Enhanced rectal absorption of amphotericin B lyophilized with glycyrrhizinate in rabbits.

The influence of bases and additives in the formulation for rectal absorption of amphotericin B (AMB) lyophilized with dipotassium glycyrrhizinate (GLYK) was investigated using rabbits in relation to an in vitro release test. The release of AMB from the fatty base of Witepsol or a medium chain triglyceride (MCT) was markedly faster than that from the hydrophilic base of macrogol. The addition of polyoxyethylene (2) lauryl ether (POE(2)LE) into the fatty bases led to a marked increase in the release rate, whereas POE(9)LE or sodium lauryl sulfate resulted in a significantly lower release rate. Animals received rectally each of seven AMB formulations of Witepsol H-15, macrogol, MCT with surfactants and aqueous solution. The absorption of the AMB lyophilized mixture with GLYK at a 1:9 molar ratio from a MCT base was significantly superior to that from macrogol. The addition of POE(2)LE into the MCT base resulted in a marked increase in bioavailability, showing the highest bioavailability of 4.9%. High serum levels of over 100 ng/ml of serum were maintained for 24 h following administration. The lowest bioavailability was 0.32% for the macrogol suppository. There was a good correlation between the release rate of AMB from the formulations and bioavailability. These results suggest that an AMB rectal formulation may provide a promising therapeutic alternative to infusion, taking into account the serum level of AMB exceeding the minimal inhibitory concentration of the infecting organism.

Effect of glycyrrhizinate on dissolution behavior and rectal absorption of amphotericin B in rabbits.

The effects of dipotassium glycyrrhizinate (GLYK) on the dissolution behavior and bioavailability of amphotericin B (AMB) were investigated. The mixtures of AMB and GLYK were prepared at different molar ratios by lyophilization. Lyophilization resulted in amorphous AMB either alone or in the mixture. Dissolution rates of AMB of the mixtures were markedly faster than that of lyophilized AMB alone, which was followed by a decrease of dissolution. The initially-enhanced dissolution rate was likely to be due to the improvement of surface wettability of drug particles with GLYK rather than the amorphous state of AMB. A phase solubility study of AMB with GLYK indicated that the increasing solubility was caused by micellar solubilization. The in vitro release rate of AMB from suppositories containing the lyophilized mixtures was significantly accelerated by increasing the amount of GLYK. The rectal absorption of AMB from suppositories containing either the drug alone, a physical mixture or a lyophilized mixture was studied using rabbits. The absorption of the mixture (AMB/GLYK = 1/9) was about 35 times greater in the area under the serum concentration-time curve (0-24 h) than that of lyophilized AMB alone. These results suggest that GLYK is useful for improving the dissolution property of AMB and the bioavailability of the drug incorporated in suppositories.

[Echocardiographic and endomyocardial biopsy findings of right-sided hypertrophic obstructive cardiomyopathy].

Echocardiographic and histological studies were performed for four patients with hypertrophic cardiomyopathy (HCM) with right-sided obstruction (group A) and for five HCM patients without right-sided obstruction (group B). The clinical diagnosis of HCM was established by cardiac catheterization and right and left ventriculography for all nine patients, and confirmed by necropsy in one patient in group A. M-mode and cross-sectional echocardiography were performed in all. Endomyocardial biopsy of the right ventricular septum was performed for all four patients in group A and for three patients in group B. M-mode echocardiography demonstrated no characteristic features suggesting right intraventricular obstruction, but cross-sectional echocardiograms, especially with short-axis views, reliably indicated conspicuous rightward septal protrusions in right-sided obstructive HCM. Histological changes in the right ventricular septum consisting of fibrosis of the interstitium and disarray of myocardial fibers were more striking in patients with HCM with right-sided obstruction than those without such obstruction.