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Although several abnormalities of lipid metabolism have been associated with abnormal cornification in humans, evidence that these lipids directly provoke abnormal scale is lacking. One recently described example of a lipid abnormality in ichthyosis is absence of the enzyme steroid sulfatase in recessive X-linked ichthyosis (RXLI). This enzyme normally desulfates cholesterol sulfate (CS) and sulfated steroid hormones, including dehydroepiandrosterone sulfate (DHEAS). As a result of this enzyme deficiency, patients with RXLI accumulate CS in their blood and skin. To determine whether sulfated sterols are the specific cause of increased scale, we applied CS, DHEAS, cholesterol, or vehicle alone to the backs of hairless mice. In animals treated with CS, but not with DHEAS or with vehicle, visible scale without erythema appeared after 1 week, peaked at 2 weeks, and then diminished. When the dose of CS was doubled, abnormal scale reappeared and then decreased again. CS-induced scale was reversible, clearing within 3 days of discontinuation of treatment. Because there was no acanthosis, dermal inflammation, abnormal transepidermal water loss, or increased labeling index, it appears that the 3-fold increase in thickness of the stratum corneum in CS-treated animals is due to a direct effect on this layer.

Ichthyosis and other disorders of cornification may occur as side effects of treatment with several hypocholesterolemic agents. Recent progress in understanding of the functional role of lipids in stratum corneum provides a new pathophysiologic basis for these earlier clinical observations. In stratum corneum, lipids are segregated within intercellular membranes, where they appear to regulate permeability barrier function and desquamation. Cholesterol is an important constituent of these membranes and may be essential to both of these functions. Perturbation of barrier function induces cholesterologenesis locally within the epidermis. Polar sterol metabolites, such as cholesterol sulfate, may also regulate epidermal sterologenesis under normal or pathologic circumstances. Cholesterol homeostasis may also modulate desquamation. For example, hairless mice fed azacosterol hydrochloride (20,25-diazacholesterol) develop a generalized scaling disorder without loss of barrier function. In these mice, total stratum corneum sterol content is markedly decreased, and topical or systemic repletion with cholesterol can correct the scaling abnormalities.

Seventy patients with metastatic renal carcinoma were randomized to receive hydroxyurea, nafoxidine, or medroxyprogesterone (Provera) orally. Sixty patients were considered evaluable, with a response rate of 5% for medroxyprogesterone (one complete remission) and hydroxyurea (one partial remission) and a response rate of 16% for nafoxidine (two complete remissions and one partial remission). Differences in response rates and duration of survival were not statistically significant. The major toxicity observed with hydroxyurea was hematologic, and the major toxic effect of nafoxidine was an ichthyosis-like skin rash. Toxicity for medroxyprogesterone was minimal.

Four patients developed hair loss, depigmentation of hair, ichthyosis, and blepharoconjunctivitis during treatment with large doses of dixyrazine (Esucos, UCB, Belgium). The hair, skin, and eyes returned to normal within 2 months of withdrawal of dixyrazine, without any other treatment.

The relationship between the structure and mechanical properties of the xerotic stratum corneum from aging and photochemotherapy were studied by scanning electron microscopy. Two different types or orthokeratosis were found in these xeroses, from which we infer that the type induced by PUVA does not represent accelerated aging. The orderly architectural pattern of the stratum corneum in xerosis induced by PUVA may be related to the microanatomy of the prominent undulations at the junction between the epidermis and the papillary dermis.

Several drugs that interfere with sterol metabolism have been associated with hyperkeratosis in man. We found that 20,25-diazacholesterol (30 to 60 mg/kg/day), administered to hairless mice that were otherwise given normal laboratory chow and water ad libitum, consistently produced ichthyosis after 6 to 9 weeks, an effect that was reversible with removal of drug or with coadministration of a high cholesterol diet. Scaling was most pronounced over the tail, but some stratum corneum retention was noted over the entire skin surface. As measured in frozen sections, stratum corneum thickness was three to 10 times thicker in treated animals than in either controls or revertants. Oil red O-stained frozen sections and freeze fracture replicas revealed decreased stratum corneum membrane lipids in the diazacholesterol-treated animals, but this finding was not specific, since a similar deficit was found in control and revertant tail stratum corneum but not in the stratum corneum from other sites. Stratum corneum lipid extracts revealed reduced total free sterols, reduced cholesterol, accumulation of several normally absent sterol precursors, and increased glycosphingolipids on thin-layer chromatography and high pressure liquid chromatography. In summary, we describe a syndrome of drug-induced ichthyosis in hairless mice that parallels the drug-induced syndrome in man. This syndrome is reversible and accompanied by distinctive abnormalities in cutaneous sterol metabolism. The diazacholesterol model may further our understanding of the pathogenesis of human keratinizing disorders and may provide a valuable analogue for testing new forms of therapy, such as retinoids, for scaling dermatoses.

