The effect of levodopa benserazide hydrochloride on homocysteinemia levels in patients with Parkinson's disease and treatment of hyperhomocysteinemia.

OBJECTIVE: This study aims to investigate hyperhomocysteinemia (HHcy) resulted from treatment in patients with Parkinson's disease (PD) and to evaluate the therapeutic outcome of HHcy. PATIENTS AND METHODS: Ninety-three newly diagnosed PD patients were divided into Madopar group (treated with Madopar) and non-Madopar group (not treated with Madopar). Plasma Hcy levels were measured. Five months later, 67 patients presenting with HHcy were randomly divided into treatment group (n = 34) (receiving methylcobalamin 500 µg, tid, and folic acid 50 mg, tid, orally) and control group (n = 33).  Madopar dosage was maintained in both groups. MRI examination was performed to detect cerebral ischemia and patients were evaluated by Webster's rating scale. Plasma Hcy levels were measured at 3-month follow-up. Webster's scores and MRI were performed at 6-month follow-up. RESULTS: At the initial visit, Hcy levels of patients of Madopar group were significantly higher than those of non-Madopar group (18.52 ± 6.48 µmol/L) vs. (15.78 ± 3.42), p < 0.05]. At 5-month follow-up, patients of the non-Madopar group presented significantly increased Hcy levels (18.97 ± 7.42 µmol/L) compare with pre-treatment Hcy levels (p < 0.05), whereas Hcy levels were slightly increased in patients of Madopar group (20.61 ± 7.87 µmol/L, p > 0.05). In the treatment group, serum Hcy levels were significantly decreased after 3-month treatment with methylcobalamin and folic acid (p < 0.01). However, serum Hcy levels were not significantly changed in patients of the control group. In addition, in the treatment group, no patient presented ischemic stroke with clinical symptoms and four patients were confirmed with new cerebral ischemic and lacunar lesions by MRI examination. However, in the control group, two ischemic strokes with clinical symptoms and 11 new cerebral ischemic and lacunar lesions were detected. Significant differences were observed between two groups (p < 0.05). Furthermore, post-treatment modified Webster scores were significantly decreased than pre-treatment scores for both groups. However, no significant differences were found between groups (p > 0.05). CONCLUSIONS: Oral administration of Levodopa in the treatment of PD can cause HHcy, which can result in increased occurrence of ischemic stroke. Supplementation of methylcobalamin and folic acid can effectively reduce Hcy level and thereby prevent the occurrence of ischemic stroke.

Dopaminergic agents and nutritional status in Parkinson's disease.

BACKGROUND: Malnutrition has been found in up to 24% of patients with Parkinson's disease; dopaminergic drugs might impair nutritional status. We evaluated the association of nutritional status with the use of dopaminergic agents. METHODS: We analyzed data from 75 elderly patients with Parkinson's disease attending a geriatric day hospital. Nutritional status was assessed by the Mini Nutritional Assessment (MNA). Dopaminergic drugs were normalized for weight. RESULTS: In linear regression, total levodopa (l-dopa) equivalent daily dose (LEDD) was associated with worse MNA (B = -0.14, 95% CI = -0.26--0.02; P = 0.019). This association remained significant only for l-dopa (B = -0.19, 95% CI = -0.32--0.52; P = 0.007), but not dopaminergic agent dosages. Increasing l-dopa dosages were associated with increasing probability of risk of malnutrition (P for trend = 0.049). CONCLUSIONS: In our population, LEDD was associated with worse nutritional status and risk of malnutrition; this association was limited to use of l-dopa.

Psychopharmacological study of agmatine in behavioral tests of schizophrenia in rodents.

