benzofurans and Basal-Ganglia-Diseases

SU-23397 is a unique new hybrid molecule, the animal profile being characteristic of neuroleptic activity. Although the trial was uncontrolled, there appears to be no doubt that SU-23397 exerts antipsychotic activity between 20 mg and 250 mg daily in severely ill schizophrenic patients. Seven of the ten subjects required at least transient antiparkinson medication. Two patients demonstrated premature ventricular contractions. One patient had infrequent PVCs at baseline which increased in frequency with rising dosage. The other patient developed frequent premature ventricular contractions only after active and medication was initiated and was subsequently withdrawn from the study.

Topics: Adult; Antipsychotic Agents; Basal Ganglia Diseases; Benzofurans; Clinical Trials as Topic; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Psychiatric Status Rating Scales; Schizophrenia; Spiro Compounds

Imaging of dopaminergic function is useful in the investigation of patients with Parkinson disease (iPD) and other extrapyramidal diseases. Using agents that bind to dopamine transporters ([123I]beta-CIT) and receptors ([123I]IBF SPECT), we investigated SPECT in 9 healthy volunteers and 24 patients for dopamine transporters as well as 15 patients for dopamine receptors. In beta-CIT SPECT studies, we examined 17 iPD patients (63.3 +/- 9.9 y/o), 3 multiple system atrophy (MSA) patients (OPCA type) (64.0 +/- 8.0 y/o), 2 vascular parkinsonism (VP) patients (71.0 +/- 0.0 y/o), 1 progressive supranuclear palsy (PSP) patient (69 y/o), 1 cortico-basal degeneration (CBD) patient (50 y/o) and nine healthy controls (39.1 +/- 9.3 y/o). For IBF SPECT studies 11 iPD patients (60.6 +/- 10.9 y/o), 3 MSA patients (2 OPCA type (50.5 +/- 3.5 y/o) and 1 SND type (65 y/o)) and 1 PSP patient (60 y/o) underwent SPECT scans after the injection of [123I]IBF. The specific to nonspecific striatal uptake ratio(St/Oc-1), ratio of putaminal uptake to caudatal uptake (Pu/Ca), and asymmetry indices (AI) were estimated. beta-CIT studies showed St/Oc-1 as follows; iPD: 2.66 +/- 1.09 (n = 17), VP: 5.73 and 7.39, MSA: 1.84 +/- 0.46 (n = 3), PSP: 2.34, CBD: 2.16. In all extrapyramidal diseases except VP, St/Oc-1 ratios were significantly lower than those in normal volunteers (6.46 +/- 1.08) (p < 0.01). Also in early-phase iPD patients (Yahr I-II), St/Oc-1 (3.16 +/- 1.49: n = 4) was significantly lower than those in normal volunteers (p < 0.01). In IBF studies, St/Oc-1 ratios were significantly higher in early-phase (Yahr I-II) iPD patients (1.82 +/- 0.25: n = 5) than those in late-phase (Yahr III-IV) iPD patients (1.38 +/- 0.32: n = 6) (p < 0.05). The Pu/Ca ratios in iPD patients (1.12 +/- 0.13) and MSA (OPCA type) patients (0.95 +/- 0.05) were higher than that in MSA (SND type) patient (0.78) and were lower than that in PSP patient (1.55). In conclusion, beta-CIT-SPECT is useful for the diagnosis of early-phase iPD patients and for differentiating VP from other extrapyramidal diseases. IBF-SPECT is useful for the diagnosis of the severity of iPD and has the possibility for ruling out MSA (SND type) or PSP from iPD. Both tracers are useful for investigating the pathophysiology of patients with iPD and other extrapyramidal diseases.

Topics: Aged; Basal Ganglia Diseases; Benzofurans; Cocaine; Dopamine Plasma Membrane Transport Proteins; Humans; Iodine Radioisotopes; Membrane Glycoproteins; Membrane Transport Proteins; Middle Aged; Nerve Tissue Proteins; Parkinson Disease; Pyrrolidines; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

To determine: (1) whether the apparent lack of efficacy of dopamine D1 (D1) antagonists in the clinic might be attributable to development of tolerance to antipsychotic effects; and (2) whether combined D1 and D2 antagonism might contribute to clozapine's clinical profile, eight Cebus apella monkeys were chronically treated with a D1 antagonist (NNC 756) ((+)-8-chloro-7-hydroxy-3-methyl-5-(7-(2,3- dihydrobenzofuranyl)-2,3,4,5-tetrahydro-1H-3-benzazepine), a D2 antagonist (raclopride) or a combination of the two antagonists. Prior neuroleptic exposure had resulted in oral dyskinesia in seven monkeys and sensitization to dystonia in all, yielding a model for acute and chronic extrapyramidal side effects (EPS). Dextroamphetamine-induced motoric unrest and stereotypies were used as a psychosis model. We found tolerance toward dystonic symptoms during D1 and D1 + D2 treatments but not during D2 treatment. D2 but not D1 or D1 + D2 antagonism caused exacerbation of dyskinesia. Both D1 and D1 + D2 antagonism were superior to D2 antagonism alone in counteracting the amphetamine-induced behaviors, with no tolerance to antiamphetamine effects. These findings suggest: (1) reasons other than tolerance (e.g., differences among antagonists) may explain the lack of efficacy in clinical trials with D1 antagonists; and (2) that D1 antagonism alone or combined and modest D1 and D2 antagonism offers the potential of antipsychotic efficacy with a lower risk of EPS than traditional D2 antagonism. Further clinical trials with D1 or combined D1 and D2 antagonists are, therefore, recommended.

