SUPPORTED BY AN EDUCATIONAL GRANT FROM WESTWOOD-SQUIBB PHARMACEUTICALS, A BRISTOL-MYERS SQUIBB COMPANY
A comparative, multicenter, double blind trial of 0.05% halobetasol propionate ointment and 0.1 % betamethasone valerate ointment in the treatment of patients with chronic, localized plaque psoriasis Gebhard Blum, MD,a and Shantaram Yawalkar, MD, DVDb
Fribourg and Basel, Switzerland In a double-blind, parallel-group, multicenter comparative trial in 84 evaluable patients with severe, localized plaque psoriasis, 0.05% halobetasol propionate ointment proved significantly superior (p = 0.02) to 0.1 %betamethasone valerate ointment with respect to the success rate, as indicated by ratings of "healed" or "marked improvement" (88.1% versus 64.3%). The therapeutic effect was observed within 5 days of the start of treatment in 76% and 67% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. Both preparations were well tolerated. Minor adverse effects at the site of application were reported in only 2% of the patients in each treatment group. Neither skin atrophy nor systemic adverse effects were observed. (J AM ACAD DERMATOL 1991;25:1153-6.)
The era of the corticosteroids began in the 1940s, mainly because of the original research work of Kendall in the United States and Reichstein in Switzerland. Because topical corticosteroids playa very important role in the treatment of inflammatory skin diseases, Maibach asserts that the development of dermatotherapy may be divided into two main periods: before corticosteroids and after corticosteroids. I Based on efficacy, topical corticosteroids are generally classifiedinto the following four groups: mildly potent (such as hydrocortisone base or acetate), moderately potent (for example, triamcinolone acetonide, flumethasone pivalate, and c1obetasone butyrate), highly potent (such as betamethasone valerate, betamethasone dipropionate, halcinonide, and halometasone) and the most potent (clobetasol 17-propionate). Halobetasol propionate (Ultravate)* ointment contains 0.05% 6-a-fluoro-c1obetasoI17-propionate as the active ingredient. In preclinical investigations,
From Hopital Cantonal" and the Medical Department,b Ciba-Geigy Ltd. Reprint requests: John R. Gibson, MD, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Avenue, Buffalo, NY
14213-1091.
16/0/32800 *The international non-proprietary name is ulobelasol.
halobetasol propionate was superior to clobetasol 17-propionate with regard to its antiinflammatory, vasoconstrictive, and antiproliferative effects. 2 In human dermal safety studies, for example, modified Draize skin sensitization test, photocontact allergy test, and phototoxicity test, no evidence of skin sensitization, photocontact allergenicity, or phototoxicity caused by either halobetasol propionate ointment or halobetasol propionate cream was observed. 3 Based on the results of the modified maximization test in guinea pigs, halobetasol propionate can be classified as having the lowest degree of contact allergenic potential. Halobetasol propionate ointment was developed mainly to treat patients with severe, localized corticosteroid-susceptible dermatoses, such as plaque psoriasis, lichen simplex chronicus, and severe atopic dermatitis. Because psoriatic plaques are thick, scaly, indurated, and dry, an anhydrous halobetasol propionate ointment with emollient properties is likely to be more effective than halobetasol propionate cream (an oil in water-emulsion) in the treatment of chronic, localized plaque psoriasis. In a double-blind, multicenter, dose-finding trial carried out by dermatologists in Germany and Switzerland on 376 patients with psoriasis, 126 of whom had severe symptoms, the success rates (described as "healed" or "marked improvement")
1153
Journal of the American Academy of Dermatology
1154 Blum and Yawalkar Table I. Characteristics of evaluable trial population Halobetasol propionate ointment Olaracteristic
n
No. of patients Age (yr) 18-30 31-50 51-79 Sex Males Females Duration of present attack Up to 100 days >100 days Extent of disease Up to 9% 10 to 20% Lesions located on the scalp
I
Betamethasone valerate ointment
I
%
n
42
100,0
42
100.0
8 19 15
19,1 45.2 35.7
13 17 12
31.0 40,S 28.5
27 15
64.3 35,7
28 14
66.7 33.3
35 7
83.3 16.7
31 11
73.8 26.2
25 17 4
59,S 40,S 9.5
25 17 5
59.5 40.5 11.9
were 77%, 90%, and 80% with 0.02% halobetasol propionate ointment, 0.05% halobetasol propionate ointment, and 0.05% clobetasol 17-propionate ointment, respectively, forthe severe symptoms category. 4 These results clearly show that the optimum therapeutic effect of a topical corticosteroid depends not only on the potency of the corticoid molecule but also on the concentration of the active ingredient in its formulation. In addition, the vehicle also plays an important role. In another double-blind, parallel-group, multicenter trial performed by dermatologists in South Mrica on 134 patients with severe, plaque psoriasis, 0.05% halobetasol propionate ointment was directionally more effective than 0.05% clobetasol 17propionate ointment (success rate, 96% versus 91 %). Adverse effects were reported in 7% of the patients treated with halobetasol propionate ointment and in 12% of those treated with clobetasol17-propionate ointment. 5 In view of the worldwide use of 0.1 % betamethasone 17-valerate ointment for the treatment of chronic corticosteroid-susceptible dermatoses, a comparison between 0.05% halobetasol propionate ointment and 0.1% betamethasone valerate ointment was carried out by five dermatologists in Switzerland on 95 patients with severe, chronic, localized plaque psoriasis.
