New insights in Parkinson's disease therapy: can levodopa-induced dyskinesia ever be manageable.
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Animals↗
Biomedical subjects
L Grégoire
Publications and source records attributed to L Grégoire.
Effects of acute and repeated treatment with a novel dopamine D2 receptor ligand on L-DOPA-induced dyskinesias in MPTP monkeys.
(S)-(-)-3-(3-(methylsulfonyl)phenyl)-1-propylpiperidine ((-)-OSU6162) is a phenylpiperidine derivative which exhibits low affinity to the dopamine D2 receptor in vitro. However, in vivo, positron emission tomography scanning studies show that the compound displaces the selective dopamine D2 receptor antagonist, raclopride. We have evaluated, in this study, the effect of (-)-OSU6162, on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesias in a primate model of Parkinson's disease. Five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-DOPA were used in this study. The monkeys were housed in observation cages equipped with an electronic motility monitoring system. They were injected subcutaneously (s.c.) with L-DOPA methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-DOPA/benserazide) alone or in combination with (-)-OSU6162 (1.0, 3.0, 6.0 or 10 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-DOPA/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of (-)-OSU6162 with L-DOPA/benserazide produced a significant reduction in L-DOPA-induced dyskinesias. This improvement in L-DOPA-induced dyskinesias occurred mainly at the onset of the L-DOPA/benserazide effect as reflected by an increase in the duration of the "ON" state without dyskinesias up to 3.4 fold after (-)-OSU6162 co-administration as compared to L-DOPA/benserazide alone. The anti-dyskinetic effect of (-)-OSU6162 was maintained during 14 days and no tolerance to this effect was observed. Our data suggests that (-)-OSU6162 could be of significant clinical value to reduce L-DOPA-induced dyskinesias in fluctuating advanced Parkinson's disease patients.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Antidyskinetic effect of JL-18, a clozapine analog, in parkinsonian monkeys.
Clozapine reduces L-3,4-dihydroxyphenylalanine (L-Dopa)-induced dyskinesias in parkinsonian patients. To test if the antidyskinetic effect of clozapine is related to antagonism at the dopamine D(4) receptor, we investigated the effect of 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1, 4]benzodiazepine (JL-18), a structural analog of clozapine which is more selective for this receptor. Four 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)-treated cynomolgus monkeys with a stable parkinsonian syndrome and reproducible dyskinesias to L-Dopa were used in this study. They were injected subcutaneously (s.c.) with L-Dopa methyl ester (125 mg per animal) plus benserazide (50 mg per animal; L-Dopa/benserazide) alone or in combination with JL-18 (at the doses of 0.1, 0.3, or 0.9 mg/kg, s.c.). Subcutaneous injection of sterile saline was used as control. L-Dopa/benserazide increased locomotion and improved parkinsonism but also induced dyskinesias. Co-administration of JL-18, at low doses (0.1, 0.3 mg/kg) with L-Dopa/benserazide, produced a dose-dependent reduction in L-Dopa-induced dyskinesias without a parallel return to parkinsonism. The present results suggest that novel selective dopamine D(4) receptor antagonists may represent a useful tool to reduce L-Dopa-induced dyskinesias.
Analysis of Variance↗
Antiparkinsonian effect of a new selective adenosine A2A receptor antagonist in MPTP-treated monkeys.
BACKGROUND: Chronic treatment with L-3,4-dihydroxyphenylalanine (L-dopa) is often associated with motor side effects in PD patients. The search for new therapeutic approaches has led to study the role of other neuromodulators including adenosine. Among the four adenosine receptors characterized so far, the A2A subtype is distinctively present on striatopallidal output neurons containing enkephalin and mainly bearing dopamine (DA) D2 receptors (indirect pathway). Studies in DA-denervated rats suggest that blockade of adenosine A2A receptors might be used in PD. OBJECTIVE: To evaluate the antiparkinsonian effect of a new selective adenosine A2A receptor antagonist, KW-6002, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. METHODS: In the present study, we used six MPTP-exposed cynomolgus monkeys already primed and exhibiting L-dopa-induced dyskinesias to evaluate both the antiparkinsonian and dyskinetic effect upon challenge with two oral doses (60 and 90 mg/kg) of KW-6002 administered alone or in combination with L-dopa/benserazide (50/12.5 mg). RESULTS: KW-6002 administered alone produced a dose-dependent antiparkinsonian response that reached the level of efficacy of L-dopa/benserazide but was less likely to reproduce dyskinesias in these animals. When co-administered, KW-6002 potentiated the effects of L-dopa/benserazide on motor activity (up to 30%) without affecting the dyskinetic response. CONCLUSION: Adenosine A2A receptor antagonists have antiparkinsonian effects of their own with a reduced propensity to elicit dyskinesias. They might therefore be useful agents in the treatment of PD.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
D1 receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys.
