Miocamycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Miocamycin is an orally administered 16-membered macrolide antimicrobial drug. It has a spectrum of in vitro activity similar to that of erythromycin, inhibiting a range of Gram-positive and Gram-negative organisms, atypical microbes and some anaerobes. Importantly, miocamycin demonstrates greater in vitro potency than erythromycin against several pathogens including Legionella pneumophila, Mycoplasma hominis, and Ureaplasma urealyticum. Equally noteworthy is its activity against erythromycin-resistant staphylococcal and streptococcal species expressing inducible-type resistance. Miocamycin possesses poor overall activity against Haemophilus influenzae and is inactive against Enterobacteriaceae. Penetration of miocamycin into body tissues and fluids is both rapid and extensive. The 3 major metabolites of miocamycin possess antimicrobial activity and may contribute to the therapeutic efficacy of the drug. Clinical data indicate that miocamycin is useful in the treatment of upper and lower respiratory tract infections in both adult and paediatric patients. Miocamycin is also effective in the treatment of urogenital tract infections caused by Chlamydia trachomatis or U. urealyticum. Several studies suggest that miocamycin is at least as effective as erythromycin in these indications; however, comparisons with newer macrolide agents have yet to be performed. In other studies, miocamycin proved to be a useful agent in the treatment of periodontal infections and as anti-infective prophylaxis in dental surgery. Miocamycin appears to have a tolerability profile qualitatively similar to that of other macrolides, with gastrointestinal and skin disorders being the most commonly reported adverse events. Current data suggest that the potential for drug interactions with miocamycin is low, with the possible exceptions of carbamazepine and cyclosporin. Thus, although further confirmation and elaboration of various aspects of its efficacy and tolerability profile is needed, at this stage miocamycin offers a useful alternative oral therapy to erythromycin for the treatment of uncomplicated community-acquired respiratory tract infections and nongonococcal urethritis.

High uptake of RSU 1069 and its analogues melanotic melanomas.

RSU 1069 and RSU 1164 are electron affinic agents that contain a nitro group together with a weakly basic alkylating aziridine moiety, and they represent lead compounds in the development of dual-function, bioreductive, hypoxic cell radiosensitizers. We studied the pharmacokinetics of these drugs in mice carrying KHT sarcoma. Lewis lung carcinoma, and B16 melanoma. Following an i.p. dose of 80 mg/kg, absorption was rapid and the elimination t1/2 was in the region of 30 min for both agents. Maximal tumour levels were 91, 16 and 19 microgram/ml for RSU 1069 and 109, 26 and 28 microgram/ml for RSU 1164 in. the B16, KHT and Lewis lung tumours, respectively. In B16 melanoma these levels corresponded to tumour:plasma ratios of 3.8 for RSU 1069 and 3.7 for RSU 1164. Cellular uptake of RSU 1069, RSU 1164 and a related compound, RB 7040, was measured in vitro as a function of extracellular pH. Melanotic cells from both B16 melanoma and HX118, a human tumour xenograft, showed substantially greater accumulation of these weakly basic sensitizers than any other cell type examined. Ratios of intra-:extracellular concentration (Ci/Ce) for RSU 1069 were around unity and independent of pH for Lewis lung cells and HX34 amelanotic melanoma cells, whereas ratios of up to 3 and 5 were obtained in B16 and HX118 cells, respectively. The highest measured value of Ci/Ce was 15 for RSU 1164 in HX118 cells at pH 8.4; this compares with a ratio of 1.5 for HX34 cells at the same pH. These studies indicate that the high levels of uptake of the weakly basic sensitizers into melanotic melanoma in vivo is a cell-mediated phenomenon and may be due to a lower average intracellular pH in the melanotic cells.