PATIENTS AND METHODS Patients. After excluding II patients because of protocol violation or noncompliance, the evaluable population
%
of this double-blind, parallel-group, multicenter trial consisted of 84 patients, 55 men and 29 women. Their ages ranged from 18 to 79 years, with a median of 42 years. Patients with severe, localized plaque psoriasis covering up to 20% of the total body surface and suited to topical therapy mentioned in the trial plan were admitted to the trial. Patients with psoriatic erythroderma, generalized pustular psoriasis, generalized guttate, or plaque psoriasis more widespread than 20% of the body surface were excluded from the trial. Other exclusion criteria were age less than 18 years; mild or moderately severe psoriasis; pregnancy, breast feeding; concomitant tuberculosis, syphilitic, or viral infections; diabetes mellitus; leukemia; parasitic infestations; and perioral dermatitis. The two treatment groups were comparable with regard to the number of patients, age, sex, duration of present attack, and severity and extent of the disease (Table 1), Protocol. The treatment allocation was in accordance with a predetermined randomization list. The trial medications were identical in appearance and were supplied in identical tubes. Each medication pack comprised eight tubes containing 30 gm of the trial preparation. The medication packs had consecutive numbers. To ensure randomized allocation of the treatment, each patient was given the medication from the pack with the lowest available number. The tear-off label from each used tube was affixed to the title page of the case record form. Before the start of treatment with topical corticosteroids, a 10% salicylic acid ointment was applied twice a day for 2 or 3 days to remove the scales. Two nonoccluded applications per day were permitted, and the duration of treatment was 28 days. The maximum number oftubes (30 gm each) to be used during the trial period was eight. The follow-up vis-
Volume 25 Number 6, Part 2 December 1991
Halobetasol vs betamethasone in plaque psoriasis 1155
Table II. Global evaluation of therapeutic effects 0.05 % Halobetasol propionate ointment Therapeutic effects
n
Healed Marked improvement Moderate improvement Poor or no improvement Total
15 22 4 I
42
I
%
I
35.7 } 52.4 9.5 2.4 100.0
its were scheduled for days 7, 14, 21, and 28, and the disease severity was rated with a 4-point scale. The permissible range for the last visit was from day 25 to day 30. Informed consent was obtained from all patients. Onset of therapeutic action, indicated by the first sign of improvement, and adverse effects caused by the trial preparation were recorded. At the end of the trial treatment, a global assessment of therapeutic effect was recorded by the investigator according to a consistent 4-point scale (1, healed; 2, marked improvement; 3, moderateimprovement; and 4, slight or no improvement). The patient's observations on the cosmetic acceptability and ease of application of the trial preparations were entered on the case record form. Statistical analysis. Nonparametric methods with a significance level of p -< 0.05 were used for the assessment of relevant parameters in the statistical analysis. RESULTS
Onset of therapeutic effect was reported within 5 days of the start of treatment in 76.2% and 66.7% of the patients in the halobetasol propionate ointment and betamethasone valerate ointment treatment groups, respectively. With a pooling of results assessed as "healed" and "marked improvement," the success rates obtained were 88.1 % and 64.3% in patients treated with halobetasol propionate and betamethasone valerate ointments, respectively (Table II). The difference between the success rates was statistically significant in favor of halobetasol propionate ointment (two-tailed Fisher Exact Test, p = 0.02). Adverse effects were reported in only 2% of the patients in each treatment group. A burning sensation of moderate intensity, which resulted in discontinuation of treatment, was reported at the site of application in a patient treated with halobetasol propionate ointment; a mild secondary infection and moderately severe pruritus were observed at the site of application in a patient treated with betamethasone valerate ointment. Neither skin atrophy nor
0.05% Betamethasone valerate ointment
% Successful
88.1
n
9 18 10 5 42
I
%
