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).     

Chemotherapy-induced anemia in patients with primary lung cancer.

To elucidate the factors which influence the value of hemoglobin, the nadir value of hemoglobin, frequency of blood transfusion and prognostic value of blood transfusion in patients with primary lung cancer during intensive chemotherapy, the hematological features of 124 patients entered into a randomized phase III study containing cisplatin were retrospectively analyzed. There was no difference in the percent nadir hemoglobin value of the first course of chemotherapy (% of pretreatment value) in any of the subgroups with respect to sex, body weight loss, performance status, age, stage, number of metastatic sites or treatment arms. The only predictive indicator for the nadir hemoglobin value in the first course of chemotherapy was the pretreatment value of hemoglobin. The equation for the regression line was y = 1.07 + 0.73x (R2 = 0.663, p < 0.001). The lowest nadir hemoglobin value (% of pretreatment value) during all chemotherapy courses was significantly lower in the subgroups older than 60 years and those with body weight loss. There was an inverse correlation between the accumulated dose of cisplatin and the lowest nadir hemoglobin value (p < 0.05). The frequency of blood transfusion in patients with more than two metastatic sites was significantly higher than in those with one or no metastatic sites (p < 0.05). Survival of patients who had required blood transfusion after chemotherapy was significantly shorter than that of patients who had not (p < 0.05).     

Usefulness of body surface mapping to differentiate patients with Brugada syndrome from patients with asymptomatic Brugada syndrome

We attempted to determine the usefulness of body surface mapping (BSM) for differentiating patients with Brugada syndrome (BS) from patients with asymptomatic Brugada syndrome (ABS). Electrocardiograms (ECG) and BSM were recorded in 7 patients with BS and 35 patients with ABS. Following the administration of Ic antiarrhythmic drugs, BSM was recorded in 5 patients with BS and 16 patients with ABS. The maximum amplitudes at J0, J20, J40 and J60 were compared between the 2 groups, as were 3-dimensional maps. The maximum amplitudes at J0, J20 and J60 under control conditions were larger in patients with BS than in patients with ABS (P < 0.05). A three-dimensional map of the ST segments under control conditions in patients with BS showed a higher peak of ST elevation in the median precordium compared to that for patients with ABS. Increases in ST elevation at J20, J40 and J60 following drug administration were greater in patients with BS than in patients with ABS (P < 0.05). Evaluation of the change in amplitude of the ST segment at E5 caused by Ic drug administration was also useful for differentiating between the 2 groups. In conclusion, BSM was useful for differentiating patients with BS from those with ABS.     

Y-29794--a non-peptide prolyl endopeptidase inhibitor that can penetrate into the brain.

A novel non-peptide prolyl endopeptidase (PPCE) inhibitor, Y-29794, has been identified. Y-29794 selectively and competitively inhibited rat brain PPCE (Ki = 0.95 nM) in a reversible manner. Ex vivo study demonstrated that Y-29794 could penetrate into brain to exhibit dose-dependent and long-lasting inhibition. Furthermore, Y-29794 was found to potentiate the effect of TRH on the release of ACh in the rat hippocampus. These results indicate that Y-29794 is an orally active, potent and specific PPCE inhibitor and should be of value in studies on the physiological role of the enzyme in neuropeptide metabolism especially in memory process.     

Grading score system: A method for evaluation of the degree of senescence in Senescence Accelerated Mouse (SAM)

For evaluation of the degree of senescence in SAM-P, accelerated senescence prone mouse, formerly called SAM or prone series or P-series, consisting of SAM-P/1, SAM-P/2, SAM-P/3 and SAM-P/4 corresponding to P-1, P-2, P-3 and P-4 series, respectively, in the previous reports, and in SAM-R, accelerated senescence resistant mouse, formerly called resistant series or R-series, consisting of SAM-R/1, SAM-R/2 and SAM-R/3 corresponding to R-1, R-2 and R-3 series, respectively, in the previous reports, the grading score system was adopted. The items to be examined in this system include 11 categories selected from the clinical signs and gross lesions considered to be associated with the aging process. The degree of the senescence in each category was graded from 0 to 4 according to the detailed criteria devised in our laboratory. After 8 months of age each mouse was examined every 4 months, and some of the mice were examined after 2 months of age.In almost all categories, the grading score and incidence began to increase from 4 or 6 months of age and continued to increase with advancing age in both SAM-P and SAM-R. The increase, however, was more marked in SAM-P than in SAM-R. The slow but steady increase in the SAM-R levelled out at 24 months of age and was comparable to that of 12 months of age in SAM-P. In both SAM-P/1 at 8 months of age and SAM-R/2 at 12 months of age, there was a significant reverse correlation between total score of this grading score system and length of residual life after examination.Systematic and extensive studies using the grading score system showed that if the validity of the system is, based on “irreversibility” and “universality” of the changes in     

