Is bortezomib,a proteasome inhibitor,effective in treating cancer-associated weight loss? Preliminary results from the North Central Cancer Treatment Group

Background Weight loss predicts a poor prognosis for cancer patients, and previous studies have implicated the ubiquitin–proteasome pathway as a major mediator of cancer-associated weight loss. The recent emergence of bortezomib, a proteasome inhibitor, now allows testing on whether proteasome inhibition is effective therapy for cancer-associated weight loss.Methods This study represents a subanalysis from two prior antineoplastic trials in patients with adenocarcinoma of the pancreas. The first included 46 patients with metastatic pancreatic cancer who were treated with single-agent bortezomib (intravenous doses of 1.5 or 1.3 mg/m² on days 1, 4, 8, and 11 of a 21-day cycle). The second included 42 patients with pancreatic cancer treated with single-agent octreotide (200 or 500 g subcutaneously three times a day). The FACT-C questionnaire provided appetite and related data for bortezomib-treated patients. Serial weight data were available from both trials. Such data from the octreotide trial were utilized for comparative purposes because the latter holds no track record in treating cancer-associated weight loss.Results Bortezomib- and octreotide-treated patients were roughly comparable at baseline, and neither agent demonstrated notable antineoplastic effects. FACT-C data suggested stable appetite, but high patient dropout rates invite caution in interpretation. For example, in response to I have a good appetite, mean scores for bortezomib-treated patients were 45 at baseline (n=42), 45 at the end of cycle 1 (n=26), and 44 at the end of cycle 2 (n=9). In contrast, weight data appeared more straightforward to interpret: direct comparisons of mean change in weight from baseline between bortezomib- and octreotide-treated patients showed no significant differences between groups.Conclusions These preliminary results suggest that bortezomib shows negligible favorable effects on cancer-associated weight loss in patients with metastatic pancreatic cancer. We conclude that further study of bortezomib specifically in this setting and for this indication is not warranted.     

High performance liquid chromatographic determination of 3-methylflavone-8-carboxylic acid, the main active metabolite of flavoxate hydrochloride in human urine

High performance liquid chromatographic (HPLC) method was presented for the determination of 3-methylflavone-8-carboxylic acid as the main active metabolite of flavoxate hydrochloride (FX) in human urine. The proposed method was based on using CN column with mobile phase consisting of acetonitrile-12 mM ammonium acetate (40:60, v/v) and adjusted to apparent pH 4.0 with flow rate of 1.5 ml min(-1). Quantitation was achieved with UV detection at 220 nm. The proposed method was utilized to the determination of dissolution rate for tablets containing flavoxate hydrochloride. The urinary excretion pattern has been calculated using the proposed method.     

Nanoparticulate Assembly of Mannuronic Acid-and Guluronic Acid-Rich Alginate: Oral Insulin Carrier and Glucose Binder

The relationship of high and low molecular weight mannuronic acid (M)- and guluronic acid (G)-rich alginate nanoparticles as oral insulin carrier was elucidated. Nanoparticles were prepared through ionotropic gelation using Ca^2 +, and then in vitro physicochemical attributes and in vivo antidiabetic characteristics were examined. The alginate nanoparticles had insulin release retarded when the matrices had high alginate-to-insulin ratio or strong alginate–insulin interaction via O-H moiety. High molecular weight M-rich alginate nanoparticles were characterized by assemblies of long polymer chains that enabled insulin encapsulation with weaker polymer–drug interaction than nanoparticles prepared from other alginate grades. They were able to encapsulate and yet release and have insulin absorbed into systemic circulation, thereby lowering rat blood glucose. High molecular weight G- and low molecular weight M-rich alginate nanoparticles showed remarkable polymer–insulin interaction. This retarded the drug release and negated its absorption. Blood glucose lowering was, however, demonstrated in vivo with insulin-free matrices of these nanoparticles because of the strong alginate–glucose binding that led to intestinal glucose retention. Alginate nanoparticles can be used as oral insulin carrier or glucose binder in the treatment of diabetes as a function of its chemical composition. High molecular weight M-rich alginate nanoparticles are a suitable vehicle for future development into oral insulin carrier. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:4353–4363,2013     

