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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.

The phospholipid pattern of the involved and the uninvolved epidermis from 48 psoriatic patients and of the normal epidermis from 23 healthy controls was determined by thin-layer chromatography. A higher amount of total phospholipids was found only in the involved psoriatic epidermis, whereas significant alterations in the phospholipid pattern were observed in the psoriatic lesion and in the lesion-free epidermis. Namely, the decrease of phosphatidylserine and the increase of phosphatidylinositol were identically present in both the involved and the uninvolved psoriatic epidermis. It seems likely that these alterations in the phospholipid pattern in psoriasis may be related to subclinical alterations of the epidermis in this disease.

The sensitive step of inhibition of chondrogenesis in vitro by retinoids was investigated in modified micromass cultures of limb bud mesenchymal cells from mouse embryos of day 11 and 12. Evaluation of chondrogenesis was performed after alcian blue staining, using a simple random hit counting of cartilage nodules. All-trans-retinoic acid, 13-cis-retinoic acid, and a newly developed arotinoid, RO 13-6298, were tested for their ability to inhibit chondrogenesis. We found that inhibition of chondrogenesis depended on the dosage and the duration of treatment with the different retinoids. Further analysis showed that chondrogenesis in limb bud mesenchymal cells from the proximal part was irreversibly inhibited after one hour of treatment, whereas distal cells showed a reduction of cartilage development only after a treatment period of 12 and more hours. In respect to the doses of the retinoids, proximal cells were about one magnitude more vulnerable than distal cells. These proximo-distal differences were obtained with 13-cis-retinoic acid at 10 micrograms/ml, with all-trans-retinoic acid at 1 microgram/ml and with arotinoid RO 13-6298 with 10 ng/ml. It is supposed that the late blastemal stage of chondrogenic differentiation before the onset of matrix synthesis is the step which is most vulnerable to retinoid treatment.

Doses of 3 mg/kg Ro 10-9359 (in arachis oil) were daily administered to adult female Wistar rats by gastric tube for a period of 10 days. Control animals received corresponding quantities of arachis oil only. The body weight of all rats was registered daily. Samples of jejunum and ileum were processed for quantitative histochemical analysis of neutral alpha-glucosidase kinetics and for three-dimensional evaluation of the mucosal architecture. In addition, mucosal scrapings were prepared from these intestinal segments, and the specific sucrase activity was determined. For each animal data were pooled and analyzed by Wilcoxon (Wn) test. Body weight and all registered parameters in the jejunum of treated animals remained unchanged as compared to the controls. In the ileum, however, we found under aromatic retinoid an increase of sucrase activity (P = 0.02) and of mucosal surface per unit serosal area (P less than 0.05). The hydrolytic activity of neutral alpha-glucosidase (Vmax) showed a clear trend to increase at both the villus base and apex, whereas the apparent substrate affinity (Km) remained unaltered. Our results show that, in closes of 3 mg/kg/day, aromatic retinoid induces (1) an increase in mucosal surface area, apparently due to hyperproliferation of the absorptive epithelium in ileum, which could facilitate its absorptive capacity and (2) an increase of specific sucrase activity, which could result in an enhanced carbohydrate assimilation. These findings indicate that Ro 10-9359 in addition to its effects on keratinizing epithelia exerts a distinct influence on the structure and function of the intestinal epithelium.

The morphological alterations of involved skin in three different types of parapsoriasis were investigated in 9 patients by electron microscopy. Pityriasis lichenoides chronica (PLC) is characterized by a lymphohistiocytic dermal infiltrate and by epidermotropic histiocytic cells, which penetrate up to the horny layer. In parapsoriasis en plaques (PeP) and in parakeratosis variegata (PV) the dermal infiltrate is mainly composed of lymphocytoid cells, some of which, particularly in PV, reveal the features of Sézary-Cells (11% and 30% respectively). The epidermis is predominantly invaded by partly atypical lymphoid cells. In some instances membrane contacts between Langerhans cells, keratinocytes and atypical lymphoid cells can be observed. The increased number of epidermotropic cells and the increase of atypical lymphoid cells in the dermal infiltrate are the main ultrastructural features of the malignant transformation of PV. Finally, an important difference between PLC and the other two types of parapsoriasis is the fact that in PLC epidermotropic cells are mostly of histiocytic origin, whereas in PeP and PV they are mainly lymphocytes. The electron microscopic findings support the opinion that PLC should not be considered as a type of parapsoriasis and that PeP and PV probably correspond to prelymphoma.

