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.

Inhalation of hydrogen gas elevates urinary 8-hydroxy-2'-deoxyguanine in Parkinson's disease.

Hyposmia is one of the earliest and the most common symptoms in Parkinson's disease (PD). The benefits of hydrogen water on motor deficits have been reported in animal PD models and PD patients, but the effects of hydrogen gas on PD patients have not been studied. We evaluated the effect of inhalation of hydrogen gas on olfactory function, non-motor symptoms, activities of daily living, and urinary 8-hydroxy-2'-deoxyguanine (8-OHdG) levels by a randomized, double-blinded, placebo-controlled, crossover trial with an 8-week washout period in 20 patients with PD. Patients inhaled either ~1.2-1.4% hydrogen-air mixture or placebo for 10 minutes twice a day for 4 weeks. Inhalation of low dose hydrogen did not significantly influence the PD clinical parameters, but it did increase urinary 8-OHdG levels by 16%. This increase in 8-OHdG is markedly less than the over 300% increase in diabetes, and is more comparable to the increase after a bout of strenuous exercise. Although increased reactive oxygen species is often associated with toxicity and disease, they also play essential roles in mediating cytoprotective cellular adaptations in a process known as hormesis. Increases of oxidative stress by hydrogen have been previously reported, along with its ability to activate the Nrf2, NF-κB pathways, and heat shock responses. Although we did not observe any beneficial effect of hydrogen in our short trial, we propose that the increased 8-OHdG and other reported stress responses from hydrogen may indicate that its beneficial effects are partly or largely mediated by hormetic mechanisms. The study was approved by the ethics review committee of Nagoya University Graduate School of Medicine (approval number 2015-0295). The clinical trial was registered at the University Hospital Medical Information Network (identifier UMIN000019082).

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

Clinical application of a card-type odor identification test to olfactory assessment in Parkinson's disease.

OBJECTIVES: Current studies have provided valuable evidence that Parkinson's disease (PD) is closely associated with olfactory loss and that the use of olfactory testing is regarded as one of the potential screening tools for early diagnosis of PD. METHODS: Twenty-six patients with PD, age- and sex-matched 14 patients with other neurological diseases and 10 healthy controls were evaluated the sense of smell by the Open Essence (OE). RESULTS: The motor performance of the patients with PD was assessed using the Hoehn and Yahr scale. The OE scores for patients with PD were significantly lower than those with both the patients with other neurological diseases and controls. There was no significant difference of the OE scores between patients with other neurological diseases and controls. In the PD group, the OE score was not correlated with gender, smoking habit, disease duration, age at examination, or cognitive status. However, the OE scores were significantly correlated with Hoehn and Yahr stages. CONCLUSION: OE was found to be practically self-administered, time-saving, reliable, and inexpensive method for correct diagnosis of olfactory dysfunction associated with PD.

[Prevalence of neurological complications in Japanese patients with AIDS after the introduction of HAART].

We investigated trends in neurological complications of infection with human immunodeficiency virus (HIV) in Japan after the introduction of highly active antiretroviral therapy (HAART). Two questionnaire surveys were performed in hospitals treating acquired immunodeficiency syndrome (AIDS) to compare two periods: immediately after the introduction of HAART (1999-2001); and a few years later (2002-3). Neurological complications accompanied 15.9% in 1999-2001 and 9.8% in 2002-3. Neurological complications developed without HAART in about 80% of cases. Neurological complications developed as the first AIDS-defining disease for 8.3% of AIDS patients in 1999-2001 and for 5.4% in 2002-3. Prevalences of HIV encephalopathy and myelopathy decreased markedly over the study period, as reported in other developed nations. However, prevalences of cytomegalovirus encephalitis, PML and primary brain lymphoma did not decrease. PML and primary brain lymphoma occurred in patients who received HAART and whose CD4 counts were relatively high during the study period. This is probably related to the extended survival of HIV-infected individuals after the introduction of HAART as a worldwide therapy, and the reactivation of viremia or latent infection persisting within the central nervous system.

