Effect of hydroxypropyl beta cyclodextrin complexation on aqueous solubility, stability, and corneal permeation of acyl ester prodrugs of ganciclovir

In this study, we have examined a number of parameters which affect the rate of sterol desorption from a model membrane surface (a monolayer at the air/water interface) to cyclodextrins (CD) in the aqueous subphase. The desorption experiments were carried out at a constant lateral surface pressure with a zero-order trough, which allowed for a determination of desorption rates which were unaffected by monolayer substrate concentration. At a surface pressure of 20 mN/m (30 degrees C), 0.9 mM beta-CD caused a desorption of about 13 pmol of cholesterol per minute and square centimeter of monolayer area. The desorption of cholesterol proceeded linearly as a time function and was sensitive to the concentration of beta-CD in the subphase. The rate of cholesterol desorption increased as the monolayer surface pressure increased (3->35 mN/m) but decreased slightly with increasing temperature (15->30 degrees C). The rate of sterol desorption appeared to be influenced by the relative polarity of the sterols. Oxidized sterols desorbed significantly faster than cholesterol (e.g., 4-cholesten-3-one desorbed 8.4-fold faster than cholesterol), whereas less polar sterols desorbed at slower rates [e.g., 20(R)-isoheptyl-5-pregnen-3 beta-ol, a cholesterol analogue with a ten-carbon branched side chain, desorbed at 1/10 of the rate of cholesterol]. Cholesterol desorption from a monolayer membrane containing both cholesterol and a phospholipid was much slower than from a pure cholesterol monolayer. When the effect of dipalmitoylphosphatidylcholine and N-palmitoylsphingomyelin on cholesterol desorption rate was compared, it was found that cholesterol desorption was much more retarded from sphingomyelin monolayers as compared to that from phosphatidylcholine monolayers. Taken together, the results of this study show that the beta-CD-enhanced desorption of cholesterol (and other sterols) from monolayer membranes is influenced by the polarity of the desorbing molecules, as well as by lipid/lipid interactions in the membranes. Since beta-CD has no surface activity of its own, it appears to be a useful, nonintrusive catalyzer of cholesterol desorption and is expected to become a valuable probe in membrane and cell research.

The antiherpetic effects of a novel purine acyclic nucleoside, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), were compared with those of acyclovir in cell cultures and in mice. The modes of action of DHPG and acyclovir were similar in that herpes thymidine kinase phosphorylated each compound, and both agents selectively inhibited viral over host cell DNA synthesis. In 50% plaque reduction assays in Vero cells, the drugs inhibited herpes simplex virus types 1 and 2 thymidine kinase-positive strains at 0.2 to 2.4 microM. DHPG was markedly more active than acyclovir against human cytomegalovirus (50% inhibitory doses were 7 and 95 microM, respectively). Each nucleoside inhibited uninfected cell macromolecule synthesis and cell proliferation at concentrations far above those required to inhibit herpes simplex virus replication. Although the two compounds had many similarities in their behavior in vitro, the important difference was the superior performance of DHPG against herpesvirus-induced encephalitis and vaginitis in vivo. Thus, mortality in mice infected with herpesvirus type 2 was reduced 50% by daily doses of 7 to 10 mg of DHPG/kg, whereas an equally effective daily dose of acyclovir was approximately 500 mg/kg. DHPG at a daily dose of 50 mg/kg was also superior to acyclovir at 100 mg/kg per day in its inhibition of herpetic vaginal lesions in mice.

In the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease. We conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo. The study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent). In persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease.