Antiestrogens, antiandrogens.

The aim of the study was to find new antiestrogenic and antiandrogenic structures. Out of the triphenyl-alkene derivatives Panomifene (EGIS-5660) proved to be the most active antiestrogenic compound which binds to specific estrogen receptors and exhibits inhibitory effects on experimental mammary tumors both in vitro and in vivo. The investigated antiandrogenic compounds were indol and imidazole derivatives. One of these compounds a di-imidazolil derivative, GYK1-24479 inhibited the in vitro androgen (testosterone and androstenedione) biosynthesis both in vitro and in vivo in concentration/dose dependent manner, and in these respects proved to be more active than the referent ketoconazole.

Hormonal changes during a prolonged tamoxifen treatment in patients with advanced breast cancer.

The effect of tamoxifen (TAM) on the serum levels of sexual hormones and on the sex hormone-binding globulin (SHBG) was investigated in 30 postmenopausal patients with advanced breast cancer. To study the 'prolactin reserve capacity' of the pituitary gland, thyrotrophin-releasing hormone (TRH) and sulpiride-induced prolactin release were measured prior to TAM treatment, then in the 2nd and 8th week of the therapy. The TRH (400 micrograms i.v.)-induced prolactin secretion was significantly suppressed by TAM after an 8-week treatment, but only in responding cases. Maximal prolactin stimulation occurred at the 15th min after TRH injection, being equal to 5,600 +/- 800 mlU/l in cancer patients, and decreasing to 2,400 +/- 150 mlU/l after 8 weeks. TAM did not suppress the sulpiride-inducable prolactin release either in responders or in nonresponders.

Incidence of side effects during the application of placebo and active therapy (Tobanum) in patients suffering from hypertension, angina pectoris and arrhythmia.

In a single blind clinical trial the effects of Tobanum (chloranolol), a beta-adrenergic receptor blocker, on 450 patients were examined. The side effects were detected by placebo control. Complaints were recorded on a questionnaire in the placebo period as well as in the active treatment period. Every fourth patient reported complaints in the placebo period and every third had a new complaint in the active period. Qualitative and quantitative analysis of the complaints indicated that Tobanum has mainly cardiorespiratory side effects judging from the beta-blocker characteristics. The study draws attention to the need for awareness of complaints in the placebo period for correct evaluation of side effects.

Influence of GYKI-13504, a new antioestrogen, on the responsiveness of isolated uterus removed from oestradiol pretreated rats to PGF2 alpha.

The responsiveness of the uteri of ovariectomized rats pretreated either with E2 or with a new antioestrogen, GYKI-13504 or with both agents simultaneously to PGF2 alpha was studied in vitro. The treatment with E2 caused a fortyfold reduction in the responsiveness of the uterus to PGF2 alpha. GYKI-13504 itself did not influence the sensitivity of this organ significantly, but inhibited the diminishing effect of E2.

Comparison of methods to detect side-effect on clinical application of chloranolol, a beta-adrenergic receptor inhibitor.

The incidence of side-effects on administration of chloranolol (Tobanum), a beta-adrenergic receptor blocking drug, to 2066 patients with hypertension, angina pectoris or arrhythmias was measured by three different methods. In 600 patients in an efficacy trial (Group 1) both spontaneously reported complaints and objective signs were tabulated. A side effect - directed method, utilising a questionnaire containing a list of possible side-effects was also used, with the questionnaire being completed by the physician. 35 questions referred to anticipated and other side-effects. The trial was performed in two groups: in 537 patients a placebo was also given (Group 2), and in another set of 929 patients (Group 3) the questionnaire inquiry was performed uncontrolled, without placebo. All three groups were comparable in their distribution of sexes, ages and diagnoses, the mean daily dose of chloranolol its use alone or in combination, and in a similar duration of treatment. 55% of all patients received chloranolol therapy for a period of more than 3 months. The ratio of in- and outpatients was 1:5. The side-effect incidence was independent of the age and sex of the patients and of the dose of chloranolol. The incidence was also unaffected whether chloranolol was used alone or in combination. The number of side-effects differed markedly between the three groups, their ratio was 1:10:24 in Groups 1, 2 and 3. Two-thirds of the side-effects subsided spontaneously within 1 month of their onset.(ABSTRACT TRUNCATED AT 250 WORDS)

Human tolerability studies with D-Met2,Pro5-enkephalinamide.