OBJECTIVE: To determine whether dopamine (DA) D1 or DA D2 receptors are associated predominantly with the antiparkinsonian versus the dyskinetic effect of levodopa. METHODS: The authors used four L-dopa-primed, dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys to test whether acute and selective blockade of the DA D1 receptor subtype, using SCH 23390 and NNC 01-112, could reduce L-dopa-induced dyskinesias without altering the relief of symptoms. Blockade of DA receptors using sulpiride (D2) and clozapine (D1-D2-like) was studied for comparison. RESULTS: With the notable exception of the lowest dose of clozapine tested, coadministration of DA D1 or D2 antidopaminergic agents with L-dopa reduced the L-dopa-induced dyskinesias but also caused a return of parkinsonian disability. Prolonged latencies from intake of a single oral dose of L-dopa to turning "on," decreased duration of the "on" state, and a complete failure to induce benefit was also observed. CONCLUSION: Low-dose clozapine could be an effective adjunct to reduce L-dopa-induced dyskinesias without altering the relief of parkinsonian symptoms. Interactions with many neurotransmitter systems may explain the better pharmacologic profile of clozapine, including DA D4 (rather than D1), serotonin, acetylcholine, and noradrenaline. Neither dyskinesias nor antiparkinsonian effects can be ascribed solely to the D2 or D1 receptor. Thus, some cooperation between the two receptors appears necessary for these behavioral effects.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Risk factors for peak dose dyskinesia in 100 levodopa-treated parkinsonian patients.
BACKGROUND: No clinical parameter other than "sufficient" dopamine denervation and exposure to exogenous levodopa has been unquestionably linked to dyskinesia in levodopa-treated Parkinson's disease patients. METHODS: We retrospectively analyzed data on 100 consecutive patients treated with levodopa for 1 to 18 years to identify clinical risk factors for dyskinesia. The cumulative dyskinesia-free survival probability in relation to levodopa therapy was assessed using the Kaplan-Meier method. RESULTS: Overall, 56% of patients developed dyskinesia after a mean of 2.9 years, a figure similar to the average duration of levodopa treatment in the non-dyskinetic group. Dyskinetic patients were significantly younger at disease onset, but their mean latency to dyskinesia induction after levodopa initiation was not different from older dyskinetic individuals and the overall dyskinesia-free survival of younger subjects was not worse either. Dyskinetic patients were on a higher daily levodopa dose than non-dyskinetic subjects when dyskinesia emerged, but the cumulative levodopa dose used prior to dyskinesia did not discriminate dyskinetic from non-dyskinetic patients. A delay in initiating levodopa therapy of more than three years after disease onset and levodopa treatment initiation in Hoehn-Yahr stage II compared to stage I patients did not increase the probability of developing dyskinesia over time. CONCLUSIONS: Since withholding levodopa therapy did not increase the risk for dyskinesia in our patients and can delay the emergence of dyskinesia after onset of parkinsonian symptom, a trial with a dopaminomimetic agonist as initial treatment appears logical.
Adult↗
Mesencephalic grafts partially restore normal nigral dynorphin levels in 6-hydroxydopamine-lesioned rats treated chronically with L-dihydroxyphenylalanine.
An increase of dynorphin levels is commonly observed in the substantia nigra of 6-hydroxydopamine-lesioned rats chronically treated with daily injections of L-DOPA. This study investigates the potential of fetal mesencephalic grafts to restore normal levels of dynorphin in such cases. After 19 consecutive days of treatment with L-DOPA, lesioned rats with the most severe nigral cell loss showed increased levels of dynorphin in the substantia nigra ipsilateral to the lesion, as expected. The changes were assessed by standard immunohistochemical techniques combined with the use of an image analysis system. Such changes were not observed in the substantia nigra of rats that received fetal mesencephalic cells in the striatum six months prior to the beginning of the chronic treatment. However, only animals displaying heavy loss of dopaminergic neurons in the substantia nigra pars compacta showed significant changes of dynorphin levels in the substantia nigra following drug treatment. Our results show that fetal nigral cells transplanted into the striatum have the potential to prevent biochemical changes observed in the basal ganglia induced by the lesion of the nigrostriatal pathway and chronic treatment with L-DOPA. It is still hypothesized from studies in rodents that this peptide may play a role in the appearance of DOPA-induced dyskinesia, because dynorphin levels increase in the substantia nigra pars reticulata after L-DOPA treatment. If this happens to be the case, then the use of fetal nigral grafts could therefore be an important step to prevent the induction of dyskinesia after chronic L-DOPA treatment.
