Patupilone (epothilone B, EPO906) and imatinib (STI571, Glivec) in combination display enhanced antitumour activity in vivo against experimental rat C6 glioma.

PURPOSE. The microtubule-stabilizing agent patupilone (epothilone B, EPO906) and the tyrosine kinase inhibitor imatinib (STI571, Glivec) which primarily inhibits Bcr-Abl, PDGF and c-Kit tyrosine kinase receptors, were combined in vivo to determine if any interaction would occur with respect to antitumour effect and tolerability using rat C6 glioma xenografted into nude mice. METHODS. Patupilone and imatinib were administered alone or in combination at suboptimal doses. Imatinib treatment (orally once daily) was initiated 4 days after s.c. injection of rat C6 glioma cells into athymic nude mice and patupilone administration (i.v. once per week) was started 3 or 4 days after imatinib treatment. RESULTS. As a single agent, imatinib was inactive in the regimens selected (100 mg/kg: T/C 86% and 116%; 200 mg/kg: T/C 68% and 84%; two independent experiments), but well tolerated (gain in body weight and no mortalities). Patupilone weekly monotherapy demonstrated dose-dependent antitumour effects (1 mg/kg: T/C 67% and 70%; 2 mg/kg: T/C 32% and 63%; 4 mg/kg: T/C 3% and 46%). As expected, dose-dependent body weight losses occurred (final body weight changes at 1 mg/kg were -7% and -3%; at 2 mg/kg were -23% and -13%; and at 4 mg/kg were -33% and -15%). Combining 2 mg/kg patupilone and 200 mg/kg per day imatinib in one experiment produced a non-statistically significant trend for an improved antitumour effect over patupilone alone (combination, T/C 9%), while in the second experiment, enhancement was seen with the combination and reached statistical significance versus patupilone alone (combination, T/C 22%; P=0.008). Reduction of the imatinib dose to 100 mg/kg per day resulted in no enhancement of antitumour activity in combination with 2 mg/kg patupilone. Reduction of the patupilone dose to 1 mg/kg resulted in a reduced antitumour effect, and only a trend for synergy with either imatinib dose (combination, T/C 46% and 40%). Pooling the data from the two experiments confirmed a significant synergy for the combination of 2 mg/kg patupilone and 200 mg/kg per day imatinib ( P=0.032), and a trend for synergy at the 1 mg/kg patupilone dose. Reduction in the imatinib dose to 100 mg/kg per day resulted only in additivity with either dose of patupilone. Body weight losses were dominated by the effect of patupilone, since no greater body weight loss was observed in the combination groups. CONCLUSION. Combining patupilone with high-dose imatinib produced an increased antitumour effect without affecting the tolerability of treatment in a relatively chemoresistant rat C6 glioma model. Such results indicate that further evaluation is warranted, in particular to elucidate possible mechanisms of combined action.

Polymer erosion in PLGA microparticles produced by phase separation method.

This article deals with polymer erosion in biodegradable microparticles produced using the phase separation method. Poly(lactic-co-glycolic acid) copolymers with different compositions and molecular weights were employed. The microparticles were stored in phosphate buffer for 6 months. The molecular weight of the polymers was determined by size exclusion chromatography, and the weight loss was monitored gravimetrically. No weight loss was measured in the first weeks, although the molecular weight decreased significantly already from the start. After a certain storage period which was found to be specific for the type of polymer, the weight of the microparticles decreased rapidly. The start of this weight loss occurred when the molecular weight of the polymer in the degrading microparticles reached a threshold of approximately 15,000. This critical molecular weight was found to be identical for all investigated polymers, i.e. it was independent of the initial molecular weight of the polymer and of the lactic-glycolic ratio.

The GAIN (Geriatric Anorexia Nutrition) Registry: The Impact of Appetite and Weight on Mortality in A Long-term Care Population.

