ergoline and dironyl

Eight ergot alkaloids and ergoline derivatives, effective prolactin inhibitors, were tested for activity against DMBA-induced rat mammary carcinomas. Compounds were administered daily, 5 times/week for 4 weeks, and rats were observed for an additional 4 weeks. Groups treated with androgen and estrogen were used as positive controls. Those ergot compounds and ergolines that proved to be highly effective in reducing tumor size or in inducing regression of tumors to nonpalpability were Deprenon (D-6-methyl-8-ergolin-I-ylacetic acid amide) and ergocryptine; effective to an intermediate degree were Dironyl [N-(D-6-methyl-8-isoergolin-I-yl)-N',N'-diethylurea], ergocornine, and Lysenyl [N-(D-6-methyl-8-isoergolenyl)-N',N'-diethyl-urea]; and effective to a minimal degree were Lergotrile (2-chloro-6-methylergoline-8beta-acetonitrile), CB-154, and 6605-VUFB (D-6-methyl-8-cyanomethylergolin-I). Remission of many individual carcinomas was brief, and duration of complete regression (all tumors in the rat were nonpalpable) was less than 10 weeks.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Acetonitriles; Androstanols; Animals; Breast Neoplasms; Bromocriptine; Drug Evaluation, Preclinical; Ergolines; Ergot Alkaloids; Estradiol; Female; Humans; Lisuride; Mammary Neoplasms, Experimental; Prolactin; Rats; Urea

The objective of the work was to compare the effectiveness and tolerance of a single administration of 1 mg cabergoline and 10-day administration of 1.5 mg terguride divided into three doses after 8-hour intervals, in the indication of arrest of lactation after an abortion during the second trimester.. Prospective clinical study. NAME AND PLACE OF DEPARTMENT: Gynaecological and Obstetric Clinic. First Medical Faculty Charles University and General Faculty Hospital Prague, Apolinárská 18, Prague 2.. During the period between January and October 2000 to 41 patients after abortion induced during the 2nd trimester terguride, 0.5 mg after 8-hour intervals, was administered for a 10-day period. During the subsequent period from November 2000 to September 2001 to 43 patients cabergoline was administered in a single dose within 12 hours after the abortion. During hospitalization the patients were asked daily for their subjective evaluation of the effect of treatment (vertigo, palpitations, headache, nausea, vomiting, abdominal pain, sleepiness, secretion from the breast, tension in the breasts) and the doctor evaluated the success of treatment objectively. Within 21 days after the abortion the patients were addressed over the phone on subjective and objective effects of treatment. For statistical evaluation Fisher's exact bilateral test was used.. The "cabergoline" group displayed, as compared with the "terguride" group, significantly fewer undesirable effects (p < 0.01). No significant difference was found between groups (p = 0.1) as regards the necessity to repeat administration of the drug. None of the undesirable effects were so serious to call for interruption of treatment.. Arrest of lactation during the second trimester of gestation is an integral part of care of the patient. Symptoms associated with lactation are adversely accepted by the patient. The incidence of undesirable effects after a single dose of cabergoline is significantly lower as compared with 10-day administration of terguride. A single dose of cabergoline during hospitalization improves the patients' compliance and thus the effect of treatment. Cabergoline can be used as the drug of first choice for arrest of lactation after abortion during the second trimester of pregnancy.

Topics: Abortion, Induced; Adolescent; Adult; Cabergoline; Drug Administration Schedule; Ergolines; Female; Humans; Lactation; Lisuride; Pregnancy; Pregnancy Trimester, Second; Prospective Studies

Hyperprolactinemia can successfully be treated by dopaminagonists such as bromocriptin or lisuride. About 10% of patients complain about side effects like orthostatic hypotension, nausea or vomiting, which may lead to discontinuation of treatment. We therefore conducted a study using terguride--a new dopaminagonist--in 5 patients with hyperprolactinemia and intolerable side effects under conventional treatment. Terguride is the transdihydroderivative of lisuride (Dopergin). We treated 5 patients, 2 men with macroprolactinoma and 3 women with microprolactinoma with terguride. The mean duration of treatment was 15.6 months (7-37 months). Patients were treated with up to 5 mg terguride daily. All 5 patients had a marked initial decrease of elevated prolactin levels 8 h after administration of 0.25 mg terguride orally. Three patients became normoprolactinemic after sufficient increase of the dose of terguride, 2 female patients with a microprolactinoma got eumenorrhoeic thereafter. The treatment with terguride was tolerated without side effects by all patients. There were no significant changes of the examined parameters of clinical chemistry nor the other pituitary hormones. Results of cranial computertomography did not change in 4 patients, one patient had tumor progression. Tergurid as a dopaminagonist is an effective inhibitor of prolactin with little side effects and thus a useful drug in the treatment of hyperprolactinemia.

Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Ergolines; Female; Follow-Up Studies; Humans; Hyperprolactinemia; Lisuride; Male; Middle Aged; Pituitary Neoplasms; Prolactin; Prolactinoma; Prospective Studies

Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i.v. dose of 50 micrograms and on the first and seventh day of an oral treatment with 250 micrograms, 500 micrograms and 750 micrograms b.d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH)-stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i.v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml.min-1.kg-1. The oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6 beta-OH cortisol.

Topics: Adult; Affect; Double-Blind Method; Electrocardiography; Enzyme Induction; Ergolines; Female; Half-Life; Humans; Hydrocortisone; Injections, Intravenous; Lisuride; Male; Pituitary Gland, Anterior; Pituitary Hormones; Prolactin; Psychomotor Performance; Reference Values; Sex Factors

trans-Dihydrolisuride, a partial dopamine receptor agonist, was tested for its effects on chorea in a double-blind, crossover clinical study in 10 patients with Huntington's disease. In eight patients, a neurophysiological evaluation was also performed. No reduction in choreic movements or improvement in voluntary movement performance was observed. However, in some patients, there was a slight improvement in patients' alertness and a reduction of the movement reaction time.

Topics: Adult; Affect; Aged; Awareness; Clinical Trials as Topic; Dopamine Agents; Double-Blind Method; Ergolines; Female; Humans; Huntington Disease; Lisuride; Male; Middle Aged

1. The effects of a single oral dose of the dopaminergic agonists lisuride (0.1 mg), terguride (0.25 mg) and bromocriptine (1.25 mg) on IOP were studied in eight normal volunteers using the non-contact tonometer. 2. Considering all post-dose measurements, compared with placebo, bromocriptine and lisuride but not terguride reduced IOP significantly in both eyes. 3. There was no significant difference between the ocular hypotensive effect of bromocriptine and lisuride. 4. Terguride reduced IOP significantly in the left eye at the 3 h time point after drug administration. 5. The result of this study confirms the reported ocular hypotensive effect of bromocriptine and showed that lisuride is as effective as bromocriptine in reducing IOP. 6. To evaluate the clinical importance of these drugs as ocular hypotensive agents other studies are needed using eye drops.

