A phase I study of oral LY293111 given daily in combination with irinotecan in patients with solid tumours

Summary Background: LY293111 is an oral agent known to be a leukotriene B4 (LTB4) receptor antagonist and a 5-lipoxygenase inhibitor resulting in selective inhibition of the lipoxygenase pathway. Lipoxygenases metabolize arachidonic acid and have been involved in cancer cell proliferation and survival. In addition, LY293111 has been found to be a peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist. Antineoplastic activity of LY293111 has been identified in preclinical models both alone and in combination with chemotherapy agents including irinotecan. The NCIC Clinical Trials Group studied LY293111 in combination with irinotecan to determine the recommended dose of the combination and to describe its tolerability and pharmacokinetic interaction. In addition the anti-tumour activity of LY293111 in combination with irinotecan was documented. Patients and methods: Twenty-eight patients with advanced solid tumours were treated on seven dose levels with the combination of irinotecan and LY293111. Irinotecan was administered intravenously every 21-days as a single dose. LY293111 was administered twice daily continuously by mouth. Results: Dose limiting toxicity (DLT) of grade 3 diarrhea was seen in two patients with doses of irinotecan 300 mg/m² IV every 21-days in combination with LY293111 300 mg BID. Subsequently the dose of irinotecan was decreased to 250 mg/m² IV every 21-days with escalating doses of LY293111. A DLT of grade 3 abdominal pain was seen at dose 600 mg BID of LY293111 with irinotecan 250 mg/m². The pharmacokinetics (PK) indicated that the administration of LY293111 did not have an effect on the PK of irinotecan or its metabolite SN-38. No responses were seen; seven patients had stable disease of a median duration of 4.4 months (range 2.8–13 months). Conclusion: The recommended phase II dose of LY293111 is 600 mg orally BID in combination with irinotecan 250 mg/m² IV every 21-days. Gastrointestinal adverse effects were common but could be well managed.     

The nursing management of elderly patients with pain in the community: study and recommendations

This study is designed to identify factors which influence quality of life for elderly people suffering from painful conditions. It is based upon a theoretical model of control in which mood state is used as the indicator of coping. One hundred and ninety elderly patients took part in semi-structured interviews about their pain and coping experiences, and data were also collected from their nurses in the community. Multivariate statistical analysis revealed that the key determinants of mood were having regrets about the past, being occupied, perceived level of pain control, additional personal problems (notably bereavement) and feeling informed about the painful condition. Active personal coping strategies were identified as more therapeutic than passive strategies. Nurses' data revealed that pain complaints were associated with perceived exaggeration. Few nurses used formal pain assessment. Recommendations for the management of persistent pain in the community are given.     

Use of carboxylesterase activity to remove pyrethroid-associated toxicity to Ceriodaphnia dubia and Hyalella azteca in toxicity identification evaluations

Increases in the use and application of pyrethroid insecticides have resulted in concern regarding potential effects on aquatic ecosystems. Methods for the detection of pyrethroids in receiving waters are required to monitor environmental levels of these insecticides. One method employed for the identification of causes of toxicity in aquatic samples is the toxicity identification evaluation (TIE); however, current TIE protocols do not include specific methods for pyrethroid detection. Recent work identified carboxylesterase treatment as a useful method for removing/detecting pyrethroid-associated toxicity. The present study has extended this earlier work and examined the ability of carboxylesterase activity to remove permethrin- and bifenthrin-associated toxicity to Ceriodaphnia dubia and Hyalella azteca in a variety of matrices, including laboratory water, Sacramento River (CA, USA) water, and Salinas River (CA, USA) interstitial water. Esterase activity successfully removed 1,000 ng/L of permethrin-associated toxicity and 600 ng/L of bifenthrin-associated toxicity to C. dubia in Sacramento River water. In interstitial water, 200 ng/L of permethrin-associated toxicity and 60 ng/L of bifenthrin-associated toxicity to H. azteca were removed. The selectivity of the method was validated using heat-inactivated enzyme and bovine serum albumin, demonstrating that catalytically active esterase is required. Further studies showed that the enzyme is not significantly inhibited by metals. Matrix effects on esterase activity were examined with municipal effluent and seawater in addition to the matrices discussed above. Results confirmed that the esterase retains catalytic function in a diverse array of matrices, suggesting that this technique can be adapted to a variety of aquatic samples. These data demonstrate the utility of carboxylesterase treatment as a viable step to detect the presence of pyrethroids in receiving waters.     

Sexual orientation, gender, and alcohol use in a cohort study of U.S. adolescent girls and boys

BACKGROUND: Sexual minority youth may be at elevated risk for alcohol use relative to heterosexual youth, but the reasons underlying higher rates and whether there may be gender differences in risk are not known. METHODS: Cross-sectional survey data from 9731 early and middle adolescent girls and boys in the Growing Up Today Study in 1999 were examined to assess sexual orientation and gender patterns in alcohol use. Multivariable regression models estimated associations between sexual orientation and alcohol-related behaviors, such as binge drinking and drinking before age 12 years. Models controlled for sociodemographic and psychosocial factors, with heterosexuals as the reference. RESULTS: Girls who described themselves as "mostly heterosexual" and lesbian/bisexual girls were at elevated risk compared to heterosexual girls on almost all alcohol-related behaviors and exposures. "Mostly heterosexual" boys were also at elevated risk. No significant differences in alcohol-related behaviors were observed between gay/bisexual and heterosexual boys. Gender-by-sexual orientation interactions were statistically significant for LGB but not other orientations, indicating that lesbian/bisexual girls experienced elevated risk above and beyond that of gay/bisexual boys relative to same-gender heterosexual peers. CONCLUSIONS: In early and middle adolescence, sexual minority girls and "mostly heterosexual" boys experienced consistent patterns of elevated risk for alcohol use.