dironyl and Parkinson-Disease--Secondary

Terguride, a partial dopamine agonist, was administered in a 4-week open clinical trial to 17 schizophrenic patients suffering from extrapyramidal side effects of neuroleptic treatment. The neuroleptic dosage was kept constant. The mean final daily dose of terguride reached 3.4 mg (SD = 2.0). Fourteen patients completed the trial. Total scores on the Rating Scale for Extrapyramidal Side Effects and the Brief Psychiatric Rating Scale showed a significant improvement of 69% and 40%, respectively. There was also a significant improvement in all BPRS factor scores.

Topics: Administration, Oral; Adult; Antipsychotic Agents; Dopamine Agents; Dyskinesia, Drug-Induced; Female; Humans; Lisuride; Male; Middle Aged; Neurologic Examination; Parkinson Disease, Secondary; Psychotic Disorders; Schizophrenia; Schizophrenic Psychology

While dopamine replacement remains the standard pharmacotherapy for Parkinson's disease, chronic L-dopa treatment is associated with development of debilitating motor fluctuations such as L-dopa-induced dyskinesia (LID). In this study we evaluated the effects of the partial dopamine D(2) agonist terguride on the development of LID in hemiparkinsonian mice (unilaterally lesioned with 6-hydroxydopamine). First, consistent with the partial agonist property, terguride had 1000-fold higher potency than dopamine, yet producing one-third level of maximal activation of dopamine, as assayed by [(35)S]GTPgammaS binding. Furthermore, in the absence and presence of dopamine in vitro, terguride increased and decreased striatal [(35)S]GTPgammaS binding, respectively. Next, we found that co-administration of terguride (at 0.1 and 0.5mg/kg, i.p.) with L-dopa (1.8 mg/kg) daily for 14 days, significantly attenuated the development and expression of L-dopa-induced rotational sensitization. Furthermore, the cross-challenge paradigm revealed that chronic L-dopa treatment (but not terguride) sensitized locomotor response to the dopamine D(1) agonist SKF 81297 while chronic treatment with terguride (but not L-dopa) produced sensitized locomotor responses to the adenosine A(2A) antagonist 8-(3-chlorostyryl)caffeine (CSC). Importantly, the co-administration of terguride with L-dopa did not show locomotor sensitization to either SFK 81297 or CSC upon challenge. Together, these results suggest that co-administration of partial dopamine D(2) agonists with L-dopa may prophylactically attenuate L-dopa-induced abnormal behavioral responses such as LID.

Topics: Adenosine A2 Receptor Antagonists; Animals; Antiparkinson Agents; Benzazepines; Caffeine; Corpus Striatum; Dopamine Agonists; Drug Therapy, Combination; Guanosine 5'-O-(3-Thiotriphosphate); Levodopa; Lisuride; Male; Mice; Mice, Inbred C57BL; Motor Activity; Oxidopamine; Parkinson Disease, Secondary; Random Allocation; Receptors, Dopamine D1; Receptors, Dopamine D2; Sulfur Radioisotopes

Behavioral effects of terguride, a partial dopamine D2 agonist, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys were compared with those of the dopamine agonist apomorphine and the dopamine antagonist haloperidol. Terguride alone ameliorated the parkinsonism without inducing any sign of excitability, irritability, or aggressiveness (hyperactivity). Apomorphine alone also ameliorated the parkinsonism but induced marked hyperactivity. Haloperidol alone caused worsening of the parkinsonism, inducing transient eyelid closure. In combination with apomorphine, terguride suppressed the hyperactivity induced by apomorphine without reducing its antiparkinsonian effects. Pretreatment with haloperidol suppressed both the antiparkinsonian effects and the hyperactivity induced by apomorphine. Terguride thus exhibits both antiparkinsonian and antihyperactivity effects in a monkey model of Parkinson's disease, suggesting that terguride might be beneficial for treating motor dysfunction and dopaminergic psychosis in advanced Parkinson's disease.

Topics: Aggression; Analysis of Variance; Animals; Apomorphine; Behavior, Animal; Dopamine Agents; Haloperidol; Lisuride; Macaca fascicularis; Motor Activity; MPTP Poisoning; Parkinson Disease, Secondary; Receptors, Dopamine D2; Time Factors

The mixed dopamine (DA) agonist/antagonist terguride acts as a DA antagonist on normosensitive receptors but shows DA agonistic properties at supersensitive DA receptors. Such a compound could offer an alternative to the treatment of Parkinson's disease with indirect or direct DA agonists. The present study compares the actions of terguride, 4-12 mg/kg i.p., in naive common marmosets with its effects in animals rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 2 months or 10 months previously, in order to test its antiparkinsonian efficacy. Terguride reduced locomotor activity in naive common marmosets, similar to its effects in rodents and in line with the DA antagonistic activity of the compound. In marmosets treated with MPTP 2 months previously and exhibiting pronounced behavioural motor deficits, terguride stimulated locomotor activity, showing DA agonistic properties under these conditions. In contrast, the locomotor activity of animals that had recovered from MPTP treatment 10 months previously was not altered by terguride. It is concluded that terguride has anti-akinetic efficacy in this primate model of Parkinson's disease. In addition, terguride offers a unique opportunity to differentiate, pharmacologically, the extent of dopaminergic recovery from MPTP treatment in this primate species.

Topics: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Animals; Antiparkinson Agents; Callithrix; Disease Models, Animal; Dopamine Agents; Female; Lisuride; Male; Motor Activity; Parkinson Disease, Secondary; Time Factors

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