Topics: Amphetamine; Animals; Arousal; Basal Ganglia Diseases; Benzazepines; Benzofurans; Cebus; Dopamine Agents; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Interactions; Dyskinesia, Drug-Induced; Dystonia; Male; Motor Activity; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Stereotyped Behavior

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.

Topics: Animals; Basal Ganglia Diseases; Benzazepines; Benzofurans; Cebus; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Male; Raclopride; Receptors, Dopamine D1; Time Factors

Iodine-123-IBF is a dopaminergic antagonist suitable for SPECT imaging of D2 receptors. Initial animal studies demonstrated that its affinity for D2 receptors is approximately four times that of the commonly used SPECT D2 ligand [123I]IBZM. In this study we investigated whether this higher affinity would lead to an improved accuracy in differentiating between various extrapyramidal diseases.. SPECT imaging was performed in 17 patients with idiopathic Parkinson's syndrome (IPS); 4 patients with progressive supranuclear palsy (PSP), 2 patients with multiple system atrophy (MSA) and 7 age-matched control subjects. SPECT imaging was performed 5, 60, 120 and 180 min following intravenous bolus injection of 150-250 MBq of [123I]IBF. The ratio of ligand uptake in the basal ganglia and frontal cortex was determined as a measure of receptor status.. In PSP and MSA patients, the basal ganglia-to-frontal cortex ratio reached a plateau at 2 hr; in the control subjects and the IPS patients the ratio was steadily increasing. At 3 hr the basal ganglia-to-frontal cortex ratio was 2.66 +/- 0.29 (control subjects), 3.01 +/- 0.41 (IPS), 2.09 +/- 0.22 (PSP) and 2.10 (MSA). In the IPS patients with predominantly one-sided symptoms, the striatum contralateral to symptoms showed a tendency towards relatively increased ligand uptake. Despite the higher affinity of IBF for the D2 receptor compared to IBZM, the separation of individual PSP and MSA patients from the control subjects was not as clear cut as reported for IBZM due to a relatively high variation in the control subjects. We hypothesize that the latter is due to imaging in nonequilibrium conditions.. The data suggest that IBF-SPECT can help in discriminating extrapyramidal disease. The accuracy might be improved by an administration protocol that allows imaging in "true equilibrium" conditions, such as a bolus injection followed by a constant infusion.

Topics: Aged; Aged, 80 and over; Basal Ganglia; Basal Ganglia Diseases; Benzofurans; Brain; Diagnosis, Differential; Female; Frontal Lobe; Humans; Iodine Radioisotopes; Male; Middle Aged; Parkinson Disease; Pyrrolidines; Receptors, Dopamine D2; Supranuclear Palsy, Progressive; Tomography, Emission-Computed, Single-Photon

Eight Cebus apella monkeys previously exposed to D1 and D2 antagonists were treated subcutaneously for 8 weeks with the D1 antagonist NNC 756 (0.01 mg/kg), followed by a wash-out period of 4 weeks and treatment with the D2 antagonist raclopride for 8 weeks (end doses 0.01 mg/kg). NNC 756 induced no dystonia, while marked dystonia was induced by raclopride. Mild tolerance to the dystonia-inducing effect of raclopride slowly developed. Both drugs induced significant sedation and mild bradykinesia. Sedation induced by NNC 756 was stronger than that of raclopride, while no differences were found regarding bradykinesia. The sedative effect of both NNC 756 and raclopride increased over time during chronic treatment. No changes in bradykinesia developed. No significant dyskinesia was induced by NNC 756, while raclopride significantly induced both acute and tardive oral dyskinesia. Furthermore, raclopride-induced acute dyskinesia worsened during chronic treatment. Concomitant treatment with NNC 756 tended to reduce the D1 agonist SKF 81297-induced dyskinesia and grooming, while concomitant treatment with raclopride increased SKF 81297-induced dyskinesia and tended to decrease SKF 81297-induced grooming. Chronic treatment with raclopride induced supersensitivity to both the D2/D3 agonist LY 171555 and SKF 81297, while chronic NNC 756 treatment only induced supersensitivity to SKF 81297. The findings indicate that D1 antagonists may induce less dystonia and oral dyskinesia as compared with D2 antagonists and support the hypothesis of both a permissive and an inhibitory interaction between D1 and D2 receptor systems.

Topics: Animals; Basal Ganglia Diseases; Behavior, Animal; Benzazepines; Benzofurans; Cebus; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dyskinesia, Drug-Induced; Ergolines; Grooming; Hypnotics and Sedatives; Male; Motor Activity; Quinpirole; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides