A double-blind, randomized controlled trial of duloxetine for pain in Parkinson's disease.

BACKGROUND: Duloxetine proved effective for treating pain in people with Parkinson's disease in a single-arm, open-label study. OBJECTIVE: To evaluate the efficacy of duloxetine in a double-blind, randomized, placebo-controlled trial. METHODS: We randomly assigned 46 patients with Parkinson's disease with pain to either the duloxetine 40 mg/day arm or the placebo arm. After 10 weeks, we tested the change from baseline in 24-hour average pain severity measured by a visual analogue scale. RESULTS: We could not confirm the effect of duloxetine on pain. Exploratory analyses indicated that treatment with duloxetine was associated with improved scores on the Unified Parkinson's Disease Rating Scale Part III and 3 domains of the Parkinson's Disease Questionnaire - 39. CONCLUSIONS: The study failed to provide evidence for the use of duloxetine for treating pain in people with Parkinson's disease.

The Clinical Findings Useful for Driving Safety Advice for Parkinson's Disease Patients.

Objective We conducted a study to obtain information that could be used to provide Parkinson's disease (PD) patients with appropriate advice on safe driving. Methods Consecutive PD patients who visited our office were studied. Among these patients, those who had experienced driving after being diagnosed with PD were interviewed by neurologists and a trained nurse to investigate their previous car accidents, motor function, cognitive function, sleepiness, levodopa equivalent dose (LED), and emotional dysregulation. The rates of major car accidents before and after the onset of PD were compared. Results Fifteen patients had experienced a major car accident resulting in human injury or serious property damage since the onset of PD. When the rates of major car accidents before and after the onset of PD were compared, the ratio was 4.3 [95% confidence interval (CI) 1.9-9.7]. The incidence of accidents after the onset of PD was correlated with age, disease duration, LED, the cognitive function Mini-Mental Scale Examination (MMSE), Japanese translation of the Montreal Cognitive Assessment (MoCA-J), but not the motor symptom score [Unified Pankinson's disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) score was also higher in patients with major car accidents. Conclusion The severity of symptoms (Hoehn-Yahr classification), cognitive function, and disease duration were expected to be risk factors for car accidents. However, the motor symptom score (UPDRS part III) was not associated with the incidence of major car accidents. In addition to a low cognitive function and the severity of symptoms, the QUIP score might be an independent factor that can be referenced when advising PD patients to refrain from driving.

One year safety and efficacy of inosine to increase the serum urate level for patients with Parkinson's disease in Japan.

BACKGROUND: Epidemiological studies have repeatedly reported that increased serum urate level is associated with a slower progress of Parkinson's disease (PD). The urate precursor, inosine, raises the serum urate level and is therefore a candidate for a disease modifying treatment. However, an elevated serum urate level is a risk factor for gout, urolithiasis, and cardiovascular diseases. Although there have been previous clinical studies, the use of inosine in a clinical setting is still limited, and its safety is unclear, especially in an Asian population. METHODS: We conducted a single-arm, single-center clinical trial to assess the safety of inosine for PD patients with relatively low urate levels. After informed consent, 10 subjects were orally administered inosine to maintain a target urate level between 6.0mg/dl and 8.0mg/dl for one year. All adverse effects were recorded and categorized by severity. Also, the efficacy of using inosine to raise the serum urate level was reported. RESULTS: We did not observe any adverse events requiring termination or reduction of the study drug, although uric acid crystalluria was transiently observed in a single subject. An inosine dosage of 1070 (SD=501) mg/day significantly raises the urate level from 3.5 (0.84)mg/dl at baseline to 6.68 (1.11)mg/dl at the 52nd week. CONCLUSIONS: Inosine was safely used for one year and effectively raised urate levels in a small group of subjects. Our study is the first report to use inosine for patients with PD in an Asian population.

Treatment of Myasthenia Gravis in Patients with Elderly Onset at Advanced Age.

