Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4

Risperidone is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses. Formation of 9-hydroxyrisperidone, an active metabolite, is the most important metabolic pathway of risperidone in human. In the present study, in vitro metabolism of risperidone (100 μM) was investigated using the recombinant human cytochrome P450 (CYP) enzymes CYP1A1, CYP1A2, CYP2C8, CYP2C9-arg₁₄₄, CYP2C9-cys₁₄₄, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 supplemented with an NADPH-generating system. 9-Hydroxyrisperidone was determined by a new HPLC method with an Hypersil CN column and a UV detector. Of these enzymes, CYPs 2D6, 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9-hydroxyrisperidone, with activities of 7.5, 0.4 and 0.2 pmol pmol^–1 CYP min^–1, respectively. A correlation study using a panel of human liver microsomes showed that the formation of 9-hydroxyrisperidone is highly correlated with CYP2D6 and 3A activities. Thus, both CYP2D6 and 3A4 are involved in the 9-hydroxylation of risperidone at the concentration of risperidone used in this study. This observation is confirmed by the findings that both quinidine (inhibitor of CYP2D6) and ketoconazole (inhibitor of CYP3A4) can inhibit the formation of 9-hydroxyrisperidone. Furthermore, inducers of CYP can significantly increase the formation of 9-hydroxyrisperidone in rat. The formation of 9-hydroxyrisperidone is highly correlated with testosterone 6β-hydroxylase activities, suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat. Received: 4 May 1998 / Accepted: 26 October 1998     

Testing the reliability of a new measure of life events and experiences in childhood: The Psychosocial Assessment of Childhood Experiences (PACE)

There are few well validated instruments for measuring the impact of life events and experiences in childhood and adolescence. This study examines the reliability of a new instrument, the Psychosocial Assessment of Childhood Experiences of PACE. Fifteen children and parents were interviewed on two cassions ten days apart for the main test-retest reliability study. About half of the events recorded were reported on both occasions (0.45% and 0.55% concordance). When the impact of specific events was examined much higher levels of agreement were found. Inter-rater reliability tests also yielded higher rate (Kappa 0.74 and above). Possible reasons for these important differences are discussed and the inherent methodological difficulties considered.

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Zusammenfassung Es existieren nur wenige gut validierte Meßinstrumente zur Erfassung von Lebensereignissen und Erfahrungen im Kindes- und Jugendalter. Diese Studie untersucht die Reliabilität eines neuen Verfahrens, des Psychosocial Assessment of Childhood Experiences oder PACE. 15 Kinder und Elternteile wurden zweimal im Abstand von 10 Tagen für die Überprüfung der Haupttest-Retest-Reliabilität interviewt. Ca. die Hälfte aller Ereignisse, die beim Interview berichtet wurden, wurdem beim Zweitinterview ebenfalls angegeben (Konkordanzen 0,45 und 0.55). Deutlich höhere Übereinstimmungen fanden sich bei Untersuchung der Auswirkungen spezifischer Ereignisse. Die Inter-Rater-Reliabilitätstests ergaben ebenfalls höhere Werte (Kappa 0.74). Mögliche Ursachen dieser wichtigen Unterschiede werden unter Berücksichtigung der inhärenten methodischen Schwierigkeiten diskutiert.

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Résumé II y a peu d'instruments correctement validés de mesures de l'impact des événements de vie des expériences dans l'enfance et l'adolescence. Cette étude examine la fiabilité d'un nouvel instrument, l'évaluation psycho-sociale des expériences infantiles (Psychosocial Assessment of Childhood Experiences ou PACE). 15 enfants et parents furent interrogés à deux reprises à 10 jours d'intervalle pour evaluer la fiabilité test-retest. Environ la moitié des événements rapportés le furent dans les deux occasions (0.45% et 0.55% de concordance). Quand l'impact des événements déviés spécifiques fut étudié un niveau plus élevé de concordance fut trouvé. La fidélité inter-cotateurs des tests obtinet également des taux plus élevés (kappa 0.74 et audessus). Les raisons possibles de ces différences sont discutées et les difficultés méthodologiques inhérentes prises en compte.

