Halcinonide: Review of Synthesis, Efficacy, and Safety

Introduction

Halcinonide is a topical anti-inflammatory agent. Introduction of a 9α-fluoro group to the hydrocortisone molecule resulted in an eight-fold increase in anti-inflammatory activity. Such other groups as 16α-hydroxy, 16α-methyl, 16βmethyl, 16,17-acetonide and 6α-methyl moieties have been found to diminish or eliminate mineralocorticoid activity resulting from the 9α-fluoro substituent, while retaining the enhanced anti-inflammatory activity of the halo derivative. Halcinonide lipophilicity is increased by masking the 16,17-hydroxyl groups as the acetonide, which increases the availability of the steroid at the site of action in the skin. The 21-chloro group also increased anti-inflammatory properties. Halcinonide has systemic as well as topical activity. [1]

Synthesis of Halcinonide

The synthesis of halcinonide starts with 16α-hydroxy-9α-fluorohydrocortisone (∆4-pregnene-9α-f luoro-11β, 16α,17α,21-tetrol-3,20-dione; dihydrotriamcinolone, I), which is available commercially. This tetrahydroxy steroid is slurried in acetone, and then 70% perchloric acid is added slowly. The acetonide,II (9α-fluoro-11β,16a,17,21-tetrahydroxypregn-4-ene-3,20-dioney cyclic 16,17-acetal with acetone; dihydrotriamcinolone-acetonide) precipitates spontaneously from solution. Mesyl chloride is added to the acetonide in pyridine to give the 21-mesylate derivative (dihydrotriamcinolone acetonide-21-mesylate,III). Compound III is dissolved in dimethylformamide, lithium chloride is added and the mixture is refluxed to produce halcinonide (IV), which is recrystallized from a solution of n-propanol in water. [1]

Halcinonice in the Treatment of Corticosteroid Responsive Dermatoses

Halcinonide, a new corticosteroid, appears to represent a significant advance in dermatological therapy, especially for the treatment of psoriasis and inflammatory diseases of the skin. Halcinonide differs from triamcinolone acetonide by substitution of a halogen (chlorine) for the hydroxyl group in position 21 and reduction of a double bond at position 1 and 2. A specific vehicle was formulated for this corticosteroid, with a high content of propylene glycol, but containing sufficient water to maintain proper hydration of the stratum corneum. The response obtained to therapy probably results from the potency of the corticosteroid and its appropriate vehicle. Introduction of a halogen atom at the apparently important position 21 of the triamcinolone acetonide molecule results in a very effective corticosteroid for topical therapy. [2]

Dosage and Frequency of Halcinonide Use

In a double-blind multi-centre study, comprising ninety-five patients with psoriasis and atopic dermatitis, 0-1% halcinonide cream applied once daily was equally as effective as the cream applied three times daily. However, the onset of action was more rapid when the cream was applied three times daily. In a control study once daily application of 0-1% halcinonide cream was found to be superior to the vehicle alone in the treatment of forty patients with the same diseases. That once daily application is equally as effective as three times daily application is not really surprising. The absorption of corticosteroids through human skin is a comparatively slow process, a phenomenon that has been referred to as a reservoir effect by Vickers (1963) and Feldmann & Maibach (1968). It has also been shown that very frequent applications are of no greater value. [3]

Side Effects of Halcinonide Use

Halcinonide topical, a high-potency corticosteroid, has been associated with a spectrum of adverse effects that range from localized skin reactions to systemic complications. Frequently reported cutaneous manifestations include burning, itching, irritation, rash formation, acneiform eruptions, hypertrichosis, dyspigmentation, and a wrinkled or thinned skin appearance. More severe dermatologic outcomes may involve erythema, edema, exudation, or delayed wound healing. Prolonged or extensive application may facilitate systemic absorption, leading to glucocorticoid-related effects such as weight redistribution (notably in the face and upper back), skin atrophy, impaired immune response, hyperglycemia, hirsutism, and alterations in mood, growth, or reproductive function. In rare cases, patients may develop hypersensitivity reactions, including urticaria, angioedema, and respiratory distress, which necessitate immediate medical intervention. Given these potential adverse effects, halcinonide should be administered with caution, particularly in long-term or high-dose regimens, and patients should be monitored for both dermatologic and systemic complications. [4]

References:

[1] Kirschbaum, J. (1979). Halcinonide. In Analytical Profiles of Drug Substances (Vol. 8, pp. 251-281). Academic Press.

[2] LEIBSOHN, E., & Bagatell, F. K. (1974). Halcinonide in the treatment of corticosteroid responsive dermatoses. British Journal of Dermatology, 90(4), 435-440.

[3] FREDRIKSSON, T., LASSUS, A., & BLEEKER, J. (1980). Treatment of psoriasis and atopic dermatitis with halcinonide cream applied once and three times daily. British Journal of Dermatology, 102(5), 575-577.

[4] http://www.drugs.com/mtm/halcinonide-topical.html