Urodynamic study in the differential diagnosis between multiple system atrophy and Parkinson's disease.
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Biomedical subjects
Publications and source records attributed to F Stocchi.
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In six patients with Parkinson's disease exhibiting severe "on-off" phenomena, a 200-mg intravenous bolus of either L-DOPA or of its methyl ester were equally effective in reversing motor deficits, although the duration of action of the methyl ester was shorter. There were no marked differences in pharmacokinetic parameters for L-DOPA plasma levels after administration of L-DOPA and the methyl ester. In three patients, optimal infusion rates for the maintenance of mobility were established for L-DOPA and L-DOPA methyl ester. Both drugs were able to maintain patients "on" throughout a 12-h infusion period. However, on average the optimal infusion rate of L-DOPA methyl ester was 2.7 times greater than that for L-DOPA. There was no marked difference in the plasma levels of L-DOPA achieved, but 3-O-methyl DOPA levels increased more after infusion of L-DOPA methyl ester than after infusion of L-DOPA itself. The half-life of elimination and volume of distribution of L-DOPA formed from the methyl ester were markedly increased compared with values obtained after either an intravenous bolus of methyl ester or after an intravenous infusion of L-DOPA itself. An intravenous bolus of L-DOPA methyl ester produces an equivalent magnitude of clinical response to the same dose of L-DOPA. However, higher optimal infusion rates of methyl ester than L-DOPA are required to produce continuous effect. The pharmacokinetic handling of L-DOPA methyl ester given by intravenous infusion may differ from that of L-DOPA when given by the same route.
For many patients with Parkinson disease and levodopa-related motor fluctuations, the latency to onset of action of a single dose of a levodopa preparation may be both long and variable. In an effort to find a more rapidly acting and reliable preparation of levodopa, we therefore studied the efficacy of single doses of an oral solution of 250 mg of levodopa methyl ester (ME) with benserazide, 50 mg and of a molar equivalent dose of dispersible Madopar (DM) (50/200) in 13 patients in the fasting state after overnight drug withdrawal. The response of seven of these patients was compared to that after two Sinemet 25/100. The latency to "on" was equally fast with ME and DM, and significantly faster than after standard Sinemet. The duration of "on" was similar with all three. Because of this more rapid relief of "off" periods, both ME and DM offer a potential clinical advantage over standard preparations of levodopa.
Marked, disabling fluctuations in motor performance (on-off phenomena) appear after chronic L-Dopa therapy in Parkinson's disease (PD). Intravenous infusion of L-Dopa greatly reduces these motor fluctuations, but it is not reliable as a chronic treatment. Therefore, infusion of the potent, water-soluble dopaminergic agonist lisuride has been tested. However, many patients did not respond to infusion of lisuride alone, and no clinical parameter is known to correlate with the lacking response. In order to study this problem, we performed the TRH test (200 micrograms i.v.) in 8 PD patients with severe motor fluctuations; before and during lisuride subcutaneous infusion, we measured PRL and TSH responses to TRH. Both PRL and TSH receive an inhibitory control from dopaminergic receptors on pituitary cells, whereas they are stimulated by TRH. The TRH test, given during lisuride infusion, allows an indirect evaluation of the 'brake function' of the dopaminergic system on anterior pituitary, i.e. of dopaminergic receptor sensitivity in vivo. In our study, TRH induced a significant TSH rise in all PD patients, before and during lisuride infusion. Moreover, the lisuride responders (i.e. patients showing constant 'on' period during lisuride infusion, 4 patients) showed a significant lower TSH response as compared to nonresponders. PRL levels followed the same trend without reaching statistical significance. These data are compatible with the presence, in the two groups, of a different pituitary dopaminergic sensitivity which would suggest the presence of pharmacodynamic factors associated with the lacking response to intravenous lisuride infusion.
We compared the efficacy of a single dose of an oral solution of levodopa methyl ester (ME) to that of standard levodopa, in the form of a single dose of Madopar, in reversing afternoon "off" periods in 12 patients with Parkinson's disease (PD). The highly soluble ME solution led to a significantly more rapid reversal of "off" periods. This preparation may therefore convey a clinical advantage in patients experiencing motor fluctuations whilst taking multiple daily dosages of levodopa, particularly in those with long or highly variable latency to the next "on" period.
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.
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A procedure is described for the determination of L-3,4-dihydroxyphenylalanine (L-DOPA), its metabolites and carbidopa (CD) in plasma of Parkinsonian patients by high-performance liquid chromatography with dual working-electrode coulometric electrochemical detection. An efficient sample preparation scheme is presented for the isolation of L-DOPA, its metabolites and the catecholamines from the same plasma aliquot. After a simple deproteinization with methanol containing 2% of 0.5 M perchloric acid and evaporation of the solvent, L-DOPA, its metabolites and CD were separated with a 5-micron Nucleosil C18 column. Catecholamines were extracted from the supernatant of the deproteinized plasma by ion exchange on small columns and adsorption on alumina. Recoveries were close to 100% for L-DOPA, its metabolites and CD and 70% for catecholamines. The use of the same mobile phase for the concurrent assay of L-DOPA, its metabolites and catecholamines considerably increased the throughput of samples in the chromatographic system. The dual-electrode coulometric detector afforded peak identification by comparing current ratios. Monitoring of data from patients under L-DOPA therapy is reported.