Topics: Adult; Bromocriptine; Double-Blind Method; Ergolines; Humans; Intraocular Pressure; Lisuride; Random Allocation

Terguride is an ergoline derivative with mixed agonistic/antagonistic dopaminergic activity. This led to a paradoxical suggestion that it is effective in the treatment of both schizophrenia and parkinsonism. A total of 65 in- or outpatients with parkinsonism mostly of vascular or idiopathic etiology were included in a 4-week, open, multicenter trial. Terguride was administered under an increasing dose schedule which was leveled off according to the clinical response. Mostly because of nausea, vomiting, and lack of improvement 25% of inpatients and 61% of outpatients were removed from the study. The average daily dose at the end of the trial was 4.2 mg, ranging from 1.0 to 5.5 mg. The average Simpson and Angus scale total score and performance in the Spiral Drawing Task improved significantly during the trial by 20% and 38% respectively. The following adverse effects were noted most frequently throughout the study (including those who withdrew): constipation (occurred in 42% of all ratings performed during the trial) drowsiness and nausea (16% each). Adverse circulatory effects were negligible. Psychotic symptoms, including depression, confusion, hallucinations, and paranoid syndrome, each occurred in 1 patient, i.e., at a lower rate than with other dopaminergic drugs. Scotopic electroretinograms in a subsample of 7 patients showed a significant transitory decrease in the B-wave amplitude at the end of the 1st week and a subsequent return to pretreatment values.

Topics: Adult; Aged; Aged, 80 and over; Clinical Trials as Topic; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Motor Skills; Neurologic Examination; Parkinson Disease

Clinical efficacy, prolactin (PRL)-lowering effect and tolerance of terguride (an 8-alpha-ergoline derived from Lisuride which acts as a partial dopaminergic agonist) were investigated in a double-blind study on inhibition of puerperal lactation using three different daily doses of the drug (0.25, 0.5 and 1.0 mg). With 0.5 and 1.0 daily therapeutical regimens PRL levels were suppressed in a dose-dependent manner and lactation was prevented. Terguride was highly well tolerated.

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Ergolines; Female; Humans; Lactation; Lisuride; Postpartum Period; Pregnancy; Prolactin

Terguride, the C9-10 dihydrogenated derivative of lisuride, is a new drug which inhibits pituitary prolactin (PRL) secretion. It has mixed dopaminergic-antidopaminergic and alpha 2-antiadrenergic activity, and has proved useful in the clinical management of hyperprolactinemia. However, no trial comparing its use with the standard dopamine agonist bromocriptine has been reported. We have therefore compared three doses of terguride with bromocriptine 2.5 mg and placebo in a randomized double-blind crossover trial in eight normal volunteers. Terguride showed a potent dose-dependent PRL-inhibiting and growth hormone (GH)-releasing effect, while no significant changes were observed in thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH), or luteinizing hormone (LH) in comparison to placebo. The neuroendocrine profile of terguride 1 mg was identical to that of bromocriptine, with a significant reduction in PRL still evident at 24 hours. However, in this small group of normal subjects, the side effects experienced at any dose of terguride were significantly less than with bromocriptine. Terguride 1 mg was always preferred to bromocriptine, while the lower doses were indistinguishable from placebo. Terguride is therefore likely to play an important role in the treatment of hyperprolactinemia.

Topics: Adult; Blood Pressure; Bromocriptine; Double-Blind Method; Drug Evaluation; Ergolines; Follicle Stimulating Hormone; Growth Hormone; Humans; Hydrocortisone; Lisuride; Male; Prolactin; Pulse; Random Allocation; Thyrotropin

Topics: Adult; Aged; Brain; Clinical Trials as Topic; Disability Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Motor Skills; Parkinson Disease; Receptors, Dopamine

The influence of a 3-week medication period with terguride (trans-dihydro-lisuride) in a dosage of 2 X 0.2 mg/d per os upon the 10-min resting EEG of elderly, clinically normal volunteers (mean age 70 years was investigated. Eight subjects received placebo and 7 subjects received terguride under double-blind conditions. The EEG data were analysed, inter alia, by a newly-developed method of quantification which uses information on topographical relationships of the absolute alpha-powers provided by two anterior and two posterior leads. Under terguride, but not under placebo, a significant increase of subvigilant patterns was found. If one were to disregard the baseline situation, which was characterized in the present sample by a distinct restriction of the physiological dynamics of vigilance at a reduced level (dynamic rigidity), this finding would have to be interpreted as sedation. A non-physiological pre-drug situation was indicated by marked and sustained anteriorization of alpha-activity. Taking into account our additional finding that terguride, but not placebo, eliminates this non-physiological alpha-anteriorization, we interpret the increase of subvigilant patterns in the course of the recording period as a resolution of the preexisting dynamic rigidity and, consequently, as a therapeutically desirable effect.

Topics: Aged; Alpha Rhythm; Arousal; Double-Blind Method; Electroencephalography; Ergolines; Humans; Lisuride; Middle Aged

Transdihydrolisuride is an ergot derivative with mixed agonist and antagonist effects on central dopamine receptors. We gave the drug orally (1 mg daily) to 10 patients with Huntington's disease. In seven patients, the chorea improved with no adverse effects during the study.

Topics: Adolescent; Adult; Clinical Trials as Topic; Double-Blind Method; Ergolines; Female; Humans; Huntington Disease; Lisuride; Male; Mental Processes; Middle Aged; Movement Disorders; Neuropsychological Tests; Random Allocation; Receptors, Dopamine; Time Factors

Dimers of agroclavine (1) and terguride (2), as well as a series of terguride oligomers, for example trimers (5, 6), tetramer (7), hexamer (8) and functionalized tergurides for further complex clustering were synthesized. Terguride oligomers were screened for their direct cellular toxicity on lymphoma cell lines in vitro and for their immunomodulating activities, represented by the natural killer (NK) cell-mediated cytotoxicity, as the most sensitive screening marker during immune responses. Dimers linked via aromatic spacer showed a high toxicity (1 microM) to lymphoma cells, which was not detected in other derivatives. In vitro and ex vivo experiments performed on mouse spleen lymphocytes in the presence of terguride oligomers demonstrated an immunosuppressive effect of dimers with aromatic spacer (4c-d) and NK cell stimulatory effect of terguride hexamer (8) and trimer with aliphatic spacer (5c). There is a considerable evidence that indolic part of molecule contributes to immunosuppressive action of terguride, which is potentiated in dimers carrying aromatic linker. This effect can be reversed by higher oligomerization of the respective alkaloids.