Factors that influence the eligibility of cases for inclusion in clinical trials. The Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group

BACKGROUND: It is important to minimize the incidence of ineligible cases to improve the quality of clinical trials. To determine factors which may influence the incidence of ineligible cases, the incidence of and reasons for ineligibility in clinical trials were retrospectively analyzed. METHODS: We retrospectively examined the incidence of and reasons for ineligibility for inclusion in eight clinical trials conducted by the Lung Cancer Chemotherapy Study Group of the Japan Clinical Oncology Group and four trials financed by trust funds from a pharmaceutical company. RESULTS: In these 12 clinical studies, the incidence of ineligibility was 4.2% (32/762) (range 0-10.6%). Specific factors that might influence the incidence of ineligible cases were then analyzed. There was a significant difference in the incidence of ineligibility between the methods of registration (P < 0.05). The incidences using a central registration and without using a central registration system were 2.8% (9/322) and 5.2% (23/440) respectively. We also analyzed ineligible cases in clinical studies published in the Journal of Clinical Oncology. In clinical studies published in the Journal of Clinical Oncology recently and 10 years ago, the incidences of ineligible cases were 5.0% (942/18 878) and 4.1% (206/4995) respectively. In clinical studies on lung cancer published in the Journal of Clinical Oncology from 1984 to 1995, the incidence of ineligible cases was 4.7% (900/19,116). There was no significant difference in the incidence of ineligible cases between our 12 studies and the Journal of Clinical Oncology clinical studies by the chi 2 test (P > 0.05). CONCLUSIONS: We conclude that the incidence of ineligible cases in our studies is similar to that in clinical trials published in the Journal of Clinical Oncology. Central registration systems are useful for checking for ineligibility, and to increase the quality of clinical trials.      

Reduction of oocyte lipid droplets and meiotic failure due to biotin deficiency was not rescued by restoring the biotin nutritional status

BACKGROUND/OBJECTIVESOocyte lipid droplets play a crucial role in meiosis and embryo development. Biotin is associated with fatty acid synthesis and is the coenzyme for acetyl-CoA carboxylase (ACC). The effects of a biotin deficiency on the oocyte lipid metabolism remain unknown. This study examined the effects of a biotin deficiency and its replenishment on murine 1) oocyte lipid droplet levels, 2) ovary lipid metabolism, and 3) oocyte meiosis.MATERIALS/METHODSMice were divided into 3 groups: control, biotin deficient (BD), and recovery groups. The control and BD groups were fed a control diet or BD diet (0.004 or 0 g biotin/kg), respectively. The recovery group mice were fed a BD diet until day 21, and were then fed the control diet from days 22 to 64. This study then quantified the oocyte lipid droplet levels, assessed the oocyte mitochondrial function, and examined the ability of oocytes to undergo meiosis. Ovarian phosphorylated ACC (p-ACC), lipogenesis, β-oxidation, and ATP production-related genes were evaluated.RESULTSThe BD group showed a decrease in lipid droplets and mitochondrial membrane potential and increased p-ACC levels. In the recovery group, the hepatic biotin concentration, ovarian p-ACC levels, and mitochondrial membrane potential were restored to the control group levels. On the other hand, the quantity of lipid droplets in the recovery group was not restored to the control levels. Furthermore, the percentage of oocytes with meiotic abnormalities was higher in the recovery group than in the control group.CONCLUSIONSA biotin deficiency reduced the oocyte lipid droplet levels by downregulating lipogenesis. The decreased lipid droplets and increased oocyte meiosis failure were not fully restored, even though the biotin nutrition status and gene expression of lipid metabolism was resumed. These results suggest that a biotin deficiency remains robust and can be long-lasting. Biotin might play a crucial role in maintaining the oocyte quality.