The vasoconstrictor assay in bioequivalence testing: practical concerns and recent developments.

The vasoconstrictor assay, when properly performed, is a highly reliable method to determine bioequivalence of generic formulations. Recent research has resolved some of the remaining questions concerning the practical application of the assay. Significant vehicle-related differences have been observed between the potency of different, supposedly equivalent formulations now on the market. Large differences in concentrations of the active agent in similar vehicles usually have not resulted in corresponding differences in vasoconstrictor assay results. Finally, the time course of drug effects may differ among highly potent and less potent corticosteroids. In general, the higher the potency of the topical corticosteroid, the earlier the maximal effect is observed. This finding suggests that short application of highly potent agents might minimize systemic absorption without sacrificing efficacy.

Relation of application time to bioactivity of a potent topical glucocorticoid formulation.

The vasoconstrictor assay in human beings was used to assess bioavailability during different time periods of exposure when 0.05% clobetasol propionate cream (Temovate) was applied and left on for periods of 0.5, 1.0, 1.5, and 16.0 hours and subsequently washed. Maximal responses were achieved by 1.5 hours of exposure, but there was no significant difference in intensity of vasoconstriction between 1.0, 1.5, and 16.0 hours of exposure before washing the sites. Exposures to 0.05% clobetasol propionate cream for 0.5 hour were not significantly different from 16-hour exposures to 0.05% fluocinonide cream, but exposures to 0.05% clobetasol propionate cream for 1.0, 1.5, and 16.0 hours all resulted in significant increases in vasoconstriction responses compared with fluocinonide cream applied and left on for 16 hours. Topical exposures to a superpotent topical steroid for a short time give vasoconstrictor responses equivalent to long time exposures.

The same glucocorticoid in brand-name products. Does increasing the concentration result in greater topical biologic activity?

Many topical corticosteroid formulations are available as different concentrations of the steroid in a similar vehicle. We tested the existing assumption that higher concentrations give greater biologic activity. The vasoconstriction assay was used because of its known correlation with clinical activity. Statistical analyses of the different concentrations are as follows: Kenalog creams: 0.025% is equal to 0.1% is equal to 0.5%; Aristocort creams: 0.025% is equal to 0.1% is equal to 0.5%; Aristocort ointments: 0.1% is equal to 0.5%; Aristocort creams: 0.5% is equal to 0.025% but is less than 0.1%; Hytone cream: 1.0% is equal to 2.5%; Synalar creams: 0.01% is less than 0.025% which is less than 0.2%; Topicort creams: 0.25% is equal 0.05%; and Vallisone creams: 0.1% is greater than 0.01%. The assumption that increased concentration of the same steroid in the same vehicle type will give increased biologic activity is usually, but not always, incorrect for brand-name formulations now available.

In vitro and in vivo cutaneous penetration and antifungal activity of naftifine.

The topical antifungal agent naftifine has shown considerable potency against a broad spectrum of dermatophytes. In this study, an in vitro penetration test in human cadaver skin and an in vivo tape-stripping test were used to evaluate the penetration and antifungal activity of naftifine gel 1 percent and naftifine cream 1 percent compared with other antifungal agents. In both models, Trichophyton rubrum and T. mentagrophytes were the fungal species. Results show that naftifine gel 1 percent and naftifine cream 1 percent, in vitro and in vivo, penetrate the stratum corneum in concentrations that inhibit the growth of both fungal species. Following penetration in vitro, naftifine gel and cream were significantly more active against T. rubrum than econazole nitrate cream 1 percent. Following penetration in vivo, naftifine gel and cream were as active as econazole nitrate cream 1 percent and clotrimazole cream 1 percent against T. rubrum and T. mentagrophytes.

Ciclopirox olamine lotion 1%: bioequivalence to ciclopirox olamine cream 1% and clinical efficacy in tinea pedis.