Topics: Adjuvants, Immunologic; Animals; Carbamates; Dimerization; Drug Evaluation, Preclinical; Ergolines; Female; Humans; Immunosuppressive Agents; Killer Cells, Natural; Lisuride; Mice; Mice, Inbred BALB C; Spleen; Structure-Activity Relationship; Tumor Cells, Cultured

BAM-1120, an ergoline derivative, has been found to display a relatively high affinity for dopamine D2-like receptor subtypes in a preliminary binding study. This study investigated whether BAM-1120 acts as a dopamine receptor agonist on prolactin-secreting and motor functions. BAM-1120 suppressed hyperprolactinemia induced by pretreatment with reserpine or estradiol in female rats. Furthermore, BAM-1120 was able to shrink a prolactin-secreting pituitary tumor (prolactinoma) in the estradiol-treated female rats. BAM-1120 induced rotations contralateral to the lesion side in rats with unilateral 6-hydroxydopamine-induced lesions of nigrostriatal dopamine pathway at a dose that was at least 30-fold higher than that required for the inhibition of prolactin secretion. These findings suggest that BAM-1120 is characterized as a putative dopamine D2-like receptor agonist that possesses a preference of inhibiting prolactin secretion over activating motor behaviors.

Topics: Animals; Bromocriptine; Dopamine; Dopamine Agents; Dopamine Agonists; Ergolines; Estradiol; Female; Hyperprolactinemia; Lisuride; Male; Rats; Rats, Wistar; Reserpine; Rotation; Stereotyped Behavior; Sympathectomy, Chemical; Sympatholytics

Currently, methods for calculating molecular similarity indices have been developed for comparing steric, charge density, and molecular electrostatic potential (MEP) properties. Much of the existing technology may, however, be applied to the quantitative comparison of molecular hydrophobicities. In this article we present an empirical hydrophobic similarity index. We utilize atomic hydrophobic parameters derived from a quantum mechanical semiempirical wavefunction. Hydrophobicity at points on a grid is computed with a recently introduced "molecular lipophilicity potential." The overlap of pairs of molecules is calculated with the metric introduced by Carbó. This approach is applied to a case in which steric and electrostatic criteria have already been shown to be inadequate in rationalizing selectivity, namely, requirements for recognition at the dopamine D1 and D2 receptors. We demonstrate that, for a set of dopamine agonists, D1 ligands show higher similarity in this property that D2 analogs. This indicator of similarity is more successful at accounting for D1 selectivity than previous methods.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Apomorphine; Benzazepines; Chemical Phenomena; Chemistry, Physical; Chromans; Dopamine Agonists; Drug Design; Ergolines; Indoles; Ligands; Lisuride; Models, Molecular; Phenanthridines; Quinpirole; Receptors, Dopamine D1; Receptors, Dopamine D2

The effects of cocaine alone and after pretreatment with the dopamine D2 partial agonists terguride, SDZ 208-911, and SDZ 208-912 were determined in squirrel monkeys trained to discriminate cocaine from saline using a two-lever drug discrimination procedure. When tested alone, cocaine engendered dose-related increases in the percentage of responses on the cocaine-associated lever, reaching virtually exclusive cocaine-appropriate responding after a dose of 1.0 mg/kg. Pretreatment with terguride (0.003-0.03 mg/kg), SDZ 208-911 (0.001-0.01), and SDZ 208-912 (0.003-0.018 mg/kg) did not consistently alter the discriminative stimulus effects of cocaine. Although some doses of each D2 partial agonist either increased (notably SDZ 208-911) or decreased (notably SDZ 208-912) the level of cocaine-appropriate responding engendered by low to intermediate doses of cocaine, none of the drugs reduced the percentage of cocaine-appropriate responding engendered by low to intermediate doses of cocaine, none of the drugs reduced the percentage of cocaine-appropriate responses engendered by 1.0 mg/kg cocaine. The results do not support the view that terguride, SDZ 208-911, or SDZ 208-912 would serve as functional antagonists of the subjective effects of cocaine.

Topics: Animals; Cocaine; Discrimination, Psychological; Dopamine Agonists; Dose-Response Relationship, Drug; Ergolines; Lisuride; Male; Receptors, Dopamine D2; Saimiri

Eight Cebus apella monkeys were treated with haloperidol for 2 years. Five monkeys had developed mild oral tardive dyskinesia and all were primed for neuroleptic induced dystonia, thus serving as a model for both chronic and acute extrapyramidal side effects. In this model, the partial dopamine D2 receptor agonists SDZ HDC-912, SDZ HAC-911, terguride, (-)-3-(3-hydroxyphenyl)-N-propylpiperidine) ((-)-3-PPP) and SND 919 were tested for extrapyramidal side-effect liability. Their antipsychotic potential was also tested, using a dose of dextroamphetamine producing mild stereotypy and moderate motoric unrest. For comparison, the dopamine D2 receptor agonist, LY 171555 and antagonist, raclopride were used. In contrast to the other drugs tested, SDZ HAC-911 consistently reduced oral activity, P < 0.05 (at doses from 0.005 to 0.025 mg/kg). The relative dystonic potencies were raclopride > SDZ HDC-912 > SDZ HAC-911 = terguride. Neither (-)-3-PPP nor SND 919 produced dystonia, but had observable dopamine D2 receptor agonistic effects, (-)-3-PPP producing emesis at 1-4 mg/kg and SND 919 producing motoric unrest and stereotypy at 0.05-0.25 mg/kg. Comparing the antiamphetamine effects of the more antagonist-like drugs with raclopride, the relative potencies were terguride = SDZ HAC-911 > SDZ HDC-912 > raclopride. Comparing the antiamphetamine effects of the more agonist-like drugs with LY 171555, the relative potencies were SND 919 > (-)-3-PPP > LY 171555 in relation to motoric unrest, while neither (-)-3-PPP nor LY 171555 produced inhibition of stereotypy.

