Cost-effectiveness analysis of rivaroxaban plus aspirin versus aspirin alone in secondary prevention among patients with chronic cardiovascular diseases.

PURPOSE: This study aimed to investigate the cost-effectiveness of low-dose rivaroxaban plus aspirin versus aspirin alone for patients with stable cardiovascular diseases in the Taiwan setting. METHODS: We constructed a Markov model to project the lifetime direct medical costs and quality-adjusted life-years of both therapies. Transitional probabilities were derived from the COMPASS trial, and the costs and utilities were obtained from the Taiwan National Health Insurance Database and published studies. One-way, scenario, subgroup, and probabilistic sensitivity analyses were performed to assess the uncertainty. Incremental cost-effectiveness ratio was presented as the outcome. The threshold of willingness-to-pay was set at US$76,368 (3 times the gross domestic product per capita of Taiwan). All analyses were operated by TreeAge 2019 and Microsoft Excel. RESULTS: The incremental cost-effectiveness ratios of rivaroxaban plus aspirin versus aspirin alone in the patients with stable cardiovascular diseases, coronary artery diseases, and peripheral artery diseases were US$83,459, US$69,852 and -US$13,823 per quality-adjusted life-year gained, respectively. The probabilistic sensitivity analyses showed that the probabilities of cost-effectiveness for the regimen with rivaroxaban among those with cardiovascular diseases and coronary artery diseases were 44.1% and 65.3% at US$76,368. CONCLUSION: Low-dose rivaroxaban plus aspirin is less likely to be a cost-effective alternative to aspirin in secondary prevention for the patients with stable cardiovascular diseases; however, among these patients, the regimen may have pharmacoeconomic incentives for the group merely having chronic coronary artery diseases from the Taiwan national payer's perspective. The pharmacoeconomic incentives are influenced by the drug price, event treatment fees, and willingness-to-pay threshold.

Ginsenoside Rh2 Improves Cardiac Fibrosis via PPARδ-STAT3 Signaling in Type 1-Like Diabetic Rats.

Ginsenoside Rh2 (Rh2) is an active principal ingredient contained in ginseng (Panax ginseng Meyer), a medicinal herb used to enhance health worldwide. The present study is designed to investigate the effect of Rh2 on myocardial fibrosis in diabetic rats. In a streptozotocin-induced model of type-1 diabetic rats (STZ-diabetic rats), the increased fasting blood glucose levels and heart weight/body weight (HW/BW) ratio were substantially alleviated by Rh2. Moreover, Rh2 improved cardiac performance in STZ-diabetic rats. Histological results from Masson staining showed that Rh2 attenuated cardiac fibrosis in STZ-diabetic rats. The effects of Rh2 were reversed by GSK0660 at a dose sufficient to inhibit peroxisome proliferator-activated receptor δ (PPARδ) in STZ-diabetic rats. The role of PPARδ was subsequently investigated in vitro. Rh2 restored the decreased PPARδ expression level in high glucose-cultured cardiomyocytes. Moreover, increased protein levels of fibrotic signals, including signal transducer and activator of transcription 3 (STAT3), connective tissue growth factor (CCN2) and fibronectin, were reduced by Rh2 in high glucose-cultured cardiomyocytes. These effects of Rh2 were reversed by GSK0660 or siRNA specific for PPARδ Taken together, PPARδ activation may inhibit STAT3 activation to reduce CCN2 and fibronectin expression in diabetic rats with cardiac fibrosis. Moreover, Rh2 improves cardiac function and fibrosis by increasing PPARδ signaling. Therefore, Rh2 is suitable to develop as an alternative remedy for cardiac fibrosis.

Cryptotanshinone Inhibits STAT3 Signaling to Alleviate Cardiac Fibrosis in Type 1-like Diabetic Rats.