Studies were conducted to assess the bioequivalence of a new antimycotic formulation, ciclopirox olamine lotion 1%, to an established compound, ciclopirox olamine cream 1%. Results of in vitro studies, using skin samples from human cadavers and domestic pigs, demonstrated that the two formulations equally penetrate all layers of the stratum corneum and inhibit the growth of Trichophyton mentagrophytes and Candida albicans. In vivo studies in guinea pigs and in human volunteers demonstrated the comparable therapeutic efficacy of the lotion and the cream in experimental trichophytosis. In addition, a multicenter, double-blind clinical trial was undertaken to compare ciclopirox olamine lotion 1% with the vehicle alone in the treatment of patients with tinea pedis. Patients with plantar, interdigital, or vesicular tinea pedis were enrolled in the studies. Patients were treated for 28 days. Clinical and mycological responses were determined during treatment and two weeks posttreatment. Ciclopirox olamine lotion 1% was found to be significantly more effective than its vehicle in the treatment of patients with common tinea pedis. Minor localized side effects (pruritus, burning sensation) were reported in 2% of 89 patients treated with ciclopirox olamine lotion 1%. The results demonstrate the bioequivalence of ciclopirox olamine lotion 1% and ciclopirox olamine cream 1% and confirm the clinical effectiveness and safety of the lotion in the treatment of tinea pedis, a generally recalcitrant fungal infection. It is concluded that ciclopirox olamine lotion 1% can be used as an alternative to ciclopirox olamine cream 1% for treatment of tinea pedis, tinea versicolor, tinea cruris, tinea corporis, and cutaneous candidiasis when the convenience and/or cosmetic elegance of a lotion is desired.

Percutaneous absorption of drugs.

Some practical applications of basic information in percutaneous absorption have been reviewed. Drug release from vehicles is discussed in relation to glucocorticosteroids. Penetration enhancers are reviewed with emphasis on the need for further investigations and applications of enhancers for clinical use. The role of the stratum corneum as a barrier to and a reservoir for drugs is discussed. Special problems in penetration as presented by regional anatomic variations, nails, and follicles are mentioned. Overall, we review some practical problems existing in the penetration of drugs through human skin.

Erythromycin 2 percent gel in the treatment of acne vulgaris.

A gel formulation of erythromycin 2 percent was compared with its vehicle in a double-blind multicenter study involving patients with mild to moderate acne vulgaris. In an analysis of 187 patients treated twice daily for 8 weeks, erythromycin 2 percent gel proved to be significantly more effective than vehicle in reducing the numbers of both inflammatory and noninflammatory lesions. After 8 weeks, 60 percent of erythromycin-treated patients had good or excellent responses compared with 36 percent of those using vehicle (p = 0.001); the lesions in two patients using erythromycin were completely cleared. The majority of patients had a favorable impression of the cosmetic characteristics of the gel formulation.

Are generic formulations equivalent to trade name topical glucocorticoids?

Trade name glucocorticoid formulations triamcinolone acetonide, fluocinolone acetonide, and betamethasone valerate were compared with their generic equivalents because of increasing substitution of generic formulations for trade name formulations. The vasoconstrictor assay was the method used for these comparisons. Large differences were found between generic and trade name formulations containing the same steroid in the same concentration in both cream and ointment vehicles. If generic substitutions are to be used for trade name formulations, the physician must be aware that significant differences in therapeutic effectiveness may be expected.

Efficacy of 4 percent chlorhexidine gluconate skin cleanser in the treatment of acne vulgaris.

We conducted three controlled, comparative studies to assess the effectiveness of a 4 percent chlorhexidine gluconate skin cleanser (Hibiclens) for the treatment of acne lesions in patients with acne vulgaris. In all studies, the chlorhexidine gluconate formulation achieved statistically significant reduction of the papules plus pustules count, which is generally accepted as the principal criterion of efficacy.

Correlation of the vasoconstriction assay and clinical activity in psoriasis.

A large group of glucocorticosteroid formulations were assayed by the vasoconstriction test in normal skin sites and paired comparison studies in patients with psoriasis. Excellent correlation between the vasoconstriction assay and selected paired comparison studies occurred in 20 of 23 instances. In three instances, involving two glucocorticosteroid formulations tested, correlation was absent. The vasoconstrictor assay is an inexpensive and reliable method for screening glucocorticosteroid formulations for clinical activity in psoriasis.