PURPOSE: To investigate nursing home residents at high nutritional risk to determine: 1) which baseline nutrition or health status indicators correlated with subsequent weight gain or appetite improvement; and, 2) whether a continued weight loss correlated with higher mortality. METHODS: At study entry, nutritional, health status, and demographic data were extracted from the nursing home chart or the MDS. Each subject was tracked for 6 months with survival, weight gain of 5%, and appetite improvement the primary outcome measures. RESULTS: During the 6-month study, younger age was the strongest correlate of appetite improvement. The odds of gaining weight were negatively correlated with BMI, age, and feeding dependency. Subjects who were receiving appetite stimulants (orexigenics) at study entry had a 70% greater probability of gaining weight than those who were not. A weight loss during the 6-month period was associated with a nearly two-fold increase in the likelihood of dying (adjusted RR: 1.95, 95% CI 1.43 to 2.66). CONCLUSION: The course of nutritional problems within nursing homes is highly variable. Continued weight loss, however, appears to have ominous implications for mortality. Younger residents who are not dependent on others for feeding assistance, and who receive orexigenics tend to experience weight gain.

Weight Loss: the treatment of choice for knee osteoarthritis? A randomized trial.

OBJECTIVE: We wanted to assess the effect of rapid diet-induced weight loss on the function of obese, knee osteoarthritis (OA) patients. METHODS: Eighty patients with knee OA, 89% women (n=71), were recruited. Mean (SD) body-mass index (BMI) was 35.9 (5.1) kg/m(2) and age 62.6 (11.1) years. Patients were randomized to either a low-energy diet (LED 3.4MJ/day), or a control diet (5MJ/day). The LED group had weekly dietary sessions, whereas the control group was given a booklet describing weight loss practices. Changes in body weight and body composition were examined as independent predictors of changes in knee OA symptoms. Symptoms were monitored by the Western Ontario and McMaster Universities' (WOMAC) OA index. RESULTS: The LED and control group lost a mean (SE) of 11.1 (0.6)% and 4.3 (0.6)%, respectively, with a mean difference being 6.8% (95% confidence interval (CI): 5.5 to 8.1%; P<0.0001). The decrease in body fat percent was higher in the LED group, 2.2% (1.5 to 3.0%; P<0.0001). The total WOMAC index improved in the LED group (P<0.0001), but not in the control group (P=0.12), mean difference: -219.3mm (-369.2 to -69.4mm; P=0.005). The 'Number Needed to Treat (NNT)' to ensure an improvement in WOMAC>/=50% was 3.4 (2.1 to 8.8) patients. Changes in total WOMAC index were best predicted by the reduction of body fat percent, with a 9.4% (4.8 to 13.9%) improvement in WOMAC for each percent of body fat reduced (P=0.0005). CONCLUSIONS: In our patients with knee OA, a weight reduction of 10% improved function by 28%. LED might be of advantage to control diet because of the rapidity of weight loss and a more significant loss of body fat.

Management of obesity with the new intragastric balloon.

BACKGROUND: The introduction of an endoscopically-placed Bariatric Intragastric Balloon (BIB) provided the opportunity to reexamine weight reduction methods and also study potential weight loss without resorting to surgical intervention. METHODS: 10 severely obese patients with mean age 33 years and mean body mass index 39, underwent BIB placement, 7 as a sole weight reduction procedure and 3 requiring weight reduction before repair of large incisional hernias. All patients were followed at 2-week intervals by a nurse practitioner and dietitian for 6 months. RESULTS: Mean weight loss was 18.6 kg (range 6.6-40.0), equivalent to 40% excess weight loss (EWL), range 10-81%. EWL was 54% (29-81%) in those patients who had two balloons placed, who lost an average of 30.3 kg (24.0-40.0 kg). In the patients who had only one balloon placed, mean weight loss was 10.4 kg (8.8-12.5), equal to an EWL of 19% (10-37%). CONCLUSION: These results lead us to consider BIB placement as a successful short-term measure for weight loss or for patients requiring at least weight loss before other surgery.

Increase in plasma pollutant levels in response to weight loss is associated with the reduction of fasting insulin levels in men but not in women.