The number of patients with late-onset myasthenia gravis (MG) among patients ≥50 years has been increasing recently. We encountered three patients who developed elderly-onset MG at a particularly advanced age (≥80 years). All were female and positive for anti-acetylcholine receptor antibodies. About 4 years have passed since MG onset in all three patients and symptoms have been controlled without recurrence using a combination of oral low-dose prednisolone and tacrolimus. As many cases of elderly-onset MG do not require strong immunosuppression, we recommend minimum immunosuppressive treatment to avoid adverse events, particularly in patients at an advanced age of ≥80 years.

Human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy with bulbar palsy-type amyotrophic lateral sclerosis-like symptoms.

We herein report a case of Human T-lymphotropic virus type-I (HTLV-I)-associated myelopathy with bulbar palsy-type amyotrophic lateral sclerosis-like symptoms. A 52-year-old woman developed dyslalia at approximately 40 years of age, which slowly progressed. She presented with muscular atrophy and increased tendon reflexes of the extremities as well as bulbar palsy, from which motor neuron disease was suspected. Cerebrospinal fluid (CSF) testing revealed no abnormalities except for an elevated neopterin concentration at 143.17 pmol/mL (normal ≤30 pmol/mL). Her serum and CSF anti-HTLV-I antibody titers were also high. Intravenous infusions of methylprednisolone decreased the CSF neopterin concentration to 50.33 pmol/mL. Subsequent oral prednisolone therapy was effective in alleviating the symptoms.

[Essential knowledge of drugs for neurologists on pharmacokinetics and drug development in global aspects to the world].

In the last 30 years, a lot of drugs to treat neurological disorders have been developed. Now neurology is one of the fields where the medication is the most important factor deciding the prognosis of the treated patients. Neurologists are now required to have precise knowledge of drug metabolisms and interactions on the medication to treat neurological disorders. Insert Packages contain most useful and important information for medications, however, information for the drugs are not enough to prescribe some drugs, and even though in the same drugs, information offered is different especially on drug interactions. Pharmacists and physicians should choose the drugs which offer proper and useful drug information to treat patients. Developments of drugs to treat patients are important as a physician in Japan. It can also contribute to treat patients in the all of the world. The role of neurologists is especially big because the drugs of the brain are rapidly developed than any other fields in medicine.

Cerebrospinal fluid neopterin, but not osteopontin, is a valuable biomarker for the treatment response in patients with HTLV-I-associated myelopathy.

OBJECTIVE: The concentrations of neopterin and osteopontin in the cerebrospinal fluid (CSF) were measured in patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in order to evaluate their utility as biomarkers for the treatment response. METHODS: Seven HAM/TSP patients were treated intravenously with high-dose methylprednisolone (1,000 mg/day) for 3 days. CSF samples were collected before and after the treatment. The neopterin and osteopontin concentrations were determined using high-performance liquid chromatography (HPLC) and an enzyme immunoassay, respectively. The clinical symptoms were evaluated using the Osame Motor Disability Score and the Urinary Disturbance Score. RESULTS: Four out of the seven patients showed an improvement in motor function with the treatment, and were therefore classed as responders. The pre-treatment CSF neopterin concentration exceeded the upper limit of normal in all seven of the patients, and tended to be higher in treatment responders as compared to non-responders. The CSF neopterin concentration was reduced following treatment in all patients. The mean CSF neopterin concentration significantly (p<0.01) decreased following treatment by almost 60% (from 124.1±79.9 nmol/L to 49.2±29.8 nmol/L). The mean CSF osteopontin concentration was significantly (p<0.01) higher in the HAM/TSP patients in comparison to the 18 HTLV-1-seronegative patients who were designated as controls (9.54±4.53 mg/L vs. 3.72±3.04 mg/L). No significant (p=0.47) reduction of the CSF osteopontin concentration was observed following the intravenous administration of high-dose methylprednisolone. CONCLUSION: These results indicate that the CSF neopterin concentration, but not the osteopontin concentration, is a potentially valuable biomarker for monitoring the treatment response in HAM/TSP patients. Furthermore, high pre-treatment CSF neopterin concentrations may be a predictive biomarker for a response to intravenous high-dose methylprednisolone therapy.

