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Overview of other topical retinoids
Volume 15 Number 4, Part 2 October, 1986
General discussion
punch biopsy from a lesion other than the "target" lesion being evaluated. These biopsy specimens were removed before treatment and again at the end of the study. The remainder of the subjects either did not give consent or they did not have other keloids or hypertrophic scars that could be evaluated. We did not want to bias our results by surgically manipulating the "target" lesions.
I
I
m
These "target" lesions were present for an average of 7 years, with the range being from 1 to 30 years. Most of them, by clinical definition, would be keloids. We are still examining histologic evidence in the "before" and "after" specimens of the biopsied lesions to evaluate any difference between them.
iii
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Ill I
II
Overview of other topical retinoids John S. Strauss, M.D. Iowa City, IA It is clear that tretinoin has a major place in the treatment of acne via its effect on the abnormal pattern of keratinization, the initial pathophysiologic event in the disease. However, for purposes of introduction, it is useful to compare tretinoin with another topical retinoid, motretinide (Ro 11-1430), which is currently used in Europe. Herein is an overview of several studies that have examined the efficacy of these two agents. (J AM ACADDERMATOL 15:905-906, 1986.)
In the mouse papilloma regression model used by Bollag, ~motretinide, an aromatic retinoid, produced a 50.2% tumor regression from baseline. 2 This was close to the 60.2% reduction produced by tretinoin in the same study. However, in another animal assay that measured the regression of the utriculus in hairless rhino mouse epidermis, Mezick et aP found that motretinide was much less active than tretinoin. The relative potency of tretinoin in this assay was 50 times that of motretinide. These investigators considered the utriculus assay to be useful in the quantification of the antikeratinizing activity of retinoids. The first studies of the use of motretinide in the management of acne were published by Scherrer and Ott 4 and Christiansen et al. 5 Scherrer and Ott From the Department of Dermatology, University Hospitals. Reprint requests to: John S. Strauss, M.D., Professor and Head, Department of Dermatology, University Hospitals BT2045-1, Iowa City, IA 52242.
reported that after 2 months of treatment with a 0.1% solution of motretinide in a propylene glycol-ethanol vehicle, 72% of 60 patients with acne had good improvement, 18% had moderate improvement, and 10% had no improvement. Comparable results were also seen at the end of 4 months, although one third of the patients had dropped out of the study. Theirs was an open study, with no placebo control or compm-ison drug. Considering the marked placebo effect that is common to all acne therapy trials, interpretation of these data is difficult. Christiansen et al compared a 0.1% motretinide solution in a propylene glycolethanol vehicle with a 0.05% tretinoin solution in a double-blind study of 31 patients with ache treated for 6 to 8 weeks. Both retinoids produced statistically significant reductions in the total number of acne lesions, as well as in the numbers of comedones, papules, and pustules. No statistical difference was found between the therapeutic effects of the two drugs. However, although motre9O5
906
Journal of the American Academy of Dermatology
Strauss
tinide was used in a concentration twice that o f tretinoin, the side effects of erythema and desquamation occurred at a statistically lower frequency with the use of the motretinide solution. Two subsequent double-blind, paired comparison drug trials involving 100 and 60 patients used the same tretinoin and motretinide solutions and had comparable results--roughly equal efficacy with better tolerance of motretinide.6.7 One o f these studies 7 showed tretinoin to be slightly more effective in decreasing comedone and papule counts, but the difference was not statistically significant. Once again the tolerance was better with motretinide, even when it was used twice daily in comparison with once-daily application of tretinoin. In a small study involving only 30 patients, 0.1% motretinide in a vanishing cream was therapeutically comparable with a 5 . 0 % benzoyl peroxide gel, but was better tolerated. 8 All of these studies compared motretinide with either tretinoin or benzoyl peroxide. Although the vehicle was the same in the tretinoin comparisons, a control was not incorporated into the experimental design of the protocol. Two studies have incorporated three separate treatment groups (motretinide, tretinoin, and a vehicle control). 9'1~ Christiansen et al 9 treated their patients with a 0.1% solution of motretinide in equal parts o f propylene glycol and ethanol, a 0.05% solution o f tretinoin in the same vehicle, or the vehicle alone. Applications were made twice daily for 8 weeks, and approximately 70 to 80 patients were available for analysis in each group at the end of the study. In al! groups, there was a reduction in the total number of lesions (inflamed and noninflamed). However, the decrease in lesions in the tretinointreated group was significantly greater than that produced by motretinide or the placebo, and the latter two groups did not differ significantly. W h e n comedones alone were counted, tretinoin was significantly better than motretinide, which, in turn,
