Severe psoriasis--oral therapy with a new retinoid.

Ro 10-9359 is a retinoic acid derivative, selected for study because of a better tolerance than retinoic acid, shown in animal experiments. Doses of 25 mg b.i.d., 25 mg t.i.d. and 50 mg b.i.d. were administered orally to 27 patients suffering from severe chronic generalized psoriasis. The clinical efficacy was evaluated by means of a new index, psoriasis area and severity index (PASI) based on severity and area of psoriatic lesions. At doses of 25 mg t.i.d. or 50 mg b.i.d. Ro 10--9359 proved to be an extremely potent antipsoriatic drug. A more than 90% reduction of psoriatic lesions could be seen in 10 patients out of 20 after 4-8 weeks of treatment. This good effect lasted about 5 weeks after treatment. Side effects were frequent, but mostly mild and completely reversible after termination of treatment.     

Combined treatment of psoriasis with a new aromatic retinoid (Tigason) in low dosage orally and triamcinolone acetonide cream topically: a double-blind trial

In a multicentre double-blind trial the effect of three therapy regimens was studied for 6 weeks in ninety psoriasis patients: (1) aromatic retinoid (Ro 10-9359) orally (0.50-0.66 mg/kg body weight) and placebo cream topically; (2) aromatic retinoid (Ro 10-9359) (same dosage) with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream; (3) placebo capsules with 0.1% triamcinolone acetonide and 5% salicylic acid in lanette wax cream. Regimen 1 had virtually no effect and regimen 2 gave better results than regimen 3 for almost ail parameters, although statistical significance was reached for only some of them. The 6 week double-blind period was followed by an open study in which all patients were treated according to regimen 2. The clinical result could be maintained up to the end of the study (18 weeks), when more than 60% of the patients showed good to excellent (80–100%) improvement. Most of the patients had dry lips, but generally without clinical symptoms of a cheilitis. The other well-known side-effects of retinoid were mild and relatively rare. It is concluded that the combination of the aromatic retinoid (Ro 10-9359) given in low dosage orally with corticosteroids topically is as effective as therapy with the retinoid in high dosage alone, but with markedly less side-effects.     

Subcorneal pustular dermatosis (Sneddon-Wilkinson disease)—therapeutic problems

A patient with subcorneal pustular dermatosis with a fatal outcome is presented. Treatment with corticosteroids, vitamin E, dapsone, sulphapyridine and levamisole was ineffective. Only systemic treatment with retinoic acid and a new aromatic retinoic acid derivative (Ro 10-9359) produced a satisfactory clinical response, but a complete remission was not obtained.     

Systemic treatment of psoriasis with an oral retinoic acid derivative (Ro 10-9359)

Ninety-seven patients with severe psoriasis took part in a 1-year study to evaluate the effect of a new oral synthetic retinoid (Ro 10-9359). The trial was performed in a double-blind cross-over fashion. The treatment started with either 100 mg daily of Ro 10-9359 or placebo and the maintenance dose was in most cases 50 mg. Follow-up examinations were performed monthly and the parameters erythema, desquamation, infiltration and extent of the lesions were followed. Throughout the study there was a significant to highly significant preference for Ro 10-9359 shown by all parameters. More patients were in complete remission after Ro 10-9359 periods than after placebo periods. The side-effects of Ro 10-9359 on uninvolved skin and mucous membranes seemed to be largely dose-dependent. Twenty-three patients interrupted the study, four of them because of side-effects, mainly alopecia. Laboratory examinations revealed no aberrations which could be attributed to the therapy. One patient developed hepatitis during a placebo period.     

Therapeutic evaluation of the oral retinoid Ro 10-9359 in several non-psoriatic dermatoses

Forty-five patients suffering from various genodermatoses and erythematous, scaling, non-psoriatic dermatoses were treated orally with the aromatic derivative of retinoic acid, Ro 10-9359 (Tigason). In the genodermatoses the best results were obtained in ichthyosis, keratodermias and Darier's disease (95.6% good to excellent). Among the erythematous scaling diseases, treatment was effective in lichen planus, parapsoriasis and pityriasis rubra pilaris (53.3% good to excellent results). In comparison with therapies previously employed Ro 10-9359 was more effective. No serious side-effects were noted.     

