Intravenous Levodopa Research Articles

Perioperative Use of Intravenous Levodopa as an Anti-Parkinsonian Drug: A Propensity Score Analysis.

Perioperative discontinuation of oral anti-parkinsonian medication can negatively impact the prognosis of abdominal surgery in patients with Parkinson's disease. Although intravenous levodopa may be an alternative, its efficacy has not yet been investigated. To determine the efficacy of intravenous levodopa as an alternative to oral anti-Parkinsonian drugs during gastric or colorectal cancer surgery. We identified patients with Parkinson's disease who underwent surgery for gastric or colorectal cancer between April 2010 and March 2020, using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. Patients were divided into two groups: those who received intravenous levodopa during the perioperative period and those who did not. We compared in-hospital mortalities, major complications, and postoperative length of stay between the groups after adjusting for background characteristics with overlap weights based on propensity scores. We identified 648 patients who received intravenous levodopa and 1207 who did not receive levodopa during the perioperative period. In the adjusted cohort, the mean postoperative length of stay was 24.7 and 29.0 days (percent difference, -7.7%; 95% confidence interval, -13.1 to -1.5); in-hospital death was 3.2% and 3.3% (adjusted odds ratio, 0.95; 95% CI: 0.54-1.67); and incidence of major complications were 21.4% and 19.3% (adjusted odds ratio, 0.89; 95% confidence interval, 0.70-1.13) in those with and without intravenous levodopa, respectively. Intravenous levodopa was associated with a shorter postoperative length of stay, but not with mortality or morbidity. Intravenous levodopa may improve perioperative care in patients with Parkinson's disease.

Blood-brain barrier permeability in Parkinson's disease patients with and without dyskinesia.

Recent studies on a rodent model of Parkinson's disease (PD) have raised the possibility of increased blood-brain barrier (BBB) permeability, demonstrated by histology, autoradiography, and positron emission tomography (PET). However, in human PD patients, in vivo evidence of increased BBB permeability is lacking. We examined the hypothesis that levodopa treatment increases BBB permeability in human subjects with PD, particularly in those with levodopa-induced dyskinesia (LID). We used rubidium-82 (82Rb) and PET to quantify BBB influx in vivo in 19 PD patients, including eight with LID, and 12 age- and sex-matched healthy subjects. All subjects underwent baseline 82Rb scans. Seventeen chronically levodopa-treated patients were additionally rescanned during intravenous levodopa infusion. Influx rate constant, K1, by compartmental modeling or net influx transport, Ki, by graphical approach could not be estimated reliably. However, Vd, the "apparent volume of distribution" based on the 82Rb concentration in brain tissue and blood, was estimated with good stability as a local measure of the volume of distribution. Rubidium influx into brain tissue was undetectable in PD patients with or without LID, scanned on and off drug. No significant differences in regional Vd were observed for PD patients with or without LID relative to healthy subjects, except in left thalamus. Moreover, changes in Vd measured off- and on-levodopa infusion were also not significant for dyskinetic and non-dyskinetic subjects. 82Rb PET did not reveal significant changes in BBB permeability in PD patients.

Dopamine Buffering Capacity Imaging: A Pharmacodynamic fMRI Method for Staging Parkinson Disease.

We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust and can be quantified using perfusion MRI. Here we present simulation studies based on published clinical dose-response data and an intravenous levodopa infusion. Standard pharmacokinetic-pharmacodynamic methods were used to model the response. Then the effect site rate constant ke was estimated from simulated response data plus Gaussian noise. Predicted time – effect curves sampled at times consistent with phMRI differ substantially based on clinical severity. Estimated ke from noisy input data was recovered with good accuracy. These simulation results support the feasibility of levodopa phMRI hysteresis mapping to measure the severity of dopamine denervation objectively and simultaneously in all brain regions with a robust imaging response to exogenous levodopa.

Aromatic L‐Amino Acid Decarboxylase Gene Therapy Enhances Levodopa Response in Parkinson's Disease

BackgroundAs Parkinson's disease progresses, levodopa treatment loses efficacy, partly through the loss of the endogenous dopamine‐synthesizing enzyme L‐amino acid decarboxylase (AADC). In the phase I PD‐1101 study, putaminal administration of VY‐AADC01, an investigational adeno‐associated virus serotype‐2 vector for delivery of the AADC gene in patients with advanced Parkinson's disease, was well tolerated, improved motor function, and reduced antiparkinsonian medication requirements.ObjectivesThis substudy aimed to determine whether the timing and magnitude of motor response to intravenous levodopa changed in PD‐1101 patients after VY‐AADC01 administration.MethodsParticipants received 2‐hour threshold (0.6 mg/kg/h) and suprathreshold (1.2 mg/kg/h) levodopa infusions on each of 2 days, both before and approximately 6 months after VY‐AADC01. Infusion order was randomized and double blinded. Unified Parkinson's Disease Rating Scale motor scores, finger‐tapping speeds, and dyskinesia rating scores were assessed every 30 minutes for 1 hour before and ≥3 hours after start of levodopa infusion.ResultsOf 15 PD‐1101 patients, 13 participated in the substudy. Unified Parkinson's Disease Rating Scale motor score area under the curve responses to threshold and suprathreshold levodopa infusions increased by 168% and 67%, respectively, after VY‐AADC01; finger‐tapping speeds improved by 162% and 113%, and dyskinesia scores increased by 208% and 72%, respectively, after VY‐AADC01. Adverse events (mild/moderate severity) were reported in 5 participants during levodopa infusions pre–VY‐AADC01 and 2 participants post–VY‐AADC01 administration.ConclusionsVY‐AADC01 improved motor responses to intravenous levodopa given under controlled conditions. These data and findings from the parent study support further clinical development of AADC gene therapy for people with Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Levodopa Pharmacokinetics in Brain after Both Oral and Intravenous Levodopa in One Patient with Advanced Parkinson’s Disease

Objective: One patient received oral levodopa during a study aiming for better understanding of the basal ganglia and of the mechanisms of deep brain stimulation of the subthalamic nucleus (STN DBS) with and without intravenous (IV) levodopa infusion in patients with Parkinson’s disease (PD). The results from oral and IV levodopa treatment are presented. Methods: Five patients with advanced PD were included in the original study. During planned STN DBS surgery microdialysis probes were implanted in the right putamen and in the right and left globus pallidus interna (Gpi). During the study, microdialysis was performed continuously and STN DBS, with and without IV levodopa infusion, was performed according to a specific protocol. After DBS surgery, but before STN DBS was started, one patient received oral levodopa/ benserazide and entacapone tablets out of protocol due to distressing parkinsonism. Results: The levodopa levels increased prompt in the central nervous system after the first PD medication intakes but declined after the last. Immediately the levodopa seemed to be metabolized to dopamine (DA) since the levels of DA correlated well with levodopa concentrations. Left STN DBS seemed to further increase DA levels in left Gpi while right STN DBS seemed to increase DA levels in the right putamen and right Gpi. There was no obvious effect on levodopa levels. Conclusions: The results indicate that PD patients still have capacity to metabolize levodopa to DA despite advanced disease with on-off symptoms and probably pronounced nigral degeneration. STN DBS seems to increase DA levels with a more pronounced effect on ipsilateral structures in striatum.

Is Levodopa Pharmacokinetics in Patients with Parkinson’s Disease Depending on Gastric Emptying?