Topics: Administration, Oral; Amphetamine; Animals; Antipsychotic Agents; Behavior, Animal; Benzothiazoles; Cebus; Disease Models, Animal; Dopamine Agents; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Dystonia; Ergolines; Female; Haloperidol; Lisuride; Male; Piperidines; Pramipexole; Quinpirole; Raclopride; Salicylamides; Thiazoles

The rate of brain monoamine synthesis was estimated in the rat by measuring the accumulation of dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) following inhibition of cerebral aromatic amino acid decarboxylase by NSD-1015 (475 mumol/kg, i.p., 30 min before decapitation). As expected, pretreatment with reserpine, (8.2 mumol/kg, s.c., -18 h) produced a marked and statistically significant increase in the DOPA accumulation in the ventral striatum and in the neocortex, whereas only minor changes were noted in 5-HTP accumulation in the same brain areas. The administration of terguride or quinpirole (30 mumol/kg, s.c., -65 min) resulted in both cases in an antagonism of the reserpine-induced increase in the DOPA accumulation. The effect was less marked in the neocortex than in the ventral striatum, but there was no difference between the effects produced by either compound. In contrast, the two drugs produced opposite effects on the 5-HTP accumulation in the ventral striatum as well as in the neocortex. Thus, there was a decrease and an increase in the 5-HTP accumulation by terguride and quinpirole administration, respectively. Together the results suggest that, in the reserpine treated rat, both terguride and quinpirole to the same degree stimulate dopamine receptors in the ventral striatum and noradrenaline receptors in the neocortex. To the extent that serotonin receptors in these two brain areas mediate the effects on 5-HTP accumulation of terguride and quinpirole, respectively, these receptors appear differently affected by the two compounds: stimulation by terguride and blockade by quinpirole.

Topics: Animals; Brain; Cerebral Cortex; Corpus Striatum; Dihydroxyphenylalanine; Dopamine Agents; Ergolines; Hydrazines; Lisuride; Male; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Serotonin; Reference Values; Reserpine; Serotonin

Previous work in this laboratory, as well as observations reported in the literature, indicate that the adrenal medulla contains dopamine (DA) receptors of the D-2 subtype, which among other things are capable of controlling the DA level in rat adrenal glands. To further characterize the DA receptors involved in the control of the adrenal DA level, the effects of 9 DA receptor agonists with various intrinsic activities were compared. After various periods of drug administration the rats were killed by decapitation and the DA content of the adrenal glands and the DOPAC content of the forebrain were measured by high-performance liquid chromatography with electrochemical detection. All the investigated DA receptors agonists caused an increase in adrenal DA level, although statistical significance was not reached in one case [(-)-HW 165]. Domperidone, a DA D-2 receptor antagonist which does not readily cross the blood brain barrier, blocked the DA-elevating effects of apomorphine, quinpirole, B-HT 920 and both enantiomers of 3-PPP. For the two ergolines terguride and SDZ 208-920 the blockade by domperidone was not complete, suggesting that their effects are mediated not only through DA, but also through other receptor systems. The dose of domperidone used (3 mg/kg) had but a marginal influence on brain DOPAC levels, supporting the almost exclusively peripheral effect of this agent. Our data indicate that the DA D-2 receptors which control the DA level in the adrenal medulla in rats, have characteristics similar to, though not identical with the autoreceptors in the forebrain.

Topics: 3,4-Dihydroxyphenylacetic Acid; Adrenal Medulla; Animals; Apomorphine; Azepines; Diencephalon; Domperidone; Dopamine; Dopamine Agents; Epinephrine; Ergolines; Lisuride; Male; Norepinephrine; Phenanthrenes; Piperidines; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Telencephalon

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depre

Topics: 4-Butyrolactone; Animals; Behavior, Animal; Brain; Dopamine; Dopamine Agents; Ergolines; Lisuride; Male; Motor Activity; Neurons; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Serotonin; Reserpine; Serotonin; Substantia Nigra; Time Factors

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kg d-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blocked d-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208-911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced by d-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208-911. The profiles of SDZ 208-912 and terguride were intermediary to those of SDZ 208-911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kg d-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dose d-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208-911, preclamol and terguride was accompanied only by the low dose d-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208-912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased by d-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced by d-amphetamine.

Topics: Animals; Dextroamphetamine; Dopamine Agents; Dose-Response Relationship, Drug; Ergolines; Lisuride; Motor Activity; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Stereotyped Behavior

The ergot alkaloid derivatives, lisuride (LIS) and terguride (TDHL), known to interact with central dopamine receptors as agonist and partial agonist, respectively, were studied on the field-stimulated mouse vas deferens, where recently the existence of presynaptic dopamine receptors has been evidenced. LIS was a competitive antagonist at prejunctional alpha 2 and DA1 receptors situated on the sympathetic nerve terminals of the mouse, with a pA2 value of 9.2 and 9.1, respectively. LIS was also able to antagonize the effects of LY 171555, selective DA2 agonist, but the type of interaction cannot be conceptualized in terms of competitive antagonism. Likewise, the type of interaction of TDHL with dopaminergic and adrenergic agonist-activated sites is not suggestive of a competitive antagonism. Based on these results, it seems that central and peripheral pharmacologic profiles of LIS and TDHL cannot be overlapped, LIS being a potent DA1- and alpha 2-antagonist with a high degree of specifity for these receptors.

Topics: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Binding, Competitive; Clonidine; Dose-Response Relationship, Drug; Ergolines; Lisuride; Male; Mice; Molecular Structure; Muscle Contraction; Muscle, Smooth; Quinpirole; Receptors, Dopamine; Structure-Activity Relationship; Vas Deferens

