine residue in 6-O-acylated muramyl dipeptide (MDP) on some biological activities was investigated. Methyl esterification influenced more or less the expression of all activities tested. The adjuvant and colony stimulating factor (CSF)-inducing activities of 6-O-acylated MDP analogs carrying a 3-hexadecanoyloxytetradecanoyl [C14-O-(C16)] group were stronger than those of the corresponding analogs carrying a 2-tetradecylhexadecanoyl (B30) group. Macrophage activation, i.e. induction of tumor necrosis factor (TNF) and promotion of phagocytosis, by 6-O-C14-O-(C16)-MDP methyl esters was weaker.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1991

Combined effects of synthetic lipid A analogs and muramyl dipeptide on antitumor activity against Meth A fibrosarcoma in mice.

Combined effects of chemically synthesized lipid A analogs, the compound A-171 (acylglucosamine-4-phosphate with (R)-3-hydroxytetradecanoyl and (R)-3-hydroxytetradecanoyloxy]tetradecanoyl group at the C-2 and C-3 positions), or the compound A-172 (with (R)-3-hydroxytetradecanoyloxy]tetradecanoyl and (R)-3-tetradecanoyloxytetradecanoyl group at the C-2 and C-3 positions), and muramyl dipeptide (MDP) on antitumor activity against Meth A fibrosarcoma, were examined. Meth A fibrosarcoma cells (5 X 10(5)) were inoculated intradermally into BALB/c mice on day 0, compound A-172 and/or MDP were administered intravenously (i.v.) on day 7. Although the antitumor activity by single i.v. injection of A-172 (50 micrograms/mouse) with MDP (10 micrograms) was weaker than that of 50 micrograms of synthetic lipid A analogs (506), or 10 micrograms of bacterial lipopolysaccharide (LPS) with MDP, A-172 alone and with MDP exhibited tumor inhibition rates of 49.0 and 70.6%, respectively. When A-171 (50 micrograms) with MDP (10 micrograms) was administered i.v. twice (days 7 and 10) into mice inoculated Meth A fibrosarcoma, two of five mice caused complete tumor regression. Furthermore, L929 cell lysis by the combination of A-171, A-172 with MDP was higher than that by the analogs or MDP alone, suggesting that the lipid A analogs of monosaccharide type as well as LPS are able to enhance the production of tumor necrosis factor in the presence of MDP.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Combined effects of synthetic lipid A analogs or bacterial lipopolysaccharide with glucosaminylmuramyl dipeptide on antitumor activity against Meth A fibrosarcoma in mice.

The combined effects of the synthetic glucosaminylmuramyl dipeptide (GMDP) on the antitumor activity of chemically synthesized lipid A analogs, compound A-103 (glucosamine-4-phosphate with (R)-3-tetradecanoyloxytetradecanoyl group at the C-2 and C-3 positions), Escherichia coli-type lipid A (506), Salmonella typhimurium LT-2 lipopolysaccharide (LPS) against Meth A fibrosarcoma in mice were examined. Meth A fibrosarcoma cells (5 x 10(5) were inoculated intradermally into BALB/c mice on day 0, and compound A-103 and/or GMDP was administered intravenously (i.v.) on days 7 and 9. Two i.v. injections of A-103 (50 micrograms) alone or GMDP (10 micrograms) alone induced 42.8 or 51.8% inhibition of the rate of tumor growth, however, A-103 (100 micrograms) with GMDP (10 micrograms) exhibited a high 68.7% inhibition rate 19 days after tumor inoculation. The inhibition of the tumor growth rate by the combination A-103 (100 micrograms) or 506 (50 micrograms) with GMDP (10 micrograms) was stronger than that of A-103 or 506 with MDP (10 micrograms). The combination of LPS (1 or 10 micrograms) with GMDP (10 micrograms) exhibited a higher inhibition rate than that of LPS with MDP, and three or four tumor-free mice out of five mice were observed, suggesting that the combined effect of GMDP is more potent than that of MDP. With the addition of GMDP, A-103 did not enhance the production of tumor necrosis factor (TNF) on the basis of L929 cell lysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1992

Muramyl dipeptide-induced changes in murine splenocyte responses to concanavalin A.

The effect of muramyl dipeptide (MDP) on Con A-stimulated activation of murine spleen cells was studied. MDP was found to enhance or suppress the proliferative response of splenocytes when different concentrations of Con A were used. MDP was shown to change the IL-2 content in culture supernatants of stimulated cells and to influence IL-2-dependent proliferation of Con A-blasts. A high degree of correlation was found between the proliferation of Con A-blasts and the expression of IL-2 receptors on Con A-blasts. This correlation, however, disappeared in the presence of MDP. The effects of MDP were shown to depend on the level of initial cell activity or rather on conditions leading to a given initial activity of cells.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMedDate not supplied

Improved intracellular delivery of a muramyl dipeptide analog by means of nanocapsules.

