Predicting Arsenic (As) Exposure on Human Health for Better Management of Drinking Water Sources.

Chemical pollution in the transboundary Langat River in Malaysia is common both from point and non-point sources. Therefore, the water treatment plants (WTPS) at the Langat River Basin have experienced frequent shutdown incidents. However, the Langat River is one of the main sources of drinking water to almost one-third of the population in Selangor state. Meanwhile, several studies have reported a high concentration of Arsenic (As) in the Langat River that is toxic if ingested via drinking water. However, this is a pioneer study that predicts the As concentration in the Langat River based on time-series data from 2005-2014 to estimate the health risk associated with As ingestion via drinking water at the Langat River Basin. Several time-series prediction models were tested and Gradient Boosted Tree (GBT) gained the best result. This GBT model also fits better to predict the As concentration until December 2024. The mean concentration of As in the Langat River for both 2014 and 2024, as well as the carcinogenic and non-carcinogenic health risks of As ingestion via drinking water, were within the drinking water quality standards proposed by the World Health Organization and Ministry of Health Malaysia. However, the ingestion of trace amounts of As over a long period might be detrimental to human health because of its non-biodegradable characteristics. Therefore, it is important to manage the drinking water sources to minimise As exposure risks to human health.

Predicting acute and persistent neuropathy associated with oxaliplatin.

OBJECTIVES: We sought to predict oxaliplatin-associated peripheral neuropathy during modified FOLFOX6 (mFOLFOX6) therapy. METHODS: Equal numbers of male and female patients with previously untreated, primary or recurrent colorectal cancer were followed through a first course of mFOLFOX6 with 85 mg/m² oxaliplatin every 2 weeks. Accounting for correlation among a subject's cycle, logistic regression estimated per cycle risk of acute (under 14 d) and persistent (14 d or more) neuropathy. Proportional hazards regression predicted time to persistent neuropathy. RESULTS: Among mFOLFOX6 recipients (n = 50, age 58.9 ± 10.1 y), 36% received concomitant bevacizumab. Of the total number of cycles, 94.2% (422/448) were evaluable. Most (84%) subjects reported neuropathy at least once; 74% reported acute and 48% reported persistent symptoms. On multivariate analysis, risk factors shared by acute and persistent neuropathy were body surface area >2.0, acute neuropathy in a past cycle, and lower body weight. In addition, risk of acute neuropathy decreased with age (adjusted for renal function and winter season), whereas risk of persistent neuropathy increased with cumulative dose of oxaliplatin and persistent neuropathy in a past cycle. Concomitant bevacizumab was not a risk factor when administered in stage IV disease but was associated with persistent neuropathy when administered experimentally in stage III. Females had no increased risk of either form of neuropathy. After 3 cycles, weight, body surface area, and prior acute neuropathy predicted time to persistent neuropathy. CONCLUSIONS: Routinely available clinical factors predict acute and persistent neuropathy associated with oxaliplatin. When validated, the proposed prognostic score for persistent neuropathy can help clinicians counsel patients about chemotherapy.

Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes.

OBJECTIVE: In patients with long-standing type 1 diabetes, we investigated whether improved beta-cell function can be achieved by combining intensive insulin therapy with agents that may 1) promote beta-cell growth and/or limit beta-cell apoptosis and 2) weaken the anti-beta-cell autoimmunity. RESEARCH DESIGN AND METHODS: For this study, 20 individuals (mean age 39.5 +/- 11.1 years) with long-standing type 1 diabetes (21.3 +/- 10.7 years) were enrolled in this prospective open-label crossover trial. After achieving optimal blood glucose control, 16 subjects were randomized to exenatide with or without daclizumab. Endogenous insulin production was determined by repeatedly measuring serum C-peptide. RESULTS: In 85% of individuals with long-standing type 1 diabetes who were screened for participation in this trial, C-peptide levels >or=0.05 ng/ml (0.02 nmol/l) were found. Residual beta-cells responded to physiological (mixed-meal) and pharmacological (arginine) stimuli. During exenatide treatment, patients lost 4.1 +/- 2.9 kg body wt and insulin requirements declined significantly (total daily dose on exenatide 0.48 +/- 0.11 vs. 0.55 +/- 0.13 units x kg(-1) x day(-1) without exenatide; P = 0.0062). No signs of further activation of the underlying autoimmune disease were observed. Exenatide delayed gastric emptying, suppressed endogenous incretin levels, but did not increase C-peptide secretion. CONCLUSIONS: In long-standing type 1 diabetes, which remains an active autoimmune disease even decades after its onset, surviving beta-cells secrete insulin in a physiologically regulated manner. However, the combination of intensified insulin therapy, exenatide, and daclizumab did not induce improved function of these remaining beta-cells.

Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.

Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.

Progressive reduction in body weight after treatment with the amylin analog pramlintide in obese subjects: a phase 2, randomized, placebo-controlled, dose-escalation study.

