Role of CYP2B6 and CYP3A4 in the in vitro N-dechloroethylation of (R)- and (S)-ifosfamide in human liver microsomes.

The central nervous system toxicity of ifosfamide (IFF), a chiral antineoplastic agent, is thought to be dependent on its N-dechloroethylation by hepatic cytochrome P-450 (CYP) enzymes. The purpose of this study was to identify the human CYPs responsible for IFF-N-dechloroethylation and their corresponding regio- and enantioselectivities. IFF exists in two enantiomeric forms, (R) - and (S)-IFF, which can be dechloroethylated at either the N2 or N3 positions, producing the corresponding (R,S)-2-dechloroethyl-IFF [(R, S)-2-DCE-IFF] and (R,S)-3-dechloroethyl-IFF [(R,S)-3-DCE-IFF]. The results of the present study suggest that the production of (R)-2-DCE-IFF and (S)-3-DCE-IFF from (R)-IFF is catalyzed by different CYPs as is the production of (S)-2-DCE-IFF and (R)-3-DCE-IFF from (S)-IFF. In vitro studies with a bank of human liver microsomes revealed that the sample-to-sample variation in the production of (S)-3-DCE-IFF from (R)-IFF and (S)-2-DCE-IFF from (S)-IFF was highly correlated with the levels of (S)-mephenytoin N-demethylation (CYP2B6), whereas (R)-2-DCE-IFF production from (R)-IFF and (R)-3-DCE-IFF production from (S)-IFF were both correlated with the activity of testosterone 6beta-hydroxylation (CYP3A4/5). Experiments with cDNA-expressed P-450 and antibody and chemical inhibition studies supported the conclusion that the formation of (S)-3-DCE-IFF and (S)-2-DCE-IFF is catalyzed primarily by CYP2B6, whereas (R)-2-DCE-IFF and (R)-3-DCE-IFF are primarily the result of CYP3A4/5 activity.     

Radical Resection of Periampullary Tumors in the Elderly: Evaluation of Long-term Results

Increasingly, patients of advanced age are coming for evaluation of periampullary tumors. Although several studies have demonstrated the safety of resecting periampullary tumors in older patients, few long-term survival data have been reported. Between 1983 and 1992 various periampullary masses were resected in 70 patients over age 65 (range 65–87 years). Total pancreatectomy was performed in 11 patients, and 59 patients underwent pancreaticoduodenectomy. The mean duration of hospitalization was 17 ± 15 days. Major complications occurred in 27 patients (39%), and operative mortality rate was 8.5%. Overall median survival was 24 months; and 5-year survival was 25%. Perioperative outcome was compared in patients aged 65 to 74 years and in patients ≥75 years old. The older age group required longer periods in the surgical intensive care unit postoperatively, but the long-term survival was similar in the two age groups. Radical resection with the intent to cure periampullary tumors is safe in selected patients of advanced age, and long-term survival is in the range of expected survival for younger patients with the same tumors.     

Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased expression of p21WAF1/CIP1 and prolonged progression-free survival.

PURPOSE: ARHI, an imprinted putative tumor suppressor gene, is expressed in normal ovarian epithelial cells, but its expression is down-regulated or lost in most ovarian cancer cell lines. Reexpression of ARHI in cancer cells induces p21(WAF1/CIP1), down-regulates cyclin D1 promoter activity and inhibits growth in cell culture and in heterografts. To determine the relevance of these observations to clinical cancer, we have now measured ARHI expression in normal, benign and malignant ovarian tissues using immunohistochemistry and in situ hybridization. EXPERIMENTAL DESIGN: Paraffin embedded tissues from 7 normal ovaries, 22 cystadenomas and 42 borderline lesions were analyzed using standard immunoperoxidase and in situ hybridization techniques to assess ARHI expression. In addition, immunohistochemistry against ARHI was performed on a tissue microarray containing 441 consecutive cases of ovarian carcinoma. RESULTS: Strong ARHI expression was found in normal ovarian surface epithelial cells, cysts and follicles using immunohistochemistry and in situ hybridization. Reduced ARHI expression was observed in tumors of low malignant potential as well as in invasive cancers. ARHI expression was down-regulated in 63% of invasive ovarian cancer specimens and could not be detected in 47%. When immunohistochemistry and in situ hybridization were compared, ARHI protein expression could be down-regulated in the presence of ARHI mRNA. ARHI expression was correlated with expression of p21(WAF1/CIP1) (P = 0.0074) but not with cyclin D1 and associated with prolonged disease free survival (P = 0.001). On multivariate analysis, ARHI expression, grade and stage were independent prognostic factors. ARHI expression did not correlate with overall survival. CONCLUSIONS: Persistence of ARHI expression in epithelial ovarian cancers correlated with prolonged disease free survival and expression of the cyclin dependent kinase inhibitor p21(WAF1/CIP1).     

