Potassium channel conductance: a mechanism affecting hair growth both in vitro and in vivo.

The opening of intracellular potassium channels has been suggested as a mechanism regulating hair growth. Enhancing the flux of potassium ions is a mechanism shared by several structurally diverse antihypertensive agents including minoxidil sulfate (the active metabolite of minoxidil), pinacidil, P-1075 (a potent pinacidil analog), RP-49,356, diazoxide, cromakalim, and nicorandil. Of these drugs, minoxidil, pinacidil, and diazoxide have been reported to elicit hypertrichosis in humans. This potassium channel hypothesis was examined by testing these drugs for effects on hair growth both in vitro and in vivo. For the in vitro studies, mouse vibrissae follicles were cultured for 3 d with drug and the effects on hair growth were measured by metabolic labeling. All drugs, except diazoxide, enhanced cysteine incorporation into the hair shafts of the cultured vibrissae. Diazoxide was poorly soluble and thus was tested only at low doses. Minoxidil, P-1075, cromakalim, and RP-49,356 were also evaluated in vivo by measuring hair growth effects in balding stumptail macaque monkeys. The drugs were administered topically to defined sites on balding scalps once per day for 4-5 months and the amount of hair grown was determined by monthly measurements of shaved hair weight. Three of the drugs produced significant increases in hair weight whereas, the RP-49,356 had no effect. These studies provide correlative evidence that the opening of potassium channels is an important regulatory mechanism for hair growth. This provides the impetus for further studies on this potentially important mechanism affecting hair biology.

Targeting delavirdine/atevirdine resistant HIV-1: identification of (alkylamino)piperidine-containing bis(heteroaryl)piperazines as broad spectrum HIV-1 reverse transcriptase inhibitors.

A novel class of bis(heteroaryl)piperazine (BHAP) analogs which possesses the ability to inhibit NNRTI (non-nucleoside reverse transcriptase inhibitor) resistant recombinant HIV-1 reverse transcriptase (RT) and NNRTI resistant variants of HIV-1 has been identified via targeted screening. Further investigation of the structure-activity relationships of close congeners of these novel (alkylamino)piperidine BHAPs (AAP-BHAPs) led to the synthesis of several compounds possessing the desired phenotype (e.g., activity against recombinant RTs carrying the Y181C and P236L substitutions). Further structural modifications were required to inhibit metabolism and modulate solubility in order to obtain compounds with the desired biological profile as well as appropriate pharmaceutical properties. The AAP-BHAPs with the most suitable characteristics were compounds 7, 15, and 36.

Stability of prostaglandin E1 and dinoprostone (prostaglandin E2) under strongly acidic and basic conditions.

The stability of prostaglandin E1 and dinoprostone was investigated at the extremes of the pH range (less than or equal to 3 and greater than or equal to 10) in the sequence prostaglandin E leads to prostaglandin A leads to prostaglandin B. The degradation rate is first order with hydrogen-ion and hydroxide-ion concentrations. Separation and analysis of the E prostaglandins were accomplished by TLC and UV spectrophotometry. At the lowest pH values and at elevated or low temperatures, significant amounts of 15-epiprostaglandin E were present. Apparent activation energies for the total dinoprostone loss, calculated from elevated temperature data, were 21 kcal/mole in the strongly acidic region and about 18 kcal/mole at pH 3. Corresponding studies in the alkaline region led to a derived arrhenius activation energy of 15 kcal/mole with the appearance of significant amounts of 8-isoprostaglandin E. This difference in activation energies may reflect the different mechanisms operant at high and low pH values.

Prostaglandin prodrugs. I: Stabilization of dinoprostone (prostaglandin E2) in solid state through formation of crystalline C1-phenyl esters.

Dinoprostone para-substituted phenyl esters were synthesized in attempt to improve the solid-state stability of the parent prostaglandin. A phenol series covering a wide melting-point range was employed, and a linear relationship was observed between the phenol melting points and the resulting prostaglandin C1-ester melting points. The crystalline esters showed improved solid-state stability over the parent compound, and many esters were biologically active.

Clinical comparison of abortifacient activity of vaginally administered prostaglandin E2 in two dosage forms.

PIP: The effect of prostaglandin E2 (PGE2) release rate from an intravaginal suppository on induced abortion was investigated in a randomized, double-blind study of 71 women who were 7-22 weeks pregnant. 2 dosage forms were compared. Base A was selected to provide a more hydrophilic character than base B. 6 vaginal suppositories, inserted at 4-8 hour intervals as deemed necessary for the clinical progress of abortion, were available for each patient. If abortion did not occur within 48 hours, the trial was discontinued. When time for 50% dissolution of PGE2 (t50%) was plotted as a function of pH for the 2 suppository formulations, the curve for base A was sigmoidal in shape, showing a more rapid release of PGE2 and pH increase. In contrast, base B demonstrated a t50% value of 30 hours which was independent of pH. This independence suggested the hypothesis that the clinical performance of base B would be more uniform than a base A formulation and would exhibit a longer duration of biologic action. Use of base A was found to produce a slight increase in the frequency of successful abortions (79% with base A versus 70.3% with base B). There were no significant differences in the mean times from treatment initiation to complete abortion, the number of incomplete abortions, or failure to abort between the 2 study groups. There was a nonsignificant trend toward reduced total drug use in the base A group. Examination of side effects indicated that women receiving PGE2 in base B had a greater but nonsignificant tendency to experience nausea (62.2% in group B, 58.8% in group A) and vomiting (83.8% group B, 76.5% group A); however, there was a significantly greater amount of diarrhea in the base B group (70.3%) than in the base A group (41.2%). It was concluded that there are no major differences in abortifacient efficiency or the general incidence of side effects when PGE2 therapy in 2 dosage forms is compared. However, a more hydrophilic base, which exhibits a more rapid release of PGE2, appears to slightly reduce side effects and efficacy.^ieng

Local topical delivery of drugs: a model incorporating simultaneous diffusion and metabolic interconversion between drug and a single metabolite in the skin.

A comprehensive biophysical model for the topical delivery of a drug and its single, locally active metabolite is proposed. This elaboration of the simpler case, in which the drug converts irreversibly to a pharmacologically active metabolite in the tissue, allows for enzymatic interconversion between drug and metabolite. Exact mathematical expressions give concentration-distance relationships of drug and metabolite as well as fluxes of the two molecules in terms of concentration of drug applied to the stratum corneum, permeability coefficient of drug in the stratum corneum, diffusion coefficients of drug and metabolite in the viable tissues (epidermis and dermis), rate constants for the two enzyme systems, and the thickness of the viable tissue. Constants included in the mathematical expressions can be evaluated independently by appropriate in vitro experiments with freshly excised animal skin. The model can then predict what physiochemical drug constants will lead to maximal levels of active metabolite at the site of activity within the skin.