Cryptotanshinone is an active principal ingredient isolated from Salvia miltiorrhiza (Danshen), a medicinal plant used in China to treat cardiac disorders. The objective of this study was to investigate the effect of cryptotanshinone on myocardial fibrosis in diabetic rats. In streptozotocin-induced type 1 diabetic model hyperglycemic rats (STZ-treated rats), fasting blood glucose levels and heart weight/body weight ratio were markedly increased but both were not modified by cryptotanshinone. Additionally, cardiac performance in catheterized STZ-treated rats was improved. The histological results from Masson staining showed that cryptotanshinone attenuated cardiac fibrosis in STZ-treated rats. Moreover, both the mRNA and protein levels of the signal transducer and activator of transcription 3 (STAT3), matrix metalloproteinase-9, and connective tissue growth factor were reduced by cryptotanshinone in high glucose-cultured cardiomyocytes, similar to the reductions observed in the hearts of STZ-treated rats. In conclusion, while STAT3 regulates matrix metalloproteinase-9 and connective tissue growth factor expression in diabetic rats with cardiac fibrosis, cryptotanshinone inhibited fibrosis to improve cardiac function by suppressing the STAT3 pathway. Cryptotanshinone is suitable as an alternative remedy for therapy of cardiac fibrosis. Copyright © 2017 John Wiley & Sons, Ltd.

Andrographolide inhibits nuclear factor-κB activation through JNK-Akt-p65 signaling cascade in tumor necrosis factor-α-stimulated vascular smooth muscle cells.

Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Andrographolide is the most active and critical constituent isolated from the leaves of Andrographis paniculata, a herbal medicine widely used for treating anti-inflammation in Asia. In this study, we investigated the mechanisms of the inhibitory effects of andrographolide in vascular smooth muscle cells (VSMCs) exposed to a proinflammatory stimulus, tumor necrosis factor-α (TNF-α). Treating TNF-α-stimulated VSMCs with andrographolide suppressed the expression of inducible nitric oxide synthase in a concentration-dependent manner. A reduction in TNF-α-induced c-Jun N-terminal kinase (JNK), Akt, and p65 phosphorylation was observed in andrographolide-treated VSMCs. However, andrographolide affected neither IκBα degradation nor p38 mitogen-activated protein kinase or extracellular signal-regulated kinase 1/2 phosphorylation under these conditions. Both treatment with LY294002, a phosphatidylinositol 3-kinase/Akt inhibitor, and treatment with SP600125, a JNK inhibitor, markedly reversed the andrographolide-mediated inhibition of p65 phosphorylation. In addition, LY294002 and SP600125 both diminished Akt phosphorylation, whereas LY294002 had no effects on JNK phosphorylation. These results collectively suggest that therapeutic interventions using andrographolide can benefit the treatment of vascular inflammatory diseases, and andrographolide-mediated inhibition of NF-κB activity in TNF-α-stimulated VSMCs occurs through the JNK-Akt-p65 signaling cascade, an IκBα-independent mechanism.

Protection in rats with heatstroke: hyperbaric oxygen vs activated protein C therapy.

The present study was attempted to evaluate the therapeutic effects of activated protein C and/or hyperbaric oxygen in an animal model of heatstroke. Sixty-eight minutes heat stress (43 degrees C) initiated, the anesthetized rats were randomized to several groups and administered: 1) no resuscitation (vehicle solution plus normabaric air, 2) intravenous activated protein C (1mg in 1ml of normal saline per kg of body weight), 3) hyperbaric oxygen (100% oxygen at 202kpa for 17min), and 4) intravenous activated protein C plus hyperbaric oxygen. Another group of rats exposed to room temperature (26 degrees C) was used as normothermic controls. Blood sampling was 0min, 70min, and 85min after heat stress initiated. When the vehicle-treated rats underwent heat exposure, their survival time values found were to be 19-25min. Resuscitation with activated protein C or hyperbaric oxygen significantly and equally improved survival during heatstroke (134-159min). As compared with those of activated protein C or hyperbaric oxygen alone, combined activated protein C and hyperbaric oxygen significantly had higher survival time values (277-347min). All vehicle-treated heatstroke animals displayed systemic response, hypercoagulable state, and hepatic and renal dysfunction. Combined activated protein C and hyperbaric oxygen therapy reduced these heatstroke reactions better than activated protein C or hyperbaric oxygen alone. The results indicate consequently, combined activated protein C and hyperbaric oxygen therapy heightens benefit in combating heatstroke reactions.