Botulinum A toxin was injected into the affected muscles in 20 patients with blepharospasm, 8 with torticollis and 12 with hemifacial spasm. In all cases blepharospasm and hemifacial spasm was abolished or markedly reduced. The only side effect was transient ptosis and diplopia. Patients with torticollis had a mild to moderate improvement of the dystonic posture and pain; dysphagia was the most troublesome side effect. Botulinum A toxin is an effective therapy in patients with focal dystonia and spasms.
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The dopaminergic receptors of planaria have been studied with pharmacological and biochemical criteria. Dopamine D1 selective agonists (CY 208243 (10 micrograms/ml) and SKF 38393 (10 micrograms/ml] induced in planaria typical screw-like hyperkinesias, that were inhibited by a D1 antagonist (SCH 23390 (10 micrograms/ml], but not by a D2 antagonist (sulpiride (1000 micrograms/ml]. Dopamine D2 selective agonists (PHNO (5 micrograms/ml), lisuride (5 micrograms/ml] on the contrary induced a typical "C" like curling, that was inhibited by pretreatment with D2 selective blocking agents, but not by D1 selective blocking agents. With agonists with a D1/D2 mixed action (apomorphine 60 micrograms/ml) or with amphetamine (100 micrograms/ml), the D1 type movements appeared to be more evident. Dopamine D1-selective agonists, mixed action agonists or D2-selective agonists, all induced a significant increase in levels of cAMP, that was prevented by pretreatment with the specific DA blocking agent.
1. A group of 14 fluctuating Parkinsonian patients underwent the subcutaneous Lisuride treatment, administered by an insulin delivery pump. Clinical response has been studied during a one year period. 2. Some patients (8 out of 14) were in combined therapy, assuming a relative small amount of oral L-Dopa together with subcutaneous Lisuride. 3. Lisuride confirmed, also by the subcutaneous route, its antiparkinsonian properties, without any loss of therapeutical efficacy during the 12 month period considered. 4. 7 patients dropped-out from the study, due to psychiatric or systemic side-effects and to "technical" management of the pump. 5. The only 2 patients assuming a 24 hour regimen of Lisuride infusion were among the withdrawn subjects. They were also the only to complain severe psychiatric disturbances.
The cardiovascular effects of a continuous intravenous infusion of lisuride plus oral domperidone were studied in 16 fluctuating parkinsonian patients as compared to their usual oral therapy with levodopa plus carbidopa. The study was performed using a 24-h ambulatory recording and an automatic noninvasive device for blood pressure monitoring. During lisuride infusion, a significant increase of systolic blood pressure was observed; however, in three patients, a decrease of systolic-diastolic blood pressure occurred; furthermore, a mild increase of atrial arrhythmias and, in two patients, a short run of atrial fibrillation were noted. Asymptomatic orthostatic hypotension, observed in seven patients during levodopa therapy, disappeared during lisuride infusion. Paradoxical hypertensive effects and disappearance of orthostatic hypotension observed in our patients seem related to the concurrent administration of domperidone.
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.
An analytical method is described for measuring L-3,4-dihydroxyphenylalanine (L-DOPA), 3-O-methyl-DOPA, dihydroxyphenylacetic acid, free catecholamines and the peripheral DOPA decarboxylase inhibitor, carbidopa, in plasma samples of Parkinsonian patients by using high-performance liquid chromatography. A sample preparation method is presented for the isolation of the catecholamines and L-DOPA with its metabolites. Catecholamines are extracted by weak cation exchange on small columns and subsequent adsorption on alumina. L-DOPA, 3-O-methyl-DOPA, dihydroxyphenylacetic acid and carbidopa contained in the column effluents are directly injected in the chromatographic system. The eluates are separated on a reversed-phase column, monitored by both a coulometric electrochemical detector and a fluorescence detector, connected in series. Chromatographic peaks were identified on the basis of their retentions and response ratios of the two detectors. Two examples are presented of therapeutic drug monitoring in Parkinsonian patients treated with oral doses and continuous intravenous infusion of L-DOPA.
Blink and corneal reflexes were studied in 11 patients with Huntington's chorea and the results compared with the severity of the disease. The latency of the R2 component of the blink reflex was delayed and the duration of R2 and of the corneal reflex (CR) prolonged. A greater habituation of the R2 component was found in the patients with involuntary movements in the face, and in some patients a long-lasting depression of R2 was present. A correlation was found between: (a) severity of involuntary face movements and R2 and CR latency and (b) severity of involuntary movements in the neck and latency of R2.