PD98059 is an equipotent antagonist of the aryl hydrocarbon receptor and inhibitor of mitogen-activated protein kinase kinase

Striatal dopamine transporter function and dopamine D2 receptor status were evaluated in 15 patients with early untreated Parkinson's disease using single photon emission tomography (SPECT) with 123I-Iodo-2beta-carboxymethoxy-3beta-(4-idiophenyl)tropane (beta-CIT) and 123I-Iodobenzamide (IBZM) as pre- and postsynaptic ligands. Symptoms were unilateral in five patients and bilateral but asymmetric in 10 patients. Patients with bilateral symptoms had significantly lower 18-hour striatal/cerebellar beta-CIT binding ratios (3.59 +/- 0.79) than hemiparkinsonian patients (5.76 +/- 1.48, p < 0.05) reflecting more advanced disease in this subgroup. Patients with bilateral parkinsonism were also found to have a significant side-to-side difference in striatal beta-CIT binding with more marked reduction contralateral to the presenting limb (18-hour striatal/cerebellar ratio: 4.13 +/- 0.78 [ipsilateral] versus 3.59 +/- 0.79 [contralateral], p < 0.05). Dopamine D2 receptor binding as measured by IBZM was significantly elevated contralateral to the affected side in hemiparkinsonian patients (striatal/cerebellar ratio: 2.42 +/- 0.90 [contralateral] versus 2.19 +/- 0.80 [ipsilateral], p < 0.05). This asymmetric upregulation was absent in the patients with bilateral parkinsonism (striatal/cerebellar ratio: 1.85 +/- 0.43 [contralateral to more severely affected side] versus 1.83 +/- 0.34 [ipsilateral], p > 0.05). Our data suggest that postsynaptic dopamine receptor upregulation contralateral to the presenting side occurs in untreated unilateral PD and disappears in untreated bilateral (asymmetric) PD despite a greater loss of dopamine transporter function. Combined beta-CIT and IBZM SPECT studies may be helpful to monitor the progression of nigrostriatal dysfunction in early PD.     

Clinical impact of cerebral dopamine-D2 receptor scintigraphy

The present review describes findings and clinical indications for the dopamine D2 receptor scintigraphy. Methods for the examination of D2 receptors are positron emission tomography (PET) using 11C- or 18F-labelled butyrophenones or benzamides or single photon emission tomography (SPECT) using 123l-iodobenzamide (IBZM) respectively. The most important indication in neurology is the differential diagnosis of Parkinsonism: patients with early Parkinson's disease show an increased D2 receptor binding (D2-RB) compared to control subjects. However, patients suffering from Steele-Richardson-Olszewski-Syndrome or Multiple System Atrophy show a decreased D2-RB and are generally non-responsive to treatment. Postsynaptic blockade of D2 receptors results in a drug induced Parkinsonian syndrome, which can be diagnosed by D2 scintigraphy. Further possible indications occur in psychiatry: the assessment of receptor occupancy is useful in schizophrenic patients treated with neuroleptics. Additionally, D2 receptor scintigraphy might help to clarify the differential diagnosis between neuroleptic malignant syndrome and lethal catatonia. The method might be useful for supervising neurobiochemical changes in drug dependency and during withdrawal. Assessment of dopamine D2 receptor binding can simplify the choice of therapy in depressive disorder: patients showing a low D2 binding are likely to improve following an antidepressive drug treatment whereas sleep deprivation is promising in patients with high D2 binding.     