Evaluating the driving ability in patients with Parkinson's disease using a driving simulator.

OBJECTIVE: For patients with Parkinson's disease (PD), driving is challenging due to an impaired motor function and decreased attention capabilities. This study assessed the driving capacity in PD patients by comparing neurological signs. METHODS: The driving ability of PD patients was evaluated using a driving simulator (Safety Master NT-932) that tested the reaction time in response to traffic signals and steering wheel errors. We studied the correlations between the total Unified Parkinson's Disease Rating Scale (UPDRS) score, the UPDRS part III score, the subscores of the UPDRS part III score, age, PD disease duration, braking reaction time, steering wheel errors and total scores for driving safety test results. 'On' state regular PD licensed drivers (n=42; mean age: 63 years) in Hoehn and Yahr stages II-III participated after their cognitive status was confirmed using mini-mental state examinations. RESULTS: The UPDRS scores, the UPDRS part III scores and the postural instability subscores exhibited significant (p<0.05) correlations with the number of steering wheel errors but not with the braking reaction time or the total safety scores of the test results. CONCLUSION: The UPDRS is an established evaluation method used to estimate PD signs, although it is not sufficient alone for deciding whether PD patients should be allowed to drive. Our findings suggest that determining the driving ability using a driving simulator might be a useful adjunct to UPDRS scores in the assessment of PD patients who are active drivers. Estimating the driving ability requires complex measurements, including motor performance with perception of stimuli and attention.

Effect of nicotine on the pharmacokinetics of levodopa.

OBJECTIVES: Some patients with Parkinson disease improved their symptoms on treatment with nicotine patch or gum. Nicotine has also been studied for its antidyskinetic effect on levodopa-induced dyskinesia. We determined the effects of nicotine on levodopa pharmacokinetics and gastric emptying in healthy subjects and on levodopa transport in Caco-2 monolayers in vitro. METHODS: Healthy subjects received transdermal nicotine patch application followed by oral levodopa/benserazide, 100/25 mg, in a fasting state and with enteral nutrition. Levodopa pharmacokinetics was determined, and gastric emptying was evaluated by carbon 13 ((13)C)-labeled acetic acid breath testing. In vitro studies using intestinal Caco-2 cell monolayers evaluated whether the intestinal transport of levodopa was affected by nicotine and its metabolite, cotinine. RESULT: Nicotine did not increase mean plasma concentration significantly during fasting or with enteral nutrition, although the extent of levodopa absorption was reduced by 34% to 60% in some individuals and the mean plasma concentration of levodopa was statistically decreased by nicotine in subjects who received enteral nutrition. However, gastric parameters were not significantly affected by nicotine. Nicotine and cotinine at 0.1 µmol/L significantly reduced levodopa uptake by Caco-2 cells (P < 0.01). CONCLUSIONS: We found that nicotine reduced plasma levodopa concentration in some healthy subjects but with no alteration of gastric emptying rate. In vitro, nicotine inhibited levodopa transport by Caco-2 cell monolayers in an α-methyl amino isobutyric acid-independent, 2-amino-norbornanecarboxylic acid-dependent manner. These results suggest that nicotine may inhibit the transport of levodopa by the system L-amino acid transporter.

[Myasthenia gravis complicated with optic neuritis showing anti-aquaporin 4 antibody: a case report].

We report a 33-year-old woman with myasthenia gravis (MG) who developed optic neuritis after the treatment of MG for 22 years. At 10 years of age, she was diagnosed with generalized MG (MGFA V) and at 11 years, she underwent thymectomy. She had been treated successfully only with anti-cholinesterase inhibitors for 22 years despite lasting high titer of anti-acetylcholine receptor antibody. She could manage everything in her life and had two children. At 33 years of age, she experienced acute visual loss in her left eye. Laboratory examination showed positive anti-acetylcholine receptor, antinuclear, anti-ssDNA, anti-dsDNA, anti-SS-A, and anti-aquaporin 4 (AQP4) antibodies. Brain MRI showed an enlarged left optic nerve with enhancement by gadolinium. Three courses of steroid pulse therapy did not show any effect on her visual acuity. However, plasma exchange therapy mildly ameliorated her visual acuity. Her MG symptoms were not exacerbated during the course of the optic neuritis. Furthermore blephalopstosis caused by MG has disappeared completely after the treatment with steroid pulse and plasma exchange. This case had 23 years of immunosuppressive treatment free durations with stable condition. The cause of development of optic neuritis would be her predisposed tendency other than thymectomy or treatment with immunosuppressive therapies.

