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Biomedical subjects

R Horowski

Publications and source records attributed to R Horowski.

At least 73 records · Page 4Linked to original sources
PubMed1979

Suppression of lactation with lisuride.

The influence of lisuride, a new semisynthetic ergot derivative, was investigated in women during the puerperium. Treatment with 600 or 900 micrograms lisuride over 14 days (each test group n = 25) caused an immediate drop of elevated prolactin (PRL) levels in all patients in comparison to values seen in normal, nonpregnant women (less than 30 ng/ml). Such a sharp decline was not seen in two control groups of puerperal patients, nursing as well as nonnursing, placebo-treated women. The clinical efficacy in preventing or suppressing lactation was clear cut and comparable to the known PRL lowering effect of bromocryptine. Severe side effects were not observed during lisuride treatment with these dosages. The postsuckling PRL increase was abolished by a single oral dose of lisuride (100, 200, 300 micrograms), similar to that seen with bromocrytine (2.5 mg). The inhibition was dose dependent. Only doses of 200 and 300 micrograms showed, in comparison to a placebo group, a significant long-lasting (greater than 8 h) suppression of PRL secretion.

Depression, Chemical↗
PubMed1979

Suppression of prolactin secretion by lisuride throughout the menstrual cycle and in hyperprolactinaemic menstrual disorders.

Normally menstruating volunteers as well as patients with hyperprolactinaemic menstrual disorders were treated with lisuride hydrogen maleate (200 micrograms b.i.d.), an ergoline derivative with dopaminergic properties. Within 3 h after an oral dose of 200 micrograms lisuride, PRL levels decreased significantly in all subjects to a plateau which lasted up to 3 h. Thereafter a gradual increase of serum PRL was noted. In the normally menstruating volunteers lisuride treatment did not result in any significant change of gonadotrophin or of sex steroid secretion, while both, basal as well as metoclopramide (MTCL) stimulated PRL release were significantly diminished. The inhibition of PRL secretion in patients with short luteal phases resulted in an increase of luteal progesterone output. In both treated groups ovulation occurred 1 to 5 days earlier in cycles on lisuride than in control cycles. LF-RH/MTCL tests performed in the patient bearing a pituitary prolactinoma before and after lisuride treatment revealed a continuous increase of pituitary LH pools, while PRL secretion decreased under lisuride therapy. Subsequently ovulation and menstruation occurred. The data presented demonstrate that lisuride is a potent inhibitor of PRL secretion and has proven its clinical usefulness for treatment of hyperprolactinaemic menstrual disorders. Application of lisuride resulted in an increase of luteal progesterone secretion in previously demonstrated corpus luteum insufficiency as well as in restoration of normal cyclical feedback mechanisms in tumorous hyperprolactinaemic anovulation. The MTCL-PRL stimulation test is suitable to monitor PRL suppression during lisuride treatment, while LH-RH testing reveals the effectiveness of lisuride by demonstrating an increase of pituitary gonadotrophin pools.

Adenoma↗
PubMed1978

Lisuride hydrogen maleate: evidence for a long lasting dopaminergic activity in humans.

In 12 acromegalics a single oral dose of 0.2 mg lisuride, an ergoline derivative, significantly reduced plasma PRL but not GH concentrations. Three-tenths milligram of the drug significantly reduced plasma levels of the two hormones. Four-tenths milligram of lisuride did not augment this inhibitory effect. Plasma PRL levels were suppressed in all patients, whereas GH levels were reduced by more than 50% of the base-line values in only seven patients who also responded to the administration of 2.5 mg bromocriptine (CB154). In the patients unresponsive to lisuride, CB154 also failed to change GH levels. The suppressive effect of lisuride started at 60 min (at 150 min for CB154) and plasma GH and PRL levels were still markedly suppressed at 300 min. Plasma GH and PRL concentrations were consistently reduced in two acromegalic patients during 2 weeks of chronic treatment with 0.3 mg lisuride four times a day. In six normal subjects, TRH-induced PRL release was significantly inhibited by pretreatment with 0.3 mg of the drug. The similarity in the effects of lisuride and CB154 suggests that the observed effects of lisuride on GH and PRL are attributable to the known dopaminergic activity of the drug. This conclusion is supported by the data showing that pimozide effectively counteracted the inhibitory action of lisuride on GH and PRL release. We suggest that lisuride may be of value in the medical treatment of acromegaly and hyperprolactinemic states.

Acromegaly↗
PubMed1978

Prolactin-lowering effect of low doses of lisuride in man.

