New chitosan derivatives for the preparation of rokitamycin loaded microspheres designed for ocular or nasal administration.

Acanthamoeba spp. are the causative agents of granulomatous amoebic encephalitis (GAE) and amoebic keratitis. Recent studies performed by Rassu et al. showed that, compared with the free drug, the loading of rokitamycin in chitosan microspheres improves and prolongs the in vitro antiamoebic activity of rokitamycin. This could be useful in transporting the drug for either ocular application to treat amoebic keratitis or nasal administration as an alternative route for the administration of the drug to the brain in GAE therapy. Starting from the previous study, our goal was to optimize the technological parameters in order to obtain chitosan microparticles loaded with rokitamycin and to evaluate the use of new quaternary ammonium chitosan derivatives in the preparation of spray dried microspheres containing the macrolide; these derivatives showed better characteristics (solubility, penetration enhancement) compared with chitosan itself. Toxicity studies on new polymers were performed. Spray dried loaded microspheres based on chitosan or chitosan derivatives were obtained by using appropriate preparative parameters. Microparticles containing chitosan derivatives showed similar or often better properties than formulations made of chitosan with respect to size, in vitro release behaviour and mucoadhesiveness thus making them more suitable for ocular or nasal administration. New polymers did not demonstrate cytotoxicity.

Design and synthesis of novel leucomycin analogues modified at the C-3 position. Part II: 3-O-(3-Aryl-2-propenyl)leucomycin analogues.

The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate (5), appropriate modifications including Heck reaction were performed to furnish 3-O-(3-aryl-2-propenyl)leucomycin A(7) analogues (9a-9m). These leucomycin A(7) derivatives showed improved in vitro antibacterial activities against clinically important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at the C-3 and C-3'' positions suggested that single modification at C-3 or C-3'' was effective for in vitro antibacterial activity.

Novel 16-membered macrolides modified at C-12 and C-13 positions of midecamycin A1 and miokamycin. Part 1: Synthesis and evaluation of 12,13-carbamate and 12-arylalkylamino-13-hydroxy analogues.

Design and synthesis of 16-membered macrolides modified at the C-12 and 13 positions are described. The compounds we report here have an arylalkylamino group attached to the C-12 position of the macrolactone. Both types of derivatives, 12,13-cyclic carbamates and non-carbamate analogues, were synthesized via 12-amino-13-hydroxy intermediates derived from 12,13-epoxide that was prepared by selective epoxidation at the C-12 and C-13 positions. 4'-Hydroxyl analogues were also prepared by acidic hydrolysis of a neutral sugar. These compounds were evaluated for in vitro antibacterial activity against respiratory tract pathogens. Some of these analogues exhibited an improved activity compared with the corresponding parent compound.

The post-antibiotic effects of rokitamycin (a 16-membered ring macrolide) on susceptible and erythromycin-resistant strains of Streptococcus pyogenes.

The post-antibiotic effects (PAEs) on susceptible and erythromycin-resistant strains of Streptococcus pyogenes (M phenotype and inducibly resistant) of rokitamycin and erythromycin were investigated in vitro using microbiological impedance measurement. Exposure of susceptible S. pyogenes strains to 1/4, 1/2, 1 and 2 MIC erythromycin and rokitamycin resulted in PAEs of rokitamycin in the same order of magnitude as those of erythromycin and that were dose dependent. The duration of rokitamycin PAEs in erythromycin-resistant S. pyogenes strains (M phenotype and those with inducible resistance) were comparable with those observed in susceptible strains. This was not the case for erythromycin. The investigation showed that a 16-membered ring macrolide such as rokitamycin has different PAEs from those of a 14-membered ring macrolide such as erythromycin. They also indicated that, as the PAEs of rokitamycin on the M phenotype and inducible resistant strains were comparable with those on susceptible strains, no re-evaluation of therapeutic dosing regimens was required.

Rokitamycin: bacterial resistance to a 16-membered ring macrolide differs from that to 14- and 15-membered ring macrolides.

Rokitamycin is the latest semi-synthetic 16-membered ring macrolide introduced into clinical practice. It is characterized by greater hydrophobicity, better bacterial uptake and a slower release, more cohesive ribosomal binding, and a longer post-antibiotic-effect (PAE) than can be observed with other available 14-, 15- and 16-membered ring macrolides. Rokitamycin exerts its activity on strains that harbor inducible erm genes or the efflux gene, mef(A). It has also been reported to be more active in vitro than other 16-membered ring macrolides. However, these recognized features are not fully exploited yet because current automated test procedures used in many microbiological laboratories determine susceptibility only to erythromycin or clarithromycin. Resistance to 16-membered ring macrolides cannot be predicted solely on the basis of known resistance to erythromycin or clarithromycin as revealed by an automated susceptibility assay. At least equally important is the knowledge of the bacterial resistance phenotype. This is underlined by the existence of Gram-positive coccal strains resistant to erythromycin and other 14-,15-membered ring macrolides but susceptible to 16-membered ring macrolides. Since the local prevalence of erythromycin phenotypes is generally unknown but might determine the outcome of treatment, the procedure for identifying the phenotypes in erythromycin-resistant strains (which can be easily and cheaply performed using the two- or three-disk assay) should become routine, at least in the countries in which 16-membered ring macrolides are used. This approach should help to optimize the use of macrolides, improve our knowledge of the local prevalence of phenotypes resistant to erythromycin, and offer the possibility of treating infections caused by certain types of erythromycin-resistant pathogens.

Sensitive determination of josamycin and rokitamycin in plasma by high-performance liquid chromatography with fluorescence detection.

Rokitamycin and josamycin were successfully derivatized with dansylhydrazine in 20 min at 60 degrees C. Rokitamycin and josamycin levels were determined in plasma after ion-pair extraction into hexane-isoamyl alcohol with lauryl sulphate and precolumn derivatization. Resolution was obtained by liquid chromatography with fluorescence detection (352/537 nm) in 12 min. The limit of detection was 20 ng/ml macrolide starting from 1 ml of plasma, and linearity was demonstrated between 50 and 400 ng/ml. Inter-run coefficients of variation were 10.2% at 100 ng/ml and 9.1% at 300 ng/ml. The system was reliably used for pharmacokinetic studies in plasma.

Antibióticos macrolídicos - retorno à vista? / Macrolide antibiotics, a return in sight?

O autor apresenta as perspectivas de progressos, no campo da terapêutica antimicrobiana, representadas pelo aparecimento de novos antibióticos macrolídicos com propriedades que os diferenciam, e muitas vezes os tornam mais atraentes, relativamente aos membros mais antigos da família. Compara esses novos antibióticos com a eritromicina, destacando as diferenças de propriedades farmacocinéticas e de espectro antimicrobiano. Por fim, apresenta as indicaçöes terapêuticas especiais que esses medicamentos poderäo vir a ter