dironyl and Parkinson-Disease

Drug-induced psychiatric states occur frequently in PD. In the prelevodopa era, depression and other psychiatric disorders were described in PD, but in untreated patients psychosis was rare. Since the development of levodopa and other pharmacological treatments for PD, however, psychotic symptoms have become much more common (10-50%). In some individuals these problems can be more disabling than the motor features of PD and, as a result, pose a serious threat to the patient's ability to maintain independence. The drug-induced psychoses consist of several distinct psychiatric syndromes that can be divided broadly into those occurring on a background of a clear sensorium and those which are accompanied by confusion and clouding of consciousness. Benign organic hallucinosis is the most common of these syndromes (30%). It usually occurs on a background of a clear sensorium and may not be a particularly troublesome problem if the patient is able to retain insight into the nature of these symptoms. More disabling syndromes usually include delusional thinking that is frequently paranoid, confusion and even frank delirium. Although all these psychotic syndromes can occur in isolation, there is a tendency for mild symptoms to progress to more disabling ones if adequate and timely treatment is not instituted. Abnormal dreaming and sleep disruption often precede these difficulties by weeks to months and may provide an important early clue to their onset. The mechanisms responsible for drug-induced psychotic symptoms in PD are unknown, but dopaminergic (especially mesolimbic) and serotoninergic systems are likely to be involved. The treatment of the drug-induced psychoses in PD should be undertaken in a stepwise manner. A detailed discussion of this approach, including the use of anti-PD medication adjustment, clozapine, and other medications (neuroleptic and nonneuroleptic) and ECT is provided (see Fig. 1). Although drug-induced psychoses are the most important of the drug-induced psychiatric states, mania, anxiety, and hypersexuality may also occur. Depression is also common in PD, but it is unlikely to occur as a side effect of antiparkinsonian medications.

Topics: Aged; Anxiety; Bipolar Disorder; Clozapine; Depression; Electroconvulsive Therapy; Humans; Levodopa; Lisuride; Male; Ondansetron; Parkinson Disease; Psychoses, Substance-Induced; Sexual Dysfunctions, Psychological

In a randomized double-blind study, 20 parkinsonian patients (suffering from the disease for 2-18 years), chronically treated with levodopa (500-750 mg/day for 0.5-12 years), received terguride (1 mg b.i.d.) or placebo for 4 weeks. Growth hormone (GH), prolactin (PRL), thyroid-stimulating hormone (TSH), and insulin-like growth factor (IGF-I) secretions were studied before and after the morning dose of levodopa (250 mg p.o.), both before and at the end of study period. At the beginning of the study, basal hormonal levels were within normal limits, and levodopa administration induced a significant suppression in PRL and TSH levels (both p < 0.01)) and a significant increase in GH (p < 0.01). The same results were observed at the end of the study period in the placebo group. Addition of terguride induced a significant suppression in basal PRL levels (p < 0.01), whereas levodopa-induced hormonal changes were unaffected. These data suggest that the hypothalamic dopaminergic function that controls anterior pituitary hormones is preserved in parkinsonian patients, regardless of both the duration of the disease and the long-term treatment with levodopa. The strong additional prolactin-lowering effect of terguride indicates long-lasting dopaminergic effects, as is already known from hyperprolactinemic conditions. The dopaminergic effects of levodopa on TSH, GH, and IGF-I secretion were unchanged by terguride treatment. The anti-dopaminergic effects of terguride observed in the motor system in animal studies, as well as in levodopa-induced dyskinesias in parkinsonian patients, could not be observed in the case of the dopaminergic control of anterior pituitary hormones under the conditions of this study.

Topics: Aged; Antiparkinson Agents; Dopamine Agonists; Double-Blind Method; Female; Humans; Hyperprolactinemia; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Pituitary Function Tests; Pituitary Gland, Anterior; Pituitary Hormones, Anterior

The effects of the partial dopamine agonist terguride (9,10 transdihydrolisuride; THDL) on striatal dopamine receptors were studied by its i.v. administration to 13 patients with Parkinson's disease. Patients were maintained in a steadily mobile state with abnormal involuntary movements by a constant i.v. infusion of levodopa. Terguride showed dopamine antagonist properties in nine patients. In two of these nine patients, a decrease in dyskinesia score was observed without a concomitant worsening of parkinsonian symptoms, whereas in the remaining seven, full parkinsonian akinesia followed THDL administration. The subsequent i.v. injection of the dopamine agonist lisuride reversed THDL-induced akinesia in these seven patients. In the remaining four patients, no clinically significant motor effects were observed. These results show dopamine antagonist activity of terguride in patients with Parkinson's disease treated with Levodopa. Further studies using a wider dose titration are required to evaluate the possible role of dopamine partial agonists in the therapy of levodopa-induced dyskinesias.