Iodine-123-iodobenzamide binding in parkinsonism: reduction by dopamine agonists but not L-Dopa

The aim of the present study was to investigate the effect of treatment with L-Dopa or a dopamine agonist, or both, on specific striatal 123I-iodobenzamide (IBZM) binding using an intraindividual longitudinal design. METHOD: We prospectively studied the effect of dopaminomimetic treatment on specific [123I]IBZM binding measured by SPECT in 29 patients with a clinical diagnosis of Parkinson's disease, none of whom had previously received dopaminomimetic drugs. The patients had been selected on the basis of normal subsequent specific [123I]IBZM binding, semiquantitatively calculated as the basal ganglia/frontal cortex ratio, and a positive response to the dopamine agonist apomorphine before initiation of dopaminomimetic therapy. A second 123I-IBZM SPECT investigation was performed after 3-6 mo of treatment with L-Dopa or a dopamine agonist, or both. RESULTS: Specific [123I]IBZM binding was unchanged in 10 patients treated with L-Dopa alone. However, after treatment with a dopamine agonist there was a significant decline in specific [123I]IBZM binding (p < 0.05). After treatment with a combination of L-Dopa and a dopamine agonist, specific [123I]IBZM binding was reduced without reaching a level of significance (p = 0.08). CONCLUSION: Short-term treatment with a dopamine agonist but not with L-Dopa reduces specific [123I]IBZM binding. Therefore, before performing an [123I]IBZM SPECT scan in patients previously treated with dopaminomimetic drugs, dopamine agonists should be discontinued.     

Nigrostriatal dopaminergic activities in dementia with Lewy bodies in relation to neuroleptic sensitivity: comparisons with Parkinson's disease

BACKGROUND: In dementia with Lewy bodies (DLB) mild extrapyramidal symptoms are associated with moderate reductions in substantia nigra neuron density and concentration of striatal dopamine. Many DLB patients treated with typical neuroleptics suffer severe adverse reactions, which result in decreased survival. METHODS: In a series of DLB cases, with and without neuroleptic sensitivity, substantia nigra neuron densities, striatal dopamine and homovanillic acid concentrations, and autoradiographic [3H]mazindol and [3H]raclopride binding (to the dopamine transporter and D2 receptor, respectively) were analyzed and compared to control and idiopathic Parkinson's disease cases. RESULTS: D2 receptors were up-regulated in neuroleptictolerant DLB and Parkinson's disease compared to DLB without neuroleptic exposure and controls. D2 receptors were not up-regulated in DLB cases with severe neuroleptic reactions. Dopamine uptake sites were reduced concomitantly with substantia nigra neuron density in Parkinson's disease compared to controls, but there was no significant correlation between substantia nigra neuron density and [3H]mazindol binding in DLB groups. There was no significant difference in substantia nigra neuron density, [3H]mazindol binding, and dopamine or homovanillic acid concentration between neuroleptic-tolerant and -sensitive groups. CONCLUSIONS: Failure to up-regulate D2 receptors in response to neuroleptic blockade or reduced dopaminergic innervation may be the critical factor responsible for neuroleptic sensitivity.     

Imaging D2 receptor occupancy by endogenous dopamine in humans

The impact of endogenous dopamine on in vivo measurement of D2 receptors in humans was evaluated with single photon emission computerized tomography (SPECT) by comparing the binding potential (BP) of the selective D2 radiotracer [123I]IBZM before and after acute dopamine depletion. Dopamine depletion was achieved by administration of the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT), given orally at a dose of 1 g every six hours for two days. AMPT increased [123I]IBZM BP by 28 +/- 16% (+/- SD, n = 9). Experiments in rodents suggested that this effect was due to removal of endogenous dopamine rather than D2 receptor upregulation. Synaptic dopamine concentration was estimated as 45 +/- 25 nM, in agreement with values reported in rodents. The amplitude and the variability of the AMPT effect suggested that competition by endogenous dopamine introduces a significant error in measurement of D2 receptors in vivo with positron emission tomography (PET) or SPECT. However, these results also imply that D2 receptor imaging coupled with acute dopamine depletion might provide estimates of synaptic dopamine concentration in the living human brain.     