Activated protein C improves heatstroke outcomes through restoration of normal hypothalamic and thermoregulatory function.

BACKGROUND: Human recombinant activated protein C (APC) has been found to be beneficial in treating heatstroke in both humans and rats. Here, we further investigated the possible mechanism underlying the therapeutic action exerted by APC in experimental heatstroke. METHODS: Unanesthetized and unrestrained mice were exposed to an ambient temperature of 42.4 degrees C for 1 hour to induce heatstroke. They were given normal saline or APC (5 mg/kg of body weight, intravenously) 1 hour after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored for 4 hours after cessation of heat stress. Mice that survived on day 4 of heat treatment were considered survivors. RESULTS: When the vehicle-treated mice underwent heat treatment, the fraction survival and core temperature at 4 hours of body heating were found to be 0 of 12 and 33.8 +/- 0.6 degrees C, respectively. Administration of APC 1 hour after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12 of 12) and reduced hypothermia (core temperature, 37.4 +/- 0.2 degrees C). Heat-induced apoptosis in the hypothalamus was significantly reduced by APC. The increased levels of cellular ischemia (eg, glutamate, lactate-to-pyruvate ratio, nitrite, and dihydroxybenzoic acid) and damage (eg, glycerol) markers in the hypothalamus during heatstroke were also decreased significantly by APC therapy. The hypothalamic levels of tumor necrosis factor-alpha (a proinflammatory cytokine) that are upregulated in heat-stressed mice were significantly lower in APC-administered mice. CONCLUSIONS: Our results show that human recombinant APC improves heatstroke through restoration of normal hypothalamic and thermoregulatory function.

Protective effect of transgenic expression of porcine heat shock protein 70 on hypothalamic ischemic and oxidative damage in a mouse model of heatstroke.

BACKGROUND: Transgenic mice have been used to examine the role of heat shock protein (HSP)72 in experimental heatstroke. Transgenic mice that were heterozygous for a porcine HSP70beta gene ([+] HSP72) and transgene-negative littermate controls ([-] HSP72), under pentobarbital sodium anesthesia, were subjected to heat stress to induce heatstroke. It was found that the overexpression of HSP72 in multiple organs improved survival during heatstroke by reducing hypotension and cerebral ischemia and damage in mice. Herein we attempted to further assess the effect of heat exposure on thermoregulatory function, hypothalamic integration, and survival in unrestrained, unanesthetized [+]HSP72 and compare with those of [-]HSP72. In this research with the transgenic mice, we first conducted several biochemical, physiologic and histological determinations and then investigated the beneficial effects of HSP72 overexpression on the identified hypothalamic deficits, thermoregulatory dysfunction, and mortality during heatstroke. RESULTS: We report here that when [-]HSP72 mice underwent heat stress (ambient temperature 42.4 degrees C for 1 h), the fraction survival and core temperature at 4 h after heat stress were found to be 0 of 12 and 34.2 degrees C +/- 0.4 degrees C, respectively. Mice that survived to day 4 after heat stress were considered as survivors. In [+]HSP72 mice, when exposed to the same heat treatment, both fraction survival and core temperature values were significantly increased to new values of 12/12 and 37.4 degrees C +/- 0.3 degrees C, respectively. Compared to [-]HSP mice, [+]HSP72 mice displayed lower hypothalamic values of cellular ischemia (e.g., glutamate and lactate-to-pyruvate ratio) and damage (e.g., glycerol) markers, pro-oxidant enzymes (e.g., lipid peroxidation and glutathione oxidation), pro-inflammatory cytokines (e.g., interleukin-1beta and tumor necrosis factor-alpha), and neuronal damage score evaluated 4 h after heat stress. In contrast, [+]HSP72 mice had higher hypothalamic values of antioxidant defences (e.g., glutathione peroxidase and glutathione reductase), ATP, and HSP72 expression. CONCLUSION: This study indicates that HSP72 overexpression appears to be critical to the development of thermotolerance and protection from heat-induced hypothalamic ischemic and oxidative damage.