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).     

Stereoselectivity of a potent calcium antagonist, 1-benzyl-3-pyrrolidinyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Four enantiomers (3a-d) of the title compound, YM-09730 (3), were synthesized by the reaction of (-)- or (+)-5-(methoxycarbonyl)-2, 6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid (1a or 1b) with (S)- or (R)-1-benzyl-3-pyrrolidinol (2a or 2b). [3H]Nitrendipine binding affinity and coronary vasodilating activity of these compounds were evaluated. The absolute configuration of the most potent enantiomer (3a) with the longest duration was unequivocally determined to be (S)-1,4-dihydropyridine-C4 and (S)-pyrrolidine-C3 (S,S) by X-ray crystallographic study on 3a X HBr as well as 3a X HCl. The configuration of 1a corresponds to R, and the other enantiomers of 3 were respectively determined by chemical correlation. The potency order of the four enantiomers was (S,S)-3a greater than (S,R)-3b greater than (R,R)-3d greater than (R,S)-3c. Latent chiral characters of nifedipine derivatives with the identical ester groups were assigned by comparison of their puckering modes of 1,4-dihydropyridine (DHP) rings with those found in 3a X HCl or 3a X HBr. On the basis of the assignment, it has been revealed that the (S)-DHP nifedipine derivatives possess the synperiplanar carbonyl group at C5. The conformational restriction may be a factor causing stereoselectivity of antagonism.     

A pilot study of the assessment of the quality of life, functional results, and complications in patients with an ileal neobladder for invasive bladder cancer

OBJECTIVE: To assess the functional results, health-related quality of life (QOL) outcomes, and complications in patients with an ileal neobladder in comparison to those with cutaneous diversion (ileal conduit and cutaneostomy). METHODS: Between September 1992 and February 2003, we consecutively performed an ileal neobladder (the Studer method) in 30 patients and cutaneous diversion in 38 patients. In August 2004, questionnaires were mailed to 54 patients. The questionnaire included the validated health-related quality of life (QOL) questionnaire, SF-36 General Health Survey, and a urinary incontinence questionnaire. We also evaluated the functional results in patients with an ileal neobladder and the postoperative complications in patients with both urinary diversions. RESULTS: The data from 41 patients (21 ileal neobladder procedures and 20 cutaneous diversions) were available for the analysis. No differences in the overall QOL were observed between the two groups. Complete daytime and night-time urinary continence was achieved in the 21 patients (100%) and 13 patients (61.9%), respectively. The mean value of the maximum flow rate was 15 +/- 12 mL/min in the 21 neobladder patients. There were 19 early complications in 18 patients (60.0%) and seven late complications in six patients (20.0%) with an ileal neobladder. However, there were 15 early complications in 14 patients (36.8%) and eight late complications in six patients (15.8%) with cutaneous diversions. CONCLUSION: The findings regarding the health-related QOL and the frequency of complications in the neobladder group and those in the cutaneous diversion group were similar. However, the functional results and the status of urinary continence in the neobladder patients were satisfactory.     

Destination after discharge from a senile dementia therapy ward before and after the implementation of long-term care insurance in Japan

Background: In Japan a new long‐term care insurance (LTCI) system, the so‐called ‘Kaigo‐Hoken’, was started in April 2000. The present study analyzes the change in the type of destination after discharge from a senile dementia therapy ward before and after the implementation of LTCI at Fukuoka Prefectural Onga Hospital, Japan. Methods: The present study examines data from 199 inpatients discharged from the Fukuoka Prefectural Onga Hospital that had been diagnosed with dementia and met the DSM IV criteria for Alzheimer's type, vascular dementia or other type of dementia. For the purposes of comparison two periods were defined, ‘the first period’ was defined as the period from 1 April 1999 to 31 March 2000, before LTCI was implemented, while ‘the second period’ was defined as the period from 1 April 2000 to 31 March 2001, after LTCI had started. Subject data was analyzed on the basis of where the subject had resided pre‐admission and their destination after discharge using the following classifications: nursing home or geriatric care facility, hospitalization, home and death. Results: While the certification rate of inpatients regarding long‐term care increased slightly in the second period, no significant change was observed based on where the subject had resided pre‐admission and their destination after discharge between the first and second periods. Conclusions: While LTCI is essential for Japan, it is necessary that people with dementia in senile dementia therapy wards are encouraged to return to their homes under the care and support of LTCI.     

Solitary right ventricle metastasis by renal cell carcinoma.

A 57-year-old man with a history of renal cell carcinoma presented with presyncope. He underwent nephrectomy years earlier followed by HLA-matched allogeneic peripheral-blood stem-cell transplantation. Echocardiographic investigation revealed a solitary right ventricle mass without contiguous vena caval or right atrial involvement. The mass was pathologically confirmed to be metastatic carcinoma in the right ventricular cavity. This case highlights the need to consider an underlying neoplastic syndrome in patients presenting isolated right ventricle mass by echocardiography.     