was significantly better than the placebo vehicle. As in previous studies, motretinide was better tolerated than tretinoin. Similar results were reported by Fatum et al. ~o While tretinoin was significantly more effective in reducing the number of pustules and total lesions, the three test preparations (creams this time) were equally effective in reducing comedones. In summary, although it is better tolerated and appears to have some therapeutic effect, motretinide is not as potent as tretinoin in the overall management of acne. REFERENCES
1. Bollag W: Effects of vitamin A acid (NSC-122758) on transplantable and chemically induced tumors. Cancer Chemother Rep 55:53-58, 1971. 2. Lesiewicz J, Cunningham W, Connor MJ, et al: Animal screens for retinoids, in Maibach HI, Lowe NJ, editors: Models in dermatology, vol 2. Basel, Switzerland, S. Karger, 1985, pp. 112-116. 3. Mezick JA, Bhatia MC, Capetola RJ: Topical and systemic effects of retinoids on horn-filled utriculus size in the rhino mouse: A model to quantify "antikeratinizing" effects of retinoids. J Invest Dermatol 83:110- I 13, 1984. 4. Scherrer A, Ott F: Die Lokaltherapie der Akne vulgaris mit einem aromatischen Retinoid. Praxis 65"453-455, 1976. 5. Christiansen J, Holm P, Reymann F: Treatment of acne vulgaris with the retinoic acid derivative Ro 11-1430. Dermatologica 153:172-176, 1976. 6. Braathen LR, Matheson I, Mathisen RT, et al: Et nytt retinoid Ro 11-1430 (Tasmaderm) versus Airol ved acne vulgaris. Tidsskr Nor Laegeforen 98:1006-1009, 1978. 7. Nordin K, Frediksson T, Rylander C: Ro 11-1430, a new retinoic acid derivative for the topical treatment of ache. Dermatologica 162:104-111, 1981. 8. Lassus A, Juvakoski T, Lauharanta J: Motretinide versus benzoyl peroxide in the treatment of acne vulgaris. Dermatologica 168:199-201, 1984. 9. Christiansen J, Holm P, Reymann F: The retinoic acid derivative Ro 11-1430 in ache vulgaris. Dermatologica 154:219-227, 1977. 10. Fatum B, Hansen H-HV, Mortensen E, et al: Lokalbehandling of .acne vulgaris reed A-vitaminsyrederivat motretinid (Tasmadenn| tretinoin (Airol| og placebocreme. Ugeskr Laeger 142:3364-3366, 1980.
General discussion
punch biopsy from a lesion other than the "target" lesion being evaluated. These biopsy specimens were removed before treatment and again at the end of the study. The remainder of the subjects either did not give consent or they did not have other keloids or hypertrophic scars that could be evaluated. We did not want to bias our results by surgically manipulating the "target" lesions.
I
I
m
These "target" lesions were present for an average of 7 years, with the range being from 1 to 30 years. Most of them, by clinical definition, would be keloids. We are still examining histologic evidence in the "before" and "after" specimens of the biopsied lesions to evaluate any difference between them.
iii
I
III
Ill I
II
Overview of other topical retinoids John S. Strauss, M.D. Iowa City, IA It is clear that tretinoin has a major place in the treatment of acne via its effect on the abnormal pattern of keratinization, the initial pathophysiologic event in the disease. However, for purposes of introduction, it is useful to compare tretinoin with another topical retinoid, motretinide (Ro 11-1430), which is currently used in Europe. Herein is an overview of several studies that have examined the efficacy of these two agents. (J AM ACADDERMATOL 15:905-906, 1986.)
In the mouse papilloma regression model used by Bollag, ~motretinide, an aromatic retinoid, produced a 50.2% tumor regression from baseline. 2 This was close to the 60.2% reduction produced by tretinoin in the same study. However, in another animal assay that measured the regression of the utriculus in hairless rhino mouse epidermis, Mezick et aP found that motretinide was much less active than tretinoin. The relative potency of tretinoin in this assay was 50 times that of motretinide. These investigators considered the utriculus assay to be useful in the quantification of the antikeratinizing activity of retinoids. The first studies of the use of motretinide in the management of acne were published by Scherrer and Ott 4 and Christiansen et al. 5 Scherrer and Ott From the Department of Dermatology, University Hospitals. Reprint requests to: John S. Strauss, M.D., Professor and Head, Department of Dermatology, University Hospitals BT2045-1, Iowa City, IA 52242.