Regulation of the expression of epidermal keratinocyte proliferation and differentiation by vitamin A analogs

Summary A number of vitamin A analogs (retinoids) were used to manipulate the growth of epidermal keratinocytes in culture. The retinoids used were the TMMP analog of ethyl retinoate (Ro 10-9359), 13-cis retinoic acid, all trans retinoic acid and retinol (trans). These were added to primary neonatal mouse epidermal keratinocyte cultures that proliferate, stratify, and differentiate over 2–3 weeks. [³H]Tdr labeling technics were used to quantitate proliferation. A histologic stain, and a four buffer protein extraction protocol, used in conjunction with polyacrylamide gel electrophoresis and fluorographic technics, were used to assess the differentiation of the cultures. Our results showed that all of the vitamin A analogs we tested inhibited keratinocyte proliferation. Quantitation of specific differentiation proteins showed that Ro 10-9359 and 13-cis retinoic acid partially inhibited the differentiation of the cultures. The Ro 10-9359 retinoid was unusual in that it increased the synthesis of keratohyalin granule-related proteins. These studies showed that inhibition of basal cell proliferation did not result in the obligatory expression of cell differentiation and that at least one of the events that is a part of epidermal keratinocyte differentiation can be separately controlled.These data, in part, were presented at the Proceedings of the International Dermatology Symposium in Berlin, FRG, on October 13, 1980 [33]     

Oral treatment of keratosis follicularis with a new aromatic retinoid

Four patients with extensive keratosis follicularis (Darler's disease) showed excellent clinical response to the oral administration of a new aromatic derivative of retinoic acid (RO 10-9359). Initial oral treatment with 50 to 75 mg of the drug was followed by substantial improvement in four to seven days and the lesions cleared completely after three to four weeks. Long-term treatment with 25 to 30 mg/day was sufficient to prevent recurrence. No serious side effects were seen with this dosage after several months. Some dryness of the lips and the nasal mucosa occurred and one patient experienced slight nausea. Histological investigations showed the gradual disappearance of acantholysis, dyskeratosis, and hyperkeratosis, in this order. The given therapeutic schedule is a reliable routine management for keratosis follicularis in adults.     

Treatment of congenital erythroderma ichthyosiforme in mother and son with the oral aromatic retinoid Ro 10-9359. The need for maintenance therapy

Aromatic retinoid Ro 10-9359 (Tigason) administered in the doses 25-50 mg daily to two patients (mother and son) suffering from congenital non-bullous ichthyosiform erythroderma revealed complete disappearance of the clinical signs of the disease within two weeks. A relapse was noted in one patient 1.5 months after oral treatment was discontinued. The lesions disappeared again after 30 mg of Ro 10-9359 daily within 10 days. No side-effects were recorded. The tolerance of the drug was satisfactory. The obtained data showed a high efficacy of the oral aromatic retinoid in the therapy of congenital ichthyosiform erythroderma and point to the necessity of maintainance treatment with small daily doses of retinoid for longer time periods.     

Peroral aromatic retinoid treatment of palmoplantar pustulosis: double-blind comparison of Ro 10-9359 and placebo.

Nineteen patients with chronic, recalcitrant palmoplantar pustulosis took either placebo or aromatic retinoid ethyl ester (Ro 10-9359) during a 4-month therapeutic trial. The maximal dose of Ro 10-9359 varied between 25 and 100 mg per day, according to the individual patient's tolerance. An excellent or good therapeutic response was obtained in 6 out of 9 patients on the active medication and in 2 out of 10 patients on placebo. The difference in therapeutic response between the Ro 10-9359 group and the placebo group was statistically significant (p less than 0.05). Drying and chapping of the lips was the most common side effect of Ro 10-9359 treatment.     