Topics: Adult; Aged; Dopamine Agents; Humans; Levodopa; Lisuride; Middle Aged; Parkinson Disease

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

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

Present Parkinson's disease treatment strategies are far from ideal for a variety of reasons; it has therefore been suggested that partial dopamine receptor agonism might be a potential therapeutic approach with potentially fewer side effects. In the present study, we describe the in vitro characterization of the nonergot ligand SLV308 (7-[4-methyl-1-piperazinyl]-2(3H)-benzoxazolonemonohydrochloride). SLV308 binds to dopamine D(2), D(3), and D(4) receptors and 5-HT(1) (A) receptors and is a partial agonist at dopamine D(2) and D(3) receptors and a full agonist at serotonin 5-HT(1) (A) receptors. At cloned human dopamine D(2,L) receptors, SLV308 acted as a potent but partial D(2) receptor agonist (pEC(50) = 8.0 and pA(2) = 8.4) with an efficacy of 50% on forskolin stimulated cAMP accumulation. At human recombinant dopamine D(3) receptors, SLV308 acted as a partial agonist in the induction of [(35)S]GTPgammaS binding (intrinsic activity of 67%; pEC(50) = 9.2) and antagonized the dopamine induction of [(35)S]GTPgammaS binding (pA(2) = 9.0). SLV308 acted as a full 5-HT(1) (A) receptor agonist on forskolin induced cAMP accumulation at cloned human 5-HT(1) (A) receptors but with low potency (pEC(50) = 6.3). In rat striatal slices SLV308 concentration-dependently attenuated forskolin stimulated accumulation of cAMP, as expected for a dopamine D(2) and D(3) receptor agonist. SLV308 antagonized the inhibitory effect of quinpirole on K(+)-stimulated [(3)H]-dopamine release from rat striatal slices (pA(2) = 8.5). In the same paradigm, SLV308 had antagonist properties in the presence of quinpirole (pA(2) = 8.5), but the partial D(2) agonist terguride had much stronger antagonistic properties. In conclusion, SLV308 combines high potency partial agonism at dopamine D(2) and D(3) receptors with full efficacy low potency serotonin 5-HT(1) (A) receptor agonism and is worthy of profiling in in vivo models of Parkinson's disease.

Topics: Animals; Benzoxazoles; Binding, Competitive; Brain; CHO Cells; Colforsin; Cricetinae; Cyclic AMP; Dopamine Agonists; Dose-Response Relationship, Drug; Drug Interactions; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Lisuride; Male; Molecular Structure; Parkinson Disease; Piperazines; Quinpirole; Radioligand Assay; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Dopamine D3; Recombinant Fusion Proteins; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists

The optimal combination of a dopamine D2 agonist and a D1 agonist was evaluated for symptomatic treatment of Parkinson's disease. Behavioral effects of combination treatment of the full D2 agonist quinpirole or the partial D2 agonist terguride with the full D1 agonist SKF 82958 [(I) 6-Chloro-7, 8-dihydroxy-3-allyl-1-phenyl-2, 3, 4, 5-tetra-hydro-1H-3-benzazepine] were investigated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys with attention to the induction of hyperactivity such as irritability, excitability and aggressiveness and of dyskinesias such as licking of paws, chewing and biting. Both quinpirole and SKF 82958 alone improved the parkinsonism with a slight induction of the hyperactivity and dyskinesias. Terguride also improved the parkinsonism but did not induce the hyperactivity and dyskinesias. Combination treatment of quinpirole with SKF 82958 not only showed a tendency to augment the antiparkinsonian effects but also induced the marked hyperactivity and dyskinesias. On the other hand, combination treatment of terguride with SKF 82958 also augmented the antiparkinsonian effects but did not induce any hyperactivity and dyskinesias. These findings suggest that combination therapy with a partial D2 agonist and a full D1 agonist or monotherapy with a dopamine agonist that has both partial D2 and full D1 agonist properties might be beneficial for treating motor dysfunction in Parkinson's disease without inducing dopaminergic side effects.

Topics: Animals; Benzazepines; Dopamine Agonists; Drug Therapy, Combination; Lisuride; Macaca fascicularis; MPTP Poisoning; Parkinson Disease; Receptors, Dopamine D1; Receptors, Dopamine D2

Terguride (TER), a semisynthetic derivative of lisuride, has been found to display dopamine (DA) agonist and DA antagonist effects in animals, depending on the experimental model used. TER (2 mg/day) was compared to placebo in 41 fluctuating Parkinson's disease patients to test its effect on akinesia and dyskinesia. Mean hours "off" decreased at weeks 6 and 12 (p < 0.05) in the TER group but the overall difference from the placebo group was not significant. Only the TER group displayed a decrease over time in mean Columbia University Rating Scale total score "on" and "off" (p = 0.001 and p = 0.03, respectively). Duration of involuntary movements and resulting disability were not significantly different between patients on TER and those on placebo administration. In the overall evaluation, patients preferred TER (p = 0.01). Tolerance of TER was very good in all but one patient whose wearing-off increased; no one dropped out because of side effects. This 3-month double-blind study showed that TER, added to stable doses of L-dopa, may have slight antiparkinsonian efficacy.

Topics: Adult; Aged; Dopamine; Dopamine Agents; Double-Blind Method; Drug Therapy, Combination; Drug Tolerance; Female; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease; Placebos

Topics: Dopamine Agents; Humans; Levodopa; Lisuride; Parkinson Disease

Terguride, a partial DA-agonist with both dopaminergic and antidopaminergic properties, was tested in 11 PD patients in the "decompensated" phase of the disease, characterized by the presence of dyskinesias and motor fluctuations. Combined treatment of these patients with 1 mg/day of terguride and stabilized doses of levodopa reduced the severity and frequency of dyskinesias and motor fluctuations along with a slight but significant improvement of parkinsonian clinical picture. The "modulatory" effect of terguride on DA receptors, in this experimental conditions, is discussed.

Topics: Dyskinesia, Drug-Induced; Humans; Levodopa; Lisuride; Male; Middle Aged; Parkinson Disease

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

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 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

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