The effect of agmatine in preclinical behavioral tests of schizophrenia has been examined in rodents. Agmatine at the doses of 40 and 80 mg/kg blocked conditioned avoidance responding, attenuated apomorphine induced climbing, diminished amphetamine and ketamine hyperlocomotor activity and augmented plasma prolactin levels. Pretreatment of animals with 20 mg/kg of agmatine potentiated the inhibitory effect of haloperidol (0.1 mg/kg, ip) and olanzepine (0.5 mg/kg, ip) in conditioned avoidance response test and apomorphine induced climbing. Agmatine alone at the doses tested here did not induce any cataleptic behavior in mice. However significant catalepsy was exhibited when agmatine (80 mg/kg, ip) was injected to mice pretreated with 5-HT1A receptor antagonist, WAY100, 635. These results indicate that agmatine via regulation of brain dopaminergic signaling modulates dopamine mediated behaviors. The alteration in the levels of endogenous agmatine may contribute to the genesis of psychosis and development of drugs that enhance endogenous agmatine content may be better therapeutic approach to treat schizophrenia with low incidences of extra pyramidal side effects.

Abnormal metabolic brain networks in a nonhuman primate model of parkinsonism.

Parkinson's disease (PD) is associated with a characteristic regional metabolic covariance pattern that is modulated by treatment. To determine whether a homologous metabolic pattern is also present in nonhuman primate models of parkinsonism, 11 adult macaque monkeys with parkinsonism secondary to chronic systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 12 age-matched healthy animals were scanned with [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). A subgroup comprising five parkinsonian and six control animals was used to identify a parkinsonism-related pattern (PRP). For validation, analogous topographies were derived from other subsets of parkinsonian and control animals. The PRP topography was characterized by metabolic increases in putamen/pallidum, thalamus, pons, and sensorimotor cortex, as well as reductions in the posterior parietal-occipital region. Pattern expression was significantly elevated in parkinsonian relative to healthy animals (P<0.00001). Parkinsonism-related topographies identified in the other derivation sets were very similar, with significant pairwise correlations of region weights (r>0.88; P<0.0001) and subject scores (r>0.74; P<0.01). Moreover, pattern expression in parkinsonian animals correlated with motor ratings (r>0.71; P<0.05). Thus, homologous parkinsonism-related metabolic networks are demonstrable in PD patients and in monkeys with experimental parkinsonism. Network quantification may provide a useful biomarker for the evaluation of new therapeutic agents in preclinical models of PD.

Hyperhomocysteinemia recurrence in levodopa-treated Parkinson's disease patients.

BACKGROUND: Patients with Parkinson's disease (PD) and chronically treated with L-DOPA exhibit, in a percentage of 10-30%, supra-physiological levels of plasma total homocysteinemia (tHcy). In this study, we have investigated, in a group of hyper-homocysteinemic PD patients, the time of hyper-tHcy recurrence after discontinuation of 1-month folate supplementation given to normalize plasma tHcy levels. METHODS: Plasma tHcy, cobalamin and folate were assayed before and after 1-month folate supplementation (5 mg/day), and after 2 and 4 months after folate discontinuation in 29 PD patients (16M/13F, mean age 69.4 +/- 6.9 years) stabilized on a mean L-DOPA dose of 509.4 +/- 312.1 mg/day. RESULTS: After folate supplementation, plasma tHcy levels fell within the normal range in all patients. At the 2-month control after folate discontinuation, plasma tHcy remained within physiological values in 25 out of 29 patients. Conversely, 4 months after folate discontinuation, all patients exhibited hyper-tHcy. CONCLUSIONS: One-month intake of 5 mg/day folate normalizes plasma tHcy levels in all hyper-homocysteinemic PD patients. Following folate discontinuation, hyper-tHcy recurs in all patients within 4 months. Knowledge of this time interval is useful to optimize pulses of folate therapy in hyper-homocysteinemic patients with PD.

Comparison of apomorphine and levodopa infusions in four patients with Parkinson's disease with symptom fluctuations.