21.4 } 42.9 23.8 11.9 100.0
I
% Successful
64.3
systemic adverse effects were reported in any of the patients treated. Cosmetic acceptability and ease of application were recorded as "very good" in 81 % and 55% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. DISCUSSION
Psoriasis constitutes one of the most difficult therapeutic problems confronting not only general practitioners but also skin specialists. The disease usually persists throughout the patient's life, imposing a mental strain that represents a social handicap. Until the cause of psoriasis is known, it is reasonable ,to attack the disease at the level of cutaneous inflammation and increased epidermal proliferation. During the past 100 years, methods available for the treatment of psoriasis have been supplemented by several drugs, including halogenated topical corticosteroids, which now occupy an important place in the therapeutic arsenal available in clinical practice. 6,7 Potent topical corticosteroids are effective in psoriasis because of their marked antiinflammatory, antimitotic (antiproliferative and antiepidermoplastic), immunosuppressive, and antipruritic actions. Halobetasol propionate ointment is an anhydrous ointment that contains the active ingredient dissolved in propylene glycol. This enhances its efficacy because of its optimum release from the anhydrous vehicle. Although no preservatives are added, halobetasol propionate ointment is physically and chemically stable because of the ointment character and the antimicrobial properties of propylene glycol. Halobetasol propionate ointment exerts emollient and hydrating effects on the epidermis that allow rapid penetration of the active ingredient into the skin. With a pooling of the results assessed as "healed" and "marked improvement," the success rates obtained were 88.1 % and 64.3% in patients treated
1156 Blum and Yawalkar
with halobetasol propionate and betamethasone valerate ointments, respectively (Table II). The success rate was significantly higher in the halobetasol propionate group than in the betamethasone valerate group (p = 0.02). The therapeutic effect was observed within 5 days of the start of treatment in 76% and 67% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. Both preparations were equally well tolerated. Minor, nonspecific adverse effects, such as burning sensation, pruritus, and secondary infection at the site of application, were reported in only 2% of the patients in each treatment group. Corticosteroidspecific adverse effects, such as skin atrophy, striae, steroid purpura, and any systemic effect caused by the transcutaneous systemic absorption of the corticoid, were not observed in this trial. The principal aim Of topical corticosteroid therapy is to deliver a therapeutically effective dose to the skin, with the fewest possible adverse effects on other parts of the body. Plasma cortisol studies performed with halobetasol propionate ointment in patients with psoriasis in Gennany and the United States did not reveal any clinically significant effect of the active ingredient on the hypothalamic-pituitary-adrenal axis at doses that are effective in the management of chronic, localized plaque psoriasis. 8, 9 Systemic toxicity is related to the degree of absorption of the corticoid through the skin into the systemic circulation and to the duration of treatment and area of application. The site of application is an important factor because there is a marked regional variation in percutaneous absorption of the active ingredient from a topical preparation. Halobetasol propionate has a low systemic absorption, with 2.6% of the applied dose absorbed from 0.05% halobetasol propionate ointment through the skin of normal volunteers. 2 In other double-blind clinical trials conducted on plaque psoriasis; 0.05% halobetasol propionate ointment proved directionally more effective than the comparative topical corticosteroids, namely, 0.05% clobetasol 17-propionate ointment and 0.05% betamethasone dipropionate ointment. 2 Its tolerability
Journal of the American Academy of Dermatology