Effect of renal impairment on the pharmacokinetics of memantine.

The effect of renal impairment on the pharmacokinetics of a single oral dose of memantine (10 mg) was determined in Japanese subjects. Subjects were assigned to four groups based on baseline creatinine clearance (CL(CR)): normal renal function (> 80 mL/min, n = 6), and mild (50 to ≤ 80 mL/min, n = 6), moderate (30 to < 50 mL/min, n = 6), and severe renal impairment (5 to < 30 mL/min, n = 7). Mean memantine maximum plasma concentration (C(max)) was similar in the groups (12.66, 17.25, 15.75, and 15.83 ng/mL, respectively), as was mean time to C(max) (6.2, 5.2, 4.3, and 5.4 h, respectively). However, exposure to memantine determined from mean area under the plasma concentration-time curve was 1.62-, 1.97-, and 2.33-times higher in subjects with mild, moderate, and severe renal impairment, respectively, as compared to controls with normal renal function. Mean memantine plasma elimination half-life increased according to increasing renal impairment (61.15, 83.00, 100.13, and 124.31 h, respectively), while mean cumulative urinary recovery of unchanged memantine in 72 h after dosing decreased according to increasing renal impairment (33.68%, 33.47%, 23.60%, and 16.17%, respectively). These results are the same as those in the previous study on caucasian individuals, when compared per body weight. It is suggested that the dose of memantine should be halved in patients with renal impairment.

Coadministration of domperidone increases plasma levodopa concentration in patients with Parkinson disease.

OBJECTIVES: The aim of this study was to examine the effects of the peripheral dopamine D2-receptor antagonist, domperidone, on the plasma kinetics of levodopa in patients with Parkinson disease (PD). METHODS: In a randomized crossover design, 18 hospitalized patients with PD received a single dose of levodopa/benserazide, 100/25 mg, with or without domperidone, 10 mg, under fasting conditions. Plasma levodopa concentrations were determined up to 3 hours after dose administration. RESULTS: Mean ± SEM levodopa maximum plasma concentration (Cmax) (14.1 ± 2.9 vs 9.7 ± 1.6 µmol/L; P < 0.01), plasma concentration at 30 min (C30 min) (13.7 ± 3.0 vs 8.1 ± 2.0 µmol/L; P < 0.01), and area under the plasma concentration-time curve from 0 to 3 hours (AUC0-3 hr) (15.9 ± 3.1 vs 12.1 ± 2.4 µmol/L · hour; P < 0.05) were significantly higher after coadministration of levodopa with domperidone compared to levodopa alone. Thus, domperidone increased levodopa Cmax and AUC0-3 hr by 1.5- and 1.3-fold, respectively. There were no exacerbations of PD by concomitant domperidone administration. CONCLUSIONS: The results demonstrate that coadministration of domperidone increased the bioavailability of levodopa. This may be the reason for no exacerbation of PD in concomitant administration of domperidone, a dopamine D2-receptor blocker.

Three spinocerebellar ataxia type 2 siblings with ataxia, parkinsonism, and motor neuronopathy.

Spinocerebellar ataxia type 2 (SCA2) represents a family of dominant neurodegenerative disorders that results from CAG expansion repeat mutations. The phenotype consists of some common features, most notably progressive ataxia. We describe three siblings with SCA2, manifesting parkinsonism and ataxia in the first sibling, juvenile parkinsonism in the second and motor neuronopathy in the third. Genetic examination revealed expansion to 42, 43, and 42 CAG repeats. There was no relationship between the number of repeats and phenotype. The SCA2 gene should be studied in families with heterogeneous neurodegenerative disorders, including motor neuron disease.