The effects of the enantiomers of 3-hydroxyphenyl-N-n-propylpiperidine (3-PPP) at dopamine (DA) synthesis modulating autoreceptors, measured as DOPA accumulation after decarboxylase inhibition, were assessed in vivo and in rat striatal slices. In vivo, (+)-3-PPP inhibited DOPA accumulation in the striatum, nucleus accumbens, and medial prefrontal cortex, whereas (-)-3-PPP either increased (striatal) or had no effect (accumbens, prefrontal cortex), on DOPA accumulation. In vitro, both (+)- and (-)-3-PPP reduced basal DOPA accumulation with a similar order of potency (apparent EC50 = 2.1 and 1.0 microns, respectively) and maximal effect, although they were less potent than the D2 DA receptor agonist quinpirole (EC50 = 0.15 microM). The inhibition of tyrosine hydroxylation was also observed in slices obtained from reserpine-pretreated rats and was blocked by the selective D2 DA antagonist (-)-sulpiride. This suggests that 3-PPP inhibition of DOPA accumulation was mediated directly by stimulation of DA D2 receptors. Increasing the amount of extracellular DA by depolarizing slices with 30 mM K+ did not alter the qualitative effects of either quinpirole or (+)-3-PPP. However, the stimulation of DA autoreceptors by (-)-3-PPP was no longer apparent under conditions of elevated extracellular DA. Under these depolarizing conditions, (-)-3-PPP actually antagonized the inhibitory effect afforded by either quinpirole or pergolide. A similar switch in profile was observed with transdihydrolisuride (TDHL). The data support the notion that (-)-3-PPP and TDHL are partial agonists at synthesis modulating DA autoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biogenic Monoamines; Cerebral Cortex; Corpus Striatum; Dihydroxyphenylalanine; Dopamine; Electrochemistry; Ergolines; In Vitro Techniques; Lisuride; Male; Nerve Tissue Proteins; Nucleus Accumbens; Piperidines; Potassium; Quinpirole; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereoisomerism

Transdihydrolisuride (terguride), a 9,10-dihydrogenated analogue of the ergot dopamine agonist lisuride, is characterized as partial dopamine receptor agonist at CNS level. This compound was investigated for its effects on peripheral neurotransmission in the attempt to delineate its pharmacological profile. The contractile responses of field-stimulated mouse vas deferens were slightly inhibited by terguride at very high concentrations (10(-5)-10(-2) M); the selective antagonists for alpha 2-adrenergic and dopamine receptors failed to counteract this effect. Terguride was very effective in blocking the inhibitory effects of LY 171555 (selective DA2 agonist), SK&F 38393 (selective DA1 agonist) and clonidine (selective alpha 2 agonist). In no case the antagonism was competitive: the control dose-response curves were not shifted in a parallel and dose-dependent manner. Therefore terguride displays a mixed DA1, DA2 and alpha 2 antagonistic activity.

Topics: Animals; Dopamine Agents; Electric Stimulation; Ergolines; In Vitro Techniques; Lisuride; Male; Mice; Muscle, Smooth; Vas Deferens

Topics: Animals; Brain; Cattle; Ergolines; Ergotamines; Lisuride; Rats; Receptors, Dopamine; Receptors, Dopamine D2; Species Specificity; Swine

The authors compared the arrest of lactation by terguride, lisuride and deprenone. Terguride was administered to 14 women 2 X 0.5 mg by the oral route or 4 X 0.2 mg by the oral route for 21 days, lisuride to 41 women 2 X 0.5 mg or 4 X 0.2 mg by the oral route for 21 days, deprenone to 8 women 4 X 0.5 mg per day by the oral route for 21 days. Thus treated women were compared with women where lactation was arrested by mestranol, 0.15 mg per day for 7 days (15 women) and with normally lactating puerperial women (12 women). As expected, all tested methods were effective. No serious side-effects were observed. In the overall evaluation of different procedures where we included the suppression of lactation, the drop of the prolactin level, the incidence of the rebound phenomenon and side-effects of treatment, terguride and lisuride proved more suitable than deprenone and mestranol. The results of terguride were slightly more favourable than those of lisuride.

Topics: Adult; Ergolines; Female; Humans; Lactation; Lisuride; Mestranol; Pregnancy; Prolactin

Topics: Animals; Benzazepines; Binding, Competitive; Corpus Striatum; Ergolines; Ergotamines; Lisuride; Male; Rats; Receptors, Dopamine; Spiperone

Topics: Adult; Dopamine Agents; Ergolines; Humans; Lisuride; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Schizophrenic Psychology

Topics: Ergolines; Female; Humans; Lactation; Lisuride; Pregnancy

Topics: Adolescent; Adult; Corpus Luteum; Ergolines; Female; Humans; Hyperprolactinemia; Infertility, Female; Lisuride; Menstruation Disturbances

Topics: Ergolines; Female; Humans; Lactation; Lisuride; Pregnancy; Prolactin

The partial dopamine agonist terguride (transdihydrolisuride) administered to four 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned hemiparkinsonian monkeys (at a dose of 4 mg/kg orally) induced marked contralateral turning that lasted 3.5 h. The 6-n-propyl derivative of terguride (proterguride) given to two monkeys (at a dose of 0.4 mg/kg orally) caused contralateral turning which lasted for more than 24 h but produced side effects such as dyskinesia and stereotype. After terguride treatment, cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol (MHPG) were increased, whereas concentrations of the metabolites dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) were not significantly altered.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Disease Models, Animal; Ergolines; Female; Lisuride; Macaca fascicularis; Parkinson Disease, Secondary; Pyridines; Receptors, Dopamine

Topics: Animals; Blindness; Cattle; Cattle Diseases; Ergolines; Hypersensitivity, Delayed; Leukocyte Count; Lisuride; Metipranolol; Mice; Organ Size; Propanolamines; Respiratory Tract Diseases; Spleen; Stress, Physiological; Thymus Gland; Vibration

Topics: Antiparkinson Agents; Bromocriptine; Disability Evaluation; Drug Therapy, Combination; Ergolines; Humans; Levodopa; Lisuride; Long-Term Care; Parkinson Disease; Pergolide; Receptors, Dopamine

The binding properties of [3H]terguride were studied in various regions of the rat brain. The highest density of [3H]terguride binding sites was found in the striatum and tuberculum olfactorium. In the striatum, the binding was saturable, stereoselective and of a high affinity. There was a good correlation between the inhibition of [3H]terguride and [3H]spiperone bindings by various dopaminergic agents. Drugs with affinity to another type of receptors did not displace [3H]terguride binding in the striatum; only SCH 23390 was effective. The experiments indicate a certain affinity of the ligand to D-1 receptors. Nevertheless, [3H]terguride appears to have an affinity to D-2 receptors in the striatum and, thanks to its dopamine agonistic/antagonistic profile, would be useful in the further study of dopamine receptors.

Topics: Animals; Benzazepines; Corpus Striatum; Ergolines; In Vitro Techniques; Kinetics; Lisuride; Male; Rats; Rats, Inbred Strains; Receptors, Dopamine; Spiperone

Terguride, an analogue of lisuride, decreased locomotor activity, produced cataplexy, and blocked apomorphine-induced stereotypic behavior. It did not induce stereotypies in rodents or emesis in dogs. However, in rats with unilateral 6-hydroxydopamine lesions of the substantia nigra, terguride produced contralateral rotation. Terguride bound to D-2 striatal dopamine receptors. Terguride has both agonist and antagonist actions at striatal dopamine receptors, but chronic administration did not produce behavioral supersensitivity. These pharmacologic properties differ from those of other antiparkinsonian agents; terguride may be effective for the chronic treatment of Parkinson's disease.