Effects of peribulbar bupivacaine as an adjunct to general anaesthesia on peri-operative outcome following retinal detachment surgery

Sixty premedicated, ASA physical status I or II patients weighing > 25 kg scheduled for elective retinal detachment repair were randomly assigned to receive either peribulbar block with 10 ml of 0.25% bupivacaine (block group) or intravenous morphine 150 microg.kg-1 (morphine group), prior to the induction of general anaesthesia (n = 30 in each group). Patients were evaluated for intra-operative oculocardiac reflex, peri-operative pain relief, recovery from anaesthesia and postoperative nausea and vomiting. Apart from significantly reducing the incidence of oculocardiac reflex (30% vs. 70%, p = 0.0019), peribulbar bupivacaine also attenuated the severity of the reflex. Postoperative pain relief was superior in the block group. More block group patients had the maximum recovery score in the immediate postoperative period (80% vs. 27%, p < 0. 0001) and they achieved complete recovery significantly faster than the morphine group (17.3 (14.7) min vs. 66.7 (29.7) min, p < 0.0001). The incidence (40% vs. 77%, p = 0.004) and severity of postoperative nausea and vomiting were significantly less in the block group. In summary, peribulbar bupivacaine, when administered together with general anaesthesia, attenuated oculocardiac reflex, provided comparable intra-operative and superior postoperative analgesia, resulted in significantly earlier and better recovery from anaesthesia, and significantly reduced the incidence and severity of postoperative nausea and vomiting.     

Prophylactic ondansetron in prevention of postoperative nausea and vomiting following pediatric strabismus surgery: a dose-response study

BACKGROUND: This study evaluated the antiemetic effectiveness, dose-response, and clinical usefulness of prophylactic ondansetron in the prevention of postoperative nausea and vomiting (PONV) in children undergoing strabismus repair. METHOD: The authors observed 180 children, American Society of Anesthesiologists physical status I or II, 2-12 yr of age, who were undergoing strabismus repair. After induction of anesthesia with halothane and nitrous oxide in oxygen or intravenous thiopental, children received either placebo (saline) or intravenous ondansetron in doses of 25, 50, 75, 100, and 150 /microg/kg (n = 30). The trachea was intubated and ventilation was controlled. Perioperative analgesic and fluid requirements were standardized. Episodes of nausea and vomiting were recorded for the first 24 h postoperatively. Data such as nonsurrogate (parental satisfaction scores and duration of postanesthesia care unit stay) and therapeutic (numbers needed to prevent and harm) outcome measures were collected. RESULTS: The incidences of PONV in the placebo and 25-, 50-, 75-, 100-, and 150-,microg/kg ondansetron groups were 83, 77, 47, 30, 30, and 27%, respectively. The incidence was less in the 75(P = 0.002), 100- (P = 0.002), and 150-microg/kg (P < 0.001) ondansetron groups compared with placebo. Duration of stay in the postanesthesia care unit was shorter in the 75-, 100-, and 150-microg/kg ondansetron groups (P < 0.002) compared with the placebo group. Parental assessment scores for the child's perioperative experience and the positive number needed to prevent PONV were also better and favorable in the 75-, 100-, and 150-microg/kg ondansetron groups compared with the placebo group. The incidence (P > 0.99) and severity (P = 0.63) of PONV were similar in the 75- and 150-microg/kg ondansetron groups. Surrogate, nonsurrogate, and therapeutic outcome measures revealed that 75 microg/kg ondansetron provided the same benefits as did 100 and 150 microg/kg. CONCLUSION: The routine prophylactic use of ondansetron at a dose of 75 microg/kg is as effective as 150 microg/kg in preventing PONV and improving the "true" outcome measures after strabismus repair in children.