BACKGROUND: Motor fluctuations in patients with advanced Parkinson's disease may be successfully treated with subcutaneous apomorphine infusion or intraduodenal levodopa/carbidopa infusion. No comparative trials of these two alternatives were performed. AIMS OF THE STUDY: We present a subanalysis from a randomized crossover clinical trial where levodopa infusion as monotherapy was compared with any other combination of pharmacotherapy in fluctuating patients. Four patients used apomorphine infusion and oral levodopa in the comparator arm. The results of these four patients are presented in detail. METHODS: The duration of the trial was 3 + 3 weeks. Patients were video-recorded half-hourly on two non-consecutive days of both treatment arms. Blinded video ratings were used. Patient self-assessments of motor function and quality-of-life (QoL) parameters were captured using an electronic diary. RESULTS: Ratings in moderate to severe "off" state ranged 0-44% on apomorphine infusion and 0-6% on levodopa infusion. Moderate to severe dyskinesias were not recorded in any of the treatments. QoL was reported to be improved in all patients on duodenal levodopa infusion. CONCLUSIONS: Monotherapy with duodenal infusion of levodopa was more efficacious and brought greater QoL than combination therapy with apomorphine infusion in these fluctuating patients.

[Effect of TCM treatment according to syndrome differentiation in enhancing curative effect and reducing side-effect of madopa].

OBJECTIVE: To observe the effect of TCM treatment according to syndrome differentiation in en-hancing curative effect and reducing side-effect of madopa in patients with Parkinson' s disease (PD). METHODS: The trial was conducted in 101 PD patients with a prospective stratified randomized and controlled method. They were assigned to group 1 in which the patients of rigidity were treated with Pabing Recipe 1 (PR1) plus Madopa tablets, group 2 with those of tremor given Pabing Recipe 3 (PR3) plus Madopa tablets, and group 3 given a fixed Chinese recipe plus Madopa tablets as the control. The treatment course for all the groups was 3 months. Clinical efficacy was evaluated with unified Parkinson's disease rating scale (UPDRS) and the adverse reactions observed before and after treatment. RESULTS: After treatment, the 4 partial scores and the total score of UPDRS decreased significantly in group 2 (P<0.01), and the former of them and the total score declined in group 1 and 3 (P<0.01), the improvement was better in group 1 and 2 than that in group 3 (P<0.01); the improvement rate in group 1 to 3 was 95.5%, 100.0% and 83.7%, respectively, which was significantly higher in group 1 and 2 than that in group 3 (P<0.05). CONCLUSION: TCM treatment according to syndrome differentiation could improve the clinical symptoms and reduce complications in PD patients, which could enhance curative effect and reduce side-effect of madopa.

The differential effects of 5-HT(1A) receptor stimulation on dopamine receptor-mediated abnormal involuntary movements and rotations in the primed hemiparkinsonian rat.

Serotonin 1A receptor (5-HT(1A)R) agonists have emerged as valuable supplements to l-DOPA therapy, demonstrating that they can decrease side effects and enhance motor function in animal models of Parkinson's disease (PD) and human PD patients. The precise mechanism by which these receptors act remains unknown and there is limited information on how 5-HT(1A)R stimulation impacts striatal dopamine (DA) D1 receptor (D1R) and D2 receptor (D2R) function. The current study examined the effects of 5-HT(1A)R stimulation on DA receptor-mediated behaviors. Male Sprague-Dawley rats were rendered hemiparkinsonian by unilateral 6-OHDA lesions and primed with the D1R agonist SKF81297 (0.8 mg/kg, i.p.) in order to sensitize DA receptors. Using a randomized within subjects design, rats received a first injection of: Vehicle (dH(2)O) or the 5-HT(1A)R agonist +/-8-OH-DPAT (0.1 or 1.0 mg/kg, i.p.), followed by a second injection of: Vehicle (dimethyl sulfoxide), the D1R agonist SKF81297 (0.8 mg/kg, i.p.), the D2R agonist quinpirole (0.2 mg/kg, i.p.), or l-DOPA (12 mg/kg+benserazide, 15 mg/kg, i.p.). On test days, rats were monitored over a 2-h period immediately following the second injection for abnormal involuntary movements (AIMs), analogous to dyskinesia observed in PD patients, and contralateral rotations. The present findings indicate that 5-HT(1A)R stimulation reduces AIMs induced by D1R, D2R and l-DOPA administration while its effects on DA agonist-induced rotations were receptor-dependent, suggesting that direct 5-HT(1A)R and DA receptor interactions may contribute to the unique profile of 5-HT(1A)R agonists for the improvement of PD treatment.