As reported previously D-Met2,Pro5-enkephalinamide (EA) is a highly active enkephalin analogue. To examine its human tolerability male volunteers were treated s.c. with increasing doses (0.1-30.0 mg). The observed autonomic effects were as follows: feeling of heaviness in the limbs, dry mouth, pallor of the face and conjunctival injection. There was no significant change in blood pressure, pulse and respiratory frequency. The autonomic effects appeared within 15-30 min. However, its effects on mood and wakefulness i.e. slight drowsiness, decrease in psychic tension and emotional detachment developed only later. The serum prolactin level increased dose-dependently, while the growth hormone (HGH) content showed biphasic dose-response pattern. The TSH content increased only at the highest doses applied (10.0-30.0 mg).

Functional relationships of the hypothalamic-pituitary-testicular system in Graves' disease.

An increased secretion of gonadotropic hormone was found in hyperthyroid males despite the high basal serum total testosterone and oestradiol levels. This suggests that hyperthyroidism affects the responsiveness of the hypothalamic-pituitary axis to sexual steroid hormones. While in the hyperthyroid patients the elevation of the serum testosterone level in response to chorionic gonadotropin was lower than normally, the LH and FSH responses to LRH were increased. The results indicate that male hyperthyroidism is associated with a loss of responsiveness of the Leydig-cells to adequate stimuli, to which the pituitary reacts by a compensatory increase in its LH-secretion and by an increased reactivity to LRH. It is suggested that in addition to the direct effect of the increased thyroid hormone levels, a secondary elevation of the oestradiol concentration plays a major part in the alterations in question.

Pharmacology of GYKI-41 099 (chlorpropanol, Tobanum) a new potent beta-adrenergic antagonist.

The compound GYKI-41 099, as a beta-adrenergic antagonist, is 3-8 times more potent than propranolol in vitro and in vivo. Its antiarrhythmic effectiveness surpasses that of propranolol and pindolol inhibiting the ouabain arrhythmia in dogs and cats. GYKI-41 900 has a negligible cardiodepressant activity; it is not cardioselective. The compound shows a rapid and long lasting effect. There was a prolonged elimination of the radioactivity after the injection of 14C-41 099 to rats and dogs. The half life of the unlabeled substance in humans was more than 10 hours.

Sulpiride and thyrotrophin releasing hormone loading test in patients with acromegaly.

The effects of sulpiride, a dopamine receptor blocking agent, and of thyrotrophin-releasing hormone (TRH) were studied on prolactin secretion in 17 patients with acromegaly and 25 control subjects. THe basal serum prolactin level was increased in 9 acromegalic patients. After sulpiride loading, maximum changes in prolactin level were significantly smaller in acromegalic patients, irrespective of the basal prolactin concentration. TRH loading resulted in a decrease of prolactin secretion predominantly in the patients with high basal serum hormone levels. A blunted thyrotrophin response to TSH was found only in those acromegalic patients who had concomitant thyroid disease. Higher than normal basal prolactin levels in some of the acromegalic patients and abnormal prolactin responses following sulpiride and TRH loading in most of the patients with acromegaly are attributed to deranged hypothalamo-hypophyseal regulation.

Effect of beta-blocking agents on the increased serum gastrin levels in hyperthyroidism.

In a number of hyperthyroid patients the serum gastrin level exceeds the normal range. Administration of beta-blocking agents results in a decrease of the hypergastrinaemia. The fall in the serum gastrin levels is unrelated to the effect of beta-blocking agents on peripheral thyroxine metabolism, but is associated with a decline of the plasma cAMP levels. It is suggested that, though beta adrenergic sensitivity is one of the factors of hypergastrinaemia in hyperthyroidism, other factors may be involved in its production, too.