Topics: Amphetamine; Animals; Apomorphine; Behavior, Animal; Brain; Disease Models, Animal; Ergolines; Levodopa; Lisuride; Male; Motor Activity; Parkinson Disease; Rats; Rats, Inbred Strains; Receptors, Dopamine; Stereotyped Behavior

The ergot derivative trans-dihydrolisuride (TDHL) was tested for its effects on firing rates of dopaminergic (DA) neurons located in the substantia nigra pars compacta of chloral hydrate-anesthetized rats. Using extracellular single-barreled microelectrodes, DA neurons were identified by their long duration, positive-negative action potentials and their slow bursting pattern of spontaneous firing, as well as by the location of recording sites through histological recoveries of dye deposits. Like haloperidol and clozapine, which are full DA receptor antagonists, TDHL antagonized the depression in DA neuron firing induced by systemic amphetamine. However, where full antagonists completely reversed the amphetamine effect, TDHL could do so only partially, the maximal effect being around half. Like DA agonists, but unlike DA antagonists, TDHL also depressed the spontaneous firing rates of DA neurons. But whereas the full agonist apomorphine completely inhibited firing of DA neurons, TDHL only depressed firing rates by about half, even at high doses. These data support the contention that TDHL is a partial DA agonist.

Topics: Amphetamine; Animals; Apomorphine; Clozapine; Dose-Response Relationship, Drug; Electric Stimulation; Ergolines; Haloperidol; Lisuride; Male; Neurons; Rats; Rats, Inbred Strains; Receptors, Dopamine; Substantia Nigra

The abilities of the mixed agonists/antagonists on dopamine (DA) receptors, (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [-)-3-PPP) and transdihydrolisuride (TDHL), to suppress serum prolactin levels in acutely hyperprolactinemic male and female rats were investigated. gamma-Butyrolactone was used to deplete endogenous DA and raise serum prolactin concentrations. Both (-)-3-PPP and TDHL were found to cause sexually differentiated responses: (-)-3-PPP reduced serum prolactin levels dose dependently and effectively in males but caused only a modest decrease of prolactin release in females. Moreover, (-)-3-PPP antagonized the prolactin-suppressing effects induced by the DA receptor agonist (+)-3-PPP in females. Likewise TDHL decreased prolactin secretion markedly in males while it had only slight effects in females. It can be concluded from these results that the intrinsic activities of the partial DA agonists (-)-3-PPP and TDHL are lower in female than in male rats, suggesting a reduced responsiveness of hypophyseal DA receptors in females. Since DA levels in the pituitary portal circulation are higher in female than in male rats, this study gives further support to the hypothesis claiming an inverse relationship between the intrinsic activity of a mixed agonist/antagonist and the degree of previous stimulation of its receptor.

Topics: Animals; Antiparkinson Agents; Ergolines; Female; In Vitro Techniques; Lisuride; Male; Piperidines; Pituitary Gland; Prolactin; Rats; Rats, Inbred Strains; Receptors, Dopamine; Sex Factors; Stereoisomerism

The semisynthetic lisuride derivative transdihydrolisuride (terguride, TDHL) is an effective antiparkinsonian drug. In animals, TDHL appears to possess mixed dopamine agonist-antagonist effects, but this may not be the case in man. Single doses of TDHL were given to 21 subjects with parkinsonism. Overall, TDHL 0.25-0.5 mg caused dose-related improvement in parkinsonism for periods of up to 6 h, although 8 of 21 subjects showed no improvement or deterioration with TDHL 0.5-1 mg. In three patients with levodopa-induced psychosis, the addition of TDHL 0.75 mg daily for 5-10 days did not alter the psychotic state. In three subjects with levodopa-induced dyskinesias, the addition of TDHL 0.75 mg daily for 14 days resulted in a slight increase in the severity of involuntary movements. Side-effects of TDHL, sickness and hypotension, were similar to those observed with levodopa. Transdihydrolisuride caused prolonged inhibition of prolactin release, but unlike levodopa did not elevate plasma growth hormone levels. Additionally, TDHL did cause considerable sedation. These results may be due to combined effects of TDHL on nondopamine as well as dopamine neurotransmitter systems, rather than to partial or incomplete dopamine agonist effects.

Topics: Aged; Blood Pressure; Ergolines; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Movement Disorders; Nausea; Parkinson Disease; Psychoses, Substance-Induced

In an open trial, 15 patients with PD (mostly stage V) were treated with the partial DA agonist, terguride, a derivative of lisuride. To the basic therapy, consisting of L-dopa plus benserazide and amantadine, a slowly increasing dosage of TDHL up to a maximum of 1.5 mg/day t.i.d. was added. There were 3 drop-outs; 12 patients completed the trial which lasted for 12 weeks. At this time a significant improvement in total score, bradykinesia, and functional score was seen, as well as a marked improvement in tremors score in the patients who showed this symptom (Columbia Rating Scale). As side-effects, dyskinesias occurred in two patients, psychotic symptoms in one, and marked orthostatic symptoms in one patient. No significant differences before and after 12 weeks TDHL treatment were found in the concentrations of noradrenaline, adrenaline, serotonin, and 5-hydroxy-indole-acetic-acid in plasma. It is concluded that TDHL is effective even in advanced stages of PD, and it is speculated that partial DA agonists may become important in the treatment of PD and might possibly have an advantage over "classical" DA agonists.

Topics: Aged; Aged, 80 and over; Ergolines; Female; Humans; Lisuride; Male; Motor Skills; Parkinson Disease

Two patients with macroprolactinomas were treated with the partial dopamine agonist, terguride. The prolactin (Prl) levels were lowered very effectively and in both cases the clinical symptoms improved markedly during the first days of treatment. Computerized tomography (CT) and magnetic resonance imaging (MRI) follow-up studies showed distinct tumour shrinkages which were first documented by MRI within 2 weeks of treatment. Tumour residues were, however, still demonstrable by MRI after more than one year respectively 3 months of therapy. In principal, results from both imaging techniques were comparable with the exception of the one year follow-up study of patient 1. In CT no residual tumour mass was visible whereas MRI showed only little reduction when compared to the 30th week scan. Throughout the treatment terguride was well tolerated without any side effects up to a maximal daily dosage of 3 mg given orally. Presumably the partial agonistic features of terguride contributed to the good tolerance of the treatment as compared to that of full dopamine agonists like bromocriptine of lisuride. Thus, these preliminary results indicate that terguride may be a beneficial alternative in the treatment of prolactinomas and other hyperprolactinaemic states.

