Lipid-lowering effects of two synthetic oestrogen derivatives with weak genital oestrogen properties.

The effects on serum lipids of two weak synthetic oestrogens were examined in 23 patients, 17 of whom were given cyclofenil and 6 methallenestril for a period of 10 weeks. These compounds have previously been demonstrated to have a much lower effect on the genital organs than on connective tissue compared with natural oestrogens. With both substances there were during treatment significant reductions of serum triglycerides (mean average reduction 25%) and cholesterol (20%). No side effects were noted. Previous studies have shown that the net effects of oestrogens on serum lipids depend on their formulation. This study indicates that weak synthetic oestrogens, primarily designed to influence bone and connective tissue, also have lipid-lowering properties which are unrelated to their feminizing capacity.

Improvement of lung function in a scleroderma patient treated for 12 months with cyclofenil.

A 48 year old male scleroderma patient with typical impairment of respiratory function, including low vital capacity, low static lung compliance and low diffusing capacity for carbon monoxide, was treated with cyclofenil for one year. Assessment of lung function after 3, 6 and 12 months treatment showed marked improvement of vital capacity, increased physical working capacity, less hypoxia at maximum work, increase of static lung compliance and decreases of maximal transpulmonary pressure. Closing capacity decreased, and an increase in difussing capacity for carbon monoxide was seen.

Evaluation by integrated thermography of the beneficial effect of cyclofenil in severe subcutaneous arterial insufficiency.

Integrated thermographic measurements were made in a patient suffering from a complex syndrome which included scleroderma, Osler-Weber-Rendu disease and a marked atherosclerotic circulatory insufficiency. A new anti-estrogenic drug, cyclofenil, elicited a rapid and prolonged curative effect against the entire syndrome. The circulatory amelioration was registered periodically by integrated thermography of the face and both hands. This method enables temperature distribution functions to be calculated and seems to hold considerable promise for the evaluation of circulatory changes and in particular those changes evoked by therapeutic agents.

Prolonged serum insulin decreasing effects of two synthetic somatostatin analogues studied in vivo by a new animal method. Preliminary communication.

A newly developed in vivo method, using the ob-ob strain of obese-hyperglycaemic mice with permanently very high serum insulin values, makes it possible to detect more prolonged serum insulin lowering properties than in normal animals. Two newly synthesized analogues of somatostatin, D-alanine-somatostatin and des-alanine-des glycine-des-amino-somatostatin produced a more prolonged and greater decrease in the serum insulin values of ob-ob mice than did somatostatin. Our new in vivo method makes it possible to investigate the duration of insulin suppression of new derivatives.

Scleroderma (progressive systemic sclerosis, PSS); pathophysiological, clinical and pharmacological aspects of the syndrome.

Scleroderma is an uncommon complex disease. The onset is slow and the progress is chronic. The main pathophysiological changes vary; they affect blood vessels, connective tissue, collagen fibres, cause fibrin deposition and inflammatory reactions. There may be early oedema and a wide spectrum of organic involvement. Clinically, all the fibril-containing and connective tissue organs can be attacked in various degrees. The most common organ manifestations are the Raynaud's phenomenon in the arms and hands, vascular fibrosis, stiff and hard facial skin, restriction of joint movement by pericapsular hardening, calcium deposition and capsular rigidity. In the gastrointestinal tract muscle atrophy, collagen and connective tissue damage are common, especially at the cardia. Malabsorption may occur. Progressive pulmonary fibrosis leads to cor pulmonale and respiratory insufficiency. The liver, kidneys and the endocrine glands are, however, seldom involved. Therapeutic trials have been performed using many different groups of drugs: vasodilatating agents, corticosteroids, drugs found experimentally to influence connective tissue, thyroxine and a variety of anti-rheumatic agents. In the last decade best short-term clinical results have been achieved with penicillamine, some vasodilators, chlorambucil and in recent years with cyclofenil a potent anti-oestrogen, which has marked connective tissue and collagen metabolism influencing properties. Good therapeutic effects without serious side effects have been achieved.

Sheehan's syndrome of hypothalamic origin in a woman with juvenile diabetes mellitus.

A 25-year-old woman with severe diabetes mellitus since the age of 7 developed anterior pituitary insufficiency after pregnancy toxaemia with hypofunction of the thyroid, ovaries and adrenal cortex. Following the development of Sheehan's syndrome, her insulin requirment decreased dramatically. I.v. administration of TRH, LRH and vasopressin induced nearly normal pituitary response levels of TSH, LH and plasma cortisol, indicating a hypothalamic damage as the primary aetiological factor.

Treatment of malignant metastatic pancreatic insulinoma with streptozotocin. Review of 21 cases described in detail in the literature and report of complete remission of a new case.

The possibilities of treating different types of pancreatic islet cell cancer with the active drug streptozotocin have been studied in reports of 21 patients published during the last 8 years. The unusual features of the symptomatology, dosage and injection methods, side-effects after different infusion schedules and complications of streptozotocin therapy, are compared. A new case with pancreatic carcinoma and liver metastases was treated with a total dose of 14 g streptozotocin, divided into 7 injections with an increasing interval between them. This patient underwent a marked amelioration of the disease, without serious side-effects of the streptozotocin treatment. She has been apparently well for the 22 months which have now elapsed since the beginning of treatment. This seems to be one of the longest remission periods yet published in the insulinoma literature.

Normalization of hypercalcaemia of primary hyperparathyroidism by treatment with methallenestril, a synthetic oestrogen with low oestrogenicity.

The oestrogenic compound methallenestril has a relatively low oestrogenicity but a marked growth-inhibiting property in experimental studies. Methallenestril was administered in a dose of 6 mg daily to 6 postmenopausal women with hypercalcaemia and primary hyperparathyroidism (HPT) for periods between 5 and 24 weeks. In all the patients, serum calcium was normalized during treatment, presumably due to a reduction of bone resorption since fasting urinary calcium and urinary hydroxyproline excretion were lowered as well. This pilot study indicates that certain oestrogenic compounds with high potencies for growth inhibition but with low oestrogenic properties might be worth further investigation in the medical management of primary HPT.

Effect of cyclofenil treatment on arterial insufficiency demonstrated in a patient by colour thermography.

Cyclofenil, 200 mg t.i.d., was administered for four months to a 67-year-old woman, who suffered from a combination of scleroderma, Osler-Weber-Rendu disease and a severe atherosclerotic circulatory insufficiency. The effects on the severely impaired skin circulation in the face and hands were followed and recorded by colour isothermograms, using the AGA monitor system. The treatment resulted in a marked improvement of the arterial circulation with disappearance of the Raynaud phenomenon, complete arrest of gastrointestinal bleeding, disappearance of malabsorption, and relief of the joint stiffness.

Treatment of primary hyperparathyroidism with cyclofenil--a synthetic stilbestrol derivative with minimal feminizing effects.

In eight patients with primary hyperparathyroidism (HPT) the laboratory effects of cyclofenil, which is a synthetic stilbestrol derivative with weak feminizing effects, were studied over a period of 5-13 weeks. In all the patients there were during treatment clear reductions of the serum calcium levels as well as the urinary excretions of calcium and hydroxyproline. These findings are in accordance with earlier reports that oestrogens reduce bone resorption mediated by parathyroid hormone. It has previously been demonstrated that cyclofenil can be given, on other indications, for several years to both male and female patients without oestrogenic side-effects. This pilot study, therefore, indicates that treatment with cyclofenil might be of value in some cases of primary HPT where surgery is not considered.

Evaluation of renal concentrating ability with DDAVP and pitressin.

This paper reports an attempt to develop a rapid test of the renal concentrating ability using a newly synthetized vasopressin analogue, DDAVP (1-desamino-8-D-arginine-vasopressin), which was given intravenously in a dose of 2 micrograms. Patients investigated for various endocrinological disorders were evaluated with both DDAVP and pitressin. There was a good correlation between the maximal urine osmolalities with both tests. Since DDAVP has fewer side effects and a more rapid onset of action it appears advantageous for investigations of renal concentrating ability.

