ro-13-6298 and 4-(2-(5-6-7-8-tetrahydro-5-5-8-8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic-acid

Synthetic retinoids were first evaluated 15 years ago for systemic treatment of psoriasis in the Federal Republic of Germany. Etretinate was introduced 2 years ago into the market for systemic treatment of all severe types of the disease. Today etretinate is administered as monotherapy and/or combined with other modalities (anthralin, tar, topical corticosteroids, selective UV therapy, RePUVA), which leads to successful clearing in most cases. Nevertheless, thorough consideration of the risk-benefit ratio is required in each individual patient. The advantages and disadvantages are presented that should be taken into consideration. As a rule, severe cases of psoriasis are admitted to the hospital; initial treatment is given and then continued on an outpatient basis. In some patients, particularly those with pustular eruptions and/or erythroderma, low-dosage oral etretinate may be continued for prophylactic reasons over several months or years. Since the amount of hospitalization is reduced, the overall treatment costs are reduced in spite of the high cost of the drug. The main disadvantage of oral retinoids is their teratogenicity, although no severe cases of retinoid toxicity have been reported in the last 2 years in the Federal Republic of Germany since their introduction. As a successor drug to etretinate, its free aromatic acid, Ro 10-1670 is now under clinical investigation. It seems to be clinically effective, is rapidly eliminated, and requires only 4 weeks contraception after discontinuation of oral administration. Arotinoids then follow.

Topics: Abnormalities, Drug-Induced; Acitretin; Benzoates; Chemical and Drug Induced Liver Injury; Clinical Trials as Topic; Etretinate; Humans; Lipids; Long-Term Care; Prognosis; Psoriasis; Retinoids; Risk; Skin; Tretinoin

Three retinoids of the arotinoid series, namely the free carboxylic acid Ro 13-7410, its ethyl ester Ro 13-6298, and the new arotinoid ethyl sulfone Ro 15-1570, were tested for their embryotoxic and teratogenic activity in rats. The retinoids were administered orally on either day 9 or 13 of gestation. Treatment on day 9 of gestation resulted mainly in malformations of the head and the trunk; whereas, on day 13 limb malformations were prominent. Ro 13-7410 and Ro 13-6298 were about 1000 times more embryotoxic and teratogenic than retinoic acid but induced a similar malformation pattern to retinoic acid. In contrast, the sulfur-containing arotinoid Ro 15-1570 was active at similar dose levels to retinoic acid but caused a peculiar malformation pattern on day 13 of gestation. This finding supports the hypothesis that the arotinoid ethyl sulfone Ro 15-1570 has unique biological properties, inducing no bone toxicity in adult rats and distinctly affecting limb development.

Topics: Abnormalities, Drug-Induced; Animals; Benzoates; Embryo, Mammalian; Female; Gestational Age; Pregnancy; Rats; Retinoids; Time Factors

The benzoic acid derivatives of retinoic acid, often referred to as arotinoids, are synthetic retinoids that possess some of the properties of vitamin A. In general, these retinoids have more favorable therapeutic ratios, based on acute toxicity in adults, than all-trans-retinoic acid in cancer chemoprevention. In the present study, a single dose of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoic acid (Ro 13-7410; arotinoic acid), ethyl-(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8- tetramethyl-2-naphthalenyl)-1-propen-1-yl]benzoate (Ro 13-6298; arotinoid ethyl ester), (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8, 8-tetramethyl-2-naphthalenyl)-1-propen-1-yl]phenylmethanol (Ro 13-8320; arotinoic methanol), or (E)-1,2,3,4-tetrahydro-1,1,4, 4-tetramethyl-6-[1-(4-methylphenyl)-1-propen-2-yl]naphthalene (Ro 13-9272; methyl arotinoid) was administered to pregnant Syrian golden hamsters during the early primitive streak stage of gestation. A significant increase in the numbers of litters containing one or more malformed offspring occurred at all doses of each retinoid studied. The types of malformations induced by oral arotinoid treatment were essentially identical to those found after maternal treatment with all-trans-retinoic acid or other teratogenic retinoids during the same gestational age. The results indicate that the alcohol congener was approximately 400 times more potent on a milligram per kilogram basis than all-trans-retinoic acid as a teratogen, and it was 70 times as embryolethal as all-trans-retinoic acid. The ethyl ester congener was 132 times, and the free acid 123 times, as embryolethal as all-trans-retinoic acid. On a molar basis, the arotinoic acid was at least 375 times as teratogenic as all-trans-retinoic acid and at least 140 times as teratogenic as etretinate in hamsters. Because the dose-response curves for arotinoids were significantly parallel to that for all-trans-retinoic acid, and because the spectrum of congenital defects induced by arotinoids was identical to that induced by all-trans-retinoic acid and other teratogenic retinoids, the mechanism of embryopathic action of these conformationally restricted retinoids was concluded to be similar to that of all-trans-retinoic acid.

Topics: Abnormalities, Drug-Induced; Animals; Antineoplastic Agents; Benzoates; Cricetinae; Embryo, Mammalian; Female; Mesocricetus; Pregnancy; Retinoids

Arotinoids, third generation retinoids, inhibited significantly 12-lipoxygenase in platelets and 5-lipoxygenase in human neutrophils. The doses required for inhibition of 12-lipoxygenase in platelets were as low as 1 pM and of 5-lipoxygenase in neutrophils as low as 100 pM. No cytotoxicity was observed in neutrophils at concentrations used, as assayed by exclusion of trypan blue dye. In contrast to various studies reported in the literature, arotinoids used inhibited ionophore-induced arachidonic acid (AA) release in platelets and neutrophils of humans. The doses required for 50% inhibition of AA release were between 10 pM and 75 nM for platelets and between 1 and 50 nM for neutrophils. The data suggest that arotinoids are excellent dual inhibitors of cyclooxygenase and lipoxygenase pathways of AA metabolism. The mechanism for inhibition of eicosanoids lies apparently in the inhibition of AA deacylation from phospholipid membrane. It cannot, however, be ruled out that the accumulation of AA results from arotinoid-induced stimulation of reacylation of AA into the phospholipid membrane.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Benzoates; Blood Platelets; Humans; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Neutrophils; Retinoids