Restless legs syndrome: a clinical update.

Restless legs syndrome (RLS) is a common and often disabling sensorimotor disorder. Epidemiologic studies suggest that RLS is an underrecognized and undertreated disorder affecting both children and adults. The diagnosis is based primarily on the following four essential criteria: (1) an urge to move, usually associated with paresthesias, (2) onset or exacerbation of symptoms at rest, (3) relief of symptoms with movement, and (4) symptoms manifesting in a circadian pattern. Supplemental workup including polysomnography, iron profile, and/or neuropathy screen can provide support for the diagnosis and aid in the treatment strategy. Behavioral techniques, dopaminergic agents, opiates, benzodiazepines, and antiepileptics all have potential value in treating this disorder. Dopaminergic agents continue to be the most effective RLS treatment. However, due to their potential long-term side effects, these agents should not be considered the sole treatment of choice. In the end, the therapeutic plan should be individualized to suit each patient's presentation and needs.

Hallucinations and sleep disturbances in Parkinson's disease.

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD.

Recent failures of new potential symptomatic treatments for Parkinson's disease: causes and solutions.

One major goal of current research in Parkinson's disease (PD) is the discovery of novel agents to improve symptomatic management. The object of these new treatments should be to provide effective symptom control throughout the course of the disease without the development of side effects such as motor and psychiatric complications. Results of several clinical trials of new treatment options reported in the past 2 years have shown negative or unsatisfactory results. Most of the drugs and surgical procedures used in these studies had been tested previously in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys as well as in the classic 6-hydroxydopamine-lesioned rat model. They raise several questions about the true reliability of animal studies, the adequacy of the working hypotheses and design of clinical trials, the validity of tools in current use to evaluate a specific effect, and the selectivity of the drugs used. All these factors may explain failure. This review focuses on pharmacological and surgical treatments tested to improve the management of patients with motor fluctuations and dyskinesias. Some of the recent trials and possible reasons for their lack of success are critically analysed. Finally, some suggestions to avoid further failures and improve results are proposed.

The two faces of L-DOPA: benefits and adverse side effects in the treatment of Encephalitis lethargica, Parkinson's disease, multiple sclerosis and amyotrophic lateral sclerosis.

Parkinson's disease, encephalitis lethargica, multiple sclerosis and amyotrophic lateral sclerosis patients all display two distinct types of symptoms. Some of these are due directly to a deficiency of dopamine and are quickly reduced by laevodihydroxyphenylalanine (L-DOPA). The second set, however, are the result of neurological damage caused by metabolites of dopamine, which include dopachrome and other chrome indoles that are both hallucinogenic and neurotoxic. If this hypothesis is correct, three corollaries follow. Patients of all four disorders should display excessive oxidative stress, natural methyl acceptors should delay development and elevated antioxidant supplementation, given with L-DOPA, ought to prolong the "honeymoon" period in which the benefits of the drug out weigh its subsequent disadvantages. A literature review suggests that all three corollaries are probably correct.

Nerve growth factor prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced cell death via the Akt pathway by suppressing caspase-3-like activity using PC12 cells: relevance to therapeutical application for Parkinson's disease.

Nerve growth factor (NGF) mediates a variety of nerve cell actions through receptor tyrosine kinase TrkA. It has been revealed that the Akt pathway contributes to the prevention of apoptosis. It is thought that Parkinson's disease involves apoptosis, and NGF prevents apoptosis in an in vivo model system. However, there is no evidence that the Akt pathway helps to prevent parkinsonism. Here, we report that NGF prevents apoptosis induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in PC12 cells as an in vitro model system of parkinsonism and that this survival effect diminishes on addition of LY294002, a specific inhibitor of phosphatidylinositol 3-kinase. Immunocytochemical analysis revealed that 1 mM MPTP-treated cells or dominant negative Akt-expressing cells, to which were added NGF and MPTP, undergo apoptosis. Moreover, the caspase-3-like activity is increased by addition of MPTP or MPTP with NGF and LY294002. The importance of another signal pathway is shown by PD98059, a specific inhibitor of MAP kinase (MAPK) kinase, but PD98059 does not alter the survival effect in this model system. These results indicate that the Akt pathway helps to prevent parkinsonism by suppressing caspase-3-like activity, but the MAPK pathway is not involved in the NGF-dependent survival enhancing effect in this model system.

Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group.

CONTEXT: Pramipexole and levodopa both ameliorate the motor symptoms of early Parkinson disease (PD), but no controlled studies have compared long-term outcomes after initiating dopaminergic therapy with pramipexole vs levodopa. OBJECTIVE: To compare the development of dopaminergic motor complications after initial treatment of early PD with pramipexole vs levodopa. DESIGN: Multicenter, parallel-group, double-blind, randomized controlled trial. SETTING: Academic movement disorders clinics at 22 sites in the United States and Canada. PATIENTS: Three hundred one patients with early PD who required dopaminergic therapy to treat emerging disability, enrolled between October 1996 and August 1997. INTERVENTIONS: Subjects were randomly assigned to receive pramipexole, 0.5 mg 3 times per day, with levodopa placebo (n = 151); or carbidopa/levodopa, 25/100 mg 3 times per day, with pramipexole placebo (n = 150). For patients with residual disability, the dosage was escalated during the first 10 weeks. From week 11 to month 23.5, investigators were permitted to add open-label levodopa to treat continuing or emerging disability. MAIN OUTCOME MEASURES: Time to the first occurrence of any of 3 dopaminergic complications: wearing off, dyskinesias, or on-off motor fluctuations; changes in scores on the Unified Parkinson's Disease Rating Scale (UPDRS), assessed at baseline and follow-up evaluations; and, in a subgroup of 82 subjects evaluated at baseline and 23.5 months, ratio of specific to nondisplaceable striatal iodine 123 2-beta-carboxymethoxy-3-beta-(4-iodophenyl)tropane (beta-CIT) uptake on single photon emission computed tomography imaging of the dopamine transporter. RESULTS: Initial pramipexole treatment resulted in significantly less development of wearing off, dyskinesias, or on-off motor fluctuations (28%) compared with levodopa (51%) (hazard ratio, 0.45; 95% confidence interval [CI], 0. 30-0.66; P<.001). The mean improvement in total UPDRS score from baseline to 23.5 months was greater in the levodopa group than in the pramipexole group (9.2 vs 4.5 points; P<.001). Somnolence was more common in pramipexole-treated patients than in levodopa-treated patients (32.4% vs 17.3%; P =.003), and the difference was seen during the escalation phase of treatment. In the subgroup study, patients treated initially with pramipexole (n = 39) showed a mean (SD) decline of 20.0% (14.2%) in striatal beta-CIT uptake compared with a 24.8% (14.4%) decline in subjects treated initially with levodopa (n = 39; P =.15). CONCLUSIONS: Fewer patients receiving initial treatment for PD with pramipexole developed dopaminergic motor complications than with levodopa therapy. Despite supplementation with open-label levodopa in both groups, the levodopa-treated group had a greater improvement in total UPDRS compared with the pramipexole group. JAMA. 2000;284:1931-1938.

The role of the thalamus and basal ganglia in parkinsonian tremor.

The mechanism of parkinsonian tremor may involve a central oscillator, peripheral feedback to the central nervous system (CNS), or both. The thalamus or the globus pallidus is the most likely site for a central oscillator and would be predicted to generate thalamic tremor-related activity characterized, respectively, by calcium spike-associated bursts and by maximal tremor-related activity in the pallidal relay nucleus of thalamus. Thalamic spike trains demonstrate neither of these characteristics. However, cross-correlation, latency, and transfer function analysis indicate that sensory feedback is a critical element in the relationship between thalamic activity and parkinsonian tremor. Therefore, thalamic spike train activity is most consistent with parkinsonian tremor being mediated by peripheral inputs involved in either an unstable reflex loop or sensory modulation of a central oscillator.

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery.

OBJECT: To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results. METHODS: Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. CONCLUSIONS: Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.