Therapeutic effects of nandrolone decanoate, tibolone, lynestrenol and ethylestrenol on Sjögren's syndrome-like disorder in NZB/W mice.

Growth of mononuclear cell infiltration in submandibular glands is significantly inhibited by Org OD14 (tibolone), lynestrenol and ethylestrenol given orally to New Zealand Black/White (NZB/W) mice from 26 weeks of age onwards. In addition, the extent of already established mononuclear cell infiltrations is significantly inhibited and reduced by nandrolone decanoate injected from 43 weeks of age onwards. Tibolone and nandrolone decanoate are the most potent of the four drugs. The therapeutic effect of these four steroids on the Sjögren's syndrome-like disorder in NZB/W mice is not related to their endocrine activities.

Effects of tibolone, lynestrenol, ethylestrenol, and desogestrel on autoimmune disorders in NZB/W mice.

The effects of two progestagens--lynestrenol, desogestrel--an anabolic steroid--ethylestrenol--and a compound with weak progestational, anabolic, androgenic, and estrogenic activities--tibolone--on the development of systemic lupus erythematosus and Sjögren's syndrome-like disorders were studied in the NZB/W mouse. All four compounds inhibited the expression of autoimmune disease. Tibolone was 10-40 times more potent--depending on the parameter used--in preventing symptoms of autoimmunity than the second most effective compound lynestrenol. Ethylestrenol was the third effective compound and desogestrel the least effective compound in this series. Combined with literature data, these results show that steroids with different endocrine profiles can prevent the development of autoimmunity in the NZB/W mice. Since the NZB/W mouse is a good animal model for human systemic lupus erythematosus and Sjögren's syndrome and since tibolone, lynestrenol, and ethylestrenol have endocrinological profiles which are not prohibitive for treatment of male and female patients, investigation whether these compounds have a value in the treatment of human autoimmune diseases seems warranted.

Idiopathic atrophie blanche.

Idiopathic atrophie blanche (segmental hyalinizing vasculitis; livedo reticularis with summer ulceration) is a chronic cutaneous disorder of young to middle-aged women that is characterized by persistent painful leg ulcerations. Primary lesions consist of purpuric macules and papules which undergo superficial ulceration, followed eventually by the development of irregular, atrophic, porcelain white scars with fine borders of ectatic vessels. We have studied twelve patients with idiopathic atrophie blanche by immunofluorescence, thin section light microscopy, and electron microscopy. All patients were examined extensively in order to rule out primary immunologic and vaso-occlusive disorders that may result in a similar clinical appearance. Subsequently, ten patients were treated for 1 to 12 years with combinations of phenformin and ethylestrenol. Each treated patient noted rapid improvement in existing lesions, significantly less pain, and a decrease in the development of new lesions. Side effects in all but two patients were minimal and well tolerated. Light and electron microscopic examination of early and well-developed lesions revealed fibrin plugs which first occlude superficial dermal vessels, followed by necrosis and obliteration of the affected vessel walls. Eventually, new vessel formation occurs in some areas of fibrin deposition. Polymorphonuclear leukocytes and mononuclear cells only rarely participate in this process. Although this disorder has previously been considered a localized form of cutaneous vasculitis, the absence of both leukocytes and nuclear fragmentation from the neighborhood of vascular structures in early lesions differentiates this disorder from immune complex-mediated necrotizing vasculitis. Thus the term vasculopathy describes this disorder more appropriately than the term vasculitis.

Prospective study of a phenformin-like substance (moroxydine chloride) in patients with deficient vessel wall fibrinolysis.

It is known that ethylestrenol and/or phenformin can normalize deficient fibrinolysis in the vessel walls and prevent recurrent thromboembolism (Hedner et al., 1976; Nilsson et al., 1975, 1981). Because of the side-effects of phenformin, we studied the effect of a phenformin-like substance: moroxydine chloride (Kabi 1886), which unlike phenformin, does not cause lactic acidosis. A prospective randomized clinical trial was carried out on 49 patients with a decreased release capacity of fibrinolytic activity (venous occlusion test for 20 min as described by Robertson et al. (1972) on at least two occasions. They received either moroxydine chloride in a dose of 0.04 g/kg a day or no specific treatment. Most of the patients had earlier at least one episode of deep venous thrombosis. At review 6 months after entering the trial, it was found that out of 26 patients receiving moroxydine chloride, the release capacity was normal in 16 (62%), compared with 5 (22%) of the 23 controls. Dicoumarol alone did not seem to have any effect on the fibrinolysis. The only side-effects were occasional diarrhea in two, which was controlled by reduction of the dose, and itching requiring withdrawal of the drug in one. Moroxydine chloride, thus, seems to normalize a defective release capacity of vessel wall in a fair percentage of cases.

delta 4-ethylestrenol in recurrent deep venous thrombosis.

In a study of 21 patients with recurrent venous thrombosis and/or thrombophlebitis, fibrinolytic activity measured after venous occlusion was significantly improved after treatment with 6 mg delta 4-ethylestrenol (Orgabolin) daily. Seven of the 21 patients had abnormally low vessel wall plasminogen activator content, which normalised during treatment. No tendency to develop resistance to the drug was observed during treatment for periods up to 56 months. This improvement was shown to be combined with a significant lower (p less than 0.001) incidence of thrombosis.

The value of phenformin and ethyloestrenol in the prevention of deep venous thrombosis in patients undergoing surgery.

The effect of phenformin and ethyloestrenol on the incidence of post-operative deep venous thrombosis was studied in 314 surgical patients in a double-blind randomised trial. Although the laboratory tests suggested that the regime produced an increase in activators of the fibrinolytic system, the drugs used did not lower the incidence of post-operative deep venous thrombosis. Possible explanations of this paradox are advanced.

The protective effects of ethylestrenol against acute poisoning by organophosphorus cholinesterase inhibitors in rats.

Pretreatment of rats with 10 mg of ethylestrenol (17alpha-ethylestr-4-en-17beta-ol) by force feeding twice daily for three days and once on the fourth day decreased the severity of parathion (0,0-diethyl 0-4-nitrophenyl phosphorothioate) toxicity and caused a 150% increase in the parathion LD50 in male animals. It decreased by 51% cholinesterase inhibition in the brain caused by i.p. injection of 2 mg of parathion/kg body weight but not that of an equitoxic dose (0.5 mg/kg) of its active metabolite, paraoxon (0,0-diethyl 0-4-nitrophenyl phosphate). It decreased by 29% cholinesterase inhibition in plasma following i.p. administration of parathion but caused only a 16% decrease in cholinesterase inhibition following administration of the equitoxic dose of paraoxon. It did not protect against brain cholinesterase inhibition by 4 mg/kg of parathion given i.v.; however, brain parathion levels were 16% lower in rats pretreated with ethylestrenol than in control rats. It increased the rate of inactivation of both parathion and paraoxon by liver microsomal enzyme preparations. Thus enzyme induction seems to account for the protection afforded by ethylestrenol to toxicity following poisoning by organophosphates.