Amphetamine↗
5-HT1 receptors mediating contraction in bovine cerebral arteries: a model for human cerebrovascular '5-HT1D beta' receptors.
We report on the pharmacological profile of the 5-HT receptor which induces contraction of the bovine isolated cerebral arteries. Several 5-HT receptor agonists were tested for their ability to induce vasoconstriction in bovine pial arteries and their potencies were compared to that of 5-HT. The rank order of agonist potency can be summarized as 5-carboxamidotryptamine (5-CT) = RU 24969 > or = 5-HT > sumatriptan > alpha-methyl-5-HT > methysergide > 2-methyl-5-HT > ((+-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene (8-OH-DPAT). Only methysergide induced a contraction which was smaller than that elicited by 5-HT. Antagonists with selective affinity at 5-HT1A/1B (propranolol), 5-HT1C (mesulergine), 5-HT2 (ketanserin, mianserin) and 5-HT3 (MDL 72222) sites were inactive to block the 5-HT-induced contraction. In contrast, the 5-HT1/5-HT2 receptor antagonists methiothepin and metergoline inhibited the 5-HT-induced response with relatively high affinity (pA2 = 8.16 +/- 0.26 and 6.73 +/- 0.05, respectively). Overall, this pharmacological profile indicated clearly that a 5-HT1 receptor, most closely related to the 5-HT1D subtype, is responsible for the 5-HT-induced contraction of bovine cerebral arteries. Correlation analysis of the potencies of a series of 5-HT receptor agonists and antagonists in bovine and human cerebrovascular preparations showed a highly significant positive correlation (r = 0.94, P = 0.0051).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
A highly conserved nucleotide string shared by all genomes of human papillomaviruses.
The nucleotide string TAAAACGAAAGT is the longest perfect homology shared by all sequenced human papillomavirus genomes. This nucleotide string, which was also found to be highly specific for human papillomavirus genomes, shares the same genomic position in all viral types (5' end of the E1 open reading frame) and putatively codes in every case for the same amino acids. One possible evolutionary model was used to estimate the probability of random occurrence of the nucleotide string in 10 human papillomavirus genomes. It assumed that the universal string had been subjected to the same mutation rate as the entire E1 open reading frame. The estimated probability was found to be very low, suggesting that the conservation of the string could not have resulted from random divergence and that its conservation among human papillomaviruses is likely to reflect the occurrence of biological constraints. It is speculated that this nucleotide string may be required to code for amino acids indispensable for the nuclear localization of E1-coded peptides or to bind cellular factors affecting viral replicative functions. Definitive evidence is expected to come from oligonucleotide-protein binding experiments and from site-directed mutagenesis of cloned HPV genomes. This motif, universal among human papillomaviruses, is being successfully used in the design of consensus primers from the early region.
Amino Acid Sequence↗
Correlation of functional recovery after a 6-hydroxydopamine lesion with survival of grafted fetal neurons and release of dopamine in the striatum of the rat.
Female rats were lesioned with 6-hydroxydopamine in the left substantia nigra. At least two weeks later they were tested with amphetamine (5 mg/kg, s.c.) and apomorphine (0.25 mg/kg, s.c.). A cell suspension from the ventral mesencephalon of rat embryos was distributed in three sites in a triangular fashion in the center of the denervated striatum. The amphetamine test was then repeated every month for six months. The pattern of circling to amphetamine before the graft was strictly ipsiversive in all animals. From the first month we observed a progressive change and three patterns of rotation could be observed. In 21% of animals, the total number of ipsiversive turns in 90 min actually increased but during the first 20 min the animals turned contralaterally to the lesion (and to the graft). In 38% of animals, the total number of turns switched from ipsiversive to contraversive with the animals turning initially toward the intact side and during the second half of the test toward the lesion. Finally 41% of rats progressively switched to turning only toward the intact side. In all cases, maximal contraversive turning occurred during the initial 20 min. In these rats, tyrosine hydroxylase-positive cells were detected mainly in the dorsal striatum with a few in the central portion. Moreover there was a strong correlation between the number of surviving grafted neurons and the growth of their fiber into the host striatum and the extent of recovery.(ABSTRACT TRUNCATED AT 250 WORDS)
Amphetamine↗
Reduction of postjunctional fold density and depth in dystrophic mice.