Environmental pollutants can act as endocrine modulators. In this study, we examined whether weight loss-induced changes in plasma organochlorine compounds (OC) were associated with those in plasma insulin levels. Fasting insulin and the area under the curve (AUC) of insulin after a 75-g oral glucose load, plasma levels of 1 commercial polychlorinated biphenyl (PCB) mixture (Aroclor 1260), 1 PCB congener (PCB 153), and 3 pesticides (2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), beta-hexachlorocyclohexane (beta-HCH), and hexachlorobenzene (HCB)) were measured before and after a 15-week weight loss program induced by a caloric restriction in a sample of obese men and women. Both genders showed a similar reduction in body weight (approximately 11 kg) in response to treatment, although men lost significantly more fat mass than women (mean +/- SD 9.4 +/- 4.1 v 5.9 +/- 5 kg, respectively, P <.05). Fasting insulin and AUC of insulin significantly decreased in men and women after the treatment. In response to weight loss, a significant increase in OC was observed in both genders, and this effect was more pronounced in men. The greater the increase in plasma OC levels, the greater the reduction in fasting insulin was in response to weight loss in men (-.49 < r < -.59, P <.05), but not in women (-.22 < r <.01, not significant [NS]). In both genders, no relationship was observed between changes in plasma OC levels and changes in AUC of insulin (-.41 < r < -.08, NS). In men, relationships between changes in plasma HCB, Aroclor 1260, and PCB-153 concentrations and those in fasting insulin levels in response to weight loss remained significantly correlated after correction for fat mass loss (-.46 < partial r < -.51, P values ranging from.05 to.07). These results suggest that weight loss-induced increase in plasma pollutant levels tends to be independently associated with the reduction of fasting insulin levels in men, but not in women. Further studies are needed to verify whether these findings are causally related. Copyright 2002, Elsevier Science (USA). All rights reserved.

Weight goals in a college-age population.

OBJECTIVE: Although a growing body of literature has found unrealistic weight loss goals to be common among older, primarily female, subjects, little is known about weight loss goals of younger adults. RESEARCH METHODS AND PROCEDURES: Three hundred seventy-nine college students had their height and weight taken and reported their "goal," "dream," "happy," "acceptable," and "disappointed" weights. A series of 2 (gender) x 2 (nonoverweight vs. overweight) ANOVAs were conducted with both absolute weight goals and percentage of weight loss needed to obtain those goals as dependent variables. RESULTS: When examined in terms of absolute weight goals, women generally had lower body mass index (BMI) goals than men, and nonoverweight participants had lower BMI goals than overweight participants. Surprisingly, most overweight participants would accept a weight loss that would still place them in the overweight BMI range. When examined in terms of percentage loss needed to reach those goals, only overweight women chose goal and dream weights that would require a loss greater than can be expected from nonsurgical weight-loss treatments, and all overweight participants chose happy and acceptable weights within 15% of current weight. DISCUSSION: Participants in this study had generally reasonable weight-loss goals, and even the most extreme weight loss goals were much more moderate than those found in previous studies. These results are surprising given the extreme social pressures for thinness facing young adults. Future studies should examine the variables that influence selection of goal weights and how goal weights affect actual dieting behavior.

Cardiovascular function and circadian patterns in rats after area postrema lesions or prolonged food restriction.

The role of the area postrema (AP) in baseline cardiovascular function was evaluated by radio telemetry in rats with lesions of AP (APX), along with the effect of APX on circadian patterns of cardiovascular function and ingestive behavior. Despite lesion-induced hypophagia and body weight loss, APX did not affect circadian patterns of mean arterial pressure (MAP), heart rate (HR), or ingestion but did cause a substantial decrease (-60 bpm) in resting HR. The bradycardia was not attributable to weight loss, as resting HR in weight-matched controls, though decreased from baseline, was significantly greater than that in rats with APX. In weight-matched controls, HR increased slightly when weight returned to baseline; however, the bradycardia persisted in rats with APX. These results suggest that AP contributes to resting HR, independent of weight loss or changes in circadian patterns of HR or MAP.