CO carbonylation and first evaluation as a P-gp tracer in rats

BACKGROUND: At present, several positron emission tomography (PET) tracers are in use for imaging P-glycoprotein (P-gp) function in man. At baseline, substrate tracers such as R-[(11)C]verapamil display low brain concentrations with a distribution volume of around 1. [(11)C]phenytoin is supposed to be a weaker P-gp substrate, which may lead to higher brain concentrations at baseline. This could facilitate assessment of P-gp function when P-gp is upregulated. The purpose of this study was to synthesize [(11)C]phenytoin and to characterize its properties as a P-gp tracer. METHODS: [(11)C]CO was used to synthesize [(11)C]phenytoin by rhodium-mediated carbonylation. Metabolism and, using PET, brain pharmacokinetics of [(11)C]phenytoin were studied in rats. Effects of P-gp function on [(11)C]phenytoin uptake were assessed using predosing with tariquidar. RESULTS: [(11)C]phenytoin was synthesized via [(11)C]CO in an overall decay-corrected yield of 22 ± 4%. At 45 min after administration, 19% and 83% of radioactivity represented intact [(11)C]phenytoin in the plasma and brain, respectively. Compared with baseline, tariquidar predosing resulted in a 45% increase in the cerebral distribution volume of [(11)C]phenytoin. CONCLUSIONS: Using [(11)C]CO, the radiosynthesis of [(11)C]phenytoin could be improved. [(11)C]phenytoin appeared to be a rather weak P-gp substrate

Forearm Rotation Range of Motion and Its Velocity in Eating With Chopsticks : a Comparison Among Positions of Dish

The purpose of this study was to determine range of motion of forearm rotation and its velocity in eating. Six young students (age:20.5±0.5 years [range:20-21], 2 men and 4 women) participated in this study. To measure three-dimensional motions, we used an electromagnetic tracking device system. The first sensor was attached to the dorsal/distal of forearm with sprint, and the second sensor was attached to the dorsal/medial ulna with elastic belt. The subjects ate pickles with chopsticks. At a wooden desk with 70cm height they sat on a height-adjustable chair, so their olecranon was as high as the desk top. Three positions of a dish were measured; A: at the distance of length of distal to elbow, B: at the distance of length of the upper extremity, and C: at a middle position between A and B. The results revealed that forearm rotation, range of motion and its velocity were significantly different among three conditions (one-way repeated-measure ANOVA)(p<0.05). Characteristically the motion velocity of B was lower than C, and A was lower than C (p<0.05). Findings suggest that 1) limited forearm range of motion would decrease a burden of forearm by setting a dish at B or C than A, 2) the rotation (maximal pronation and supination: 11 and 49 degrees, respectively) was similar, to a fork (maximal pronation and supination: 10 and 51 degrees, respectively), 3) C may be efficiently operated, and 4) the system may be instructed as a good equipment for eating

De muis; niet voor één gat te vangen?

Het oppakken van laboratoriummuizen heeft een effect op hun stress- en angstgerelateerde reacties. Ook de manier waarop het dier wordt opgepakt kan grote effecten hebben op het gedrag. In (gedrags-)onderzoek is het daarom van groot belang dat de handelingen met de dieren gestandaardiseerd zijn, zodat ieder dier dezelfde handeling ondergaat en dat de dieren gewend zijn aan de ingreep. Er bestaan talloze gedragsopstellingen om allerlei soorten gedragingen bij proefdieren te kunnen meten. Zelfs wanneer we ons beperken tot de muis, zijn er legio gedragstesten beschikbaar (1). Toch hebben de meeste gedragsopstellingen één ding gemeen; de muis moet bij aanvang van de test in de opstelling geplaatst worden, om er na afloop weer uitgehaald te worden (met enige uitzonderingen daargelaten; bijvoorbeeld bij een gedragsopstelling waarbij het de taak van het dier is om zijn thuiskooi te vinden of wanneer er metingen worden verricht in de thuis-kooi). Zowel het dier in de opstelling zetten als het uithalen kan een stress reactie opleveren, evengoed bij dier als mens. Bij één gedragsopstelling geldt dit in het bijzonder, namelijk het dier uit de zogenaamde Elevated Plus Maze halen. Deze opstelling bestaat uit twee open en twee gesloten armen en bevindt zich op een verhoogd platform. Muizen zijn over het algemeen niet voor één gat te vangen, en zullen vrijwel altijd proberen te ontkomen aan de hand van de onderzoeker. Voornamelijk in de nauwe omgeving van de gesloten armen. Echter, er bestaat een relatief simpele, stress verminderende manier om het dier uit de opstelling te halen: door een buis als thuiskooiverrijking te gebruiken. Deze buis kan na de test bij de opstelling gehouden worden zodat het dier op de geur afkomt en in de buis loopt waarna de buis met het dier erin naar de thuiskooi vervoerd kan worden. Deze hanteermethode zorgt voor een minder stressvolle handeling bij het dier

Motivational and control mechanisms underlying adolescent versus adult alcohol use

Increased motivation towards alcohol use and suboptimal behavioral control are suggested to predispose adolescents to alcohol use disorders (AUDs). Paradoxically however, most adolescent AUDs resolve over time without any formal intervention, suggesting adolescent resilience to AUDs. Importantly, studies directly comparing adolescent and adult alcohol use are largely missing. We therefore aimed to unravel the moderating role of age in the relation between alcohol use and motivational and control-related cognitive processes in 45 adolescent drinkers compared to 45 adults. We found that enhancement drinking motives and impulsivity related positively to alcohol use. Although enhancement drinking motives and impulsivity were higher in adolescents, the strength of the relation between these measures and alcohol use did not differ between age groups. None of the alcohol use-related motivational measures (i.e., craving, attentional bias, and approach bias) and behavioral control measures (i.e., interference control, risky decision making, and working-memory) were associated with alcohol use or differed between age groups. These findings support the role of impulsivity and affective sensitivity in adolescent drinking but question the moderating role of age therein. The current study contributes towards understanding the role of age in the relation between alcohol use and cognition

The STELLAR trial:a phase II/III randomized trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma

Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4–1.7) compared to 1.5 months (95% CI 1.4–1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2–1.6) versus 1.6 months (95% CI 1.3–1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.</p