A total of 769 neuromuscular junction profiles (on 221 muscle fibers) from 21 normal (C57BL/6J +/+), 6 heterozygous (C57BL/6J dy2J/+) and 22 homozygous dystrophic (C57BL/6J dy2J/dy2J) gastrocnemius were photographed in electron microscopy. The fast and slow twitch muscle fibers were differentiated by the width of the Z lines. The number of secondary postjunctional folds per unit length of synaptic cleft was lower in dystrophic than in normal animals. Intermediate values were obtained in heterozygous animals. The length of the postsynaptic membrane was measured and normalized by dividing it by the length of the cross-section through the synaptic cleft. This normalized length of postjunctional membrane was significantly reduced by 45% in dystrophic animals relative to normal animals and by 41% relative to heterozygous animals. The depth of the secondary folds was also significantly reduced in dystrophic animals relative to normal animals in both fast and slow twitch fibers. These morphometric changes of the postjunctional membrane were observed on NMJs whose nerve terminals were not significantly modified by the dystrophic process and were sometimes observed on apparently normal muscle fibers.
Animals↗
Repeated stimulation of the dystrophic mouse neuromuscular junctions.
Morphometric changes produced by repeated stimulation of the neuromuscular junctions (NMJs) have been studied by electron microscopy in 769 profiles of normal, heterozygous dystrophic, and dystrophic mice. The study indicates that in animals not stimulated but anesthetized for 40 min, there is no significant difference in the profile area between the normal, the heterozygous dystrophic, and dystrophic mice. There is also no significant difference between these three groups in the number of clear vesicles and of coated vesicles per micron2 of terminal. Following stimulation, the profile area of NMJs is not significantly increased in the normal and in the heterozygous dystrophic mice. However, the profile area is increased by 50% in the dystrophic animals. This is perhaps due to changes in the shape of the nerve terminal in stimulated dystrophic animals. However, the number of the clear vesicles per micron2 is significantly reduced to a similar extent in the three groups. These results indicate that the recycling of vesicular membrane is normal in dystrophic animals.
Animals↗
Non monotonic morphometric changes produced at mouse neuromuscular junctions following in vivo stimulation at various frequencies.
Morphometric changes have been studied at the mouse neuromuscular junction (NMJ) as a function of the frequency of stimulation. In vivo stimulation was made at either 10, 25, 50 or 100 Hz. No significant change in the area of NMJ profiles is observed after stimulation. This indicates that stimulation does not change the volume of the nerve terminal. There is also no change of the volume density of mitochondria. However, there are significant reductions of the numerical density on area (NA, number/micron2) of the clear vesicles following stimulation at 25, 50 or 100 Hz. The NA of clear vesicles is not further reduced following stimulation at 50 or 100 Hz than after the stimulation at 25 Hz. The numerical density on area of the coated vesicles was significantly increased following the stimulation at 25 Hz and 100 Hz. It is not increased more following stimulation at 50 Hz or 100 Hz than following stimulation at 25 Hz. One possible interpretation of the clear vesicle and the coated vesicle results is that less vesicles are liberated per sec by the NMJ with stimulation at 50 and 100 Hz than at 25 Hz because the action potential may fail to invade some terminal arborizations. The total surface density (i.e. surface of membrane in micron2 per micron3 of nerve terminal) of the clear vesicles, the coated vesicles, the vacuoles and the presynaptic plasma membrane is not changed significantly following stimulation at any frequency. This indicates that there is no net loss of membrane at any of the frequencies investigated.
Analysis of Variance↗
Comparison of five methods of cytomegalovirus antibody screening of blood donors.
A group of 120 sera from blood donors was screened by complement fixation and commercially available immunofluorescence, solid-phase fluorescence immunoassay, enzyme-linked immunosorbent assay, and indirect hemagglutination tests. Twenty-four of the sera were positive by three or more of the five tests and judged to be true positives; 89 were negative by three or more of the tests and considered to be true negatives. The tests were ranked for accuracy, sensitivity, specificity, false-positive rate, and false-negative rate. The indirect hemagglutination test scored best, followed by enzyme-linked immunosorbent assay, solid-phase fluorescence immunoassay, complement fixation, and immunofluorescence, in that order. When the tests were ranked on the basis of technical demands, turnaround time, requirement for special equipment, and subjectivity in reading, the indirect hemagglutination test again scored best, followed by solid-phase fluorescence immunoassay, enzyme-linked immunosorbent assay, immunofluorescence, and complement fixation in that order. Our findings suggest that the indirect hemagglutination test is the most reliable and effective commercially available test for the identification of those donors who are very unlikely to transmit cytomegalovirus to recipients.
Antibodies, Viral↗
[What is to be thought of the Dunlop Committee recommendation concerning the anti-ovulation pills?].
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Blood Coagulation Disorders↗
[Etiologies of shock particular to obstetrics].
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Amniotic Fluid↗
[Late puberty. Gynecologic view].
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Adolescent↗
[Recent trends in pharmacologic contraception].
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Adult↗