A lipophilic derivative of muramyl dipeptide, muramyl tripeptide cholesterol, was incorporated into poly(D,L-lactide) nanocapsules and its immunomodulating properties were assessed in vitro. The nanocapsule form was more effective than the free drug in activating rat alveolar macrophages for a cytostatic effect toward syngeneic tumor cells. Induction of NO synthase correlated with anti-proliferative activity. The time course of activation and the effect of inhibitors of endocytosis suggested that this increased efficiency was due to improved intracellular delivery by phagocytosis of nanocapsules. Such nanocapsules might be useful for immunotherapy of metastases resistant to conventional treatment, since they could overcome two problems associated with soluble muramyl peptides: rapid elimination and poor uptake by macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1995

Interferon-gamma/tumour necrosis factor-alpha synergism as a mechanism for enhanced nitric oxide production following in vivo administration of muramyl dipeptide (MDP) to mice.

The aim of the present study was to investigate the role of muramyl dipeptide (MDP) in triggering host non-specific defence mechanisms, namely its influence upon the L-arginine-dependent biotransformation pathways leading to formation of nitric oxide (NO). MDP was applied subcutaneously to mice as one or three daily injections, 300 micrograms MDP each. Production of NO by peritoneal macrophages from these animals or the capability of their splenocytes to render virgin macrophages for enhanced NO production was assayed. It has been found that macrophages from MDP-treated animals produce considerably enhanced amounts of NO and that the splenocytes secrete soluble factors providing all the signals required for induction of NO biosynthesis. Introduction of anti-IFN-gamma or anti-TNF-alpha antibodies into these splenocyte supernatants resulted in complete suppression of inducible NO production by macrophages.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1996

Further evidence on the interaction of muramyl dipeptide with the serotonergic system.

The mode of interaction between muramyl dipeptide (MDP), a compound with immunopharmacological activities, and 5-hydroxtryptamine (5-HT, serotonin) was studied in isolated nerve-smooth muscle preparations of the carp stomach. Application of exogenous 5-HT evoked direct smooth muscle contractions; electric neurogenic stimulation evoked twitches due to release of 5-HT from nerve endings. Contractions evoked by a high concentration of 5-HT (3-30 microM) were resistant to atropine and potentiated in the presence of MDP. Isamoltan (5-HTID antagonist) decreased the amplitude of contractions, whereas ketanserin (5-HT2 antagonist) and MDL 72,222 (5-HT3 antagonist) had no effect. The addition of low concentrations (0.1-1.5 microM) of 5-HT did not contract the preparation but caused a decrease in the amplitude of neurogenic twitches, which might be due to the presynaptic inhibition of serotonin release. This effect of 5-HT was not changed by isamoltan or ketanserin, but it was largely reduced in the presence of 5-HT3 antagonists tropisetron and MDL 72,222. This inhibitory effect of 5-HT on twitch amplitude was potentiated by MDP. The interaction of MDP with the serotonergic system thus involved not only potentiation of the postsynaptic effect of higher 5-HT concentrations, which might have been mediated via the 5-HT1 subsystem, but also presynaptic inhibition. MDP enhancement of 5-HT's inhibitory effect, mediated via 5-HT3 receptors, might represent a new feature in mutual 5-HT-MDP interactions.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMedDate not supplied

Muramyl dipeptide does not induce slow-wave sleep or fever in rats.

The synthetic muramyl dipeptide, N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP), is reported to increase slow-wave sleep and body temperature in cats, rabbits, and squirrel monkeys. The present study examined the ability of MDP to induce sleep and fever in rats. MDP was administered IP at 50, 250 and 500 micrograms/kg. Sleep and body temperature were monitored for 12 hr. MDP failed to affect the duration of wakefulness, S1, S2, or total (S1 + S2) slow-wave sleep. There was also no change in the latency to the first episode of S2 sleep. In contrast, rapid-eye-movement (REM) sleep was significantly suppressed for the first 6 hr after 250 and 500 microgram/kg doses of MDP. There was, however, a rebound increase in REM sleep after the initial period of suppression which resulted in no overall change in the amount of REM sleep. Body temperature was unaffected by MDP. Thus, we conclude that MDP has neither sleep-promoting nor pyrogenic actions in the rat when administered systemically at doses reported to be effective in several other species.

Acetylmuramyl-Alanyl-Isoglutamine↗