Iodine-123-iodobenzamide SPECT assessment of dopamine D2 receptor occupancy in riperidone-treated schizophrenic patients

The recently introduced neuroleptic, risperidone, was expected to block fewer dopamine D2 receptors than typical neuroleptics (e.g., haloperidol), but at comparable potency. The aim of this study was to evaluate the degree of dopamine D2 receptor occupancy in relation to the neuroleptic dosage and to correlate the findings with the presence of extrapyramidal symptoms (EPS). Additionally, the data were compared to previous iodobenzamide (IBZM) SPECT findings in patients treated with other neuroleptics, haloperidol and clozapine. METHODS: In 20 patients with schizophrenia [Diagnostic and Statistical Manual of Mental Disorders (Third Edition-Revised)] treated with mean daily doses of risperidone ranging from 0.029 to 0.128 mg/kg body weight, SPECT was performed 2 hr after intravenous injection of 185 MBq 123I-IBZM, a selective dopamine D2 receptor ligand. Striatal IBZM binding was assessed by calculating a striatal/frontal cortex ratio, expressed as a percentage of the control value. RESULTS: Selective dopamine D2 receptor binding of the ligand was reduced in all treated patients, with binding values ranging from 7% to 68%. The degree of occupancy displayed an exponential dose-response relationship (r = -0.86; p < 0.0001). The slope of the curve was between those of haloperidol and clozapine but was closer and more similar in shape to the curve of haloperidol. Extrapyramidal symptoms were observed in 8 of 20 patients with binding values between 7% and 47%. However, there was no clear relationship between the degree of receptor occupancy and the presence of EPS. CONCLUSION: The findings suggest an exponential dose-response relationship between the daily dosage of risperidone and the dopamine D2 receptor occupancy. The blockade of specific striatal IBZM binding found under therapy with risperidone is between those of haloperidol and clozapine. The dose-response curve for risperidone, however, shows greater similarity to that of haloperidol.     

Bronchioloalveolar carcinoma of the lung

Iodine-123-iodobenzamide (IBZM) is a specific antagonist of dopamine D2 receptors and usually is used to study neuropsychiatric disorders. It also has a substantial affinity for malignant melanomas. This has been attributed to specific dopamine D2 receptor binding on melanoma cells because melanocytes and dopaminergic neurons share the same ectodermal origin and are both able to produce melanin. However, IBZM binding to melanoma metastases occurs predominantly 24 hr after injection, which is much later than maximal specific D2 receptor binding is expected. Furthermore, IBZM binding is not consistent in melanoma patients. This points to another mechanism of IBZM binding to melanoma cells. The aim of this study was to characterize IBZM-binding metastatic melanoma patients clinically and histologically to shed light on the nature of this mechanism. METHODS: Twenty-one patients with proven or suspected metastases of a malignant melanoma entered this prospective study after surgical removal of the primary tumor. Whole-body scans, planar scintigrams and SPECT scans were performed 2-5 hr and 1 day after intravenous injection of 185 MBq IBZM. RESULTS: The suspected diagnosis of metastatic cancer was later confirmed in 17 patients by histology, clinical follow-up, x-ray, CT or other radiologic methods. Four patients were free of tumor tissue at the time of investigation and remained stable for 2 yr thereafter. Twelve of the 17 patients had a melanotic and 5 had an amelanotic subtype of the tumor. Iodine-123-IBZM accumulation occurred in the metastases of 10 of the 12 patients with melanotic melanoma and in 0 of the 5 patients with the amelanotic tumor type (p < 0.01; chi-square test). Furthermore, IBZM accumulation occurred in 0 of the 11 amelanotic metastases but in 20 of the 25 melanotic metastases (p < 0.001). The sensitivity is, thus, 83% for the detection of melanotic melanoma metastases on a patient basis and 80% on a lesion basis. Iodine-123-IBZM scintigraphy demonstrated one previously unknown metastasis. Six initially suspected lesions were not due to melanoma metastases and were IBZM-negative. No false-positive IBZM accumulations occurred in our patients. CONCLUSION: Iodine-123-IBZM binds to melanotic malignant melanomas with high specificity and moderate sensitivity but not to amelanotic melanomas. Our data suggest that the tracer does not bind to membrane dopamine receptors of the tumor but is built in or closely bound to intracellular melanin.     

