Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson’s disease: A single-arm,open-label,prospective, multicenter study

Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A_2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A_2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.

Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.

Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.

Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.

Trial registration: UMIN-CTR (UMIN000020288).     

Long-term skeletal stability in the treatment of mandibular prognathism with a physiological positioning strategy

Our aim was to evaluate the long-term skeletal stability of the mandible in 21 patients after orthognathic surgery with physiological positioning. The measurement points SNB, B point (X, Y), Pog (X, Y), and the angle of the ramus were measured on cephalometric photographs to assess skeletal stability preoperatively, immediately after operation, and one and two years postoperatively. In addition, we evaluated the clinical symptoms of disorders of the temporomandibular joint (TMJ). The analysis of the cephalometric photographs showed that SNB, B point X, and Pog X showed no significant differences among the postoperative time points. On the other hand, B point Y and Pog Y showed no significant differences throughout the study period. We compared the angle of the ramus before operation and two years postoperatively, and no significant difference was found. In addition, no cases showed any pathological symptoms of disorders of the TMJ two years postoperatively. The long-term stability after orthognathic surgery with physiological positioning was confirmed, and it seems to be a reliable orthognathic treatment in patients with mandibular prognathism.     

Confirmation of Age-dependence in the Leakage of Contrast Medium around the Cortical Veins into Cerebrospinal Fluid after Intravenous Administration of Gadolinium-based Contrast Agent

Purpose:It has been reported previously that intravenously administered gadolinium-based contrast agent (GBCA) leaks into the subarachnoid space around the cortical veins at 4 h after injection in all old people over 37 years, but not in younger people up to 37 years of age in 3D-real IR images. The purpose of this study was to investigate whether there was a strict threshold of 37 years of age for the leakage of the GBCA into the subarachnoid space.Methods:The subjects included 190 patients, that were scanned for 3D-real IR images at 4 hours after intravenous injection of GBCA as a diagnostic test for endolymphatic hydrops. The patient’s age ranged from 14 to 81 years. Two experienced neuroradiologists evaluated the images to determine whether the GBCA leakage around the cortical veins was positive or negative. Any discrepancies between the two observers were discussed and a consensus was obtained.A Mann–Whitney U test and receiver operating characteristic (ROC) curve analysis were used to compare the positive and the negative group and to set the age cut-off value for the prediction of GBCA leakage.Results:The GBCA leakage around the cortical veins was negative in 35 patients and positive in 155 patients. The average age was 33 ± 11 years in the negative group, and 55 ± 12 years in the positive group (P < 0.01). In the ROC analysis for the age and leakage of the GBCA, an area under the curve was 0.905 and the cut-off age was 37.317 years (sensitivity of 0.942 and specificity of 0.771).Conclusion:Intravenously administered GBCA leaks into the subarachnoid space around the cortical veins in most patients over 37 years of age. However, it should be noted that it can be found occasionally in patients under 37 years of age.     

N-terminal pro-brain natriuretic peptide predicts hospitalization for ischemic stroke in Japanese hemodialysis patients

Clinical and Experimental Nephrology - The association between N-terminal pro-brain natriuretic peptide (NT-proBNP) and stroke in Japanese hemodialysis (HD) outpatients is unclear. Therefore, in...     

Olmesartan is an angiotensin II receptor blocker with an inhibitory effect on angiotensin-converting enzyme.

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.