was similar to that of the comparative preparations. Therefore, halobetasol propionate ointment should be a welcome addition to the therapeutic armamentarium for short-term treatment of patients with chronic, localized, severe, or refractory plaque psoriasis. As a precautionary measure, treatment with ultra high-potency topical corticosteroids such as halobetasol propionate should be carried out judiciously and under medical supervision. To achieve optimum benefit with minimum adverse effects, it is .advisable to use halobetasol propionate ointment twice daily (nonocc1usive) for the first 2 weeks of short-term treatment and then to switch to a moderately potent, topical corticoid until healing takes place. A corticosteroid-free emollient cream or ointment should be applied thereafter for general skin care and for prevention of an early relapse. REFERENCES 1. Maibach HI. Percutaneous penetration of corticoids in man and unresolved problems in their efficacy. Dermatologica 1976;152(suppl 1): 11-25. 2. Loder 1S, Gibson, JR, Yawalkar SJ, et al. Halobetasol propionate. In: Maibach H, Surber C, eds. Topical corticosteroids. Basel: S Karger (in press). 3. Yawalkar SJ, Wiesenberg-Boettcher I, Gibson 1R, et at. Dermatopharmacologic investigations of halobetasol propionate in comparison with clobetasol 17-propionate. J AM ACAD DERMATOL 1991;2S(suppl):1137-44. 4. Blum G, Yawalkar SJ. A double-blind multi-center comparison of 0.02% and 0.05% CGP 14458 ointments and dermovate ointment in patients with chronic psoriasis. Chin J Dermatol1986;19:139-41. 5. Goldberg B, Hartdegen R, Presbury D, et al. A double-blind, multicenter comparison of 0.05% halobetasol propionate ointment and 0.05% clobetasol propionate ointment in patients with chronic, localized plaque psoriasis. J AM ACAD DERMATOL 1991;25(suppl):1145.8. 6. Foged EK, Schmidt H. Treatment modalities of psoriatics over a 6-year period (1975-1981). Dermatologica 1984;168: 90-3. 7. Abdallah MA, Abdel Dayem H, Youssef N. Clinical evaluations of 0.05% halometasone ointment (Sicorten) in the treatment of psoriasis. J Pan Arab League Dermatol 1990; 1:33-6. 8. Datz B, Antonin KH, Yawalkar SJ, et al. Effectofulobetasol ointment on the plasma cortisol levels in patients with psoriasis. Egypt J Dermatol Venereol1988;8:7-12. 9. Watson WA, Kalb RE, Siskin SB, et al. The safety of halobetasol 0.05% ointment in the treatment of psoriasis. Pharmacotherapy 1990;10:107-11.
A comparative, multicenter, double blind trial of 0.05% halobetasol propionate ointment and 0.1 % betamethasone valerate ointment in the treatment of patients with chronic, localized plaque psoriasis Gebhard Blum, MD,a and Shantaram Yawalkar, MD, DVDb
Fribourg and Basel, Switzerland In a double-blind, parallel-group, multicenter comparative trial in 84 evaluable patients with severe, localized plaque psoriasis, 0.05% halobetasol propionate ointment proved significantly superior (p = 0.02) to 0.1 %betamethasone valerate ointment with respect to the success rate, as indicated by ratings of "healed" or "marked improvement" (88.1% versus 64.3%). The therapeutic effect was observed within 5 days of the start of treatment in 76% and 67% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. Both preparations were well tolerated. Minor adverse effects at the site of application were reported in only 2% of the patients in each treatment group. Neither skin atrophy nor systemic adverse effects were observed. (J AM ACAD DERMATOL 1991;25:1153-6.)
The era of the corticosteroids began in the 1940s, mainly because of the original research work of Kendall in the United States and Reichstein in Switzerland. Because topical corticosteroids playa very important role in the treatment of inflammatory skin diseases, Maibach asserts that the development of dermatotherapy may be divided into two main periods: before corticosteroids and after corticosteroids. I Based on efficacy, topical corticosteroids are generally classifiedinto the following four groups: mildly potent (such as hydrocortisone base or acetate), moderately potent (for example, triamcinolone acetonide, flumethasone pivalate, and c1obetasone butyrate), highly potent (such as betamethasone valerate, betamethasone dipropionate, halcinonide, and halometasone) and the most potent (clobetasol 17-propionate). Halobetasol propionate (Ultravate)* ointment contains 0.05% 6-a-fluoro-c1obetasoI17-propionate as the active ingredient. In preclinical investigations,
From Hopital Cantonal" and the Medical Department,b Ciba-Geigy Ltd. Reprint requests: John R. Gibson, MD, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 Forest Avenue, Buffalo, NY
14213-1091.