     

Behavioral and Neurological Characteristics of a Hydranencephalic Infant

A modified Prechtl neurological examination and the Brazelton Neonatal Assessment Scale were serially administered to a hydranencephalic infant over the first eight weeks of life. Clinical, roentgenographic, neurological and behavioral findings are reported. In contrast to earlier reports, visual tracking of a moving field and auditory and visual habituation were observed. Further, in addition to previously reported reflex automatisms, the infant also possessed what are termed "socially relevant behavioral automatisms". The implications of these findings are discussed.     

Congenital leiomyoma of the distal ileum associated with ileal atresia and malrotation

A leiomyoma of the small bowel in a neonate was found causing luminal occlusion and was associated with malrotation. This association and the lack of intestinal mucosa at the level of the tumor suggest that the growth originated at or near the solid core stage of intestinal development.     

Expression of the ELAV-like protein HuR is associated with higher tumor grade and increased cyclooxygenase-2 expression in human breast carcinoma.

PURPOSE: The human ELAV (embryonic lethal abnormal vision)-like protein HuR stabilizes a certain group of cellular mRNAs that contain AU-rich elements in their 3'-untranslated region. Cell culture studies have shown that the mRNA of cyclooxygenase (COX)-2 can be stabilized by HuR. EXPERIMENTAL DESIGN: To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to overexpression of COX-2, we studied expression of HuR in 208 primary breast carcinomas by immunohistochemistry. RESULTS: There were two different staining patterns of HuR in tumor tissue of breast carcinomas: nuclear expression was seen in 61% of cases; and an additional cytoplasmic expression was seen in 30% of cases. Expression of HuR was significantly associated with increased COX-2 expression; this association was particularly significant for cytoplasmic HuR expression (P < 0.0005). We further observed a significant association of cytoplasmic (P = 0.002) or nuclear HuR (P = 0.027) expression with increased tumor grade. Only 13% of the grade 1 carcinomas showed cytoplasmic expression of HuR, compared with 46% of the grade 3 carcinomas. There was no significant correlation between HuR expression and other clinicopathological parameters such as histological type, tumor size, or nodal status as well as patient survival. CONCLUSIONS: Our results suggest that overexpression of HuR in tumor tissue may be part of a regulatory pathway that controls the mRNA stability of several important targets in tumor biology, such as COX-2. Based on our results, additional studies are necessary to investigate whether HuR might be a potential target for molecular tumor therapy.     

Randomized study of brachytherapy in the initial management of patients with malignant astrocytoma

Purpose: A randomized study was undertaken to assess the role of brachytherapy as a boost to external beam radiation therapy in the initial management of patients with malignant astrocytomas.

Methods and Materials: Inclusion criteria included the following: biopsy-proven supratentorial malignant astrocytoma of brain ≤6 cm in size, not crossing midline or involving corpus callosum, age 18–70, Karnofsky Performance Status (KPS) ≥70. Patients were randomized to external radiation therapy only delivering 50 Gray (Gy) in 25 fractions over 5 weeks or external radiation therapy plus a temporary stereotactic iodine-125 implants delivering a minimum peripheral tumor dose of 60 Gy. Patients were stratified to age ≤50 or >50, and KPS ≥90 or ≤80.

Results: There were 140 patients randomized between 1986 and 1996, 71 to the implant arm and 69 to external irradiation only. Pathologically 125 patients had necrosis noted in their tumor specimen. Factors associated with improved survival in univariate analysis were age ≤50, KPS ≥90, chemotherapy at recurrence, and reoperation at the original tumor site. The Cox proportional hazards model revealed the following significant factors: treatment at recurrence (chemotherapy or reoperation) with a relative risk (RR) of 0.6 (p = 0.004) and KPS ≥90 with a RR 0.6 (p = 0.007). Randomization to the implant arm was associated with a RR of 0.7 (p = 0.07). Median survival for patients randomized to brachytherapy or not were 13.8 vs. 13.2 months, respectively, p = 0.49.

Conclusions: We conclude that stereotactic radiation implants have not demonstrated a statistically significant improvement in survival in the initial management of patients with malignant astrocytoma.     