Conservation of baculovirus inhibitor of apoptosis repeat proteins (BIRPs) in viruses, nematodes, vertebrates and yeasts

The purpose of this study was to compare striatal D2 dopamine receptor occupancy of various typical neuroleptics and clozapine in relation to the occurrence of extrapyramidal side effects (EPS). Forty-four inpatients with schizophrenia, including 12 patients with schizodominant schizoaffective disorder, were evaluated using 123I-iodobenzamide (IBZM) and single photon emission computed tomography. Striatal D2 dopamine receptor occupancy was estimated by use of a striatal/frontal cortex ratio (ST/FC) of IBZM binding. Fourteen patients were neuroleptic-free and served as controls. Six patients were treated with clozapine and 24 patients were treated with various typical neuroleptics. ST/FC ratios in patients taking typical neuroleptics were significantly lower than those who were neuroleptic free or treated with clozapine. Patients with EPS had lower ST/FC ratios than those without EPS. A significant linear relationship between ST/FC ratios and severity of EPS estimated by the Simpson-Angus-Scale was established (r=-0.51, p=0.041).     

Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography

This double-blind, placebo-controlled study assessed pharmacologically induced endogenous dopamine (DA) release in healthy male volunteers (n=12). Changes in endogenous DA release after injection of the psychostimulant drug methylphenidate were evaluated by single-photon emission tomography (SPET) and constant infusion of iodine-123 iodobenzamide ([123I]IBZM), a D2 receptor radioligand that is sensitive to endogenous DA release. Methylphenidate induced displacement of striatal [123I]IBZM binding, resulting in a significantly decrease in the specific to non-specific [123I]IBZM uptake ratio (average: 8.6%) in comparison with placebo (average: -1.9%). Moreover, injection of methylphenidate induced significant behavioural responses on the following items: excitement, anxiety, tension, and mannerisms and posturing. The results of this study demonstrate the feasibility of using constant infusion of [123I]IBZM and SPET imaging to measure endogenous DA release after methylphenidate challenge and to investigate neurochemical aspects of behaviour.     

Blockade of subthalamic dopamine D1 receptors elicits akinesia in rats

The role of dopamine in the subthalamic nucleus to control motor behaviour was investigated in rats using bilateral microinfusions of the dopamine D1 receptor antagonist SCH23390 and the dopamine D2 receptor antagonist S(-)-sulpiride. Selective blockade of subthalamic D1 receptors, but not of D2 receptors, produced catalepsy. These findings suggest that dopamine D1 receptors within the subthalamic nucleus play a prominent role in the regulation of motor functions. Furthermore, the data point to the possibility that a reduced dopaminergic tone at subthalamic dopamine D1 receptors might contribute to akinesia in Parkinson's disease.     

In vivo visualization of pituitary dopaminergic receptors by iodine-123 methoxybenzamide (IBZM) correlates with sensitivity to dopamine agonists in two patients with macroprolactinomas

We performed in two patients with macroprolactinoma, pituitary scintigraphy with 123 iodine-methoxybenzamide (IBZM), a dopaminergic antagonist that specifically binds to the D2 dopaminergic receptors. In a 34-yr-old woman with basal PRL levels of about 2000 ng/mL, 7.5 mg/day of Bromocriptine (Br) for a month neither reduced PRL levels nor affected tumor size; in this patient single photon emission tomography SPECT failed to show any pituitary accumulation of the tracer. In the other patient, a 27-yr-old man presenting with cerebrospinal fluid rhinorrhea, basal PRL levels were at 5000 ng/mL; magnetic resonance imaging (MRI) demonstrated a huge pituitary tumor, and SPECT showed a very intense concentration of IBZM at the level of the adenoma. PRL levels fell dramatically to 530 ng/mL with only 2.5 mg/day of Br after 4 days; after 6 days with 7.5 mg/day Br, PRL levels were 63 ng/mL, and the patient underwent surgery to correct cerebrospinal fluid leakage. We conclude that, in these two patients, the pituitary scintigraphy with IBZM has given information on the density of dopamine receptors on the adenoma and has correlated with the inhibitory effect of Br on PRL secretion. Whether this tool might be of value in identifying patients with pituitary tumors potentially responsive to Br treatment is still to be investigated.     

