tretinoin and motretinide

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.

Topics: Acne Vulgaris; Administration, Topical; Clinical Trials as Topic; Double-Blind Method; Humans; Tretinoin

The retinoid drugs have profound effects on many aspects of skin biology. The exact activity profile depends on the particular analog and its route of administration. The topical retinoids used at present have marked therapeutic effects on epidermal cell production and desquamation. All-trans-retinoic acid (tretinoin) also acts on dermal connective tissue and microvasculature in a way that is less well established but may also be of therapeutic benefit. We investigated both tretinoin and motretinide in normal subjects and in patients with ichthyosis. The quantitative dansyl chloride test has been particularly useful in monitoring the desquamatory action of these topically applied retinoids. Both compounds resulted in enhanced rates of epidermopoiesis and desquamation. Marked changes in the cytochemical profile of the epidermis were also detected, changes that differed somewhat from the alterations induced by the systemic administration of etretinate. Changes in dermal structure and vascularization were monitored by A-scan ultrasound and laser Doppler flowmetry. However, only minor changes were recorded, probably because of the comparatively short application time. These newer techniques for investigating skin structure and function offer considerable opportunities for delineating the action of retinoids.

Topics: Administration, Topical; Clinical Trials as Topic; Dansyl Compounds; Double-Blind Method; Humans; Ichthyosis; Lasers; Random Allocation; Skin; Tretinoin; Ultrasonography

30 patients with acne vulgaris were treated topically with motretinide 0.1% vanishing cream or benzoyl peroxide 5% gel in an open study. Good results were obtained in both groups. Benzoyl peroxide caused local irritation in 73% of the patients, whereas motretinide was well tolerated except in 1 case. Motretinide is considered an alternative in the treatment of papulopustular acne in young adults.

Topics: Acne Vulgaris; Administration, Topical; Adolescent; Adult; Benzoyl Peroxide; Drug Evaluation; Humans; Peroxides; Tretinoin

The clinical efficacy and tolerance of a new retinoic acid derivative, Ro 11-1430, in the treatment of acne vulgaris have been compared with those of tretinoin in a double-blind trial with 60 patients during 8 weeks. The efficacy of both drugs was good. Tretinoin showed a tendency to give better effect but this was not statistically significant. However, tolerance of the new derivative was better. 48 of the patients were treated with Ro 11-1430 for another 3 months with good effect and tolerance. In a long-term study, 32 patients with previous irritation of tretinoin have been treated with Ro 11-1430 between 1.5 and 17 months with good tolerance.

Topics: Acne Vulgaris; Administration, Topical; Adolescent; Adult; Chemical Phenomena; Chemistry; Child; Clinical Trials as Topic; Double-Blind Method; Drug Tolerance; Female; Humans; Male; Tretinoin

In a double-blind randomized comparative multicenter trial, consisting of 29 patients with acne vulgaris who were unable to tolerate daily applications of retinoic acid, the retinoic acid derivative Ro 11--1430 (0.1% vanishing cream) was compared in a 6--8 weeks topical treatment with vanishing cream alone (placebo). Regarding efficacy, for most criteria measured the response was always better with Ro 11--1430 than with placebo, although the differences were not always statistically significant for several reasons, one probably being the small number of patients in the trial. Regarding tolerance, both treatments were satisfactory. Ro 11---1430 and placebo did not differ significantly regarding frequency and severity of erythema, desquamation and burning. These results suggest that treatment with Ro 11--1430 should be considered in acne patients who are unable to use retinoic acid due to severe local reactions.

Topics: Acne Vulgaris; Adolescent; Adult; Child; Clinical Trials as Topic; Double-Blind Method; Drug Hypersensitivity; Female; Humans; Male; Placebos; Random Allocation; Tretinoin

In a double-blind controlled multicenter trial consisting of 257 patients with acne vulgaris an 8-week topical treatment with the retinoic acid derivative Ro 11-1430 (0.1% lotion) was compared with vitamin A acid (0.05% lotion) and the lotion alone (placebo). In reducing the number of comedones vitamin A acid was superior to Ro 11-1430, which was significantly better than placebo. The reduction in number of papules and pustules was not statistically significant on either treatment. Local side effects, i.e. erythema, desquamation, burning and pruritus occurred more frequently and were more severe on vitamin A acid than on Ro 11-1430 and placebo which did not differ. No correlation was found between incidence and severity of local reactions and therapeutic effect.

Topics: Acne Vulgaris; Administration, Topical; Clinical Trials as Topic; Drug Eruptions; Drug Evaluation; Erythema; Humans; Pruritus; Tretinoin; Vitamin A

In a double-blind, randomized, group-comparative clinical trial, 31 patients with acne vulgaris received topical treatment for 6-8 weeks with a lotion containing either 0.05% retinoic acid or 0.1% of the retinoic acid derivative Ro 11-1430. The side-effects erythema, desquamation and burning were significantly less frequent with Ro 11-1430 than with retinoic acid. The treatments appeared to be approximately equally effective in reducing the number of acne elements, but due to the limited number of patients studied, the trial was admittedly not sufficient to detect differences with regard to therapeutic efficacy.

Topics: Acne Vulgaris; Administration, Topical; Clinical Trials as Topic; Drug Eruptions; Drug Evaluation; Erythema; Humans; Tretinoin; Vitamin A

The transplacental pharmacokinetics of single teratogenic doses of etretinate and motretinide were compared with particular emphasis on distribution and concentrations in the exposed embryos of the free acid metabolite, etretin. The three aromatic retinoids were also tested for their direct inhibitory effect on chondrogenesis in the limb bud mesenchymal cell "micromass" culture assay. After a standard dose of 100 mg/kg administered on day 11 of gestation in NMRI mice, all three compounds were teratogenic, but they differed from each other in potency. Etretinate was most active as a teratogen, equalling the potency of our standard all-trans-retinoic acid; every exposed fetus was deformed with severe shortening of all limb bones as well as cleft palate. Etretin was less potent than etretinate, and motretinide was considerably less active as a teratogen than the other two. In the in vitro assay, only etretin suppressed chondrogenesis and this activity was equivalent to that of all-trans-retinoic acid (IC50 of 12 ng/ml). Both etretinate and motretinide (which contain an ethyl ester and ethylamide terminal group, respectively) were essentially inactive in vitro, demonstrating the fact that a free carboxylic group may be a requirement for the in vitro suppression of chondrogenesis. These differences between the results obtained in vivo and in vitro could be resolved by pharmacokinetic investigations using HPLC methods. Both etretinate and motretinide were metabolized in vivo to etretin, their likely common teratogenic metabolite. The high teratogenic potency of etretinate was probably the result of high concentrations as well as AUC values of its metabolite etretin in the embryo. On the other hand, the comparatively low teratogenicity of motretinide could be related to approximately 5 x lower embryonic peak levels as well as AUC values of etretin. A comparison of these results with those previously obtained for all-trans- and 13-cis-retinoic acids confirms the correlation between embryonic exposure and teratogenic potency in the mouse. Our results indicate that pharmacokinetic studies are essential for the interpretation of relative teratogenic potencies of retinoids as well as apparent differences between in vivo and in vitro teratogenesis. A free carboxyl group at the terminal end of the tetraene chain was necessary for high activity of the retinoids studied.

Topics: Abnormalities, Drug-Induced; Acitretin; Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Etretinate; Female; Maternal-Fetal Exchange; Mice; Mice, Inbred Strains; Molecular Structure; Placenta; Pregnancy; Tretinoin

Topics: Animals; Cell Transformation, Neoplastic; Etretinate; Female; Humans; Keratins; Male; Middle Aged; Neoplasm Recurrence, Local; Papilloma; Skin Neoplasms; Tretinoin; Urinary Bladder Neoplasms

Utilizing the phenomenon of metabolic cooperation in Chinese hamster V79 cells, we have studied the effects of agents which suppress the 12-tetradecanoyl-phorbol-13-acetate (TPA) enhancement of transformation in vitro, on the TPA suppression of cell-cell communication. None of the agents tested, namely all-trans-retinoic acid, the trimethyl methoxyphenyl analogue of N-ethyl-retinamide, soybean trypsin inhibitor, antipain nor superoxide dismutase, decreased the enhanced recovery effect of TPA on metabolic cooperation. One of the compounds, retinoic acid, significantly increased the % recovery above that observed for TPA alone.

Topics: Animals; Antipain; Cell Communication; Cell Line; Cell Transformation, Neoplastic; Cricetinae; Oligopeptides; Phorbols; Superoxide Dismutase; Tetradecanoylphorbol Acetate; Tretinoin; Trypsin Inhibitors

The effect of retinoids on the induction of both epithelial and mesenchymal tumors of the rat kidney by a single dose of 40 mg/kg dimethylnitrosamine was tested using 13-cis-retinoic acid and the trimethylmethoxy phenyl analog of retinoic acid ethylamide. 13-cis-retinoic acid was administered for 3 weeks, 10 weeks, or 26 weeks, post-carcinogen treatment, in order to coincide with known morphological phases occurring within the kidney which culminated in the development of macroscopic tumors. The ethylamide analog and placebo beadlets were administered for the 26 week period only. None of the retinoid schedules significantly influenced the survival of the animals, nor the incidences of renal mesenchymal tumors or renal cell adenomas/adenocarcinomas. Tumor latency, histological grade or frequency of metastatic invasion were also unaltered by the treatments. Possible reasons for the observed lack of effect are discussed, including speculation regarding the potency of this single-dose model of chemical carcinogenesis.