reported that after 2 months of treatment with a 0.1% solution of motretinide in a propylene glycol-ethanol vehicle, 72% of 60 patients with acne had good improvement, 18% had moderate improvement, and 10% had no improvement. Comparable results were also seen at the end of 4 months, although one third of the patients had dropped out of the study. Theirs was an open study, with no placebo control or compm-ison drug. Considering the marked placebo effect that is common to all acne therapy trials, interpretation of these data is difficult. Christiansen et al compared a 0.1% motretinide solution in a propylene glycolethanol vehicle with a 0.05% tretinoin solution in a double-blind study of 31 patients with ache treated for 6 to 8 weeks. Both retinoids produced statistically significant reductions in the total number of acne lesions, as well as in the numbers of comedones, papules, and pustules. No statistical difference was found between the therapeutic effects of the two drugs. However, although motre9O5
906
Journal of the American Academy of Dermatology
Strauss
tinide was used in a concentration twice that o f tretinoin, the side effects of erythema and desquamation occurred at a statistically lower frequency with the use of the motretinide solution. Two subsequent double-blind, paired comparison drug trials involving 100 and 60 patients used the same tretinoin and motretinide solutions and had comparable results--roughly equal efficacy with better tolerance of motretinide.6.7 One o f these studies 7 showed tretinoin to be slightly more effective in decreasing comedone and papule counts, but the difference was not statistically significant. Once again the tolerance was better with motretinide, even when it was used twice daily in comparison with once-daily application of tretinoin. In a small study involving only 30 patients, 0.1% motretinide in a vanishing cream was therapeutically comparable with a 5 . 0 % benzoyl peroxide gel, but was better tolerated. 8 All of these studies compared motretinide with either tretinoin or benzoyl peroxide. Although the vehicle was the same in the tretinoin comparisons, a control was not incorporated into the experimental design of the protocol. Two studies have incorporated three separate treatment groups (motretinide, tretinoin, and a vehicle control). 9'1~ Christiansen et al 9 treated their patients with a 0.1% solution of motretinide in equal parts o f propylene glycol and ethanol, a 0.05% solution o f tretinoin in the same vehicle, or the vehicle alone. Applications were made twice daily for 8 weeks, and approximately 70 to 80 patients were available for analysis in each group at the end of the study. In al! groups, there was a reduction in the total number of lesions (inflamed and noninflamed). However, the decrease in lesions in the tretinointreated group was significantly greater than that produced by motretinide or the placebo, and the latter two groups did not differ significantly. W h e n comedones alone were counted, tretinoin was significantly better than motretinide, which, in turn,
was significantly better than the placebo vehicle. As in previous studies, motretinide was better tolerated than tretinoin. Similar results were reported by Fatum et al. ~o While tretinoin was significantly more effective in reducing the number of pustules and total lesions, the three test preparations (creams this time) were equally effective in reducing comedones. In summary, although it is better tolerated and appears to have some therapeutic effect, motretinide is not as potent as tretinoin in the overall management of acne. REFERENCES
1. Bollag W: Effects of vitamin A acid (NSC-122758) on transplantable and chemically induced tumors. Cancer Chemother Rep 55:53-58, 1971. 2. Lesiewicz J, Cunningham W, Connor MJ, et al: Animal screens for retinoids, in Maibach HI, Lowe NJ, editors: Models in dermatology, vol 2. Basel, Switzerland, S. Karger, 1985, pp. 112-116. 3. Mezick JA, Bhatia MC, Capetola RJ: Topical and systemic effects of retinoids on horn-filled utriculus size in the rhino mouse: A model to quantify "antikeratinizing" effects of retinoids. J Invest Dermatol 83:110- I 13, 1984. 4. Scherrer A, Ott F: Die Lokaltherapie der Akne vulgaris mit einem aromatischen Retinoid. Praxis 65"453-455, 1976. 5. Christiansen J, Holm P, Reymann F: Treatment of acne vulgaris with the retinoic acid derivative Ro 11-1430. Dermatologica 153:172-176, 1976. 6. Braathen LR, Matheson I, Mathisen RT, et al: Et nytt retinoid Ro 11-1430 (Tasmaderm) versus Airol ved acne vulgaris. Tidsskr Nor Laegeforen 98:1006-1009, 1978. 7. Nordin K, Frediksson T, Rylander C: Ro 11-1430, a new retinoic acid derivative for the topical treatment of ache. Dermatologica 162:104-111, 1981. 8. Lassus A, Juvakoski T, Lauharanta J: Motretinide versus benzoyl peroxide in the treatment of acne vulgaris. Dermatologica 168:199-201, 1984. 9. Christiansen J, Holm P, Reymann F: The retinoic acid derivative Ro 11-1430 in ache vulgaris. Dermatologica 154:219-227, 1977. 10. Fatum B, Hansen H-HV, Mortensen E, et al: Lokalbehandling of .acne vulgaris reed A-vitaminsyrederivat motretinid (Tasmadenn| tretinoin (Airol| og placebocreme. Ugeskr Laeger 142:3364-3366, 1980.