Levodopa uptake from the gastrointestinal tract in patients with Parkinson’s disease (PD) can be affected by delayed gastric emptying (GE). This might lead to fluctuating levodopa levels resulting in increased motor fluctuations. Continuous dopaminergic stimulation (CDS) improves motor fluctuations and could be a result of smoothening in levodopa uptake. In this study we wanted to study the levodopa pharmacokinetics peripherally in PD patients with motor fluctuations and investigate the relation between levodopa uptake and GE and the effect of CDS. PD patients with wearing off (group 1) and on-off syndrome (group 2) were included. Breath tests were performed to evaluate the half time (T1/2) of GE. Concomitantly 1 tablet of Madopark® was given and the levodopa concentrations in blood and subcutaneous (SC) tissue were analyzed for both groups. Group 2 was then given a 10-d continuous intravenous levodopa treatment and the tests were repeated. Higher levels of levodopa in group 1 compared to group 2 in blood (p = 0.014) were seen. The GE was delayed in both group 1 (p < 0.001) and group 2 (p < 0.05) compared to a reference group with healthy volunteers with T1/2 median values 105 and 78 min vs. 72 min. There was no difference in GE between the two PD groups (p = 0.220) or in group 2 before and after infusion period (p = 0.861). CDS resulted in lower levodopa levels in blood (p < 0.001) and SC tissue (p < 0.01). In conclusion, PD patients in early complication phase have a more favourable levodopa uptake than patients later in disease. We found delayed GE in PD patients with motor fluctuations but no obvious relation between GE and levodopa uptake or GE and PD stage. The effect of CDS indicates no effect of CDS on the mechanisms of GE but on the mechanisms of levodopa uptake.

Flow-metabolism dissociation in the pathogenesis of levodopa-induced dyskinesia.

Levodopa-induced dyskinesia (LID) is the most common, disruptive complication of Parkinson's disease (PD) pharmacotherapy, yet despite decades of research, the changes in regional brain function underlying LID remain largely unknown. We previously found that the cerebral vasomotor and metabolic responses to levodopa are dissociated in PD subjects. Nonetheless, it is unclear whether levodopa-mediated dissociation is exaggerated in LID or distinguishes LID from non-LID subjects. To explore this possibility, we used dual-tracer positron emission tomography to quantify regional cerebral blood flow and metabolic activity in 28 PD subjects (14 LID, 14 non-LID), scanned before and during intravenous levodopa infusion. Levodopa-mediated dissociation was most prominent in the posterior putamen (P < 0.0001) and greater in LID than in non-LID and test-retest subjects. Strikingly, LID subjects also showed increased sensorimotor cortex (SMC) activity in the baseline, unmedicated state. Imaging data from an independent PD sample (106 subjects) linked these differences to loss of mesocortical dopamine terminals in advanced patients. In aggregate, the data suggest that LID results from an overactive vasomotor response to levodopa in the putamen on a background of disease-related increases in SMC activity. LID may thus be amenable to treatment that modulates the function of these 2 regions.

The Human Experience with Intravenous Levodopa.

Objective: To compile a comprehensive summary of published human experience with levodopa given intravenously, with a focus on information required by regulatory agencies.Background: While safe intravenous (IV) use of levodopa has been documented for over 50 years, regulatory supervision for pharmaceuticals given by a route other than that approved by the U.S. Food and Drug Administration (FDA) has become increasingly cautious. If delivering a drug by an alternate route raises the risk of adverse events, an investigational new drug (IND) application is required, including a comprehensive review of toxicity data.Methods: Over 200 articles referring to IV levodopa were examined for details of administration, pharmacokinetics, benefit, and side effects.Results: We identified 142 original reports describing IVLD use in humans, beginning with psychiatric research in 1959–1960 before the development of peripheral decarboxylase inhibitors. At least 2760 subjects have received IV levodopa, and reported outcomes include parkinsonian signs, sleep variables, hormone levels, hemodynamics, CSF amino acid composition, regional cerebral blood flow, cognition, perception and complex behavior. Mean pharmacokinetic variables were summarized for 49 healthy subjects and 190 with Parkinson's disease. Side effects were those expected from clinical experience with oral levodopa and dopamine agonists. No articles reported deaths or induction of psychosis.Conclusion: At least 2760 patients have received IV levodopa with a safety profile comparable to that seen with oral administration.

Orthostatic stability with intravenous levodopa.

Intravenous levodopa has been used in a multitude of research studies due to its more predictable pharmacokinetics compared to the oral form, which is used frequently as a treatment for Parkinson’s disease (PD). Levodopa is the precursor for dopamine, and intravenous dopamine would strongly affect vascular tone, but peripheral decarboxylase inhibitors are intended to block such effects. Pulse and blood pressure, with orthostatic changes, were recorded before and after intravenous levodopa or placebo—after oral carbidopa—in 13 adults with a chronic tic disorder and 16 tic-free adult control subjects. Levodopa caused no statistically or clinically significant changes in blood pressure or pulse. These data add to previous data that support the safety of i.v. levodopa when given with adequate peripheral inhibition of DOPA decarboxylase.

Parkinson's Disease: Increased Motor Network Activity in the Absence of Movement

We used a network approach to assess systems-level abnormalities in motor activation in humans with Parkinson's disease (PD). This was done by measuring the expression of the normal movement-related activation pattern (NMRP), a previously validated activation network deployed by healthy subjects during motor performance. In this study, NMRP expression was prospectively quantified in (15)O-water PET scans from a PD patient cohort comprised of a longitudinal early-stage group (n = 12) scanned at baseline and at two or three follow-up visits two years apart, and a moderately advanced group scanned on and off treatment with either subthalamic nucleus deep brain stimulation (n = 14) or intravenous levodopa infusion (n = 14). For each subject and condition, we measured NMRP expression during both movement and rest. Resting expression of the abnormal PD-related metabolic covariance pattern was likewise determined in the same subjects. NMRP expression was abnormally elevated (p < 0.001) in PD patients scanned in the nonmovement rest state. By contrast, network activity measured during movement did not differ from normal (p = 0.34). In the longitudinal cohort, abnormal increases in resting NMRP expression were evident at the earliest clinical stages (p < 0.05), which progressed significantly over time (p = 0.003). Analogous network changes were present at baseline in the treatment cohort (p = 0.001). These abnormalities improved with subthalamic nucleus stimulation (p < 0.005) but not levodopa (p = 0.25). In both cohorts, the changes in NMRP expression that were observed did not correlate with concurrent PD-related metabolic covariance pattern measurements (p > 0.22). Thus, the resting state in PD is characterized by changes in the activity of normal as well as pathological brain networks.

Constipation triggered the malignant syndrome in Parkinson’s disease

A 69-year-old, chronically constipated patient with Parkinson's disease developed fecal impaction and the malignant syndrome simultaneously, even while the patient was taking anti-parkinsonian drugs as prescribed. Administration of intravenous levodopa and oral Dai-kenchu-tou, an herbal medicine with serotonergic 5-HT3 receptor agonistic property successfully ameliorated his clinical symptoms. Constipation may trigger worsening of Parkinson's disease and occurrence of the malignant syndrome by affecting levodopa absorption. Further, improved bowel motility may prevent worsening of Parkinson's disease and occurrence of the malignant syndrome.

The effect of peripheral enzyme inhibitors on levodopa concentrations in blood and CSF

Levodopa combined with a dopa-decarboxylase inhibitor, such as carbidopa, shifts the metabolism to the COMT pathway. Adding the peripheral acting COMT inhibitor entacapone provides improvement for patients with PD suffering from motor fluctuations. We studied the effects of the enzyme inhibitors entacapone and carbidopa on the levodopa concentrations in CSF and in blood. Five PD patients with wearing-off underwent lumbar drainage and intravenous microdialysis. Samples were taken 12 h daily for 3 days. Day 1; intravenous levodopa was given, day 2; additional oral entacapone 200 mg tid, day 3; additional oral entacapone 200 mg tid and carbidopa 25 mg bid. Levodopa in CSF and in dialysates was analysed. The AUC for levodopa increased both in blood and CSF when additional entacapone was given alone and in combination with carbidopa. The C(max) of levodopa in both CSF and blood increased significantly. Additional entacapone to levodopa therapy gives an increase of C(max) in CSF and in blood. The increase is more evident when entacapone is combined with carbidopa.