The effect of alclometasone dipropionate cream 0.05% on the hypothalamic-pituitary-adrenal axis of normal volunteers.

In an open study of ten evaluable normal volunteers, 30 g of alclometasone dipropionate cream 0.05% was applied to 80% of body surface each morning and evening for 21 days. A plastic body suit effectively occluded the treated area for 12 hours/day. As demonstrated by continued normal levels of 8 a.m. plasma cortisol and 24-hour urinary 17-hydroxysteroid and free cortisol, no suppression of the hypothalamic-pituitary-adrenal axis occurred. Local adverse reactions were mild and transient.

Enhanced percutaneous penetration with 1-dodecylazacycloheptan-2-one.

1-Dodecylazacycloheptan-2-one (Azone) is a new agent that enhances the percutaneous absorption of a number of different chemicals. This report delineates the enhancement of penetration of clindamycin phosphate, erythromycin base, fusidate sodium, fluorouracil, desonide, amcinonide, and triamcinolone acetonide. For this purpose 1-dodecylazacycloheptan-2-one can be used in concentrations as low as 1%. It is colorless, relatively odorless, nontoxic, and can be applied neat to human skin without any irritation.

Topical clindamycin therapy for acne vulgaris. A cooperative clinical study.

Eleven institutions participated in an eight-week controlled clinical study to evaluate treatment of acne vulgaris with topical clindamycin hydrochloride and clindamycin phosphate. Three hundred fifty-eight patients with comparable baseline pustule, papule, and nodule counts applied 1%, clindamycin hydrochloride, 1% clindamycin phosphate, or a hydroalcoholic vehicle twice daily. Every two weeks, lesions were counted, and patients' evaluations of their acne conditions were scored. By week 8, pustule and papule counts in the groups who were receiving clindamycin were significantly lower than those in the group receiving placebo. Also, more patients who were receiving clindamycin thought their acne improved by week 8 (with significantly higher change-in-acne scores) than did the patients receiving placebo. Patients receiving clindamycin reported 12 episodes of diarrhea; only one episode was considered to be treatment related. These results substantiate the clinical impression that topical clindamycin is effective treatment for acne.

Topical drug effects on normal and proliferating epidermal cell models.

The effects of 28 different antiproliferative agents applied topically to normal and hyperproliferative hairless mouse skin were studied. Epidermal cell hyperproliferation was induced by an essential fatty acid-deficient diet or by irradiation with short-wavelength ultraviolet (UV) energy. Epidermal DNA synthesis was measured by hydroxyapatite column chromatography. We compared the effects of these drugs used on normal and hyperproliferative hairless mouse skin with clinical responses in patients with psoriasis treated using the same topical preparations. For most of the drugs tested, the normal and essential fatty acid-deficient mouse model effects showed a good correlation with clinical responses seen in treated patients with psoriasis. The short-wavelength UV energy-treated mouse model effects showed a poorer clinical correlation, perhaps partially caused by wide variations in DNA synthetic rates encountered in the epidermis in this model.

Six-month controlled study of effect of desoximetasone and betamethasone 17-valerate on the pituitary-adrenal axis.

Twenty-two patients were treated with desoximetasone emollient cream 0.25% twice daily without occlusion for 6 months. Patients applied the medication to approximately one-third of their body over psoriatic lesions. Corticosteroid plasma cortisol values decreased to below normal limits in nine patients before the 6-month study was terminated. In four of these the plasma cortisol spontaneously returned to normal despite therapy; in four other patients, however, the plasma cortisol was still suppressed at the end of 5 months of continual therapy but returned to normal within 7 days of discontinuation of the medication. In one patient, lost to further follow-up at 5 1/2 months of therapy, the trend at the fourth month was an increase in plasma cortisol to within one unit of normal range. Betamethasone 17-valerate 0.1% cream applied twice daily did not suppress plasma cortisol in twenty-three patients similarly tested. The clinical response to desoximetasone emollient cream was significantly better than to betamethasone valerate cream. This study closely approximates the way in which many patients with steroid-responsive dermatoses use potent topical steroids, namely over a long time period and without occlusion.