Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.

BACKGROUND: Cellular energetics play an important role in Parkinsons disease etiology, but no treatments directly address this deficiency. Our past research showed that treatment with febuxostat and inosine increased blood hypoxanthine and ATP in healthy adults, and a preliminary trial in 3 Parkinson's disease patients suggested some symptomatic improvements with no adverse effects. METHODS: To examine the efficacy on symptoms and safety in a larger group of Parkinsons disease patients, we conducted a single-arm, open-label trial at 5 Japanese neurology clinics and enrolled thirty patients (nmales = 11; nfemales = 19); 26 patients completed the study (nmales = 10; nfemales = 16). Each patient was administered febuxostat 20 mg and inosine 500 mg twice-per-day (after breakfast and dinner) for 8 weeks. The primary endpoint was the difference of MDS-UPDRS Part III score immediately before and after 57 days of treatment. RESULTS: Serum hypoxanthine concentrations were raised significantly after treatment (Pre = 11.4 µM; Post = 38.1 µM; P < .0001). MDS-UPDRS Part III score was significantly lower after treatment (Pre = 28.1 ±â€Š9.3; Post = 24.7 ±â€Š10.8; mean ±â€ŠSD; P = .0146). Sixteen adverse events occurred in 13/29 (44.8%) patients, including 1 serious adverse event (fracture of the second lumbar vertebra) that was considered not related to the treatment. CONCLUSIONS: The results of this study suggest that co-administration of febuxostat and inosine is relatively safe and effective for improving symptoms of Parkinsons disease patients. Further controlled trials need to be performed to confirm the symptomatic improvement and to examine the disease-modifying effect in long-term trials.

Effects on caregiver burden of a donepezil hydrochloride dosage increase to 10 mg/day in patients with Alzheimer's disease.

BACKGROUND: In this study, we evaluated changes in functioning and caregiver burden in Alzheimer's disease (AD) patients after a dosage increase that was made based on pharmacists' evaluation of AD patients' behavior in daily life. METHODS: Pharmacists used a checklist, a questionnaire, and the Repetitive Saliva Swallowing Test (RSST) to gather data on the daily life of AD patients taking donepezil 5 mg/day and their caregivers. In 27 cases, pharmacists suggested a dosage change to 10 mg/day to AD patients' physicians. Pharmacists then evaluated these patients for 16 weeks after the increase to determine changes in functional assessment staging, caregiver burden, and swallowing function. RESULTS: During the 16-week study, 20 of the 27 patients showed at least one-stage improvement in relation to the five assessed aspects of daily life (time/place, speech, bathing, dressing, and toileting). The mean score for caregiver burden due to personal strain was significantly lower after the dosage increase than before (5.15±3.76 at baseline; from 3.89±3.42 at week 4 to 3.59±3.90 at week 16; P<0.05), as was the mean score due to role strain (2.19±2.80 at baseline; 1.56±2.64 at week 8; P<0.05). After the dosage increase, the impaired swallowing function that accompanies AD was improved in the patients with swallowing problems, as indicated by a higher mean RSST score (1.22±0.67 at baseline; from 2.78±1.72 at week 4 to 2.78±1.79 at week 16; P<0.05). CONCLUSION: The dosage increase not only decreased caregiver burden, but also appeared to improve impaired swallowing function. Medication therapy management by pharmacists of AD patients, including the use of a checklist, contributed to the correct use of donepezil and improved quality of life for caregivers.

Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose?

Gabapentin enacarbil is a prodrug of the anticonvulsant gabapentin. The efficacy and safety of gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (RLS) has been evaluated in several clinical trials in the United States and Japan. Although most clinical trials assessed gabapentin enacarbil at doses greater than 600 mg/day and demonstrated the overall safety and efficacy (defined as improvements in the coprimary endpoints of the international RLS rating scale [IRLS] total score and Clinical Global Impression-Improvement response), the US Food and Drug Administration approved the 600 mg once-daily dosage because doses higher than 600 mg/day were considered to provide no additional benefits and were associated with higher rates of adverse events, such as somnolence and dizziness. Nonetheless, the results of clinical trials and post hoc meta-analyses have indicated that the 1,200 mg once-daily dosage was the most validated gabapentin enacarbil treatment for not only subjective RLS symptoms but also severe sleep disturbance associated with RLS. A Japanese dose-finding study showed that 900 mg/day, the intermediate dose between 600 and 1,200 mg, failed to show a significant improvement in IRLS total score, probably because many of the patients who discontinued treatment did so early, suggesting that a half-landing dose may cause more adverse effects than favorable ones in some RLS patients early in the treatment. Gabapentin enacarbil may have two distinct therapeutic doses for the treatment of RLS: 600 mg/day or lower doses for the treatment of subjective RLS symptoms and 1,200 mg/day or higher doses for the treatment of both subjective RLS symptoms and associated problems such as severe sleep disturbances.

