Leishmania donovani in hamsters: stimulation of non-specific resistance by novel lipopeptides and their effect in antileishmanial therapy.

Several novel type of lipopeptides were synthesized and evaluated for their ability to stimulate non-specific resistance against Leishmania donovani infection. Peritoneal macrophages isolated from young male hamsters treated with muramyl dipeptide (MDP) and various synthetic lipopeptides (6 mg/kg i.p.) 7 days earlier, were cultured in vitro and challenged 24 h later with L. donovani promastigotes. One lipopeptide, Central Drug Research Institute (CDRI) compound 86/450, exhibited significantly higher immunostimulatory activity than MDP. Its prophylactic activity was further confirmed in hamsters by giving 2 split doses of 3 mg/kg of the compound spaced at 2 weeks, i.e. on day -7 and +7 of challenge with L. donovani amastigotes. The prophylactic effect lasted for 7 days following the last treatment with compound 86/450. The antileishmanial action of sodium stibogluconate (SAG) was also found to be enhanced by 16% in hamsters primed with compound 86/450.

Immunostimulant activity of a novel lipopeptide and its protective action against Leishmania donovani.

Novel lipopeptides 84/201 and 86/450 synthesized in this laboratory stimulated antibody and delayed type hypersensitivity (DTH) response to ovalbumin in guinea pigs. Lipopeptide 86/450 also stimulated antibody and DTH responses in albino mice and enhanced nonspecifically macrophage migration index (MMI), phagocytic activity and incorporation of [14C] glucosamine in peritoneal macrophages of the treated animals. Proliferative response of splenocytes from lipopeptide 86/450 treated animals was significantly higher than that from untreated controls. Peritoneal macrophages from lipopeptide 86/450 treated mice were less susceptible to Leishmania donovani promastigote invasion when co-cultured in vitro. The treated animals on challenge with L. donovani promastigote/amastigote showed 80 to 90% lower intake of infection than the control animals.

Leishmania donovani in hamsters: stimulation of non-specific resistance by some novel glycopeptides and impact on therapeutic efficacy.

Several glycopeptides structurally related to muramyl dipeptide (MDP) have been synthesized and evaluated for their ability to stimulate the non-specific resistance of hamsters against L. donovani infection. These compounds have been named CDRI compounds. The synthetic procedure used for compounds 86/448 and 84/212 is described. MDP and its synthetic congeners were administered as immunostimulants at a prophylactic dose of 3 mg/kg at two weeks interval. The challenge infection (1 x 10(7) amastigotes i.c./hamster) was given in between two doses of the compounds. One of the glycopeptides, CDRI comp. 86/448, has been found to be significantly more potent than MDP, effecting 92% inhibition of the challenge dose, whereas MDP produced only 26.5% inhibition. The effect of comp. 86/448 lasted until day 7 of challenge. The efficacy of sodium stibogluconate was appreciably improved in hamsters treated with comp. 86/448.

Adjuvant activity of some nonpyrogenic hydrophobic analogues of muramyl dipeptide in enhancing the primary humoral and cell mediated immune responses in guinea pig model.

Five muramyl dipeptide analogues synthesized by derivatization of gamma-carboxyl of D-isoglutamine residue of MDP into alkyl amides or incorporation of lysine residue at the site via epsilon-NH2 function were evaluated for immuno-adjuvant activity. Derivatization of gamma-carboxyl of D-isoglutamine into butyl, octyl and dibutyl residues stimulated delayed type of hypersensitivity (DTH) response, the maximum stimulation being observed with octyl amide. Introduction of lauryl amide residue abolished DTH response. The antibody response was impaired with all the alkyl amide analogues except for the lysyl amide derivative with which the response was higher than MDP. Correlation was observed between DTH response and macrophage migration.