Ramipril improves oxidative stress-related vascular endothelial dysfunction in db/db mice

Endothelial dysfunction often precedes Type 2 diabetes-associated cardiovascular complications. One important cause of endothelial dysfunction is oxidative stress, which can lead to reduced nitric oxide (NO) bioavailability. In this study, we examined the effects of ramipril (an angiotensin-converting enzyme inhibitor, ACEI) on reactive oxygen species (ROS) production and endothelium-dependent vasodilation using a Type 2 diabetic (db/db) murine model. Plasma concentration of 8-isoprostane ([8-isoP]) was measured and used as an indication of the amount of ROS production. Six weeks of ramipril (10 mg/kg/day) treatment significantly reduced [8-isoP] and improved acetylcholine(ACh)-induced vasodilation in db/db mice without altering responses in wild-type (WT) mice. Responsiveness of smooth muscle cells to NO, assessed by sodium nitroprusside-induced vasodilation, was not different between db/db and WT mice regardless of ramipril or vehicle treatment. Our results suggest that ramipril specifically improved endothelium-dependent vasodilation in Type 2 diabetic mice, possibly by reducing ROS levels.     

Using the Skindex-16 and Common Terminology Criteria for Adverse Events to assess rash symptoms: results of a pooled-analysis (N0993)

Background

Historically, skin toxicity has been assessed in prospective clinical trials using the clinician-reported National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE). The patient-reported Skindex-16 measures symptoms and perceptions of toxicity. This study was designed to compare information provided by these two measures.

Methods

Data were compiled from three placebo-controlled North Central Cancer Treatment Group studies (N06C4, N03CB, N05C4) having rash prevention as the primary objective. All used the Skindex-16 and CTCAE at baseline, weekly during treatment and during a minimum 2-week follow-up period. Statistical procedures, including Pearson correlations, were utilized to determine relationships between adverse event (AE) grades and Skindex-16 scores.

Results

Four hundred and twelve individual patients provided data (median age, 61; 134 male). Patients' Skindex-16 score results show a 0.9 overall mean (range 0–6 with 6 being worse symptoms), a 0.4 baseline mean (range, 0–4.3) and a 1.3 end-of-treatment mean (range, 0–5.9). Ninety-three, 142 and 177 patients experienced a grade 0, 1 and 2+ CTCAE skin toxicity, respectively. Baseline Skindex-16 scores had relatively low correlation with CTCAE grades. The correlation of rash grade with Skindex-16 scores ranged from r?=?0.49 with the function subscale to r?=?0.62 with the symptom subscale. The highest correlations of the maximum grade of any dermatological AE with the Skindex-16 were r?=?0.48 for the total score and r?=?0.55 for the symptom subscale.

Conclusions

The data reported support the decision to include both measures in a clinical trial to assess the patient experience, as each measure may specifically target varying symptoms and intensities.     

Nutritional and socio-economic determinants of cognitive function and educational achievement of Aboriginal schoolchildren in rural Malaysia

A community-based cross-sectional study was carried out among Aboriginal schoolchildren aged 7-12 years living in remote areas in Pos Betau, Pahang, Malaysia to investigate the potential determinants influencing the cognitive function and educational achievement of these children. Cognitive function was measured by intelligence quotient (IQ), while examination scores of selected school subjects were used in assessing educational achievement. Blood samples were collected to assess serum Fe status. All children were screened for soil-transmitted helminthes. Demographic and socio-economic data were collected using pre-tested questionnaires. Almost two-thirds (67·6?%) of the subjects had poor IQ and most of them (72·6?%) had insufficient educational achievement. Output of the stepwise multiple regression model showed that poor IQ was significantly associated with low household income which contributed the most to the regression variance (r2 0·059; P?=?0·020). Low maternal education was also identified as a significant predictor of low IQ scores (r2 0·042; P?=?0·043). With educational achievement, Fe-deficiency anaemia (IDA) was the only variable to show significant association (r2 0·025; P?=?0·015). In conclusion, the cognitive function and educational achievement of Aboriginal schoolchildren are poor and influenced by household income, maternal education and IDA. Thus, effective and integrated measures to improve the nutritional and socio-economic status of rural children would have a pronounced positive effect on their education.