Impact of Istradefylline on Levodopa Dose Escalation in Parkinson's Disease: ISTRA ADJUST PD Study, a Multicenter, Open-Label, Randomized, Parallel-Group Controlled Study.

INTRODUCTION: A higher levodopa dose is a risk factor for motor complications in Parkinson's disease (PD). Istradefylline (IST) is used as adjunctive treatment to levodopa in PD patients with off episodes, but its impact on levodopa dose titration remains unclear. The objective of this study was to investigate the effect of IST on levodopa dose escalation in PD patients with wearing-off. METHODS: This was a multicenter, open-label, randomized, parallel-group controlled study (ISTRA ADJUST PD) in which PD patients experiencing wearing-off (n = 114) who were receiving levodopa 300-400 mg/day were randomized to receive IST or no IST (control). Levodopa dose was escalated according to clinical severity. The primary endpoint was cumulative additional levodopa dose, and secondary endpoints were changes in symptom rating scales, motor activity determined by a wearable device, and safety outcomes. RESULTS: The cumulative additional levodopa dose throughout 37 weeks and dose increase over 36 weeks were significantly lower in the IST group than in the control group (both p < 0.0001). The Movement Disorder Society Unified Parkinson's Disease Rating Scale Part I and device-evaluated motor activities improved significantly from baseline to 36 weeks in the IST group only (all p < 0.05). Other secondary endpoints were comparable between the groups. Adverse drug reactions (ADRs) occurred in 28.8% and 13.2% of patients in the IST and control groups, respectively, with no serious ADRs in either group. CONCLUSION: IST treatment reduced levodopa dose escalation in PD patients, resulting in less cumulative levodopa use. Adjunctive IST may improve motor function more objectively than increased levodopa dose in patients with PD. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs031180248.

Evaluating the impact of adjunctive istradefylline on the cumulative dose of levodopa-containing medications in Parkinson's disease: study protocol for the ISTRA ADJUST PD randomized, controlled study.

BACKGROUND: Levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD) more than 50 years after its clinical introduction. However, the onset of motor complications can limit pharmacological intervention with levodopa, which can be a challenge when treating PD patients. Clinical data suggest using the lowest possible levodopa dose to balance the risk/benefit. Istradefylline, an adenosine A2A receptor antagonist indicated as an adjunctive treatment to levodopa-containing preparations in PD patients experiencing wearing off, is currently available in Japan and the US. Preclinical and preliminary clinical data suggested that adjunctive istradefylline may provide sustained antiparkinsonian benefits without a levodopa dose increase; however, available data on the impact of istradefylline on levodopa dose titration are limited. The ISTRA ADJUST PD study will evaluate the effect of adjunctive istradefylline on levodopa dosage titration in PD patients. METHODS: This 37-week, multicenter, randomized, open-label, parallel-group controlled study in PD patients aged 30-84 years who are experiencing the wearing-off phenomenon despite receiving levodopa-containing medications ≥ 3 times daily (daily dose 300-400 mg) began in February 2019 and will continue until February 2022. Enrollment is planned to attain 100 evaluable patients for the efficacy analyses. Patients will receive adjunctive istradefylline (20 mg/day, increasing to 40 mg/day) or the control in a 1:1 ratio, stratified by age, levodopa equivalent dose, and presence/absence of dyskinesia. During the study, the levodopa dose will be increased according to symptom severity. The primary study endpoint is the comparison of the cumulative additional dose of levodopa-containing medications during the treatment period between the adjunctive istradefylline and control groups. Secondary endpoints include changes in efficacy rating scales and safety outcomes. DISCUSSION: This study aims to clarify whether adjunctive istradefylline can reduce the cumulative additional dose of levodopa-containing medications in PD patients experiencing the wearing-off phenomenon, and lower the risk of levodopa-associated complications. It is anticipated that data from ISTRA ADJUST PD will help inform future clinical decision-making for patients with PD in the real-world setting. TRIAL REGISTRATION: Japan Registry of Clinical Trials, jRCTs031180248 ; registered 12 March 2019.

Effect of istradefylline on mood disorders in Parkinson's disease.

Depression is the most common psychiatric complication in patients with Parkinson's disease (PD). Istradefylline, a new anti-parkinsonian agent with completely different mechanism, improves depression-like symptoms in an experimental disease model; however, there is no report of its effects in PD patients. In this study, the effectiveness of istradefylline for treatment of mood disorders in patients with PD was examined in an open-label trial. Thirty PD patients were enrolled. All patients had scores of higher than cut-off level in at least one of the following batteries: Snaith-Hamilton Pleasure Scale Japanese version (SHAPS-J), Apathy scale, or Beck Depression Inventory-2nd edition (BDI). Following study enrollment, all patients received 20 mg of istradefylline, and the dose was increased to 40 mg after 4 weeks. Results from these 3 batteries and the Unified Parkinson's Disease Rating Scale (UPDRS) score were assessed every 2-4 weeks until 12 weeks and the changes in these scores were analyzed. Following administration of istradefylline, the scores of SHAPS-J, Apathy scale, and BDI were significantly improved over time. Significant improvement was also found in the UPDRS score; however, no significant correlation was observed between the score change in these 3 batteries and UPDRS motor function. This is the first study to show the effectiveness of istradefylline for treatment of mood disorders in PD independent of improvement of parkinsonian motor symptoms. In the future, this should be confirmed in a double-blind placebo-controlled trial.