Clofazimine is a valuable drug which is used worldwide in the treatment of leprosy. Unfortunately, patients often resist its use because ichthyosis is a frequent side effect. The use of 25 percent urea in an emollient lotion appears to relieve the ichthyosis and, consequently, encourages the continued use of this drug.

This paper describes the cutaneous side-effects which appeared in 5 patients under Lithium medication for manic-depressive disease: 2 cases with facial and dorsal acne, 1 case with generalized pruritus with burning sensations on the tongue and tumefaction of the lips, 1 case with endogenous generalized psoriasis and 1 case with palmo-plantar hyperkeratosis, ichthyosis and associated with euthyroid goitre. The lithium content of the tissues was assayed by flame spectrophotometry of calcinated biopsy material taken from the epidermis, the dermis and the subcutaneous adipose tissue from 4 of our 5 cases. An experimental investigation was carried out in guinea pigs fed with lithium salts during 6 months. The cation was assayed in samples of epidermis, dermis and perirenal adipose tissue. A study of the accumulation of lithium in epidermal, dermal and adipose tissue is thus added to the studies already published regarding the accumulation of this ion in other tissues.

Although the new synthetic retinoids are effective when administered systemically, they have not been shown to be effective as topical agents. We compared the topical activity of six synthetic retinoids (two arotinoids, etretinate, all-trans- and 13-cis-tetrazole-retinamide, isotretinoin, and tretinoin) on tail skin in the diazacholesterol-fed mouse model of ichthyosis. Responses were assessed clinically and by measurement of stratum corneum thickness. Although the arotinoids dramatically reduced scaling, they were toxic at concentrations above 0.1%, as was etretinate at 1.0% or greater. Lower concentrations were effective without producing local or systemic toxic reactions. Clinical responses were paralleled by equivalent decrements in stratum corneum thickness, which also permitted quantitative comparisons. The order of potency for the retinoids was as follows: arotinoids, etretinate, tetrazole-retinamides, tretinoin = isotretinoin, vehicle. These results demonstrate that (1) the synthetic retinoids hold promise as topical agents; (2) irritation is not an absolute requirement for topical retinoid activity; and (3) the diazacholesterol-fed mouse offers a new assay of topical retinoid potency in a well-defined animal model of ichthyosis.

84 patients of leprosy including 15 female patients were treated with Clofzimine on a predetermined dosage regimen. 76 of these were cases of recurrent lepra reaction; 4 cases of proven DDS resistance, 3 of these being complicated by lepra reaction; and 4 were cases of reactional state in Borderline leprosy near the lepromatous end of the spectrum. The common side effect in all cases consisted of red and dark skin pigmentation of varying intensity occuring within 10 weeks of the commencement of therapy. The intensity of the colour was proportionate to the density of the infiltration. Ichthyosis occurred in 66.6% of cases. While the pigmentation was accepted by the patients in general, 10% of the patients considered ichthyosis as stigmatising. While side effects like anorexia, diarrhoea, enlargement of lymph glands and liver, corneal xerosis and loss of weight were self correcting, severe gastrointestinal manifestation, i.e. severe abdominal pain, vomiting and diarrhoea were observed in 9 patients, 5 of whom were females. Mortality was high in the females. On an incidental finding the Isonizair reduced the severity of the manifestations, it was supplemented in 10 cases on Clofazimine therapy and was found to minimise the side effects and the pigmentation due to Clofazimine. Hydration therapy for the ichthyosis and instillation of normal saline and liquid paraffin for corneal xerosis were found to be very useful.

Nafoxidine is a nonsteroidal antiestrogen available as an investigational agent from the Investigational Drug Branch of the National Cancer Institute. It has been used effectively in the treatment of breast cancer patients. A cumulative response rate of 31% is reported for a total of 200 patients treated with this drug. Most patients have been treated with a dose of 60 mg three times a day. Side effects include dryness of skin, photosensitivity reactions and, less commonly, partial hair loss. There is a strong correlation of response to nafoxidine with the presence of estrogen receptor in the tumor and also with the response to previous hormonal treatment. Nafoxidine is a useful addition to the list of hormonal treatments in the therapy of breast cancer.