Phase I and pharmacokinetic study of BMS-188797, a new taxane analog, administered on a weekly schedule in patients with advanced malignancies.

PURPOSE: The purpose of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary activity of BMS-188797 administered weekly. EXPERIMENTAL DESIGN: Patients with advanced malignancies were treated with escalating doses of BMS-188797 on a weekly schedule as a 1-h i.v. infusion. Plasma sampling was performed to characterize the pharmacokinetics of BMS-188797. RESULTS: Eighteen patients with advanced malignancies were enrolled at three dose levels ranging from 35 to 65 mg/m(2). The number of patients evaluated at each dose level was as follows: 35 mg/m(2) (n = 3); 50 mg/m(2) (n = 9); and 65 mg/m(2) (n = 6). At 65 mg/m(2), three of six patients had a DLT (one had grade 4 neutropenia lasting >7 days, and two had grade 3 diarrhea). Expansion of the 50-mg/m(2) dose cohort to nine patients established this dose as the MTD, with one patient experiencing a DLT (grade 4 neutropenia with fever). Two partial responses were observed (lung cancer, 7+ months; ovarian cancer, 6+ months durations), as well as two minor responses (esophageal cancer, 5 months; ovarian cancer, 5 months). Both patients with partial responses had been clinically resistant to paclitaxel. Plasma pharmacokinetic mean values of maximum concentration (C(max)) and area under the curve (AUC(0-48)) increased in a dose-dependent manner within the range of doses used in this study, and in three of four patients, the DLTs correlated with AUC. CONCLUSIONS: The MTD and the recommended Phase II dose of weekly BMS-188797 is 50 mg/m(2). The drug demonstrates antitumor activity in taxane-refractory solid tumors and is now being evaluated in combination with carboplatin.     

Modulation of resistance to idarubicin by the cyclosporin PSC 833 (valspodar) in multidrug-resistant cells

Idarubicin (IDA) is an anthracycline anticancer drug utilized in the treatment of acute leukemias. There are conflicting data published with regard to the cross-resistance of IDA in multidrug-resistant (MDR) cells expressing P-glycoprotein (P-gp). We evaluated the cytotoxicity and cellular accumulation of IDA in a panel of anthracycline-selected MDR cell lines. Leukemia K562/R7 cells and sarcoma MES-SA/Dx5 cells expressing high levels of the MDR1 (ABCB1) gene were resistant to IDA (42-fold and 150-fold, respectively). In both of these cell lines, resistance to IDA was equivalent to that for doxorubicin, the drug used to select for the MDR variants. The P-gp inhibitor PSC 833 (valspodar) at 2 microM completely restored sensitivity to IDA. IDA accumulation was decreased 12-fold in MES-SA/Dx5 cells vs parental cell line, and drug uptake was restored to control levels by PSC 833. Reduced intracellular IDA was correlated with P-gp content by flow cytometry. Experiments in NIH3T3 murine cells transfected with the human MDR1 gene substantiated the findings of cross-resistance to IDA and reversal of resistance by PSC 833. Our data indicate that IDA is a high-affinity substrate for P-gp.     

Sensors in neonatal monitoring: current practice and future trends.

Monitoring the status of preterm infants in the Neonatal Intensive Care Unit (NICU) provides a unique and challenging environment for the design, function and use of sensor-based monitoring equipment. This article presents an overview of sensor-based instrumentation used in the NICU for physiological and chemical status monitoring, and discusses some of the key sensing principles currently in use. The clinical demand for reliable patient data at acceptable cost is driving the development of new types of monitoring technologies, in particular for continuous blood-chemistry analysis. We describe some of the new sensor-based products finding their way into the NICU, together with a review of the more promising emerging sensor technologies that might eventually be incorporated into routine neonatal monitoring practice.     

Validation of a Limited Sampling Model to Determine Etoposide Area Under the Curve

Study Objective . To validate the utility of a previously reported 3-point limited sampling model (LSM) for determining etoposide area under the curve to infinity (AUC_∞). Design . Secondary analysis of data from two clinical trials of etoposide. Setting . University medical center clinical research center. Patients . Thirty-four patients with different malignancies. Interventions . Etoposide was administered as a 2-hour infusion to 34 patients. Serial plasma samples were drawn over 24 hours after the infusion and analyzed for etoposide by high-performance liquid chromatography. Measurements and Main Results . The 3-point LSM AUC was compared with a 14-point actual AUC calculated by the linear trapezoidal rule. Actual and predicted AUC_∞ by the LSM were highly correlated (r=0.97, p<0.0001). The LSM predictions had a mean absolute error of 10.9% (95% CI −14.1, −5.3) and a mean error of −9.7% (95% CI 6.9, 14.9). Nine patients with poor AUC_∞ estimations by the LSM (error > 12%) tended to have abnormally low or high peak concentrations. Conclusion . Our findings suggest the development of more robust LSM using other techniques, such as pharmacostatistical models, that can accommodate a greater degree of pharmacokinetic variability. (Pharmacotherapy 1997;17(5):887–890)     

Methodologic problems in clonogenic assays of spontaneous human tumors

Summary Colony formation in soft agar was used to investigate growth properties and drug sensitivity in 102 tumor specimens from 91 patients. Sufficient colony growth for sensitivity testing with various drugs was obtained in 36 of 67 specimens (54%) with adequate cell yield and pathologically documented malignancy. Room temperature (20–24° C) is superior to both 4° C and 37° C for 12–36 h storage and transport of malignant effusions. By contrast, fine mincing in sterile saline or balanced salt solution, and refrigerated storage (4° C) appear optimal in experiments with three solid tumors. The use of buffered NH₄Cl to lyse red blood cells markedly reduced plating efficiencies, and also reduced the percentage of tumors in which drug sensitivities could be tested from 64% to 38%. Several combinations of potential growth factors and culture media have been tested. Insulin enhanced plating efficiency (PE) in all six adenocarcinomas tested. Drug sensitivity of tumors was not affected by varying plating efficiency up to five-fold in two tumors. In eleven cases tumor cells were exposed to combinations of two or more drugs, and results assessed for evidence of drug interactions. In almost all cases, these two-drug combinations produced additive cell killing rather than either antagonistic or greater-than-additive effects.     

Epilepsy and serotonin (5HT): Variations of 5HT-related genes in temporal lobe epilepsy

Several lines of evidence point to the role of serotonin (5HT) neurotransmission in the epileptogenesis. The present preliminary study investigated possible association of the temporal lobe epilepsy (TLE) with the polymorphisms in several 5HT-related genes, including serotonin transporter (5HTT), monoamine oxidase A (MAO-A) and serotonin receptors 5HT-1A, 5HT-1B and 5HT-2C. All participants (101 TLE patients and 170 healthy controls) were unrelated individuals of Croatian origin. 5HT-1B allele 861G was found to be slightly overrepresented in the patient group (p = 0.0385). No significant differences between groups were observed for the other tested polymorphisms. Within the limitations imposed by the size of our sample, negative findings suggest that the respective loci do not make considerable contribution to the etiopathogenesis of TLE. Further examination of 5HT-1B gene, which yielded positive result at a trend level, is possibly warranted.