16/0/32800 *The international non-proprietary name is ulobelasol.
halobetasol propionate was superior to clobetasol 17-propionate with regard to its antiinflammatory, vasoconstrictive, and antiproliferative effects. 2 In human dermal safety studies, for example, modified Draize skin sensitization test, photocontact allergy test, and phototoxicity test, no evidence of skin sensitization, photocontact allergenicity, or phototoxicity caused by either halobetasol propionate ointment or halobetasol propionate cream was observed. 3 Based on the results of the modified maximization test in guinea pigs, halobetasol propionate can be classified as having the lowest degree of contact allergenic potential. Halobetasol propionate ointment was developed mainly to treat patients with severe, localized corticosteroid-susceptible dermatoses, such as plaque psoriasis, lichen simplex chronicus, and severe atopic dermatitis. Because psoriatic plaques are thick, scaly, indurated, and dry, an anhydrous halobetasol propionate ointment with emollient properties is likely to be more effective than halobetasol propionate cream (an oil in water-emulsion) in the treatment of chronic, localized plaque psoriasis. In a double-blind, multicenter, dose-finding trial carried out by dermatologists in Germany and Switzerland on 376 patients with psoriasis, 126 of whom had severe symptoms, the success rates (described as "healed" or "marked improvement")
1153
Journal of the American Academy of Dermatology
1154 Blum and Yawalkar Table I. Characteristics of evaluable trial population Halobetasol propionate ointment Olaracteristic
n
No. of patients Age (yr) 18-30 31-50 51-79 Sex Males Females Duration of present attack Up to 100 days >100 days Extent of disease Up to 9% 10 to 20% Lesions located on the scalp
I
Betamethasone valerate ointment
I
%
n
42
100,0
42
100.0
8 19 15
19,1 45.2 35.7
13 17 12
31.0 40,S 28.5
27 15
64.3 35,7
28 14
66.7 33.3
35 7
83.3 16.7
31 11
73.8 26.2
25 17 4
59,S 40,S 9.5
25 17 5
59.5 40.5 11.9
were 77%, 90%, and 80% with 0.02% halobetasol propionate ointment, 0.05% halobetasol propionate ointment, and 0.05% clobetasol 17-propionate ointment, respectively, forthe severe symptoms category. 4 These results clearly show that the optimum therapeutic effect of a topical corticosteroid depends not only on the potency of the corticoid molecule but also on the concentration of the active ingredient in its formulation. In addition, the vehicle also plays an important role. In another double-blind, parallel-group, multicenter trial performed by dermatologists in South Mrica on 134 patients with severe, plaque psoriasis, 0.05% halobetasol propionate ointment was directionally more effective than 0.05% clobetasol 17propionate ointment (success rate, 96% versus 91 %). Adverse effects were reported in 7% of the patients treated with halobetasol propionate ointment and in 12% of those treated with clobetasol17-propionate ointment. 5 In view of the worldwide use of 0.1 % betamethasone 17-valerate ointment for the treatment of chronic corticosteroid-susceptible dermatoses, a comparison between 0.05% halobetasol propionate ointment and 0.1% betamethasone valerate ointment was carried out by five dermatologists in Switzerland on 95 patients with severe, chronic, localized plaque psoriasis.