Lisuride, a new semisynthetic ergot derivative, effectively decreased the TRH-induced hyperprolactinaemia in healthy female volunteers at a dose of 300 microgram given orally. Basal prolactin levels were suppressed after a single dose of 100 and 200 microgram lisuride. This effect was still present 6 h after administration. Two hundred microgram lisuride also decreased the high serum prolactin levels produced by im injection of 50 mg sulpiride, and conversely, sulpiride injection abolished the prolactin lowering effect of lisuride. These results demonstrate that in man too lisuride is a very potent prolactin-lowering agent. In addition, the data support the hypothesis of a predominant role of dopaminergic mechanisms in the regulation of prolactin secretion.

Administration, Oral↗
PubMed1978

A new method for automatic registration of stereotyped behaviour in the rat.

A new and sensitive method for registering stereotyped behaviour in the bucco-oral region of the rat is described. These stereotypies, which can be induced by amphetamines and apomorphine, are regarded as an expression of the activation of dopaminergic receptors within the nigro-neostriatal pathway. The method is based on the fact that it is particularly easy in animals placed in restraining cages to induce stereotyped chewing, licking and gnawing movements which are received by special pick-ups in the head region of the animals and registered automatically and continuously via electro-mechanical transformers or by direct measurement of the change in the electrical resistance of the system. With this well-reproducible procedure it is possible to recognize and quantify the stereotypy-inducing effect of amphetamines and apomorphine and the influence of neuroleptic agents and tricyclic antidepressants on this effect. In comparison to previously described procedures, this method has the advantage of not being dependent on observation of the animals and of being highly suitable for the demostration of dose-effect and time-effect relationships.

Animals↗
PubMed1977

Effect of prolactin inhibitory agents on the ectopic anterior pituitary and the mammary gland in rats.

The purpose of the present study was to investigate the biological effectiveness of two highly potent prolactin (PRL) inhibitors, lisuride hydrogen maleate (LMH) and 2-Br-alpha-ergocryptine (CB-154), in the absence of hypothalamic factors acting directly at the level of the anterior pituitary. Hypophysectomized female rats bearing 4 transplanted pituitaries beneath the kidney capsules were treated with oestradiol benzoate (OeB) and progesterone (P) with or without simultaneous administration of LHM or CB-154 for 22 days in order stimulate or inhibit lobula-alveolar growth of the mammary glands. In addition to the investigation of the mammary glands by DNA determination and assessment of the histological pictures, the aim of this study was directed towards the influence of the substances tested at the level of the anterior pituitary remote from the hypothalmus. In this connection the changes in the different cells within the ectopic pituitaries as revealed by immunoenzyme-cytochemical studies were investigated. The results obtained support the classical view of a neuroendocrine regulation of mammary gland growth and the importance of oestrogens, P and PRL within this system. Both ergot derivatives LHM and CB-154 were able to antagonize the stimulatory effect of OeB combined with P on the mammary gland. With regard to the mechanism of action of LHM and CB-154 it is concluded that both substances act via a direct action on dopaminergic receptors within the ectopic anterior pituitary.

Animals↗
PubMed1976

Direct dopaminergic action of lisuride hydrogen maleate, an ergot derivative, in mice.

Lisuride hydrogen maleate induced stereotyped behaviour in normal as well as in reserpinized mice. It antagonized the motor depression and hypothermia induced by reserpine. On i.p. administration the compound was about as effective as apomorphine and D-amphetamine. As with apomorphine and in contrast to D-amphetamine the effects of lisuride hydrogen maleate in reserpinized mice were not impaired by additional treatment with alpha-methyl-p-tyrosine methylester. In untreated mice, the substance was very potent in lowering body temperature with significant hypothermia measured after dosages as low as 0.10 mg/kg i.p. Occurrence of stereotyped behaviour and hypothermia could be prevented by the dopaminergic antagonist haloperidol. From these data it is concluded that lisuride hydrogen maleate in addition to its interaction with serotoninergic systems is a potent dopaminergic agonist with a probably direct action on dopaminergic receptors. Further arguments in support of such an action of lisuride hydrogen maleate are, in addition to biochemical data, its serum prolactin lowering effect in rats, its strong emetic action in dogs and its effects on rat behaviour.

Animals↗
PubMed1976

Influence of dopaminergic agonists and antagonists on serum prolactin concentrations in the rat.