Stability of retinoids in culture. All-trans-retinoic acid, 13-cis-retinoic acid and etretinate in the culture of human keratinocytes, B16 mouse melanoma cells and HeLa cells

The stability of all-trans-retinoic acid, 13-cis-retinoic acid and Ro10-9359 (etretinate) in culture was analyzed by measuring the amount of each retinoid in culture medium with HPLC. In cultures of human keratinocytes and B16 mouse melanoma cells (K440B), all-trans-retinoic acid was fairly stable, but it disappeared rapidly in cultures of HeLa cells. In general, 13-cis-retinoic acid was more unstable. When all-trans- or 13-cis-retinoic acid was used, the 13-cis or all-trans forms also appeared in the culture medium as a result of cis-trans isomerization. Human epidermal keratinocytes were able to de-esterify Ro10-9359, and Ro10-1670 was also detected in the culture medium. K440B cells had a strong capacity for de-esterifying Ro10-9359. When 10 nmole/ml Ro10-9359 was added to the culture, about 1 nmole/ml of Ro10-1670 was maintained from 24 to 96 h later. In the HeLa cells culture, no Ro10-1670 was detected after the addition of 1 nmole/ml Ro10-9359. These results indicate that, in the tissue culture system, the pharmacokinetics of each retinoid depended upon its concentration, the cell type and the cellular density.     

Oral treatment of great ichthyotic disorders by ethylester retinoid (author's transl)]

Observations of 3 different great ichthyotic disorders, no longer responding to local keratolytics and to oral vitamin A are reported: a case of erythrokeratoderma variabilis, one of ichthyosiform erythroderma, and one of bullous ichthyosiform hyperkeratosis. After a week of oral treatment by the ethylester retinoid (Ro 10-9359), the hyperkeratotic component of each disease already improved dramatically. A maintenance treatment had to be continued. With equal or superior keratolytic effects, the retinoid has lower toxicity and less important side-effects than retinoic acid itself. The ethylester retinoid is nowadays the choice oral treatment in these great hyperkeratotic disorders.     

INFLUENCE OF VITAMIN E ON THE EFFECT OF VITAMIN A DERIVATIVES ON DIGESTIVE GLANDS OF RATS

This study was designed to investigate the influence of d-α-tocopheryl acetate on the toxic effect of retinoic acid and retinoid (Ro 10-9359) on pancreaticobiliary and gastric secretion after the administration of large doses for 3 weeks to albino rats. The toxicity of retinoic acid on body weight and exocrine function, and the morphologic changes in the main digestive glands of the rat are greater than with retinoid. It is clear that vitamin E may suppress or counteract the undesirable toxic effects of retinoic acid and retinoid and appears to promote the function of the main digestive glands of rats.     

In vitro and in vivo regulation of transglutaminase activity of mouse epidermal cells by various vitamin A compounds

In vitro and in vivo effects of various vitamin A analogues on the transglutaminase activity of mouse epidermal cells were investigated. In vitro addition of all-trans-retionic acid (retinoic acid), retinyl acetate, or Ro 10-9359 (etretinate) to a culture medium induced transglutaminase activity in a transformed mouse epidermal cell line (PAM 212 cells). Induction by a new synthetic vitamin-A-like compound (E-5166, polyprenoic acid derivative) was significant but less marked than that by other vitamin A analogues. Simultaneous addition of retinoic acid and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), which also induces transglutaminase, did not cause any increase in transglutaminase activity. These retinoic acid derivatives inhibited the proliferation of PAM 212 cells at concentrations of 10^–5–10^–6 M in the culture medium. In vivo analysis consisted of oral administration of retinoic acid and Ro 10-9359 to adult mice. These mice were found to have increased liver transglutaminase activity in the soluble fraction but not in the particulate fraction. Orally administered retinoic acid did not induce transglutaminase activity in the epidermis in the whole skin. These results suggest that retinoids modify transglutaminase activity and epidermal proliferation and differentiation in vitro, but the induction of the enzyme seems not to be related to the clinical effects of orally administered retinoids on various skin diseases.     

Metabolism of an aromatic retinoid Ro 10-9359 by cultured human epidermal keratinocytes

Summary An aromatic retinoid Ro 10-9359 is metabolized after absorption from intestine to form Ro 10-1670 which is an active therapeutic compound. The epidermal keratinocytes, a main target tissue of retinoid therapy in dermatology, was examined in the capacity to metabolize the retinoid. The culture of human epidermal keratinocytes was treated with 10^-6 M Ro 10-9359 and the metabolites released in the medium was analyzed by HPLC. The HPLC profile showed a distinct peak of Ro 10-1670. The human skin fibroblasts, HeLa cells, Chang liver cells and 3T3 cells were less active in metabolizing Ro 10-9359, and only a small amount of Ro 10-1670 was detected in the culture of human skin fibroblasts treated with 10^-6 M Ro 10-9359 for 2 days. When these cells were disrupted by a glass homogenizer, and incubated with Ro 10-9359, no Ro 10-1670 formation was detected.     