Hairless female Ng/-mice were irradiated by UV-light for 16 h daily over a period of 24 weeks. Monooxygenase activities were measured in liver and skin, and an induction of the aryl-hydrocarbon hydroxylase was detected in liver by both fluorometric and radiochemical methods, whereas no induction of this enzyme could be demonstrated in the skin.

The effect of oral aromatic retinoid Ro 10-9359 in a high dosage (25 mg/kg/day) on guinea pig epidermis was investigated by light and electron microscopy. The induced morphological alterations showed two different stages: (a) In the injury stage, seen aftr one week of retinoid administraion, the epidermis was mainly characterized by lack of the horny layer and vacuolar cytoplasmic disintergration of the malpighian layer with intracellular edema and accumulation of some PAS-positive material. Tonofilaments and desmosomes were markedly reduced, keratinosomes were increased in number. (b) In the recovery stage, seen after 3 weeks of administration, the horny layer had reappeared, the edematous and vacuolar changes were diminished and the epidermis became slightly acanthotic. Hypergranulosis with numerous spongiform keratohyalin granules was a prominent feature. The number of tonofilaments, desmosomes, and keratinosomes showed a clear tendency to normalization. In conclusion, high systemic doses of aromatic retinoid initially exert a cytotoxic, keratolytic, and mucoplastic effect on the normal guinea pig epidermis. Nevertheless, the affected keratinocytes adapt themselves, despite the further administration of the drug, showing a gradual restoration of these changes and a stimulation of epidermal proliferation, leading to acanthosis.

The effect of long-term ultraviolet irradiation on the connective tissue of the skin was investigated in 25 naked (Ng/-) mice which received a total daily radiant dose of 40 +/- 2 J/cm2 for a period of 8.5 months. The produced alterations were very similar to those found in actinic elastosis of humans, as assessed by histologic and electron-microscopic criteria.

Arotinoid ethyl ester (RO 13-6298) is a new and very potent retinoid that exerts a profound influence on epithelial and mesenchymal differentiation in doses 500 times lower than those of compounds of the first and second retinoid generation. In the present study the teratogenicity of arotinoid ethyl ester was investigated in NMRI mice employing different treatment schedules. Recording of abnormalities was performed on day 18 (day 0 = day of conception) according to Wilson and with cleared skeletal preparations. Intraperitoneal application of the drug at a dosage of 10 micrograms/kg/day for three consecutive days (days 9-11 or 12-14) caused severe malformations, particularly in the skeletal system and the cavernous organs. Skeletal elements were reduced in number, shortened, or abnormally shaped. Ossification was diminished. Atresia of anus and urethra were frequent. Single application of 200 micrograms/kg between days 8 and 14 also caused multiple and severe malformations. However, no stage-specific pattern of abnormalities was detectable. Some skeletal malformations indicated more or less vulnerable stages that were in concordance with special developmental steps. Others, however, seemed to be equally susceptible over a longer period, eg, rays 1 and 5 of the hand or foot and the development of the mandibular joints. The pattern of abnormalities caused by these very low doses of RO 13-6298 is comparable to that obtained with other retinoids and is achieved within the same relative dose-response range. Preconceptional treatment of the animals did not induce any malformations.

