Exposure-Response of Palonosetron for Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients.

OBJECTIVES: Extrapolation of efficacy from adult populations to pediatrics may be appropriate if it is reasonable to assume that the 2 populations have similar disease progression and response to intervention. When full extrapolation of efficacy is deemed appropriate, the pediatric dose can be determined by "matching" exposure to a drug with that observed in adult patients. This approach has been used in certain therapeutic areas to alleviate the burden of pediatric clinical trials. We present here a case in which exposure matching is not appropriate. METHODS: Data analyses including pharmacokinetics and exposure-response were performed using data obtained from 2 pediatric chemotherapy-induced nausea and vomiting trials for intravenously administered palonosetron (Aloxi; a 5-HT3 receptor antagonist) injection and the results were compared with adult findings. RESULTS: At the approved doses for adults (0.25 mg) and pediatric patients (20 µg/kg), mean systemic exposure (area under the curve) of palonosetron in pediatric patients was approximately 3-fold higher than that in adults, whereas the response rate was similar between the 2 populations. Across pediatric patients, those younger than 6 years of age appeared to have a higher response than those ages 6 years or older, even though estimated systemic exposure was comparable between these age groups. CONCLUSIONS: Overall, these analyses provide an example in which pediatric and adult exposure data alone are insufficient to adequately identify effective pediatric doses and raise questions about the appropriateness of exposure matching for other drugs in the same therapeutic class. In such cases, pediatric dose-ranging and efficacy studies are needed.

Effects of off-pump coronary artery bypass grafting on patient outcome.

BACKGROUND: Cardiopulmonary bypass (CPB) is associated with postoperative myocardial stunning, hypothermia, formation of microemboli, and systemic inflammatory response syndrome, all of which may prolong recovery from coronary artery bypass grafting (CABG) surgery. This study sought to compare outcomes in patients undergoing CABG off pump versus on pump. METHODS: Outcomes, including mortality and several morbidities, were reviewed in 1,623 on-pump patients and 683 off-pump patients. Morbidities assessed included postoperative bleeding, incidence of multiorgan dysfunction, and neurologic complications. Chi-square and t-test analysis were used to determine statistical significance. RESULTS: Mortality was 42% lower in the off-pump group than the on-pump group. Both critical care and total hospital length of stay were significantly shorter in the off-pump group. The incidence of postoperative bleeding requiring transfusion or a return to the operating room was reduced by 29% in the off-pump group and the incidence of multiorgan dysfunction was reduced by 31%. The off-pump patients also presented a significantly lower incidence of cerebral vascular accidents and seizures than on-pump patients. CONCLUSIONS: We conclude that there is an association between improved patient outcome and off-pump CABG surgery. The outcomes of this study show a statistically significant decrease in mortality, critical care length of stay, total hospital stay, incidence of bleeding requiring transfusion or return to the operating room, amount of blood transfused, incidence of multiorgan dysfunction, cerebral vascular accidents, and seizures in off-pump patients when compared with on-pump patients. Such results support the use of myocardial revascularization off pump as an alternative to CABG surgery on pump. CABG surgery off pump may allow a better postoperative clinical course in patients who are candidates for the procedure.

The performance of loghman-hakim drug and poison information center from 2006 to 2008.

Drug and poison information centers have a critical role in fulfillment of rational drug use programs. The Loghman-Hakim Drug and Poison Information Center (LHDPIC) has been established in 2006. The main mission of this center is to provide accurate, unbiased and up-to-date information on medications and poisons for the health care team and the public. This center has received more than 9000 telephone calls since its establishment. The aim of this study was to evaluate the recorded queries in the LHDPIC in the past 3 years. A descriptive analysis was conducted on all recorded inquiries to the center from March 2006 to March 2008. Data such as patient age and sex, identity of the callers, question categories and information resources were obtained from the recorded calls and were analyzed. During the period of evaluation, a total of 9694 telephone calls were recorded. The patients' age ranged between 18-40 years old (49.42%) containing 61% female and 39% male. Most of the recorded calls were from patients' relatives (49%) and then the patients (45.2%) themselves. The most frequent questions were about drug indications (24%), adverse drug reactions (20.14%) and drug evaluation (17.64%). Antidepressants (12.42%), antimicrobials (12%) and analgesics (11.17%) were the most frequent drug classes that were inquired. The LHDPIC has an important role for providing of drug information for the lay public, but more efforts are still needed to encourage health care professionals to utilize services provided by this center.

PtdIns(3,5)P2 is required for delivery of endocytic cargo into the multivesicular body.

The endocytic pathway transports cargo from the plasma membrane to early endosomes, where certain cargoes are sorted to the late endosome/multivesicular body. Biosynthetic cargo destined for the lysosome is also trafficked through the multivesicular body. Once delivered to the multivesicular body, cargo destined for the interior of the lysosome is selectively sorted into vesicles that bud into the lumen of the multivesicular body. These vesicles are released into the lumen of the lysosome upon the fusion of the multivesicular body and lysosomal limiting membranes. The yeast protein Fab1, which catalyzes the production of phosphatidylinositol (3,5) bisphosphate [PtdIns(3,5)P2], is necessary for proper sorting of biosynthetic cargo in the multivesicular body. Utilizing an endocytosis screen, we isolated a novel allele of FAB1 that contains a point mutation in the lipid kinase domain. Characterization of this allele revealed reduced PtdIns(3,5)P2 production, altered vacuole morphology, and biosynthetic protein sorting defects. We also found that endocytosis of the plasma membrane protein Ste3 is partially blocked downstream of the internalization step, and that delivery of the dye FM4-64 to the vacuole is delayed in fab1 mutants. Additionally, Ste3 is not efficiently sorted into multivesicular body vesicles in fab1 mutants and instead localizes to the vacuolar limiting membrane. These data show that PtdIns(3,5)P2 is necessary for proper trafficking and sorting of endocytic cargo through the late endosome/multivesicular body.