CONTEXT: In previous 1-yr trials, treatment with pramlintide (120 microg), an analog of the beta-cell hormone amylin, induced sustained reductions in A1C and body weight in insulin-using subjects with type 2 diabetes. OBJECTIVE: To assess the potential of pramlintide as an antiobesity agent, we assessed the weight effect, safety, and tolerability of pramlintide in non-insulin-treated obese subjects with and without type 2 diabetes at doses greater than previously studied. DESIGN/SETTING: We performed a randomized, double-blind, placebo-controlled, multicenter study. PATIENTS: A total of 204 obese subjects [80/20% female/male, age 48 +/- 10 yr, and body mass index 37.8 +/- 5.6 kg/m(2) (mean +/- SD)] participated in the study. INTERVENTION: For 16 wk, without concomitant lifestyle intervention, subjects self-administered pramlintide (nonforced dose escalation < or = 240 microg) or placebo via sc injection three times a day before meals. MAIN OUTCOME MEASURES: Weight, waist circumference, tolerability, and safety were the main outcome measures. RESULTS: Pramlintide was generally well tolerated, with 88% of subjects able to escalate to the maximum dose of 240 microg. Withdrawal rates were similar between placebo (25%) and pramlintide-treated subjects (29%). Subjects completing 16 wk of pramlintide treatment experienced placebo-corrected reductions in body weight of 3.7 +/- 0.5% (3.6 +/- 0.6 kg; P < 0.001) and waist circumference (3.6 +/- 1.1 cm; P < 0.01). Approximately 31% of pramlintide-treated subjects achieved > or =5% weight loss (vs. 2% placebo; P < 0.001). More pramlintide than placebo-treated subjects reported improvements in appetite control (72% vs. 31%), weight control (63% vs. 24%), and overall well-being (52% vs. 17%). No unexpected safety signals were observed. The most common adverse event reported was mild, transient nausea. Pramlintide-treated subjects not reporting nausea experienced weight loss similar to those who did (3.6 +/- 0.5% and 3.9 +/- 0.5%, respectively). CONCLUSION: These results support continued evaluation of pramlintide as a potential treatment for obesity.

Pramlintide treatment reduces 24-h caloric intake and meal sizes and improves control of eating in obese subjects: a 6-wk translational research study.

Evidence from rodent studies indicates that the beta-cell-derived neurohormone amylin exerts multiple effects on eating behavior, including reductions in meal size, intake of highly palatable foods, and stress-induced sucrose consumption. To assess the effect of amylin agonism on human eating behavior we conducted a randomized, blinded, placebo-controlled, multicenter study investigating the effects of the amylin analog pramlintide on body weight, 24-h caloric intake, portion sizes, "fast food" intake, and perceived control of eating in 88 obese subjects. After a 2-day placebo lead-in, subjects self-administered pramlintide (180 microg) or placebo by subcutaneous injection 15 min before meals for 6 wk without concomitant lifestyle modifications. Compared with placebo, pramlintide treatment elicited significant mean reductions from baseline in body weight on day 44 (-2.1 +/- 0.3 vs. +0.1 +/- 0.4%, P < 0.001), 24-h caloric intake (-990 +/- 94 vs. -243 +/- 126 kcal on day 3, P < 0.0001; -680 +/- 86 vs. -191 +/- 161 kcal on day 43, P < 0.01), portion sizes, and caloric intake at a "fast food challenge" (-385 +/- 61 vs. -109 +/- 88 kcal on day 44, P < 0.05). Pramlintide treatment also improved perceived control of eating, as demonstrated by a 45% placebo-corrected reduction in binge eating scores (P < 0.01). The results of this translational research study confirm in humans various preclinical effects of amylin agonism, demonstrating that pramlintide-mediated weight loss in obese subjects is accompanied by sustained reductions in 24-h food intake, portion sizes, fast food intake, and binge eating tendencies.

Low-dose pramlintide reduced food intake and meal duration in healthy, normal-weight subjects.

OBJECTIVE: We previously reported that a single preprandial injection (120 microg) of pramlintide, an analog of the beta-cell hormone amylin, reduced ad libitum food intake in obese subjects. To further characterize the meal-related effects of amylin signaling in humans, we studied a lower pramlintide dose (30 microg) in normal-weight subjects. RESEARCH METHODS AND PROCEDURES: In a randomized, double-blind, placebo-controlled, cross-over study, 15 healthy men (age, 24 +/- 7 years; BMI, 22.2 +/- 1.8 kg/m(2)) underwent a standardized buffet meal test on two occasions. After an overnight fast, subjects received a single subcutaneous injection of pramlintide (30 microg) or placebo, followed immediately by a standardized pre-load meal. After 1 hour, subjects were offered an ad libitum buffet meal, and total caloric intake and meal duration were measured. RESULTS: Compared with placebo, pramlintide reduced total caloric intake (1411 +/- 94 vs. 1190 +/- 117 kcal; Delta, -221 +/- 101 kcal; -14 +/- 9%; p = 0.05) and meal duration (36 +/- 2 vs. 31 +/- 3 minutes; Delta, -5.1 +/- 1.4 minutes; p < 0.005). Visual analog scale profiles of hunger trended lower and fullness higher during the first hour after pramlintide administration. In response to the buffet, hunger and fullness changed to a similar degree after pramlintide and placebo, despite subjects on pramlintide consuming 14% fewer kilocalories. Visual analog scale nausea ratings remained near baseline, without differences between treatments. Plasma peptide YY, cholecystokinin, and ghrelin concentrations did not differ with treatment, whereas glucagon-like peptide-1 concentrations after meals were lower in response to pramlintide than to placebo. DISCUSSION: These observations add support to the concept that amylin agonism may have a role in human appetite control.