ABSTRACT
A novel non-pyrogenic carbocyclic muramyl dipeptide (MDP) analogue, N-¿trans-2-[[2'-(acetylamino)cyclohexyl]oxy]acetyl¿-L-alanyl-D-glutamic acid, was obtained by replacement of the N-acetylmuramic acid part and the D-isoglutamine residue of the MDP molecule by a trans-2-[[2'-(acetylamino)cyclohexyl]oxy]acetyl moiety and D-glutamic acid, respectively. The title compound was selected as a promising candidate for further evaluation among several related analogues on the basis of an immunorestoration test in mice. This novel nor-MDP analogue protects mice against the immunosuppressive effect of cyclophosphamide and increases the nonspecific resistance of mice against fungal infection. It is an immunomodulator which enhances the maturation of lymphocytes B to plasma cells and increases the activity of lymphocytes B and lymphocytes T as well as that of macrophages but does not alter the number of these cells.
Subject(s)
Acetylmuramyl-Alanyl-Isoglutamine/analogs & derivatives , Acetylmuramyl-Alanyl-Isoglutamine/chemical synthesis , Adjuvants, Immunologic/chemical synthesis , B-Lymphocytes/immunology , Macrophages/immunology , Plasma Cells/immunology , T-Lymphocytes/immunology , Acetylmuramyl-Alanyl-Isoglutamine/chemistry , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/pharmacology , Animals , B-Lymphocytes/cytology , B-Lymphocytes/drug effects , Cyclophosphamide/toxicity , Female , Immune Tolerance/drug effects , Immunosuppressive Agents/toxicity , Indicators and Reagents , Lymphocyte Activation/drug effects , Macrophages/drug effects , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Plasma Cells/drug effects , Spleen/immunology , Stereoisomerism , T-Lymphocytes/drug effectsABSTRACT
The synthesis and some immunological characteristics of a new desmuramyl dipeptide 7-oxooctanoyl-L-alanyl-D-isoglutamine (LK-409) are presented. The effects of this compound were compared with those of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). The influence of LK-409 on the number of B and T cells in spleen and the number of peritoneal macrophages was studied; Jerne's plaque forming cells assay was performed to monitor the effect of B cell differentiation. The blast transformation of T cells stimulated with concanavalin A was used to detect the influences on T lymphocytes. The activation of macrophages was studied as well. In contrast to MDP, LK-409 was apyrogenic in the doses applied but had similar immunomodulatory properties. Tested immunological properties and the absence of pyrogenicity and low toxicity make LK-409 a candidate for an immunomodulatory drug and a model molecule suitable for studying and understanding the dual activity of the MDP and its analogues.
Subject(s)
Adjuvants, Immunologic/pharmacology , B-Lymphocytes/drug effects , Dipeptides/pharmacology , Macrophages, Peritoneal/drug effects , T-Lymphocytes/drug effects , Acetylmuramyl-Alanyl-Isoglutamine/immunology , Acetylmuramyl-Alanyl-Isoglutamine/pharmacology , Animals , B-Lymphocytes/immunology , Cell Count/drug effects , Dipeptides/chemical synthesis , Dipeptides/immunology , Female , Hemolytic Plaque Technique , Lymphocyte Activation/drug effects , Macrophages, Peritoneal/immunology , Mice , Pyrogens , Spleen/cytology , Spleen/drug effects , Superoxides/metabolism , T-Lymphocytes/immunologyABSTRACT
The effect of food and metoclopramide on the pharmacokinetics of bromocriptine was investigated in 7 healthy subjects. Plasma concentrations of bromocriptine were measured by radioimmunoassay after a single oral dose of 7.5 mg bromocriptine. Maximal plasma concentrations of bromocriptine were slightly lower when the drug was given after breakfast. Bioavailability of the drug was not significantly reduced by food nor by metoclopramide pre-treatment. Side effects of bromocriptine were considerably reduced by metoclopramide pre-treatment (0.5 mg/kg); the decrease was about 83% as estimated from Table II.