Effects of a Dopamine Agonist on the Pharmacodynamics of Levodopa in Parkinson Disease

Treatment of Parkinson disease commonly includes levodopa and dopamine agonists; however, the interaction of these 2 drugs is poorly understood. To examine the effects of a dopamine agonist on the motor response to levodopa. Double-blind, randomized, placebo-controlled, crossover clinical trial. Ambulatory academic referral center. Patients Thirteen patients with idiopathic Parkinson disease taking levodopa and experiencing motor fluctuations and dyskinesia. Eligible individuals were randomly assigned to receive pramipexole dihydrochloride or placebo for 4 weeks followed by a 2-hour intravenous levodopa infusion on consecutive days at 2 rates and with blinded assessments. They were then crossed over to the alternate oral therapy for 4 weeks followed by levodopa infusion and reassessment. Change in finger-tapping speed, measured using the area under the curve (AUC) for finger taps per minute across time; peak finger-tapping speed; duration of response; time to "ON" (defined as a 10% increase in finger-tapping speed above baseline); walking speed; and dyskinesia AUC. Pramipexole with levodopa infusion increased finger-tapping speed beyond the change in baseline by a mean (SE) of 170 (47.2) per minute x minutes (P = .006) and more than doubled the AUC for finger-tapping speed. Pramipexole increased peak finger-tapping speed by a mean (SE) of 18 (8.5) taps per minute (P = .02) and improved mean (SE) walking speed (15.9 [0.70] vs 18.9 [0.70] seconds, P = .004). Pramipexole prolonged duration of response after levodopa infusion and shortened time to ON. Pramipexole increased mean (SE) baseline dyskinesia scores (26.0 [5.85] vs 12.1 [5.85] points, P = .05) and peak dyskinesia scores with levodopa infusion. Pramipexole augmented the motor response to levodopa beyond a simple additive effect and increased the severity of levodopa-induced dyskinesia. When considering a combination of these therapies, an appropriate balance should be maintained regarding gain of motor function vs worsening of dyskinesia. Trial Registration clinicaltrials.gov Identifier: NCT00666653.

Dopaminergic Suppression of Brain Deactivation Responses during Sequence Learning

Cognitive processing is associated with deactivation of the default mode network. The presence of dopaminoceptive neurons in proximity to the medial prefrontal node of this network suggests that this neurotransmitter may modulate deactivation in this region. We therefore used positron emission tomography to measure cerebral blood flow in 15 Parkinson's disease (PD) patients while they performed a motor sequence learning task and a simple movement task. Scanning was conducted before and during intravenous levodopa infusion; the pace and extent of movement was controlled across tasks and treatment conditions. In normal and unmedicated PD patients, learning-related deactivation was present in the ventromedial prefrontal cortex (p < 0.001). This response was absent in the treated condition. Treatment-mediated changes in deactivation correlated with baseline performance (p < 0.002) and with the val(158)met catechol-O-methyltransferase genotype. Our findings suggest that dopamine can influence prefrontal deactivation during learning, and that these changes are linked to baseline performance and genotype.

Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

We compared the metabolic and neurovascular effects of levodopa (LD) therapy for Parkinson's disease (PD). Eleven PD patients were scanned with both [15O]-H2O and [18F]-fluorodeoxyglucose positron emission tomography in the unmedicated state and during intravenous LD infusion. Images were used to quantify LD-mediated changes in the expression of motor- and cognition-related PD covariance patterns in scans of cerebral blood flow (CBF) and cerebral metabolic rate for glucose (CMR). These changes in network activity were compared with those occurring during subthalamic nucleus (STN) deep brain stimulation (DBS), and those observed in a test-retest PD control group. Separate voxel-based searches were conducted to identify individual regions with dissociated treatment-mediated changes in local cerebral blood flow and metabolism. We found a significant dissociation between CBF and CMR in the modulation of the PD motor-related network by LD treatment (p < 0.001). This dissociation was characterized by reductions in network activity in the CMR scans (p < 0.003) occurring concurrently with increases in the CBF scans (p < 0.01). Flow-metabolism dissociation was also evident at the regional level, with LD-mediated reductions in CMR and increases in CBF in the putamen/globus pallidus, dorsal midbrain/pons, STN, and ventral thalamus. CBF responses to LD in the putamen and pons were relatively greater in patients exhibiting drug-induced dyskinesia. In contrast, flow-metabolism dissociation was not present in the STN DBS treatment group or in the PD control group. These findings suggest that flow-metabolism dissociation is a distinctive feature of LD treatment. This phenomenon may be especially pronounced in patients with LD-induced dyskinesia.