Topics: Animals; Dimethylnitrosamine; Female; Isotretinoin; Kidney Neoplasms; Rats; Rats, Inbred Strains; Time Factors; Tretinoin

Topics: Adenosine Triphosphatases; Animals; Cell Differentiation; Cell Line; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Cricetinae; Embryo, Mammalian; Mice; Phorbols; Retinol-Binding Proteins; Sister Chromatid Exchange; Tetradecanoylphorbol Acetate; Tretinoin; X-Rays

Topics: Animals; Antineoplastic Agents; Dogs; Etretinate; Isotretinoin; Male; Mice; Rats; Tretinoin; Vitamin A

Induction of Epstein-Barr virus (EBV) early antigen after treatment with various combinations of croton oil and n-butyrate was markedly inhibited by retinoids 7901, 7902, Ro 10-9359 and Ro 11-1430. Possible administration of retinoids to virus capsid antigen IgA antibody-positive individuals in high-risk areas for nasopharyngeal carcinoma to prevent EBV activation and development of this cancer is discussed.

Topics: Butyrates; Croton Oil; Etretinate; Herpesvirus 4, Human; Humans; Nasopharyngeal Neoplasms; Tretinoin; Virus Activation; Vitamin A

When treated with a retinoic acid analog (Ro 11-1430), the Swarm rat chondrosarcoma regressed (t 1/2 = 11-12 days) with a rapid removal of tumor proteoglycan, histologic evidence of mineralization, and cartilage proteoglycan synthesis was suppressed down to a value of 1% of the control. During the first 3 weeks of treatment, the newly synthesized proteoglycan was similar both in aggregation and size to the proteoglycan present in the control. However, after 5 weeks of treatment synthesis shifted to a small nonaggregating proteoglycan with longer glycosaminoglycan chains now containing dermatan sulfate, possibly representing a switch in proteoglycan synthesized. Heparan sulfate was also detected. Unlabeled proteoglycan released from the tissue during Ro 11-1430 treatment was large (Kav = 0.25 on Sepharose CL-2B) but incapable of aggregation, suggesting the initial proteolytic cleavage was in or near the hyaluronic acid-binding region of the proteoglycan. Degradative enzyme activity varied during the period of treatment. Since other tissues remained histologically normal during the treatment with Ro 11-1430, this drug may have possible therapeutic value.

Topics: Animals; Chondrosarcoma; Glycosaminoglycans; Heparitin Sulfate; Male; Proteoglycans; Rats; Sarcoma, Experimental; Tretinoin

The entire corneal epithelium of each of 42 rabbits was removed bilaterally. Tretinoin or 0.5% or 0.1% ethylretinamide drops were applied topically five times a day to the eyes of one-half of the experimental animals, and peanut oil was applied to the eyes of the other half (the controls). The healing of the denuded corneas of the animals receiving tretinoin or 0.5% ethylretinamide was significantly more advanced than the healing of the corneas of the control animals. The 0.1% ethylretinamide solution did not enhance the healing process.

Topics: Animals; Cornea; Corneal Diseases; Epithelium; Female; Male; Rabbits; Time Factors; Tretinoin; Wound Healing

Oral retinoids have been largely introduced in the management of psoriasis. The beneficial effect, however, differs according to the clinical type and requires an appropriate dosimetry: Pustular types respond rapidly and sufficiently to high initial doses (75 mg/d). In psoriatic erythroderma low initial doses (35 mg/d) seem indicated increasing the dose to 50 mg/d after 2-4 weeks. In chronic stationary psoriasis medium doses (50 mg/d) should be given as adjuvant treatment, combined with anthralin or UVB (SUP). In severe cases oral retinoids can be administered with systemic PUVA (RePUVA). Cheilitis, mucosal dryness and hair loss may appear temporarily as dose dependent side-effects. No hepatotoxicity was found. Interactions with serum triglycerides were seen, particularly in patients with diabetes, obesity, alcoholism and elevated triglyceride levels before treatment. Beside the compound Ro 10-9359 new synthetic derivatives are under investigation, either for topical therapy (Ro 11-1430), or for systemic therapy in lower doses (Ro 12-7554). Their mechanisms of action are still unknown. New findings suggest that retinoids may exert an immunomodulatory effect on dermal cells, in addition to their influence on keratinocytes.

Topics: Dose-Response Relationship, Drug; Drug Therapy, Combination; Etretinate; Humans; Psoriasis; PUVA Therapy; Tretinoin

Modification of sister chromatid exchanges and radiation-induced transformation in mouse C3H/10T 1/2 and Syrian hamster embryo cells by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate and two retinoids, the trimethylmethoxyphenyl analog of N-ethyl retinamide and beta-all-trans-retinoic acid, has been studied. 12-O-tetradecanoylphorbol-13-acetate alone enhances, and retinoids alone reduce radiation-induced transformation. When both compounds were present, the retinoids not only reduced the oncogenic effects of radiation but completely eliminated the promoting effects of 12-O-tetradecanoylphorbol-13-acetate. These results were not paralleled by changes in sister chromatid exchange frequencies, indicating that, while sister chromatid exchanges may be useful as indicators of primary carcinogen mutagens, they may have little utility when secondary agents after the response of cells to a primary initiator.

Topics: Animals; Cell Division; Cell Survival; Cell Transformation, Neoplastic; Cells, Cultured; Cocarcinogenesis; Cricetinae; Crossing Over, Genetic; Mice; Phorbols; Sister Chromatid Exchange; Tetradecanoylphorbol Acetate; Tretinoin