[Clinical features of idiopathic restless legs syndrome in Japanese patients].

BACKGROUND: Little is known about the diagnosis and management of restless legs syndrome (RLS) in Japanese neurology clinics. OBJECTIVE: To validate the diagnostic criteria of the International RLS Study Group (IRLSSG) and the treatment algorithm of the Mayo Clinic in a Japanese neurology clinic setting and to clarify the features of Japanese patients with idiopathic RLS. METHODS: Patients with RLS symptoms were examined by a neurologist and the assessment included neurological examination, tests for periodic limb movements (PLM) and dopaminergic response, and the clinical diagnosis was made according to IRLSSG diagnostic criteria. Patients diagnosed with idiopathic RLS were treated with dopaminergic agents and the efficacy was evaluated. RESULTS: The study subjects were 151 Japanese patients who presented with RLS symptoms. Idiopathic RLS was diagnosed in 113 patients, secondary RLS in 16 and RLS mimics in 22. The cause of RLS mimics was either myelopathy, radiculopathy or neuropathy in 11 patients. The mean age of patients with idiopathic RLS was 50.1 (SD 20.0) years, 63% were woman, 97% had daily RLS, 31% had family history (40% of the early-onset subgroup), 86% reported unpleasant sensations in the lower legs, 43% had PLM in the daytime suggested immobilization test, 81% suffered from insomnia, 49% had limitations of work and activities, 71% reported impaired mood, 27% had consulted physicians about their symptoms, 4% had been diagnosed with RLS, 73% improved after dopaminergic treatments, and 33% experienced complete remission. CONCLUSIONS: The clinical features of Japanese patients with idiopathic RLS were identical to those reported in western countries, which suggests that IRLSSG diagnostic criteria and Mayo Clinic treatment algorism are valid in Japanese neurology clinics. Both patients and physicians were not fully aware of RLS in this country. Neurological examination was important in excluding RLS mimics and making a diagnosis of RLS.

An intradialysis diagnostic test for restless legs syndrome: a pilot study.

BACKGROUND: Restless legs syndrome (RLS) is common in dialysis patients, but a simple diagnostic test is not available. STUDY DESIGN: Diagnostic test study. SETTING & PARTICIPANTS: 32 patients with RLS and 29 patients without RLS in 2 dialysis centers. INDEX TEST: The suggested immobilization test (SIT) was performed during dialysis for at least 30 minutes, and periodic limb movements (PLMs) were assessed by means of electromyography of the anterior tibialis muscles using a Holter monitor as an electromyographic monitoring device. We also assessed changes in number of leg movements on the 30-minute SIT (SIT-PLM) after 4 weeks of treatment with the dopamine agonist pergolide. REFERENCE TEST OR OUTCOME: Clinical review by a neurologist, International RLS Rating Scale (IRLSRS) score, and changes in IRLSRS score after pergolide treatment. RESULTS: PLMs on the 30-minute SIT during dialysis were identified in 20 of 32 patients with RLS and 3 of 29 control participants. Sensitivity and specificity of PLMs on the 30-minute SIT during dialysis for RLS diagnosis were 63% and 90%, respectively. SIT-PLM correlated with IRLSRS total score at diagnosis (r = 0.53; P = 0.03), suggesting that SIT-PLM measures the general severity of RLS in uremic patients. Treatment with the dopamine agonist pergolide significantly reduced the IRLSRS total score (from a mean of 24.9 +/- 9.1 [SD] to 9.5 +/- 6.8; P < 0.01) and SIT-PLM (from 41.9 +/- 24.2 to 11.3 +/- 12.3; P < 0.01), but correlation between changes in SIT-PLM and those in IRLSRS score was not significant (r = 0.27; P = 0.3). LIMITATIONS: Poor correlation may be caused by the small sample size. Time available for the SIT was limited because of the patient's condition during dialysis. Time of day during SIT, mental-alerting activities during SIT, or hemodialysis therapy itself may influence the severity of PLMs. CONCLUSIONS: A Holter-monitored SIT during dialysis is a valid method for the diagnosis of RLS and to evaluate the effect of treatment with pergolide in uremic patients.

Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.