A CASE OF METASTATIC YOLK SAC TUMOR OF TESTIS IN A CHILD

We report a case of testicular yolk sac tumor in a child aged 3 years and 6 months with multiple bulky metastases to lung and retroperitoneum (stage 11182). After three courses of chemotherapy with a PV 8 regimen (cisplatin, vinblastine and bleomycin). complete and partial responses were obtained for lung and retroperitoneal lymph node metastases, respectively. The patient was followed-up closely. However, on the basis of a re-elevated alpha-letoprotein (AFP) after 4 months' follow-up, he was treated with three courses of salvage chemotherapy with a modified VAB-6 regimen (cyclophosphamide. etoposide. actinomycin D, bleomycin and cisplatin), lollowed by retroperitoneal lymph node dissection. Histologically, only necrotic tissue was found. There is no evidence of recurrence 24 months after lymphadenectomy. There is very little information in the literature on the appropriate management of postchemotherapy residual mass in pediatric testicular tumors.     

Surgical treatment for ischemic mitral regurgitation: strategy for a tethered valve.

Recently, ischemic mitral regurgitation (IMR) has been shown to be an individual risk factor for ischemic heart disease. The main mechanism of IMR is tethering of the leaflet secondary to left ventricular (LV) dilatation. In this situation, surgical treatment for IMR has been limited to ring annuloplasty with varying degrees of effectiveness. However, mid-term follow-up studies have shown that the results obtained with this approach are not satisfactory. Therefore, there has been a need to develop additional techniques to achieve more secure repair of IMR. The characteristics of the mitral leaflet configuration in IMR are apical displacement of the leaflets relative to the annulus, concavity of the leaflets, and a dilated annulus. Our basic strategy for a tethered mitral valve is rigid ring annuloplasty and inward correction of the outwardly displaced papillary muscle. For the latter correction, we employ the overlapping method or septal anterior ventricular exclusion (SAVE) procedure for LV volume reduction in cases of broad antero-septal infarction, or elevate the posterior papillary muscle by folding the LV wall at the root of the posterior papillary muscle via a small incision in the inferior wall in cases of infero-posterior infarction. An additional procedure is chordal cutting in combination with rigid ring annuloplasty and papillary muscle imbrication in combination with LV volume reduction. We have successfully combined these methods with the aid of detailed echocardiographic studies in individual patients. However, long-term follow-up will be necessary before this approach can be routinely adopted.     

Human serum albumin incorporating synthetic heme: red blood cell substitute without hypertension by nitric oxide scavenging

The administration of extracellular, hemoglobin-based oxygen carriers often elicits an acute increase in blood pressure by vasoconstriction. This side effect is now recognized to be due to the depletion of nitric oxide (endothelial-derived relaxing factor) by the extravasuated hemoglobins. We have recently found that the administration of a recombinant human serum albumin (rHSA)-based oxygen carrier involving synthetic tetraphenyporphinatoiron(II) derivative (FeP) (rHSA-FeP) does not induce such hypertensive action, because of its low permeability through the vascular endothelium. The heart rate responses after the rHSA-FeP injection were also negligibly small. Visualization of the intestinal microcirculatory changes clearly revealed the widths of the venule and arteriole to be fairly constant. The entirely synthetic rHSA-FeP becomes a promising material as a new type of red blood cell substitute.     

Compatibility in vitro of albumin-heme (O(2) carrier) with blood cell components

Recombinant human serum albumin including 2-[8-[N-(2-methylimidazolyl)]octanoyloxymethyl]-5,10,15,20-tetrakis(alpha,alpha,alpha,alpha-o-pivaloylamino)phenylporphinatoiron(II) (albumin-heme; rHSA-FeP) is a synthetic hemoprotein that has sufficient capability to reversibly bind and release O(2) under physiological conditions (pH 7.3, 37 degrees C) similar to hemoglobin and myoglobin. In order to use this albumin-based O(2) carrier as a new class of red blood cell substitutes, its compatibility with blood cell components carefully was investigated in vitro. After the addition of the rHSA-FeP solution into whole blood at 10, 20, and 44 vol %, the FeP concentration in the plasma phase remained constant for 6 h at 37 degrees C in each group, and no significant time dependence was observed in the numbers of red blood cells, white blood cells, or platelets. The microscopic observations clearly showed that the shapes of the red blood cells had not been deformed during the measurement period. With respect to the blood coagulation parameters (prothrombin time and activated partial thromboplastin time), the coexistence of rHSA-FeP had only a negligibly small influence. Also the blood compatibility under dynamic flow conditions was evaluated using a microchannel array flow analyzer. All these results suggest that the albumin-heme has no effect on the morphology of blood cell components in vitro.     

Functional linkage of the cardiac ATP-sensitive K+ channel to the actin cytoskeleton

The role of the cytoskeleton in the rundown and reactivation of adenosine triphosphate (ATP) sensitive K⁺ channels (KATP channels) was examined by perturbing selectively the intracellular surface of inside-out membrane patches excised from guinea-pig ventricular myocytes. Actin filament-depolymerizing agents (cytochalasins and desoxyribonuclease I) accelerated channel rundown, while actin filament stabilizer (phalloidin) or phosphatidylinositol biphosphate (PIP₂; inhibitor of F-actin-severing proteins) inhibited spontaneous and/or Ca²⁺-induced rundown. When rundown was induced by cytochalasin D or by long exposure to high Ca²⁺, channel activity could not be restored by exposure to MgATP, but application of F-actin with MgATP could reinstitute channel activity. The processes of rundown and reactivation of cardiac K_ATP channels may thus be influenced by the assembly and disassembly of the actin cytoskeletal network, which provides a novel regulatory mechanism of this channel.