Metabolic brain networks associated with cognitive function in Parkinson's disease

The motor manifestations of Parkinson's disease (PD) have been linked to an abnormal spatial covariance pattern involving basal ganglia thalamocortical pathways. By contrast, little is known about the functional networks that underlie cognitive dysfunction in this disorder. To identify such patterns, we studied 15 non-demented PD patients using FDG PET and a voxel-based network modeling approach. We detected a significant covariance pattern that correlated ( p < 0.01) with performance on tests of memory and executive functioning. This PD-related cognitive pattern (PDCP) was characterized by metabolic reductions in frontal and parietal association areas and relative increases in the cerebellar vermis and dentate nuclei. To validate this pattern, we analyzed data from 32 subsequent PD patients of similar age, disease duration and severity. Prospective measurements of PDCP activity predicted memory performance ( p < 0.005), visuospatial function ( p < 0.01), and perceptual motor speed ( p < 0.005) in this validation sample. PDCP scores additionally exhibited an excellent degree of test–retest reliability (intraclass correlation coefficient, ICC = 0.89) in patients undergoing repeat FDG PET at an 8-week interval. Unlike the PD-related motor pattern, PDCP expression was not significantly altered by antiparkinsonian treatment with either intravenous levodopa or deep brain stimulation (DBS). These findings substantiate the PDCP as a reproducible imaging marker of cognitive function in PD. Because PDCP expression is not altered by routine antiparkinsonian treatment, this measure of network activity may prove useful in clinical trials targeting the progression of non-motor manifestations of this disorder.

Intravenous levodopa administration in humans based on a two-compartment kinetic model

Levodopa, when combined with a decarboxylase inhibitor, essentially delivers dopamine directly to the brain, with no net effect on brain blood vessels. For future neuroimaging studies of Parkinson disease and Tourette syndrome, we sought to rapidly produce a biologically relevant levodopa concentration in plasma and then maintain that concentration long enough to assess motor, cognitive, emotional, and neuroimaging responses, while minimizing side effects in levodopa-naive individuals. Based on available pharmacokinetic data and a two-compartment model, we designed a decreasing-exponential-rate infusion to meet these goals. This report gives results of double-blind levodopa and placebo infusions in six healthy subjects. Mean plasma levodopa concentrations were within 3% of their 1200 ng/mL target at 20 and 40 min into the infusion, and within 20% between ∼12 and 90 min. Levodopa significantly reduced serum prolactin and raised serum growth hormone concentrations. Volunteers had no significant side effects.

Network modulation in the treatment of Parkinson's disease

It has been proposed that deep brain stimulation (DBS) of the subthalamic nucleus (STN DBS) and dopaminergic therapy ameliorate the symptoms of Parkinson's disease through similar functional mechanisms. We examined this notion using PET to compare the metabolic effects of these treatment approaches. Nine Parkinson's disease patients (age 61.7 +/- 11.1 years) were scanned ON and OFF STN stimulation and nine others (age 60.0 +/- 9.3 years) were scanned ON and OFF an individual titrated intravenous levodopa infusion. The two treatment groups were matched for baseline disease severity as well as clinical response to therapy. Similarities and differences in the effects of treatment on regional metabolism were assessed using statistical parametric mapping (SPM). In addition, we used network analysis to assess the effect of therapy on the expression of an abnormal Parkinson's disease-related spatial covariance pattern (PDRP). We found that both STN DBS and levodopa therapy were associated with significant (P < 0.001) metabolic reductions in the putamen/globus pallidus, sensorimotor cortex and cerebellar vermis, as well as increases in the precuneus (BA 7). The metabolic effects of the two interventions differed in the STN and medial prefrontal cortex, with relative increases with stimulation in the former structure and decreases in the latter. Network quantification disclosed reductions in PDRP activity with both interventions, which correlated with clinical improvement (P < 0.05). The degree of network modulation by therapy did not differ significantly for the two treatment approaches (P > 0.6). These findings support the results of previous imaging studies indicating that effective symptomatic therapies for Parkinson's disease involve a common mechanism. The modulation of pathological brain networks is a critical feature of the treatment response in parkinsonism.