In vivo efficacy of SM-20302, a GP IIb/IIIa receptor antagonist, correlates with ex vivo platelet inhibition in heparinized blood but not in citrated blood

This study analyzed temporal changes of striatal dopamine-D2 receptor binding during the course of different extrapyramidal movement disorders using 123I-iodobenzamide (IBZM) SPECT. METHODS: Eighteen patients (9 with Parkinson's disease, 9 with parkinsonian plus syndrome) were followed for 11-53 mo. Dopamine-D2 receptor binding was assessed using 123I-IBZM SPECT at the beginning and at the end of the follow-up period. SPECT data were acquired 120 min postinjection of 3-5 mCi 123I-IBZM. A semiautomated algorithm was applied to the raw data for semiquantitative evaluation of regional cerebral receptor binding. RESULTS: Intraobserver (r = 0.992) and interobserver (r = 0.930) variance was low for the semiautomated interpretation of the SPECT examination of the dopaminergic D2 receptor binding, reflecting a highly reproducible SPECT algorithm. Mean specific dopamine-D2 receptor binding was lower in patients with parkinsonian plus syndrome compared to patients with Parkinson's disease on the initial (p < 0.001) as well as the follow-up study (p < 0.001). In patients with Parkinson's disease, we observed an unaffected receptor binding compared to a reduced binding of radiotracer in patients with parkinsonian plus syndrome during the course of the disease (p < 0.001). CONCLUSION: During the follow-up, patients with Parkinson's disease showed a constant dopamine-D2 receptor binding. In contrast, patients with parkinsonian plus syndrome revealed a decline of the binding of dopamine-D2 receptor. These findings are in agreement with histopathological data that demonstrated a preserved dopamine-D2 receptor status in patients with Parkinson's disease and a decline of the dopamine-D2 receptors in patients with parkinsonian plus syndrome. SPECT examinations using 123I-IBZM are useful for assessing dynamic changes of dopamine-D2 receptors in extrapyramidal movement disorders. Semiquantitative SPECT evaluations may provide valuable information for clinical management and prognosis of the patient with extrapyramidal movement disorders.     

Modulatory effects of L-DOPA on D2 dopamine receptors in rat striatum, measured using in vivo microdialysis and PET

Putative modulatory effects of L-3,4-dihydroxyphenylalanine (L-DOPA) on D2 dopamine receptor function in the striatum of anaesthetised rats were investigated using both in vivo microdialysis and positron emission tomography (PET) with carbon-11 labelled raclopride as a selective D2 receptor ligand. A single dose of L-DOPA (20 or 100mg/kg i.p.) resulted in an increase in [11C]raclopride binding potential which was also observed in the presence of the central aromatic decarboxylase inhibitor NSD 1015, confirming that the effect was independent of dopamine. This L-DOPA evoked D2 receptor sensitisation was abolished by a prior, long-term administration of L-DOPA in drinking water (5 weeks, 170mg/kg/day). In the course of acute L-DOPA treatment (20mg/kg), extracellular GABA levels were reduced by approximately 20% in the globus pallidus. It is likely that L-DOPA sensitising effect on striatal D2 receptors, as confirmed by PET, may implicate striato-pallidal neurones, hence a reduced GABA-ergic output in the projection area. Since the L-DOPA evoked striatal D2 receptor supersensitivity habituates during long-term treatment, the effects reported here may contribute to the fluctuations observed during chronic L-DOPA therapy in Parkinson's disease.     

