Semisynthetic modifications of hemiaminal function at ornithine unit of mulundocandin, towards chemical stability and antifungal activity.

Mulundocandin (1), is an echinocandin class of lipopeptide. It has wide spectrum of antifungal activity against Candida and Aspergillus species. Semisynthetic modification at Ornithine-5-hydroxyl (hemiaminal function) of 1 was carried out to improve solution stability and hence in vivo activity. Synthesis of ether (C-OR), thioether (C-SR) and C-N linkage at hemiaminal function have been described. All synthetic analogues were evaluated for their stability in aqueous solution and found to be more stable than mulundocandin. Antifungal activity of Orn-5 analogues was evaluated both in vitro against Candida albicans and Aspergillus fumigatus by agar well method and in vivo (oral and intraperitoneal) in C. albicans infected Swiss mice. Results of in vivo assays of analogues 2-9 by the oral route suggests that the introduction of either oxygen nucleophiles (-OR) or sulphur nucleophiles (-SR), at either Orn-5 or at both Orn-5 and HTyr-4 positions, results in retaining the activity of the parent compound with improved aqueous stability in most cases. Compound 9 has shown improved antifungal activity in comparison to mulundocandin by oral application in Swiss mice.

Methylsulfomycin I, a new cyclic peptide antibiotic from a Streptomyces sp. HIL Y-9420704.

Methylsulfomycin I (1) is a new cyclic peptide antibiotic isolated from the fermentation broth of a Streptomyces sp. HIL Y-9420704. Its structure was elucidated by NMR and GC-MS. The in vitro activity (MIC) against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-, and teicoplanin-resistant strains, is described.

Mathemycin B, a new antifungal macrolactone from actinomycete species HIL Y-8620959.

A new macrocyclic lactone antibiotic mathemycin B (1) was isolated from the fermentation broth of an Actinomycete sp. culture Y-8620959. The structure of 1 was elucidated by high-resolution MS and interpretation of 2D NMR results. Mathemycin B is active against a variety of phytopathogenic organisms.

Balhimycin, a new glycopeptide antibiotic produced by Amycolatopsis sp. Y-86,21022. Taxonomy, production, isolation and biological activity.

A new glycopeptide antibiotic, balhimycin, has been isolated from the fermentation broth of a Amycolatopsis sp. Y-86,21022. Balhimycin belongs to the vancomycin class of glycopeptides and contains a dehydrovancosamine sugar. The biological activity of balhimycin has been compared extensively with that of vancomycin against methicillin resistant staphylococci and also against anaerobes. Balhimycin is marginally superior to vancomycin in its in vitro activity against anaerobes and in its bactericidal properties.

Controlled delivery of pilocarpine. 1. In vitro characterization of Gelfoam matrices.

The potential of Gelfoam absorbable gelatin sponge as a carrier for ophthalmic delivery of pilocarpine was examined. Prolonged in vitro release of pilocarpine was achieved through pharmaceutical modification of the device by embedding a retardant in the pores. The device embedded with cetyl ester wax released pilocarpine in a zero-order pattern (release exponent = 0.93 +/- 0.04) for up to 5 hr. This result corresponded well with a linear penetrant uptake by this device. The device impregnated with polyethylene glycol 400 monostearate exhibited anomalous drug transport with a release exponent of 0.63 +/- 0.02. The absorption of water by this retardant and the formation of a gel layer on the surface slowed the penetration of the release medium into the deeper sections of the matrix, as well as the rapid outward diffusion of drug, resulting in a prolonged release of pilocarpine.

Evaluation of a total T3 assay on the Stratus fluorometric enzyme immunoassay system.

The Stratus total triiodothyronine (T3) immunoassay is an automated fluorometric enzyme immunoassay that utilizes a mouse monoclonal anti-T3 antibody preimmobilized onto glass fiber paper. The rate of formation of the enzyme product, as measured by front surface fluorometry, is inversely proportional to Total T3 concentration in the sample. The authors evaluated this method with respect to precision, sensitivity, interfering factors, and correlation with a radioimmunoassay. The overall, between-run, and within-run precision of the assay measured at three concentration levels for a total of 60 determinations each using immunoassay control materials, ranged from 2.5% to 14.3%. A total of 200 specimens, including 40 classified as hyperthyroid, and 38 classified as hypothyroid were analyzed in duplicate by the Stratus (STR) system and by a commercially available radioimmunoassay method. The coefficient of correlation obtained was 0.97. Icteric, hemolyzed, azotemic, and lipemic samples were included in the comparison and do not appear to have any interfering effect on the assay. The range of the assay is from 0.8 to 12 nmol/L. In summary, the Stratus Total T3 immunoassay offers the advantages of sensitivity, specificity, and automation with a throughput rate of 45 samples/h.

Effects of perfluorochemical emulsion components on human albumin binding of warfarin.

Warfarin binding by human albumin (HSA) is altered in the presence of a perfluorochemical (PFC) emulsion. To determine which PFC emulsion component(s) was responsible for these changes, the effects of the components on this interaction were determined. Fluorescence titrations and ultrafiltration were used to monitor the effects of the components on HSA binding of 2 and 10 micrograms/ml warfarin at room temperature. Component concentrations ranged up to that present in the emulsion except for yolk phospholipids which have limited buffer solubility. For solubility reasons, oleic acid and phospholipids were studied in the presence of pluronic F-68. At 0.5% HSA pluronic F-68 caused a significant displacement of bound warfarin, while glycerol had little effect on warfarin binding. At concentrations of 20% of that in the PFC emulsion oleic acid with pluronic F-68 caused a significant increase in warfarin binding. This was followed by a very large displacement of bound warfarin at the emulsion concentrations of oleic acid and pluronic F-68. The phospholipid component had no specific effect on warfarin binding. A combination of the 4 components had an effect very similar to that of only oleic acid with pluronic F-68. At 2% HSA the combined components caused an increase in warfarin binding while at 4% HSA the combined components had little, if any, effect on warfarin binding. Thus, changes in HSA binding of warfarin in the presence of a PFC emulsion can be attributed to the oleic acid and, to a smaller degree, pluronic F-68 components of the emulsion.

Stereochemistry of the epoxydon group antibiotic G7063-2 isolated from a Streptomyces species HPL Y-25711.

The absolute configuration of the ring system of the antibiotic G7063-2 has been established as being the same as that reported for terreic acid, based on circular dichroism data. During structure elucidation experiments, reaction with ethereal diazomethane gave an adduct whose structure is proposed.