Effect of coadministration of corticosteroids on the development of contact sensitization.

BACKGROUND: Transdermal administration of drugs can increase patient compliance and reduce side effects, but it can also cause contact sensitization. Corticosteroids frequently are used to suppress the local immune response; however, their use as a pretreatment for transdermal system application sites is not practical. OBJECTIVE: Our purpose was to determine the feasibility of suppressing contact sensitization by delivering a corticosteroid with the transdermal delivery systems. METHODS: Materials were applied continuously for 3 weeks to the same (protocol SS) or different (protocol AS) skin sites. Skin flux and appearance of sensitization were determined. RESULTS: Coadministration of hydrocortisone reduced the incidence of sensitization by d-chlorpheniramine and benzoyl peroxide from 45% to 7.5% and from 20% to 2.3%, respectively, under protocol SS. Under protocol AS, sensitization by d-chlorpheniramine was reduced from 15% to 1%. Frequent exposure to the sensitizer plus corticosteroid induced tolerance to the sensitizer. CONCLUSION: Sensitization by moderately immunogenic drugs after any length of exposure may be reduced to acceptable levels by the coadministration of hydrocortisone.

In vitro cutaneous biotransformation of propranolol.

The metabolism of propranolol by human skin and by several cell preparations has been investigated in vitro. The major metabolites produced by human skin in organ culture and by keratinocytes were N-desisopropylpropranolol (DIP), propranolol glycol (GLY), and naphthoxylactic acid (NLA). Formation of GLY and NLA was linear with incubation time up to 6 d and was directly proportional to propranolol concentration. Fibroblasts and melanocytes also produced GLY and NLA, but appeared to have lower propranolol-biotransforming activity than keratinocytes. The three metabolites detected arise from side-chain oxidation of propranolol, and the use of specific enzyme inhibitors determined that monoamine oxidase and cytochrome P450 isozymes are involved in their formation. Aldehyde and alcohol dehydrogenases are also probably involved in the formation of NLA and GLY, but attempts to inhibit these enzyme systems were inconclusive, possibly due to the chemical instability of the intermediate aldehyde resulting from monoamine oxidase activity. No evidence was found for conjugation or ring oxidation by the skin or isolated cells. Induction of keratinocyte differentiation with Ca++ or phorbol ester treatment resulted in an increase of overall biotransformation and the NLA/GLY ratio.

A disinfectant delivery system for control of micro-organisms in urine collection bags.

We developed a formaldehyde delivery system for urine collection bags and evaluated its effectiveness in suppressing the growth of bacteria in simulated human urine. The system was composed of paraformaldehyde in a polymeric carrier. We determined that inoculation of small numbers of Escherichia coli and Pseudomonas aeruginosa in urinary bags with a continuous flow of synthetic urine (40-80 ml h-1) quickly gives rise to high levels of contamination. This single tablet delivery system, however, proved bacteriostatic or bactericidal for both organisms over the 10-day lifespan. The formaldehyde concentration in the synthetic urine was c. 90 micrograms ml-1 or more during tests.

Testing of controlled-release transdermal dosage forms. Product development and clinical trials.

In vitro techniques have been developed that are predictive of drug permeation through skin. Methods also have been developed to determine the skin irritation potential of a drug substance during the preclinical stages of transdermal dosage form development. Clinical studies are performed to test for skin irritation, contact sensitization, plasma levels of drug, and efficacy of the dosage form. In theory, these studies should be predictive of a dosage form's performance in routine clinical use. This may not be the case, however; contact sensitization cannot be predicted with absolute certainty beforehand in animals. This article discusses various aspects of testing transdermal dosage forms and how the results of these tests correlate with what happens when a transdermal dosage form is put into routine clinical use.