Effects of serotonin 5‐HT1A agonist in advanced Parkinson's disease

Intermittent stimulation of striatal dopaminergic receptors seems to contribute to motor dysfunction in advanced Parkinson's disease (PD). With severe dopaminergic denervation, exogenous levodopa is largely decarboxylated to dopamine in serotonergic terminals. If 5-HT1A autoreceptors regulate dopamine as well as serotonin release, in parkinsonian patients inhibition of striatal serotonergic neuron firing might help maintain more physiological intrasynaptic dopamine concentrations and thus ameliorate motor fluctuations and dyskinesias. To evaluate this hypothesis, effects of a selective 5-HT1A agonist, sarizotan, given orally at 2 and 5 mg twice daily to 18 relatively advanced parkinsonian patients, were compared with baseline placebo function during a 3-week, double-blind, placebo-controlled, proof-of-concept study. Sarizotan alone or with intravenous levodopa had no effect on parkinsonian severity. But at safe and tolerable doses, sarizotan coadministration reduced levodopa-induced dyskinesias and prolonged its antiparkinsonian response (P < or = 0.05). Under the conditions of this study, our findings suggest that 5-HT1A receptor stimulation in levodopa-treated parkinsonian patients can modulate striatal dopaminergic function and that 5-HT1A agonists may be useful as levodopa adjuvants in the treatment of PD.

A collaborative study on the malignant syndrome in Parkinson's disease and related disorders

We report the results of a collaborative study on malignant syndrome (MS) that developed in patients being treated with levodopa and other anti-parkinsonian drugs. We analyzed clinical features, laboratory findings, precipitating events, and risk factors for poor outcome. The study was conducted in five centers in Japan. Patients who developed MS between January 1991 and December 1997 were included. The enrollment criteria used were the same as those for neuroleptic MS proposed by Levenson et al. (1985). A total of 99 episodes were encountered in 93 patients (72 with Parkinson's disease and 21 with secondary parkinsonism); one patient had four recurrences of MS and three patients had two recurrences. High fever was the most frequent clinical manifestation of MS followed by worsening of parkinsonism, and then altered levels of consciousness. Serum creatine kinase was abnormally elevated in all the patients studied. Life-threatening complications were rhabdomyolysis, disseminated intravascular coagulation, and acute renal failure. The most frequent precipitating event was discontinuation or dose reduction of anti-parkinsoian drugs, particularly levodopa. No drug was the exception in the precipitation of MS. Intercurrent infection was the next most common precipitating event. MS developed without drug withdrawal or infection in some patients. In five patients, severe ‘wearing off’ phenomenon was the only event preceding the onset of MS. Hot weather and dehydration appeared to be the cause in three patients. Among the total of 99 episodes, patients recovered to the pre-MS state following 68 episodes (68.7%); in the remaining 31.3%, patients failed to recover to their previous state. Older age, higher Hoehn and Yahr stage during the symptomatic phase of MS, higher akinesia score, and the absence of wearing off phenomenon prior to developing MS were associated with poor outcome. The most frequently used treatments of MS were intravenous fluid, levodopa, dantrolene sodium, and intragastric bromocriptine. Early introduction of treatment is important. Any elevation of body temperature during the course of anti-parkinsonian drug treatment should be considered as MS until proved otherwise.