Action of 13-cis-retinoic acid and aromatic retinoid on several cutaneous parameters in hyperseborrheic rats

Castrated rats submitted to androgenic stimulation present hyperseborrhea with an increase in foamy cells associated with an increase in cutaneous lipids and a change in the number of epidermal cell layers. 13-cis-retinoic acid and aromatic retinoid (Ro 10-9359) were given orally during 17 days (10 mg/kg) to castrated rats which had received a testosterone implant. Cyproterone acetate was chosen as the antiandrogenic drug; it was given at doses of 10 mg/kg i.m. once every other day. As opposed to cyproterone acetate, the two substances studied had no effect on the seminal vesicle and ventral prostate. 13-cis-retinoic acid and retinoic aromatic acid increased the total number of epidermal layers: In the case of 13-cis-retinoic acid, the increase involves especially the nonnucleated cell layers, whereas with retinoid aromatic acid it involves the nucleated cell layer. The number of sebaceous glands is not changed by either products, on the other hand, the number of foamy cells is considerably decreased and the weight of cutaneous lipids is decreased as well.     

Etretinate may work where acitretin fails

Acitretin (Ro 10-1670, Neotigason), a second-generation monoaromatic retinoid, is the main acid derivative and active metabolite of etretinate (Ro 10-9359, Tigason). Three patients who were unresponsive to treatment with acitretin but who responded to etretinate are reported. Twenty-nine patients in the U.K. are currently receiving etretinate on a named-patient basis. Possible explanations for the functional discrepancy between the two drugs are discussed.     

Oral retinoid (Ro 10-9359) in children with lamellar ichthyosis, epidermolytic hyperkeratosis and symmetrical progressive erythrokeratoderma

8 children with lamellar ichthyosis, 1 with epidermolytic hyperkeratosis and 5 with symmetrical progressive erythrokeratoderma were treated with a new aromatic retinoid (Ro 10-9359). Clinical improvement was dramatic. The children acquired an appearance never obtained before with other managements. The treatment had to be maintained to prevent recurrence. The tolerance to the drug was good. The side-effects were minimal and tended to disappear after several months of treatment. Our results suggest that because of its efficacy, good tolerance and easy administration, the oral retinoid Ro 10-9359 is at present the treatment of choice for the great ichthyotic disorders of children.     

RETINOID STIMULATES EPIDERMAL OUTGROWTH OF PIG SKIN EXPLANTS

Using a pig explant culture system, the effects of retinoids on pig epidermal cells were studied. Ro 10-9359 slightly stimulated epidermal outgrowth, but this effect was not significant. Ro 10-1670 (a metabolite of Ro 10-9359) significantly stimulated epidermal outgrowth. Cytochalasin B and colchicine markedly inhibited the stimulatory effect of Ro 10-1670, but hydroxyurea or cycloheximide did not completely block this stimulatory effect. During a migratory period, cytochalasin B completely blocked it. Neither Ro 10-1670 nor Ro 10-9359 effected a change in mitotic index. Histological studies revealed that Ro 10-1670-treated epidermal cells did not form any keratin layers. These results suggest that Ro 10-1670 stimulated outgrowth, particularly migratory outgrowth, of epidermal cells, resulting in reduced keratin formation.     

The retinoic acid derivative Ro 11-1430 (Tasmaderm) in patients with acne vulgaris not tolerating retinoic acid. A controlled multicenter trial against placebo.

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.     

Occurrence of gouty tophi following acitretin therapy

Acitretin (Ro 10-1670 or Neotigason), a free acid and the main metabolite of etretinate (Ro 10-9359 or Tigason), is the most recent of the retinoids used orally in the treatment of psoriasis and numerous other dermatoses exhibiting disorders of keratinization. In the majority of cases, its side-effects are similar to those of hypervitaminosis A.