Inhibitors of dopaminergic neurotransmission, such as reserpine (RES), given alone or combined with alpha-methyl-p-tyrosine (alpha-MpT)or Ro 4-4602, as well as haloperidol (HAL) and sulpiride (SUL), induced highly elevated serum prolactin (Prl) concentrations in intact rats. In contrast, the dopaminergic agonists apomorphine (APO), lisuride hydrogen meleate (LHM), D-amphetamine (AMPH), piribedil and L-dopa greatly lowered the high serum Prl concentrations in female rats induced by i.p. pretreatment with 2 mg/kg RES. Additional inhibition of catecholamine synthesis in RES-treated animals by alpha-MpT abolished the effect of AMPH, which indicates that the effect of this compound is mediated through newly synthesized dopamine (DA), while the effect of APO and LHM remained unchanged. Inhibition of dopa decarboxylation by Ro 4-4602 within the whole body abolished the effect of L-dopa, while lower dosages of Ro 4-4602, which do not penetrate the blood-brain barrier, had less effect. The noradrenergic receptor-stimulating agent clonidine (CLON) had no Prl-lowering effect in RES-treated female rats. In hypophysectomized rats bearing 4 pituitaries transplanted under the kidney capsule, APO and LSM still lowered serum Prl concentrations, while AMPH had no effect; SUL produced a strong increase. These results support the hypothesis that DA has a dominant role as an inhibitor of Prl secretion by acting itself as the Prl inhibiting factor (PIF) on dopaminergic receptors located within the pituitary.

Animals↗
PubMed1976

Effect of the ergot derivative lisuride hydrogen maleate on serum prolactin concentrations in female rats.

The influence of a new synthetic ergot derivative, lisuride hydrogen maleate (LHM) on serum prolactin (PRL) concentrations was investigated in female rats using different test models: 1. in reserpine (R)-pretreated intact females, and 2. in ovariectomized (OVX) estradiol benzoate (E2)-primed animals with or without an additional pretreatment with R. In all the models used LHM was strongly effective in lowering serum PRL. Doses from 0.025 to 0.5 mg/kg LHM, given orally as well as subcutaneously, suppressed serum PRL. Depending on the dose used, the serum PRL was lowered to a different extent for up to 12 h. LHM was at least as effective as the well-known potent inhibitor of PRL secretion CB-154 in lowering serum PRL in OVX rats primed with E2. The effects of R, E2, and LHM are described in relation to their mode of action within the hypothalamic-hypophyseal system which regulates PRL secretion. While the increase in serum PRL induced by R seems to be directly relatable to its known catecholamine depletion, the circadian rhythm of PRL secretion induced by E2 seems to be influenced or mediated by central neural mechanisms. The effects of LHM on serum PRL in these test models can be related to its dopaminergic action and constitute further evidence for the central functions of dopaminergic mechanisms in the regulation of PRL secretion.

Animals↗
PubMedDate not supplied

Effectiveness of the dopamine agonist lisuride in the treatment of acromegaly and pathological hyperprolactinemic states.

We have studied the effects of the chronic administration of the dopamine agonist lisuride (L) in 21 acromegalics (group 1) and in 25 patients with pathological hyperprolactinemia (group 2). Before starting the treatment levels of PRL and/or GH were determined during acute tests with L (0.3 mg po) or TRH (0.2 mg iv). L was given in doses ranging between 0.4 and 2.4 mg/day. GH and/or PRL were determined at monthly intervals, TRH (6 patients of group 1 and 10 of group 2) was repeated during L therapy. In 10 patients of group 1 GH levels were reduced below 10 ng/ml by L therapy; in the remaining patients GH levels were reduced by 50% of the pretreatment values or they were unchanged. The correlation (p less than 0.01) found between GH levels during acute and chronic L administration indicates that GH changes after acute test are predictive of the outcome of the treatment. In all patients PRL was reduced during the therapy to at least 50% of the basal values and in most patients PRL fell to the normal range. No correlation was found between PRL levels during acute and chronic L administration. During the therapy TRH still increased GH levels in most patients whereas it failed to raise PRL. The withdrawal of L was followed by a rapid return of GH to the pretreatment values whereas PRL showed a slower increase. In acromegalics whose GH was lowered by L there was also a marked amelioration of clinical and metabolic parameters. The lowering of PRL was accompanied by the resumption of ovulatory menses even in patients with tumoral hyperprolactinemia. Males reported improvement in sexual performance. An improvement of visual field occurred in 1 patient. In 1 patient with a large prolactinoma serial computerized tomography scans performed during 2 yr of treatment showed a marked reduction of the tumor size.

Acromegaly↗
PubMedDate not supplied

Lisuride, a dopamine receptor agonist with 5-HT2B receptor antagonist properties: absence of cardiac valvulopathy adverse drug reaction reports supports the concept of a crucial role for 5-HT2B receptor agonism in cardiac valvular fibrosis.

OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.

Adverse Drug Reaction Reporting Systems↗