In 64 patients with psoriasis and in 54 persons without any skin disease the amount of zinc was estimated in plasma and in the erythrocytes using atomic absorption spectrophotometry. The findings showed an elevated plasma level and a lower zinc content of blood erythrocytes in psoriasis. Both values were statistically significant. No relation was found between these changes and the percentage skin surface covered by psoriatic lesions. The disturbed distribution of zinc in psoriasis may be due to disturbances if histidine metabolism or to changes of the permeability of the cell membranes associated with this skin disease.

One hundred and 18 children with various clinical types of vitiligo, were treated with oral trimethylpsoralen (Trisoralen, P. B. Elder Co.) followed by exposure to sunlight or an artificial ultraviolet radiation source. In 61 of the adult patients, more than 80% of the vitiliginous areas became repigmented, 18 patients re-pigmented 50-80%, 13 repigmented less than 50% and 8 patients failed to repigment at all. In all of the children, more than 80% of the treated vitiliginous patches became repigmented. No side effects were observed. A follow-up study of the retention of the new pigment revealed that 72 adults (out of 76 followed-up) and 10 children (out of 11) without any treatment had retained 95% or more of the new pigment, 18 months after the completion of treatment. Oral trimethylpsoralen is therefore suggested for the treatment of vitiligo.

The influence of all-trans retinoic acid, 13-cis retinoid acid and two aromatic retinoids (Ro 10-1670, Ro 11-1430) on the chondrogenic differentiation of mesenchymal cells in vitro was studied electron-microscopically. Organ cultures of limb buds from mouse embryos (Day 11) and high-density cultures of embryonic-mouse mesenchymal cells (Day 12) were used as experimental models. After a 6-day culture in the control medium, the development of hyaline cartilage was observed in both systems. In cultures which were treated with retinoids from Day 1 through Day 3 and then incubated in the control medium for 3 more days, the mesenchymal cells still maintained the morphological features of the blastema stage; cartilage synthesis was reduced (low retinoid concentrations) or completely absent (high retinoid concentrations). These findings indicate that the treatment of embryonic-mouse mesenchymal cells with retinoids induces a persistent and dose-dependent inhibition of chondrogenic differentiation, which in quantitative terms, is variably expressed during treatment with different retinoids. These inhibitory effects of retinoids on chondrogenesis are probably implicated in the pathogenetic mechanisms of their teratogenic action in vivo.

In recent years the search for new retinoids, safer and more potent than the available compounds, has led to the development of arotinoids. In preliminary clinical trials, arotinoid ethyl ester [(E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]benzoic acid ethyl ester; TTNPB ethyl ester] was found to be highly effective in the treatment of severe and etretinate-resistant dermatoses. Using adult hairless mice, embryonic mouse limb-bud cultures and keratinocyte cultures as experimental models, we have performed morphological, autoradiographic and biochemical studies on the effects of arotinoid ethyl ester on epithelial differentiation in vivo and in vitro. Arotinoid ethyl ester stimulates proliferation of both embryonic and adult mouse epidermis. However, it inhibits the differentiation of embryonic epidermis and enhances that of adult epidermis. Arotinoid ethyl ester induces a decrease in the cyclic AMP content of cholera toxin-stimulated keratinocytes but fails to alter cyclic AMP concentrations in keratinocytes not treated with cholera toxin.

In patients treated with oral retinoids the recovery of Propionibacterium acnes and other anaerobic bacteria in the skin is markedly reduced, whereas an increased colonization of the skin and a significant rise in the incidence of cutaneous staphylococcal infections are observed. Since very little is known about the effects of retinoids on bacteria, in the present study we investigated the influence of 4 retinoids (isotretinoin, etretinate, arotinoid ethyl ester, arotinoid sulfone) in 15 different concentrations on the growth of 10 Gram-positive and Gram-negative bacteria in vitro and on their susceptibility to 10 antibiotics. It was found that all retinoids were not capable of affecting either the growth of bacteria or their susceptibility to antibiotics. It seems reasonable, therefore, to assume that the retinoid-induced changes in cutaneous bacterial flora in vivo are due to mechanisms other than to the direct action of these compounds on bacteria.