Dopamine agonists in Parkinson's disease: a look at apomorphine

Apomorphine is a D1 and D2 dopamine receptor agonist with anti-parkinsonian properties qualitatively similar to those seen with L-dopa. It was first used in the treatment of Parkinson's disease by Schwab in the 1950s but owing to its short duration of action, the need for parenteral administration, and adverse reactions including nausea, vomiting, postural hypotension and sedation, it was not widely prescribed. In the early 1970s, Cotzias confirmed its potent anti-parkinsonian effects and that some of its secondary effects were diametrically opposite to those seen with L-dopa. The advent of peripheral dopamine receptor antagonist drugs, which counteract the unwanted effects of apomorphine, and the development of new drug delivery systems including insulin pens and ambulatory mini pumps have led to the resurrection of apomorphine for the treatment of Parkinson's disease. Over the last five years in Europe, the drug has proved to be a major advance in the treatment of refractory "on-off" oscillations in Parkinson's disease. It has also been used as a diagnostic test for dopaminergic responsiveness in Parkinson syndromes and tremors of uncertain aetiology. The drug has also proved particularly useful in dealing with certain "off-period" disabilities, including pain, bladder dysfunction, dystonia and gastro-intestinal symptoms. Continuous steady state infusion of apomorphine by mini-pump may reduce the severity of "on" phase dyskinesias over time. The drug has also proved useful in the clinical pharmacological investigation of the pathophysiology of the motor response to dopaminergic drugs in Parkinson's disease and the occurrence of involuntary movement sequences. Neuropsychiatric side-effects are relatively infrequent when compared with ergolene dopamine agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Polymorphisms of dopamine receptor and transporter genes and Parkinson's disease

Disturbances of the dopamine system are involved in the pathogenesis of idiopathic Parkinson's disease (PD). Although genetic factors may play a role in the etiology of PD, there is little direct evidence implicating a specific gene. We conducted a study to test the hypothesis that allelic variations of the dopamine receptors (D2, D3, D4) and the dopamine transporter (DAT) contribute to the susceptibility to PD. Association analyses of 70 Japanese PD patients and the same number of age-matched controls did not reveal any association between alleles of the D2, D3 or D4 receptor genes or the DAT gene and PD. Thus, our results suggest that factor(s) other than allelic variations of these key proteins in the dopamine system contribute to the susceptibility to PD.     

Effect of coadministration of glutamate receptor antagonists and dopaminergic agonists on locomotion in monoamine-depleted rats

Combinations of dopaminergic agonists with glutamate receptor antagonists have been suggested to be a possible alternative treatment of Parkinson's disease. To gain further insights into this possibility, the antagonist of the competitive AMPA-type glutamate receptor NBQX and the ion-channel blocker of the NMDA glutamate receptor (+)-MK-801 in combination with the dopamine D1 receptor agonists: SKF 38393, SKF 82958 and dihydrexidine; the dopamine D2 receptor agonist bromocriptine and the dopamine-precursor L-DOPA were tested in rats pretreated with reserpine and alpha-methyl-p-tyrosine. MK-801 on its own induced locomotor behaviour and potentiated the antiakinetic effects of dihydrexidine and L-DOPA but not of the other dopamine agonists tested. NBQX neither on its own nor coadministered with the dopamine agonists tested had an antiakinetic effect. These results indicate that agents, blocking the ion-channel of the NMDA receptor, might be useful adjuvants to some but not all dopaminomimetics in therapy of Parkinson's disease. The same does not seem to be true for the AMPA-antagonist NBQX.     

Nigral glutathione deficiency is not specific for idiopathic Parkinson's disease

The consistent findings of decreased levels of the major antioxidant glutathione in substantia nigra of patients with idiopathic Parkinson's disease (PD) has provided most of the basis for the oxidative stress hypothesis of the etiology of PD. To establish whether a nigral glutathione deficiency is unique to PD, as is generally assumed, or is present in other Parkinsonian conditions associated with nigral damage, we compared levels of reduced glutathione (GSH) in postmortem brain of patients with PD to those with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). As compared with the controls, nigral GSH levels were decreased in the PD and PSP patient groups (P < 0.05 for PD [-30%], PSP [-21%]), whereas a similar decrease in the MSA patient group did not reach statistical significance (P = 0.078, MSA [-20%]). GSH levels were normal in all examined normal and degenerating extra-nigral brain areas in PSP and MSA. A trend for decreased levels of uric acid (antioxidant and product of purine catabolism) also was observed in nigra of all patient groups (-19 to -30%). These data suggest that glutathione depletion, possibly consequent to overutilisation in oxidative stress reactions, could play a causal role in nigral degeneration in all nigrostriatal dopamine deficiency disorders, and that antioxidant therapeutic approaches should not be restricted to PD.     