The effect of soy isoflavones on the development of intestinal neoplasia in Apc mouse

Data from epidemiological studies suggest that isoflavones in soy may have a protective effect on the development of colon cancer in humans. Therefore, we have investigated whether soy isoflavones will inhibit intestinal tumour development in Apc^Min mice. The mice were fed a Western-type high risk diet (high fat, low fibre and calcium) containing two different isolates of soy protein as a protein source. For the control and test groups this resulted in the administration of about 16 and 475 mg of total isoflavones per kg diet, respectively. As a positive control, a third group of mice was administered a low isoflavone diet supplemented with 300 ppm sulindac. No significant differences in the incidence, multiplicity, size and distribution of intestinal tumours were observed between Min mice fed low and high isoflavone-containing diets. However, a clear reduction in the number of small intestinal tumours was observed for the sulindac diet. Thus, in contrast to epidemiological studies, our results demonstrate that high amounts of soy isoflavones present in a Western-type high risk diet do not protect against intestinal tumour development in a relevant animal model such as the Min mice.     

Quality of life in patients with glioblastoma multiforme participating in a randomized study of brachytherapy as a boost treatment

OBJECT: Until recently the assessment of outcome in patients treated for glioma has emphasized length of survival with the evaluation of quality of life (QOL) limited to unidimensional, mostly physical, measures. The authors report the multidimensional assessment of QOL as part of a randomized clinical trial of brachytherapy as a boost in the initial treatment of patients with glioblastoma multiforme. METHODS: A questionnaire previously developed by the senior authors and psychometrically validated was completed by patients on randomized entry into the study and at follow-up review every 3 months thereafter. The questionnaire was presented in a linear-analog self-assessment format. Karnofsky Performance Scale (KPS) scores were also recorded on each occasion. No differences were found between patients in either arm of the study (conventional radiation therapy consisting of 50 Gy in 25 fractions or conventional radiation plus a brachytherapy boost of a minimum peripheral tumor dose of 60 Gy) in KPS and QOL scores during the 1st year of follow-up review. However, there was a statistically significant deterioration in patients' overall KPS scores during the 1st year of follow up compared with baseline scores. Of QOL items evaluated, statistically significant deteriorations were found in self care, speech, and concentration, and on subscale analyses, cognitive functioning and physical experience (symptoms) deteriorated significantly during the 1st year of follow up, compared with baseline values. The correlation between QOL and KPS scores was low. CONCLUSIONS: Future studies in patients harboring malignant gliomas must incorporate measures assessing QOL because traditional measures focusing on physical or neurological functioning give an incomplete assessment of the patient's experience.     

Reducing weight gain in children through enhancing physical activity and nutrition: the APPLE project.

OBJECTIVE: Community-based lifestyle intervention may offer the best means of reducing the global epidemic of childhood obesity and its consequences, yet few successful interventions have been reported. The objective was to determine whether increasing extra-curricular levels of activity could reduce weight gain in children. METHODS: A controlled intervention study was conducted using standardised methods to assess outcomes. Two comparable relatively rural communities in Otago, New Zealand formed intervention and control settings. Height, weight, waist circumference and participation in physical activity (by accelerometry) were measured at baseline and at 1 year in 384 children aged 5 to 12 years representing the majority of children in this age group in intervention and control communities. Community Activity Co-ordinators were employed at each school in the intervention area. Their brief was to widen exposure to activity and engage children not interested in traditional sporting activities by encouraging lifestyle-based activities (e.g. walking) and non-traditional sports (e.g. golf and taekwondo) during extra-curricular time at school, after school and during vacations. Simple dietary advice was offered and the wider community was encouraged to participate. RESULTS: Average accelerometry counts at 1 year were 28% (95% CI: 11 to 47%) higher in intervention compared with control children after adjusting for age, sex, baseline values and school. Intervention children spent less time in sedentary activity (ratio 0.91, p = 0.007) and more time in moderate (1.07, p = 0.001) and moderate/vigorous (1.10, p = 0.01) activity. Adjusted mean BMI Z-score was lower in intervention relative to control children by -0.12 units (95% CI: -0.22 to -0.02). CONCLUSION:. An intervention designed to maximise opportunities for physical activity during extra-curricular time at school and during leisure time through the provision of community-based Activity Co-ordinators significantly increased participation in physical activity and slowed unhealthy weight gain in primary school-aged children.