nystatin-a1 and Leukopenia

A comprehensive comparative analysis of the structure-antifungal activity relationships for the series of biosynthetically engineered nystatin analogues and their novel semisynthetic derivatives, as well as amphotericin B (AMB) and its semisynthetic derivatives, was performed. The data obtained revealed the significant influence of the structure of the C-7 to C-10 polyol region on the antifungal activity of these polyene antibiotics. Comparison of positions of hydroxyl groups in the antibiotics and in vitro antifungal activity data showed that the most active are the compounds in which hydroxyl groups are in positions C-8 and C-9 or positions C-7 and C-10. Antibiotics with OH groups at both C-7 and C-9 had the lowest activity. The replacement of the C-16 carboxyl with methyl group did not significantly affect the in vitro antifungal activity of antibiotics without modifications at the amino group of mycosamine. In contrast, the activity of the N-modified derivatives was modulated both by the presence of CH3 or COOH group in the position C-16 and by the structure of the modifying substituent. The most active compounds were tested in vivo to determine the maximum tolerated doses and antifungal activity on the model of candidosis sepsis in leukopenic mice (cyclophosphamide-induced). Study of our library of semisynthetic polyene antibiotics led to the discovery of compounds, namely, N-(L-lysyl)-BSG005 (compound 3n) and, especially, L-glutamate of 2-(N,N-dimethylamino)ethyl amide of S44HP (compound 2j), with high antifungal activity that were comparable in in vitro and in vivo tests to AMB and that have better toxicological properties.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Cyclophosphamide; Drug Evaluation, Preclinical; Leukopenia; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Nystatin; Polyenes; Sepsis; Small Molecule Libraries; Structure-Activity Relationship

In the present study, we have evaluated prophylactic role of various immunomodulators viz. lipopolysachharide, protein A and tuftsin to impart protection against experimental candidiasis in leukopenic mice. Both free as well as liposomised form of nystatin was not effective enough in offering complete cure against less susceptible isolate of Candida albicans (JNMCR) infection in immunodebilitant mice. Interestingly, the pretreatment of leukopenic mice with immunomodulators before challenging them with C. albicans increased therapeutic efficacy of the nystatin against systemic candidiasis. Efficacy of the treatment was evaluated on the basis of survival of the animals as well as fungal load in systemic circulation and various organs viz. liver, kidney, spleen and lungs of the treated animals.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida albicans; Candidiasis; Drug Compounding; Drug Resistance, Fungal; Female; Immunologic Factors; Intercalating Agents; Kidney; Leukopenia; Lipopolysaccharides; Liposomes; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Nystatin; Staphylococcal Protein A; Tuftsin

Infections of children with malignant disease, especially of the lympho-reticular system, are characterized by their severity, with a high mortality, as a consequence of defective immunocompetence. According to the immunosurveillance theory, temporary immune defects could have even facilitated the malignant growth. The neoplastic disease itself contributes to the immunodeficiency by multiple mechanisms. The powerful cytostatic-cytocidal drugs reduce the immune response also, especially in the phases of bone marrow depression. Granulocytopenia shows the most significant correlation with the incidence of serious infections. The different forms of hospital infections have been reviewed and classified as 1. bacterial, fungal and, rarely, (but most dangerous) protozoal infections, 2. endogenous infections with the patient's own anaerobic intestinal flora and 3. viral infections. The perspectives of up-to-date chemotherapy and management of the immunodeficiency e.g. with leucocyte transfusions, and attempts to prevent infection are discussed.

Topics: Amphotericin B; Antineoplastic Agents; Bacterial Infections; Blood Transfusion; Child; Communicable Diseases; Cross Infection; Humans; Immunologic Surveillance; Immunosuppression Therapy; Leukocytes; Leukopenia; Miconazole; Mycoplasma Infections; Mycoses; Neoplasms; Nutrition Disorders; Nystatin; Patient Isolation; Protozoan Infections; Tetracyclines; Virus Diseases

Topics: Aged; Anemia; Anti-Bacterial Agents; Blood Cell Count; Blood Cells; Blood Chemical Analysis; Blood Transfusion; Bone Marrow Cells; Bone Marrow Examination; Chromosome Aberrations; Female; Humans; Karyotyping; Leukopenia; Middle Aged; Nystatin; Pneumonia; Prednisone; Primary Myelofibrosis; Splenectomy; Thrombocytopenia