Research on social support in health: current status and new challenges

Both Lesch-Nyhan syndrome and Parkinson's disease are associated with decreased brain dopamine, yet each disorder is characterized by a different set of motor symptoms. Lesch-Nyhan syndrome is manifested in early childhood, while parkinsonism usually does not appear until adulthood, suggesting that age at the time of dopamine loss is one determinant of the effects of neurotransmitter deficiency. Support for this view is found in studies of animals given dopamine-depleting lesions at different ages and then tested in adulthood. Animals lesioned as neonates show a supersensitivity to dopamine agonists, especially D1-dopamine receptor agonists, and to MK-801, an NMDA receptor antagonist. In addition, neonatally treated animals show a 'priming' effect following repeated exposure to D1-dopamine agonists. Animals depleted of dopamine as adults are more supersensitive to agonists acting on the D2-dopamine receptor, and do not evidence priming to dopamine agonists or an enhanced response to MK-801. These differential pharmacological profiles suggest that the changes in neurotransmitter systems following dopamine depletion are, at least in part, determined by age at the time of the lesion.     

Intrastriatal infusion of lisuride--a potential treatment for Parkinson's disease? Behavioral and autoradiographic studies in 6-OHDA lesioned rats

The present study examined the effect of chronic intrastriatal infusion of the dopamine receptor agonist lisuride on apomorphine-induced rotational behaviour and on D2-dopamine receptors in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopaminergic pathway. The completeness of the lesion of the right ascending nigrostriatal dopaminergic pathway was confirmed by apomorphine-induced rotation and [3H]-mazindol autoradiography. The intrastriatal infusion of lisuride (0.5 microgram/h) into the lesioned striatum for 2 weeks induced an immediate but temporary spontaneous contralateral rotation and a reduction of apomorphine-induced rotation of 47.2% relative to pre-lisuride infusion. The density of D2-receptors in the lisuride-infused striatum was significantly decreased by 40% relative to vehicle-infused 6-OHDA lesioned rats. The level of D2-dopamine receptors returned to normal levels 3 weeks after the termination of lisuride infusion. These results show that the intrastriatal infusion of lisuride reverses the behavioural and D2-dopamine receptor changes present in the 6-OHDA lesion rat model of Parkinson's disease.     

A comparison of the clinical efficacy and patient acceptability of terbutaline Turbuhaler and salbutamol Rotahaler, in adult patients with asthma

Fifteen Thai patients with Parkinson's disease (7 females, 8 males) were enrolled in an open label trial of pergolide (a new dopamine agonist) to evaluate its safety and efficacy. Inpatients and outpatients from Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand from 1992 to 1994 were included in the study with a total duration of 18 weeks. Both de novo patients and patients who were being treated with levodopa without dopamine agonist and were obtaining a less than optimal response at both visit 1 and visit 2 were all enrolled in this study. At entry into the study, 3 patients had Hoehn and Yahr stage I, 7 patients at stage II, 3 patients at stage III, and 2 patients at stage IV. Pergolide dosage was gradually built up until an optimal dosage was achieved. The average dose of pergolide during the study was 0.94 mg/day (range 0.075 to 8 mg/day). All patients completed the study and no patients dropped out. Two patients (13.33 per cent) experienced nausea (on 0.4 mg/day and 0.075 mg/day), two patients (13.33 per cent) experienced sleepiness (0.50 mg/day and 0.075 mg/day) and one patient (6.67 per cent) unsteadiness on walking (0.50 mg/day). There was one patient who required pergolide up to 8 mg/day which is higher than the recommended dosage (5 mg/day) but this patient experienced no adverse effects and his disabled dyskinesic was abolished. Our study demonstrated the good toleration and efficacy of pergolide treatment for Thai patients with Parkinson's disease. This new dopamine agonist stimulates both D1 and D2 receptors in comparison to other dopamine agonists (bromocriptine and lisuride) which stimulate only D2 receptors.