PATIENTS AND METHODS Patients. After excluding II patients because of protocol violation or noncompliance, the evaluable population
%
of this double-blind, parallel-group, multicenter trial consisted of 84 patients, 55 men and 29 women. Their ages ranged from 18 to 79 years, with a median of 42 years. Patients with severe, localized plaque psoriasis covering up to 20% of the total body surface and suited to topical therapy mentioned in the trial plan were admitted to the trial. Patients with psoriatic erythroderma, generalized pustular psoriasis, generalized guttate, or plaque psoriasis more widespread than 20% of the body surface were excluded from the trial. Other exclusion criteria were age less than 18 years; mild or moderately severe psoriasis; pregnancy, breast feeding; concomitant tuberculosis, syphilitic, or viral infections; diabetes mellitus; leukemia; parasitic infestations; and perioral dermatitis. The two treatment groups were comparable with regard to the number of patients, age, sex, duration of present attack, and severity and extent of the disease (Table 1), Protocol. The treatment allocation was in accordance with a predetermined randomization list. The trial medications were identical in appearance and were supplied in identical tubes. Each medication pack comprised eight tubes containing 30 gm of the trial preparation. The medication packs had consecutive numbers. To ensure randomized allocation of the treatment, each patient was given the medication from the pack with the lowest available number. The tear-off label from each used tube was affixed to the title page of the case record form. Before the start of treatment with topical corticosteroids, a 10% salicylic acid ointment was applied twice a day for 2 or 3 days to remove the scales. Two nonoccluded applications per day were permitted, and the duration of treatment was 28 days. The maximum number oftubes (30 gm each) to be used during the trial period was eight. The follow-up vis-
Volume 25 Number 6, Part 2 December 1991
Halobetasol vs betamethasone in plaque psoriasis 1155
Table II. Global evaluation of therapeutic effects 0.05 % Halobetasol propionate ointment Therapeutic effects
n
Healed Marked improvement Moderate improvement Poor or no improvement Total
15 22 4 I
42
I
%
I
35.7 } 52.4 9.5 2.4 100.0
its were scheduled for days 7, 14, 21, and 28, and the disease severity was rated with a 4-point scale. The permissible range for the last visit was from day 25 to day 30. Informed consent was obtained from all patients. Onset of therapeutic action, indicated by the first sign of improvement, and adverse effects caused by the trial preparation were recorded. At the end of the trial treatment, a global assessment of therapeutic effect was recorded by the investigator according to a consistent 4-point scale (1, healed; 2, marked improvement; 3, moderateimprovement; and 4, slight or no improvement). The patient's observations on the cosmetic acceptability and ease of application of the trial preparations were entered on the case record form. Statistical analysis. Nonparametric methods with a significance level of p -< 0.05 were used for the assessment of relevant parameters in the statistical analysis. RESULTS
Onset of therapeutic effect was reported within 5 days of the start of treatment in 76.2% and 66.7% of the patients in the halobetasol propionate ointment and betamethasone valerate ointment treatment groups, respectively. With a pooling of results assessed as "healed" and "marked improvement," the success rates obtained were 88.1 % and 64.3% in patients treated with halobetasol propionate and betamethasone valerate ointments, respectively (Table II). The difference between the success rates was statistically significant in favor of halobetasol propionate ointment (two-tailed Fisher Exact Test, p = 0.02). Adverse effects were reported in only 2% of the patients in each treatment group. A burning sensation of moderate intensity, which resulted in discontinuation of treatment, was reported at the site of application in a patient treated with halobetasol propionate ointment; a mild secondary infection and moderately severe pruritus were observed at the site of application in a patient treated with betamethasone valerate ointment. Neither skin atrophy nor
0.05% Betamethasone valerate ointment
% Successful
88.1
n
9 18 10 5 42
I
%
21.4 } 42.9 23.8 11.9 100.0
I
% Successful
64.3
systemic adverse effects were reported in any of the patients treated. Cosmetic acceptability and ease of application were recorded as "very good" in 81 % and 55% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. DISCUSSION
Psoriasis constitutes one of the most difficult therapeutic problems confronting not only general practitioners but also skin specialists. The disease usually persists throughout the patient's life, imposing a mental strain that represents a social handicap. Until the cause of psoriasis is known, it is reasonable ,to attack the disease at the level of cutaneous inflammation and increased epidermal proliferation. During the past 100 years, methods available for the treatment of psoriasis have been supplemented by several drugs, including halogenated topical corticosteroids, which now occupy an important place in the therapeutic arsenal available in clinical practice. 6,7 Potent topical corticosteroids are effective in psoriasis because of their marked antiinflammatory, antimitotic (antiproliferative and antiepidermoplastic), immunosuppressive, and antipruritic actions. Halobetasol propionate ointment is an anhydrous ointment that contains the active ingredient dissolved in propylene glycol. This enhances its efficacy because of its optimum release from the anhydrous vehicle. Although no preservatives are added, halobetasol propionate ointment is physically and chemically stable because of the ointment character and the antimicrobial properties of propylene glycol. Halobetasol propionate ointment exerts emollient and hydrating effects on the epidermis that allow rapid penetration of the active ingredient into the skin. With a pooling of the results assessed as "healed" and "marked improvement," the success rates obtained were 88.1 % and 64.3% in patients treated
