Comparative Health-Care Cost Advantage of Ipratropium over Tiotropium in COPD Patients

Objective: To compare the total direct health-care costs of patients treated with tiotropium and ipratropium. Methods: We conducted a cohort study of health-care costs in British Columbia, Canada, by comparing new patients on tiotropium with new patients on ipratropium. Direct health-care costs for study patients were measured in the first 2 years after initiating inhaled anticholinergic treatment. Differences in direct health-care costs between tiotropium and ipratropium patients were estimated by using quantile regression. We analyzed cost differences in the 10th percentile, median, and 90th percentile of patients by cost. High-dimensional propensity score analysis was used as a method of adjustment for potential confounding factors. Results: The study population had 3,140 tiotropium patients and 26,182 ipratropium patients. Higher health system costs in patients who started on tiotropium instead of ipratropium were observed in patients in the median and 10th percentile. The magnitude of these increases was comparable to the price difference between the two drugs. Health system costs in the 90th percentile were not significantly different between tiotropium and ipratropium patients. Conclusions: The results of this study did not support the preferential use of tiotropium over ipratropium as a basis for savings in direct health-care costs

Original Research Oral Quercetin Supplementation and Blood Oxidative Capacity in Response to Ultramarathon Competition

Previous research indicates that ultramarathon exercise can result in blood oxidative stress. The purpose of this investigation was to examine the efficacy of oral supplementation with quercetin, a naturally occurring compound with known antioxidant properties, as a potential countermeasure against blood oxidative stress during an ultramarathon competition. In double-blind fashion, 63 participants received either oral quercetin (250 mg, 4×/day; 1,000 mg/day total) or quercetin-free supplements 3 weeks before and during the 160-km Western States Endurance Run. Blood drawn before and immediately after (quercetin finishers n = 18, quercetin-free finishers n = 21) the event was analyzed for changes in blood redox status and oxidative damage. Results show that quercetin supplementation did not affect race performance. In response to the ultramarathon challenge, aqueous-phase antioxidant capacity (ferric-reducing ability of plasma) was similarly elevated in athletes in both quercetin and quercetin-free treatments and likely reflects significant increases in plasma urate levels. Alternatively, trolox-equivalent antioxidant capacity was not altered by exercise or quercetin. Accordingly, neither F2-isoprostances nor protein carbonyls were influenced by either exercise or quercetin supplementation. In the absence of postrace blood oxidative damage, these findings suggest that oral quercetin supplementation does not alter blood plasma lipid or aqueous-phase antioxidant capacity or oxidative damage during an ultramarathon challenge

Heme Oxygenase, a Novel Target for the Treatment of Hypertension and Obesity?

Heme oxygenase (HO) is the rate-limiting enzyme in the metabolism of heme-releasing bioactive molecules carbon monoxide (CO), biliverdin, and iron, each with beneficial cardiovascular actions. Biliverdin is rapidly reduced to bilirubin, a potent antioxidant, by the enzyme biliverdin reductase, and iron is rapidly sequestered by ferritin in the cell. Several studies have demonstrated that HO-1 induction can attenuate the development of hypertension as well as lower blood pressure in established hypertension in both genetic and experimental models. HO-1 induction can also reduce target organ injury and can be beneficial in cardiovascular diseases, such as heart attack and stroke. Recent studies have also identified a beneficial role for HO-1 in the regulation of body weight and metabolism in diabetes and obesity. Chronic HO-1 induction lowers body weight and corrects hyperglycemia and hyperinsulinemia. Chronic HO-1 induction also modifies the phenotype of adipocytes in obesity from one of large, cytokine producing to smaller, adiponectin producing. Finally, chronic induction of HO-1 increases oxygen consumption, CO 2 , and heat production and activity in obese mice. This review will discuss the current understanding of the actions of the HO system to lower blood pressure and body weight and how HO or its metabolites may be ideal candidates for the development of drugs that can both reduce blood pressure and lower body weight

Bilirubin, Renal Hemodynamics, and Blood Pressure

Bilirubin is generated from the breakdown of heme by heme oxygenase and the reduction of biliverdin by the enzyme biliverdin reductase. Several large population studies have reported a significant inverse correlation between plasma bilirubin levels and the incidence of cardiovascular disease. Protection from cardiovascular disease is also observed in patients with Gilbert\u27s syndrome which is a disease characterized by mutations in hepatic UGT1A1, the enzyme responsible for the conjugation of bilirubin into the bile. Despite the strong correlation between plasma bilirubin levels and the protection from cardiovascular disease, the mechanism by which increases in plasma bilirubin acts to protect against cardiovascular disease is unknown. Since the chronic antihypertensive actions of bilirubin are likely due to its renal actions, the effects of moderate increases in plasma bilirubin on renal hemodynamics as well as bilirubin\u27s potential effects on renal tubule function will be discussed in this review. Mechanisms of action as well as the potential for antihypertensive therapies targeting moderate increases in plasma bilirubin levels will also be highlighted

Chronic Treatment With a Carbon Monoxide Releasing Molecule Reverses Dietary Induced Obesity In Mice