[Clinical investigation of the 8 cases with AIDS (acquired immunodeficiency syndrome)-associated progressive multifocal leukoencephalopathy (PML)].

We experienced 8 cases of progressive multifocal leukoencephalopathy (PML) complicated by human immunodeficiency virus (HIV) type-1 infection from 1985 to 1999. These cases showed dementia, bradykinesia, dysarthria, hemiparesis, and so on. All of the cases were severely immunocompromised hosts, because none had more than 150/mm3 CD4 + lymphocytes; indeed, 5 of the cases were below 20/mm3. Other neurological complications except PML were primary CNS lymphoma, HIV encephalitis, and CMV encephalitis. The mean life durations was 7.6 months after the first symptom appeared, for all but one of the patients; the exceptional patient lived for 24 months after. Autopsy studies of the central nervous systems were performed for 7 cases, all of which showed extensive demyelinating lesions of the white matter, and in some cases these extended into the spinal cord. In contrast to Western countries, in Japan there have been few reports of AIDS-associated PML. Thus, this report was thought to be important here.

[A case of Crow-Fukase syndrome showing improvement following excision and irradiation of bone lesions].

A 57-year-old woman suffering from pleural and pericardial effusion, pulmonary hypertention, lymphadenopathy, hepatosplenomegaly, edema, hypertrichosis, small hemangioma and polyneuropathy was diagnosed as Crow-Fukase syndrome. Osteoctomy of the left second rib and irradiation of this rib and the left iliac bone were performed. Serum vascular endothelial growth factor (VEGF) level decreased to less than one-half the level before the operation (from 5,180 to 2,150 pg/ml). Immediately after the operation, pleural and pericardial effusions due to hyperpenetration improved, and polyneuropathy and hypertrichosis due to hypervasularity also gradually improved. The resected lesion was histopathologically found to be of a plasmacytoma of the IgG lambda type. Since the level of VEGF in the tissue specimen was much lower (116 pg/ml) than that in the serum, VEGF could not have been produced by the plasmacytoma.

[Immunosuppressive-associated encephalopathy in bone marrow transplant recipients].

We studied clinical features of immunosuppressive (cyclosporine, tacrolimus) associated encephalopathy in bone marrow transplant patients. 378 cases of allogeneic bone marrow transplant recipients over fifteen years old of chronic and acute leukemia (CML, ANLL, ALL) (n = 311), myelodysplastic syndrome (MDS) (n = 42) and severe aplastic anemia (SAA) (n = 25) were investigated. Immunosuppressive associated encephalopathy occurred in 12 cases. The rate of incidence was significantly higher in SAA and MDS (7 cases) than in leukemia. The cases which showed typical radiological abnormality in MRI were limited in SAA and hypoplastic MDS. 10 cases died, which revealed worse than an overall survival rate of recipients without immunosupressive-associated encephalopathy. 5 of 7 cases in SAA and MDS had taken cyclosporine as treatment of the disease before bone marrow transplantation and that might influence the incidence of encephalopathy.

[A clinical study of pachymeningitis].

We report five patients with cranial and spinal pachymeningitis not associated infections or tumors. The underlying causes of pachymeningitis in four patients were Sjögren syndrome, Wegener's granulomatosis, microscopic polyangitis, and dermatomyositis, respectively. In one patient, the cause was unknown. Cerebrospinal fluid analysis showed an increase in cells in only one patient and elevated protein levels in three patients. Blood test revealed an inflammatory disease except in one patient. The anti-nuclear antibody was present in four of five patients examined, and P-ANCA was present in two out of four patients. The prognosis was good except in one patient of Wegener's granulomatosis. We reviewed 48 previously reported cases of pachymeningitis were not associated infections or tumors. The lesions of pachymeningitis were more localized in the cranial dura than the spinal dura, and many cases had immunological abnormalities.