Treatment of progressive systemic sclerosis (scleroderma, PSS) with a new drug influencing connective tissue.

Cyclofenil is a new diphenyl ethylene derivative related to stilboestrol without oestrogenicity but with marked effects on connective tissue metabolism. The drug has been tested, in a daily dose of 200mg X3, in six patients with progressive systemic sclerosis (PSS) to analyze the expected beneficial effects on the PSS symptoms. The typical skin hardness, joint and muscle rigidity, and reduced breathing capacity were improved to varying dgrees. The only side-effect was a slight transient liver enzyme elevation in 1 out of 6 patients. A slight increase was found in urinary calcium and hydroxyproline excretion. In several cases serum calcium, cholesterol, triglyceride and in some cases the serum uric acid levels were decreased. The ANF titres diminished to varying degrees in 4 out of 6 patients. These results indicate that further detailed clinical and laboratory studies on the therapeutic potential of cyclofenil in PSS and other diseases affecting connective tissue seen to be justified.

Recurrent and reversible cerebellar ataxia with concomitant episodes of hyperthyroidism: a new autoimmune syndrome.

A new disorder with possible autoimmune background is described in a 67-year-old man. He had experienced episodes of cerebellar ataxia induced by infections over the last 40 years. In 1963 he had thyrotoxicosis. The patient underwent bilateral subtotal thyroidectomy. Recently it has been possible to detect involvement also of his remaining thyroid gland, with findings compatible with hyperthyroidism concomitant with his cerebellar atixia.

Cyclofenil in the treatment of scleroderma - a general view on the results after treating 29 cases.

Results are presented from an open treatment of 29 patients suffering from progressive systemic sclerosis (PSS) with cyclofenil, an oestrogenlike non-steroid compound with very low oestrogenicity, which was recently claimed to be effective in this disorder. The treatment resulted in significant improvement of the skin condition and regress of ulcerations, Raymaud's phenomenon, joint pain and stiffness. Most of the patients experienced an increased sense of well-being. A slight elevation of ASAT and ALAT was noted in seven patients and weight gain in two. Present data do not permit an assessment of whether the treatment might influence the visceral changes. A multi-centre controlled study is in progress.

Cyclofenil versus placebo in progressive systemic sclerosis. A one-year double-blind crossover study of 27 patients.

Cyclofenil was evaluated versus placebo in the treatment of progressive systemic sclerosis (PSS, scleroderma) in a 2 x 6-month double-blind crossover study. The mean duration of disease was six years. Of 38 patients entering the study, 27 completed both periods. Reasons for drop-outs were very high liver transaminases in three cases, cardiac death in two, and drug allergy, alcoholic problems, suspected congestive heart failure, reactivation of tuberculosis, arteriosclerotic heart disease, and lethal progression of PSS in one case each. No fatality was attributed to cyclofenil. Liver enzyme abnormalities were seen in 13 of 35 active drug periods and in 5 of 30 placebo periods. Cutaneous and visceral involvement were assessed by a large battery of subjective parameters and objective tests. Overall improvement was seen during 17 drug periods and nine placebo periods (N.S.), but a paired comparison of the status at the end of each treatment period resulted in the following distribution: 15 were improved at the end of the drug period, four at the end of placebo period (p less than 0.01) and eight were unchanged. In patients with a disease duration of five years or less, joint stiffness and pain were less on drug than on placebo treatment (p less than 0.05). In the whole group, oesophageal peristalsis improved (p less than 0.05). Blood folate increased (p less than 0.01). Working capacity was lower after the drug period than after the placebo period (p less than 0.05). Several other parameters, however, did not change significantly. Cyclofenil appears to be a promising drug in the treatment of PSS and should be tested further in controlled long-term studies.