Topics: Adenoma; Adult; Ergolines; Female; Follow-Up Studies; Humans; Lisuride; Pituitary Neoplasms; Prolactin; Receptors, Dopamine; Thyrotropin-Releasing Hormone; Tomography, X-Ray Computed

The incorporation of 3H-17-beta oestradiol (3H-E2) and 3H-Tergurid (3H-Te) in the uteri of sexually immature rats was monitored for 16 hours following the treatment of the animals with Tergurid, a semisynthetic ergot alkaloid [chemically acid N-(D-6-methyl-8-isoergolin-I-yl)--N',N'-diethylurea maleate; VUFB-6638]. The differences in the incorporation of 3H-Te in relation to the presence of ovarial steroids (E2 and progesterone) were investigated for the same period of time in the adult ovariectomized rats. In all the time intervals under study, the average values of 3H-E2 activities in the uteri of juvenile rats treated with Tergurid were lower than in the controls. This decrease was statistically significant (P less than 0.05) eight hours after treatment. The time course of the incorporation of 3H-Te in the uteri of the experimental and control animals was about the same. The activities of incorporated 3H-Te in the uteri of adult rats treated with E2 were higher in all the intervals, the difference being statistically significant after two hours and 16 hours (P less than 0.05) and after four hours (P less than 0.01). Progesterone did not induce any significant differences in the incorporation of 3H-Te. These results suggest that the increased incorporation of Tergurid in the uteri of adult rats is due to a direct influence of E2. It has been demonstrated by trials on juvenile rats that Tergurid does not combine with oestrogenic receptors. As suggested by the decreased weights of the uteri of juvenile rats treated with Tergurid, the uterine cells are unable to react to exogenous administration of E2.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Age Factors; Animals; Ergolines; Estradiol; Female; Kinetics; Lisuride; Organ Size; Ovariectomy; Progesterone; Rats; Rats, Inbred Strains; Uterus

Terguride, is an 8 - alpha - ergoline derived from lisuride, acts as a partial dopamine (DA) agonist. The effect and tolerance of terguride has been investigated by an acute administration of 0.2 mg p.o. to 8 normal women, 8 patients with hyperprolactinaemia and 8 women with puerperal hyperprolactinaemia. Prolactin (PRL) levels were markedly suppressed in all subjects, with no significant differences between the groups. Treatment for 5 days with terguride 0.4 mg/day or 0.8 mg/day was studied as an inhibitor of lactation. PRL levels were suppressed in a dose-related manner. No untoward side-effects were noted.

Topics: Adult; Dose-Response Relationship, Drug; Ergolines; Female; Humans; Hyperprolactinemia; Lactation; Lisuride; Postpartum Period; Pregnancy; Prolactin; Time Factors

The pharmacokinetics of oral terguride 1 mg was evaluated in a single-dose study in 8 patients with a prolactinoma and one with acromegaly. A radioreceptor assay was used to measure the plasma levels of terguride. The peak plasma concentration (2.3 +/- 0.7 ng/ml, mean +/- SEM) was attained within 1 h of drug administration. Moment analysis gave a mean residence time of 4.3 +/- 0.6 h. Plasma prolactin was also determined by radioimmunoassay. The plasma prolactin was reduced to 30 +/- 3% of its pretreatment value after 4 h.

Topics: Acromegaly; Adult; Ergolines; Female; Half-Life; Humans; Kinetics; Lisuride; Male; Middle Aged; Pituitary Neoplasms; Prolactin

The long term effectiveness and tolerance of terguride, a new ergot derivative, as initial therapy were evaluated in 20 patients with pathological hyperprolactinemia (PHP; group A) and 7 patients with acromegaly. We also studied 10 patients with PHP whose treatment was changed from bromocriptine or lisuride to terguride (group B). Terguride, given for at least 6 months in divided doses ranging from 0.25-1.50 mg/day to group A patients, resulted in normal (11 patients) or markedly reduced plasma PRL levels. Gonadal function was restored in all but 2 patients in this group, and the tumors shrank in 3 of 5 patients with a macroprolactinoma and in 1 of 3 patients with a microprolactinoma. In group B patients, positive effects of the previous treatment on PRL levels, gonadal function, and tumor growth were maintained by terguride. Terguride suppressed plasma GH levels below 50% of baseline in 4 of the 7 acromegalic patients. Two of the 27 patients initially treated with terguride complained of mild nausea and postural hypotension only after the first dose (0.25 mg) of the drug. No patient in group B had any side-effects during terguride, with the exception of 1 patient who was also intolerant to bromocriptine. We conclude that terguride is an effective well tolerated dopaminergic agent in PHP.

Topics: Acromegaly; Adenoma; Adolescent; Adult; Ergolines; Female; Humans; Hyperprolactinemia; Lisuride; Male; Menstruation; Middle Aged; Pituitary Neoplasms

Topics: Acromegaly; Adolescent; Adult; Aged; Ergolines; Female; Humans; Hyperprolactinemia; Lisuride; Male; Middle Aged; Pregnancy

Topics: Animals; Dopamine; Ergolines; Estradiol; Hypertrophy; Lisuride; Male; Pituitary Gland, Anterior; Rats; Rats, Inbred Strains

Terguride, a derivative of lisuride, has been shown to possess a mixed dopaminergic-antidopaminergic activity in experimental models. We have studied the effects on PRL and GH levels of 0.2 mg po of terguride in 8 normal subjects, in 15 patients with pathological hyperprolactinemia (PHP) and in 17 patients with active acromegaly. In PHP, PRL levels were significantly reduced up to 300 min after terguride with a nadir (45 +/- 4.0% SE) significantly lower (p less than 0.05) than the one observed in the 8 normal subjects (72 +/- 3.5%). There was no significant difference in plasma PRL levels after 0.2 mg terguride or lisuride in 7 out of 15 patients tested with both drugs. Terguride did not significantly modify GH levels in PHP and in normals but when considering basal and peak (occurring between 60 and 150 min) GH values, a significant difference was found (p less than 0.01). Mean peak of GH did not differ significantly between PHP (5.0 +/- 1.1 ng/ml) and normals (6.8 +/- 1.7 ng/ml). Plasma GH levels of 17 acromegalics were not modified by 0.2 mg of terguride but were significantly reduced by 2.5 mg of bromocriptine. Terguride and bromocriptine reduced PRL levels in acromegalics (p less than 0.01) without any significant difference between the two drug. 0.2 mg terguride bid given for 15 days to 7 healthy volunteers significantly reduced both basal and sulpiride (25 mg im)-stimulated PRL levels. Side effects were observed only in 4 out of 47 subjects tested with terguride and in 8 out of 34 tested with bromocriptine.