Daily step count and all-cause mortality in a sample of Japanese elderly people: a cohort study.

BACKGROUND: This study aimed to examine the relationship between pedometer-assessed daily step count and all-cause mortality in a sample of elderly Japanese people. METHODS: Participants included 419 (228 males and 191 females) physically independent, community-dwelling 71-year-old Japanese people. The number of steps per day was measured by a waist-mounted pedometer for seven consecutive days at baseline. Participants were divided into quartiles based on their average number of steps/day (first quartile, < 4503 steps/day; second quartile, 4503-6110 steps/day; third quartile, 6111-7971 steps/day; fourth quartile, > 7972 steps/day) and were followed up over a mean period of 9.8 years (1999-2010) for mortality. RESULTS: Seventy-six participants (18.1%) died during the follow-up period. The hazard ratios (adjusted for sex, body mass index, cigarette smoking, alcohol intake, and medication use) for mortality across the quartiles of daily step count (lowest to highest) were 1.00 (reference), 0.81 (95%CI, 0.43-1.54), 1.26 (95%CI, 0.70-2.26), and 0.46 (95%CI, 0.22-0.96) (P for trend = 0.149). Participants in the highest quartile had a significantly lower risk of death compared with participants in the lowest quartile. CONCLUSION: This study suggested that a high daily step count is associated with a lower risk of all-cause mortality in physically independent Japanese elderly people.

Pharmacokinetics of Levodopa before and after Gastrointestinal Resection in Parkinson's Disease.

INTRODUCTION: Levodopa (LD) is important in the clinical treatment of Parkinson's disease (PD), and the changes of its pharmacokinetics may affect the clinical outcome. LD is mainly absorbed in the upper intestine; thus, the pharmacokinetics of LD may change after gastrointestinal operation. Here, we present the case of a patient who underwent resection of the intestine and compared his LD pharmacokinetics before and after resection. CASE PRESENTATION: A 72-year-old Japanese male PD patient developed jaundice and was diagnosed with cholangiocarcinoma. Pancreaticoduodenectomy was performed and part of the stomach, total duodenum, and part of the jejunum were resected. The patient had been treated with LD, and his pharmacokinetics was checked twice at the age of 68 years. Because LD is absorbed in the duodenum and jejunum, we checked his pharmacokinetics again after the operation. The results before the operation were almost similar; however, in comparison, the area under the curve and peak drug concentration was reduced, and the time-to-peak drug concentration and elimination halftime were elongated after the operation. CONCLUSION: Physicians must pay attention to the change of LD pharmacokinetics after gastrointestinal operation.

Posterior reversible encephalopathy syndrome due to hypercalcemia associated with parathyroid hormone-related peptide: a case report and review of the literature.

We herein report the case of a 58-year-old man with advanced esophageal carcinoma who developed posterior reversible encephalopathy syndrome (PRES). He initially presented with a severe consciousness disturbance. A subsequent examination revealed hypercalcemia and an elevated serum parathyroid hormone-related peptide (PTHrP) level. Magnetic resonance imaging performed on admission and 24 days later showed reversible widespread white matter abnormalities, which confirmed a diagnosis of PRES. The patient's clinical and radiological manifestations improved upon normalization of the serum calcium level. To the best of our knowledge, this is the first report describing hypercalcemia-induced PRES occurring in association with elevated PTHrP.

A case of Creutzfeldt-Jacob disease with bilateral vocal fold abductor paralysis.

Bilateral vocal fold abductor paralysis was seen in a patient with Creutzfeldt-Jacob disease. After tracheotomy, the patient showed disappearance of reduced oxygen saturation with high-pitched inspiratory stridor and pulling phenomenon of the supraclavicular region and larynx. Electromyographic examinations of the intrinsic laryngeal muscles, including the thyroarytenoid and posterior cricoarytenoid muscles, demonstrated that there was no apparent action potential in those muscles during spontaneous respiratory movements, and there was no abnormal potential for those muscles at rest. By pushing the infrasternal region of the patient on the expiration, normal motor unit action potential could be seen in the posterior cricoarytenoid muscle on the next inspiration. Based on those findings, we concluded that bilateral vocal fold abductor paralysis in this case of Creutzfeldt-Jacob disease was not induced by disorders of the degeneration of motor nucleus in the ambiguus as in multiple system atrophy, but by a disorder of the upper motor neuron.