Rina Ando

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 Parkinsons 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.

Pharmacokinetics and safety/efficacy of levodopa pro-drug ONO-2160/carbidopa for Parkinson's disease

We conducted a phase I study investigating the efficacy, safety, and tolerability of ONO-2160, a newly developed levodopa pro-drug, and carbidopa compared with levodopa and carbidopa to stabilize levodopa plasma concentration fluctuations in Japanese patients with Parkinsons disease. In an open-label two-period design, patients (n = 12) with Parkinsons disease received levodopa and carbidopa for 3 days before 7 days of treatment with ONO-2160 and carbidopa. Patients were primarily evaluated using the Unified Parkinsons Disease Rating Scale Part III, a Parkinsons disease symptom diary, and analysis of adverse events. Pharmacokinetic analysis of plasma levodopa concentration was also performed. ONO-2160 and carbidopa therapy stabilized effective plasma levodopa concentration. No adverse events with safety concerns were observed. The combination of ONO-2160 and carbidopa produced a prolonged and stable plasma levodopa concentration with a reduction in Unified Parkinsons Disease Rating Scale Part III total scores. The combination was well tolerated, with no safety concerns, when administered to Japanese patients with Parkinsons disease.

Modafinil alleviates levodopa-induced excessive nighttime sleepiness and restores monoaminergic systems in a nocturnal animal model of Parkinson's disease

Treatment with dopaminergic agents result excessive daytime sleepiness (EDS) and some studies have shown the benefit of using modafinil for treating excessive daytime sleepiness of Parkinsons disease (PD) patient. We investigated whether modafinil have ameliorative properties against levodopa induced excessive nighttime sleepiness (ENS) in MPTP-treated murine nocturnal PD model. Our EEG analyses of whole day recordings revealed that modafinil reduce ENS of this nocturnal PD models with levodopa medications. Therefore, we investigated whether, modafinil post-treatment followed by MPTP shows any effect on monoamine contents of brain and found to robustly increased noradrenaline (NA) concentration of MPTP treated mice. Modafinil post-treatment, in neurorestorative context (5 days post-lesion) led to increased striatal dopamine (DA) concentrations of MPTP-treated mice. Here, we first confirmed that modafinil ameliorates levodopa induced excessive sleepiness and restores monoaminergic systems. The arousal and anti-parkinsonian effects displayed by modafinil indicate that in combination with dopaminergic agents, modafinil co-administration may be worthwhile in trying to suppress the excessive daytime sleepiness and progressive dopaminergic neuron loss in PD.

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 Parkinsons 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 Pankinsons disease rating scale (UPDRS) part III at the time of the study]. The Questionnaire for Impulsive-Compulsive Disorders in Parkinsons 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.

Falling after Starting Running in a Case of Myoclonus Epilepsy Associated with Ragged-red Fibers with a 8344A>G mtDNA Mutation

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344A>G mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.

DAT SPECT may have diagnostic value in prodromal SCA2 patients with parkinsonism

INTRODUCTION Although spinocerebellar ataxia type 2 (SCA2) is classified as hereditary spinocerebellar degeneration, some patients present with parkinsonism before developing cerebellar ataxia. METHODS 123I-metaiodobenzyl guanidine (123I-MIBG) myocardial scintigraphy and/or dopamine transporter single photon emission computed tomography (DAT SPECT) using 123I-ioflupane (123I-FP-CIT) were performed for the six patients from three SCA2 families. RESULTS 123I-MIBG myocardial scintigraphy showed reduced cardiac uptake in four of five patients and an association with Lewy body disease was suggested. DAT SPECT showed decreased uptake in the striatum in all four patients who were scanned, including one patient without parkinsonism. When patterns of uptake were compared to those with Parkinsons disease, most of the patients had minimal reduction of uptake in the putamen. CONCLUSION DAT SPECT is expected to be useful in differentiating SCA2 from Parkinsons disease, making an early diagnosis, and allowing early therapeutic intervention.

cascade stomach associated with delayed-on or no-on phenomenon in a patient with Parkinson's disease

Delayed-on and no-on phenomena have sometimes been reported in patients with Parkinson’s disease (PD), in whom there is a delayed or no response to an oral dose of levodopa. These phenomena are mainly thought to result from gastrointestinal absorption failure, which is caused by delayed gastric emptying, taking protein-rich food, and decreased gastric acid secretion. To improve levodopa absorption, we prescribe oral dispersible levodopa in combination with a prokinetic drug such as domperidone to accelerate gastric emptying or ascorbic acid for increase gastric acidity, but this is not always effective. We present a 68-year-old woman who developed muscle stiffness in her right arm at 59 years and was diagnosed with PD at 60 years, when treatment including levodopa was started. Beginning at age 65, she began to complain of walking difficulty including freezing of gait or senile gait, and motor fluctuations such as the wearing-off phenomenon and dyskinesia were observed. On referral to our hospital, plasma levodopa concentrations were measured after taking levodopa/carbidopa/entacapone in the morning and afternoon. This showed almost flat levodopa levels after morning dosing concomitant with no improvement in motor symptoms (Fig. 1A). She subsequently complained of mild abdominal bloating, for which upper gastrointestinal tract barium radiography was undertaken. When her stomach was filled with barium, we observed a separate fluid level confined to the fundus of the stomach. This revealed an atypical form of the stomach, called cascade stomach. When she bent forward, we could see barium flowing from the fundus down to the body of the stomach (Fig. 1B). We recommended that she bend forward several times after taking levodopa preparations in the future. We measured plasma levodopa concentrations again in the morning. This showed that plasma levodopa levels increased within 1 hour after dosing, and her motor symptoms greatly improved, including control of gait disturbance (Fig. 1C). Lewy bodies are considered to appear in the dorsal nucleus of the vagus nerve from an early stage in patients with PD, and it has been reported that constipation can precede motor symptoms of PD by more than 10 years. Concerning

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.