Topics: Acromegaly; Adolescent; Adult; Bromocriptine; Ergolines; Female; Growth Hormone; Humans; Lisuride; Male; Middle Aged; Prolactin; Time Factors

Terguride, a mixed agonist-antagonist of central dopamine receptors, was administered to eight patients with Parkinson's Disease. The clinical symptomatology of all patients improved significantly. The maximum neurological effect of terguride was noted at the highest daily dose (1.2 mg) after 21 days of treatment in all subjects, with a statistically significant average of 50.6% neurological improvement on the Webster scale in respect to admission. All single scores of the Webster scale decreased significantly: swing of the arms, facial expression, bradikinesia, rigidity and gait, particularly. No significant adverse reactions were observed during treatment. Our study in drug-free parkinsonian patients demonstrated that terguride is able to improve the neurological symptoms similar to DA agonists, but without their typical side effects.

Topics: Aged; Disability Evaluation; Dopamine; Drug Evaluation; Ergolines; Female; Humans; Lisuride; Male; Middle Aged; Nervous System; Parkinson Disease

Topics: Acromegaly; Adult; Aged; Ergolines; Female; Growth Hormone; Humans; Hyperprolactinemia; Lisuride; Male; Middle Aged; Prolactin

The 9,10-transdihydro analogue of the dopaminergic ergot derivative lisuride, transdihydrolisuride (TDHL) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl in striatum (0.1-10 mg/kg i.p.), in the dopamine rich part of the limbic system (at 3 mg/kg i.p.) and in the neocortex (0.3-10 mg/kg i.p.). At a low dose (0.03 mg/kg) however, TDHL inhibited dopa accumulation in the limbic system. In gamma-butyrolactone-pretreated rats TDHL not only inhibited the accumulation of dopa in striatum and in the dopamine-rich part of the limbic system but also antagonized the inhibitory effect of lisuride on dopa accumulation. The accumulation of 5-hydroxytryptophan was reduced in striatum, in parts of the limbic system and neocortex only at high doses of TDHL (3 and 10 mg/kg i.p.). TDHL (0.03 or 3 mg/kg i.p.) did not change the alpha-methyl-p-tyrosine methylester HCl-induced disappearance of dopamine but accelerated the disappearance of noradrenaline at a dose of 3 mg/kg in all brain regions studied. The striatal level of dihydroxyphenylacetic acid was increased by TDHL dose dependently, the maximum effect being only half of that induced by haloperidol. TDHL (0.3 and 3 mg/kg i.p.) stimulated the accumulation of 3-methoxytyramine and normetanephrine following monoamine oxidase (MAO) inhibition with pargyline. The data suggest that TDHL is a mixed agonist-antagonist at central dopamine receptors. Under normal conditions the antagonistic component appears to predominate in the nigrostriatal and mesolimbic system. The stimulation of noradrenaline turnover was most likely due to an adrenoceptor antagonistic action of TDHL.

Topics: 3,4-Dihydroxyphenylacetic Acid; 5-Hydroxytryptophan; Animals; Aromatic Amino Acid Decarboxylase Inhibitors; Brain; Catecholamines; Dihydroxyphenylalanine; Ergolines; Lisuride; Male; Methyltyrosines; Rats; Rats, Inbred Strains; Receptors, Dopamine

Plasma levels and urinary excretion of the dopamine agonist, transdihydrolisuride (TDHL), were measured by radioimmunoassay in healthy male volunteers given TDHL 50 micrograms i.v. and oral doses of 200, 400 and 800 micrograms. Plasma prolactin was also measured by radioimmunoassay. Following i.v. injection, the concentration of TDHL declined with a half-life of 37 +/- 19 min. The total clearance was 38 +/- 27 ml/min/kg and the apparent volume of distribution was 1.3 +/- 0.41/kg. The bioavailability of oral TDHL was proportional to the dose; after 200, 400 and 800 micrograms the bioavailability was 20 +/- 25%, 31 +/- 24% and 48 +/- 26%. TDHL was almost totally metabolized and less than 0.5% of the dose was excreted unchanged in urine in 24 h. Plasma prolactin levels were depressed by 66 +/- 15%, 75 +/- 11% and 80 +/- 7% after TDHL 200 micrograms, 400 micrograms and 800 micrograms. The effect lasted for more than 12 h after the lowest dose and for more than 24 h after 400 and 800 micrograms. Side effects, mainly nausea and headache, only occurred at the two highest dose levels.

Topics: Adult; Biological Availability; Ergolines; Humans; Kidney; Kinetics; Lisuride; Male; Prolactin; Radioimmunoassay

The development of a sensitive radioreceptor assay (RRA) for transdihydrolisuride (TDHL) and lisuride, as well as the synthesis of tritiated TDHL, is described. The method is based upon the competition between 3H TDHL and TDHL or lisuride for rat brain dopaminergic receptors. Linear calibration graphs were obtained in the range of 0.2-9 pmol for an ergot derivative. Relative affinities of the main metabolites, deethylated and dideethylated on the urea part of the molecule are 3.6% and 1.5%, respectively, as compared to the parent drug. To verify the method, plasma levels of TDHL were determined in rats after oral administration.

Topics: Animals; Antibody Specificity; Ergolines; Female; Hydrogen-Ion Concentration; Kinetics; Lisuride; Radioligand Assay; Rats; Rats, Inbred Strains

Topics: Adult; Animals; Apomorphine; Behavior, Animal; Body Temperature; Catalepsy; Ergolines; Female; Haloperidol; Humans; Lisuride; Male; Mice; Motor Activity; Prolactin; Rats; Rats, Inbred Strains

Topics: Administration, Oral; Animals; Body Weight; Drug Synergism; Ergolines; Female; Lactation; Lethal Dose 50; Lisuride; Oxytocin; Pregnancy; Prolactin; Urea