1156 Blum and Yawalkar
with halobetasol propionate and betamethasone valerate ointments, respectively (Table II). The success rate was significantly higher in the halobetasol propionate group than in the betamethasone valerate group (p = 0.02). The therapeutic effect was observed within 5 days of the start of treatment in 76% and 67% of the patients treated with halobetasol propionate and betamethasone valerate ointments, respectively. Both preparations were equally well tolerated. Minor, nonspecific adverse effects, such as burning sensation, pruritus, and secondary infection at the site of application, were reported in only 2% of the patients in each treatment group. Corticosteroidspecific adverse effects, such as skin atrophy, striae, steroid purpura, and any systemic effect caused by the transcutaneous systemic absorption of the corticoid, were not observed in this trial. The principal aim Of topical corticosteroid therapy is to deliver a therapeutically effective dose to the skin, with the fewest possible adverse effects on other parts of the body. Plasma cortisol studies performed with halobetasol propionate ointment in patients with psoriasis in Gennany and the United States did not reveal any clinically significant effect of the active ingredient on the hypothalamic-pituitary-adrenal axis at doses that are effective in the management of chronic, localized plaque psoriasis. 8, 9 Systemic toxicity is related to the degree of absorption of the corticoid through the skin into the systemic circulation and to the duration of treatment and area of application. The site of application is an important factor because there is a marked regional variation in percutaneous absorption of the active ingredient from a topical preparation. Halobetasol propionate has a low systemic absorption, with 2.6% of the applied dose absorbed from 0.05% halobetasol propionate ointment through the skin of normal volunteers. 2 In other double-blind clinical trials conducted on plaque psoriasis; 0.05% halobetasol propionate ointment proved directionally more effective than the comparative topical corticosteroids, namely, 0.05% clobetasol 17-propionate ointment and 0.05% betamethasone dipropionate ointment. 2 Its tolerability
Journal of the American Academy of Dermatology
was similar to that of the comparative preparations. Therefore, halobetasol propionate ointment should be a welcome addition to the therapeutic armamentarium for short-term treatment of patients with chronic, localized, severe, or refractory plaque psoriasis. As a precautionary measure, treatment with ultra high-potency topical corticosteroids such as halobetasol propionate should be carried out judiciously and under medical supervision. To achieve optimum benefit with minimum adverse effects, it is .advisable to use halobetasol propionate ointment twice daily (nonocc1usive) for the first 2 weeks of short-term treatment and then to switch to a moderately potent, topical corticoid until healing takes place. A corticosteroid-free emollient cream or ointment should be applied thereafter for general skin care and for prevention of an early relapse. REFERENCES 1. Maibach HI. Percutaneous penetration of corticoids in man and unresolved problems in their efficacy. Dermatologica 1976;152(suppl 1): 11-25. 2. Loder 1S, Gibson, JR, Yawalkar SJ, et al. Halobetasol propionate. In: Maibach H, Surber C, eds. Topical corticosteroids. Basel: S Karger (in press). 3. Yawalkar SJ, Wiesenberg-Boettcher I, Gibson 1R, et at. Dermatopharmacologic investigations of halobetasol propionate in comparison with clobetasol 17-propionate. J AM ACAD DERMATOL 1991;2S(suppl):1137-44. 4. Blum G, Yawalkar SJ. A double-blind multi-center comparison of 0.02% and 0.05% CGP 14458 ointments and dermovate ointment in patients with chronic psoriasis. Chin J Dermatol1986;19:139-41. 5. Goldberg B, Hartdegen R, Presbury D, et al. A double-blind, multicenter comparison of 0.05% halobetasol propionate ointment and 0.05% clobetasol propionate ointment in patients with chronic, localized plaque psoriasis. J AM ACAD DERMATOL 1991;25(suppl):1145.8. 6. Foged EK, Schmidt H. Treatment modalities of psoriatics over a 6-year period (1975-1981). Dermatologica 1984;168: 90-3. 7. Abdallah MA, Abdel Dayem H, Youssef N. Clinical evaluations of 0.05% halometasone ointment (Sicorten) in the treatment of psoriasis. J Pan Arab League Dermatol 1990; 1:33-6. 8. Datz B, Antonin KH, Yawalkar SJ, et al. Effectofulobetasol ointment on the plasma cortisol levels in patients with psoriasis. Egypt J Dermatol Venereol1988;8:7-12. 9. Watson WA, Kalb RE, Siskin SB, et al. The safety of halobetasol 0.05% ointment in the treatment of psoriasis. Pharmacotherapy 1990;10:107-11.