ABSTRACT: Chronic, low level treatment with a carbon monoxide releasing molecule (CO-RM), CORM-A1, has been shown to prevent the development of obesity in response to a high fat diet. The objective of this study was to test the hypothesis that chronic, low level treatment with this CO-RM can reverse established obesity via a mechanism independent of food intake. Dietary induced obese mice were treated with CORM-A1, the inactive compound iCORM-A1, or saline every 48 hours for 30 weeks while maintained on a high fat (60%) diet. Chronic treatment with CORM-A1 resulted in a 33% decrease from initial body weight over the 30 week treatment period while treatment with iCORM and saline were associated with 18 and 25% gain in initial body weight over the same time frame. Chronic treatment with CORM-A1 did not affect food intake or activity but resulted in a significant increase in metabolism. CORM-A1 treatment also resulted in lower fasting blood glucose, improvement in insulin sensitivity and decreased heptatic steatosis. Chronic treatment with CO releasing molecules can reverse dietary induced obesity and normalize insulin resistance independent of changes in food intake or activity. These findings are likely though a mechanism which increases metabolism

Heme Oxygenase Inhibition Increases Blood Pressure In Pregnant Rats

Background During normal gestation, the placenta is a relatively hypoxic organ and, as such, is subject to significant oxidative stress. In the preeclamptic patient, inadequate remodeling of the maternal vasculature severely exacerbates placental oxidative stress, which has been shown to be an important component of maternal hypertension. There is emerging evidence that Heme Oxygenase-1 (HO-1) acts as an important regulator of placental and cardiovascular function during normal pregnancy. Here, we have examined the effect of Heme Oxygenase (HO) inhibition in late gestation on maternal blood pressure, angiogenic balance, and placental oxidative stress in pregnant rats. Methods HO activity was inhibited with tin mesoporphyrin (SnMP), which was administered on gestational day 14, and blood pressure was measured on gestational day 19. Placental angiogenic balance and plasma Vascular Endothelial Growth Factor (VEGF) were determined by sandwich enzyme-linked immunosorbent assay. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was measured by lucigenin chemilluminescence. Results In response to SnMP treatment, maternal mean arterial pressure (MAP) was significantly increased (99±1 vs. 113±2mm Hg; P \u3c 0.05; n = 15 per group). Placental soluble fms-like tyrosine kinase-1 (sFlt-1) (631±47 vs. 648±26 pg/mg; P = 0.76) levels in the placenta were not affected by HO inhibition. Additionally, there was no significant difference in free VEGF in the maternal circulation (287±22 vs. 329±14 pg/ml; P = 0.11). There was, however, a significant decrease in placental VEGF (23±2 vs. 16±1 pg/mg; P \u3c 0.05) and a significant increase in placental NADPH oxidase activity in SnMP-treated rats (2021±238 vs. 3005±301 RLU/min/mg; P \u3c 0.05). Conclusions Our Results demonstrate that HO is an important regulator of blood pressure and an important antioxidant in the developing placenta

Biliverdin Reductase Isozymes In Metabolism

The biliverdin reductase (BVR) isozymes BVRA and BVRB are cell surface membrane receptors with pleiotropic functions. This review compares, for the first time, the structural and functional differences between the isozymes. They reduce biliverdin, a byproduct of heme catabolism, to bilirubin, display kinase activity, and BVRA, but not BVRB, can act as a transcription factor. The binding motifs present in the BVR isozymes allow a wide range of interactions with components of metabolically important signaling pathways such as the insulin receptor kinase cascades, protein kinases (PKs), and inflammatory mediators. In addition, serum bilirubin levels have been negatively associated with abdominal obesity and hypertriglyceridemia. We discuss the roles of the BVR isozymes in metabolism and their potential as therapeutic targets

Inhalation of Carbon Monoxide Is Ineffective as a Long-Term Therapy To Reduce Obesity In Mice Fed a High Fat Diet

Background: Previous studies have demonstrated that induction of heme oxygenase-1 results in weight loss in several rodent models of obesity. However, the specific role of the heme oxygenase-1 metabolite, carbon monoxide (CO), in this response has yet to be established. We recently reported that chronic treatment with CO releasing molecules results in prevention of weight gain in mice fed a high fat diet. In the present study, we sought to determine the effect of chronic CO inhalation on the development and reversal of high fat diet induced obesity. Results: CO inhalation at both levels initially resulted in a prevention and reversal of body weight and fat mass over the first 10 weeks of treatment, however, this effect was not sustained. CO inhalation in the prevention groups also had an early effect to lower fasting blood glucose but this effect also was not sustained. Conclusions: Our results demonstrate that CO inhalation has a transient effect to prevent and reduce body weight which is not sustained chronically in mice fed a high fat diet. These results suggest that chronic CO inhalation therapy is not an effective treatment to induce long term weight loss

Sex-Dependent Effects of HO-1 Deletion From Adipocytes In Mice

Induction of heme oxygenase-1 (HO-1) has been demonstrated to decrease body weight and improve insulin sensitivity in several models of obesity in rodents. To further study the role of HO-1 in adipose tissue, we created an adipose-specific HO-1 knockout mouse model. Male and female mice were fed either a control or a high-fat diet for 30 weeks. Body weights were measured weekly and body composition, fasting blood glucose and insulin levels were determined every six weeks. Adipocyte-specific knockout of HO-1 had no significant effect on body weight in mice fed a high-fat diet but increased body weight in female mice fed a normal-fat diet. Although body weights were not different in females fed a high fat diet, loss of HO-1 in adipocytes resulted in significant alterations in body composition. Adipose-specific HO-1 knockout resulted in increased fasting hyperglycemia and insulinemia in female but not male mice on both diets. Adipose-specific knockout of HO-1 resulted in a significant loss of HO activity and a decrease in the protein levels of adiponectin in adipose tissue. These results demonstrate that loss of HO-1 in adipocytes has greater effects on body fat and fasting hyperglycemia in a sex-dependent fashion and that expression of HO-1 in adipose tissue may have a greater protective role in females as compared to males