Comparative assessment of efficacy and safety of ambrisentan and bosentan in patients with pulmonary arterial hypertension: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.

Cost-effectiveness analysis of branded and authorized generic celecoxib for patients with chronic pain in Japan.

OBJECTIVES: The aim of this study was to examine the cost-effectiveness of branded and authorized generic (AG) celecoxib for chronic pain patients with osteoarthritis (OA), rheumatoid arthritis (RA), and low back pain (LBP), using real-world cost information for loxoprofen and pharmacotherapy for gastrointestinal bleeding. METHODS: This cost-effectiveness analysis was performed as a long-term simulation using the Markov model from the Japanese public healthcare payer's perspective. The analysis was conducted using loxoprofen with real-world weighted price by branded/generic distribution (hereinafter, loxoprofen with weighted price) as a comparator. In the model, we simulated the prognosis of patients with chronic pain by OA, RA, and LBP treated with loxoprofen or celecoxib, over a lifetime period. RESULTS: A cost-increase of 129,688 JPY (1,245.00 USD) for branded celecoxib and a cost-reduction of 6,268 JPY (60.17 USD) for AG celecoxib were recognized per patient in lifetime horizon, compared to loxoprofen with weighted price. No case was recognized to reverse the results of cost-saving by AG celecoxib in one-way sensitivity analysis. The incremental cost-effectiveness ratio of branded celecoxib attained 5,403,667 JPY/QALY (51,875.20 USD/QALY), compared to loxoprofen with the weighted price. CONCLUSION: The current cost-effectiveness analysis for AG celecoxib revealed its good value for costs, considering the patients' future risk of gastrointestinal injury; also, the impact on costs due to AG celecoxib against loxoprofen will be small. It implies that the disadvantage of AG celecoxib being slightly more expensive than generic loxoprofen could be offset by the good cost-effectiveness during the prognosis.

Safety assessment of desaminotyrosine: Acute, subchronic oral toxicity, and its effects on intestinal microbiota in rats.

In this work, the acute and subchronic toxicities of desaminotyrosine (DAT) by oral administration in SD rats and its effects on the intestinal microflora were investigated. The acute toxicity test showed that DAT is a low-toxic substance with a LD50 of 3129 mg/kg. The subchronic toxicity test showed that DAT has no toxicity at a low dose (125 mg/kg/day). However, DAT exhibited obvious toxicities to food intake, liver, kidney, and lung at higher dose (250 mg/kg/day and 500 mg/kg/day). DAT inhibited the food intake of rats in a dose-dependent manner. Serum biochemical analysis showed that DAT can increase the serum glucose level of rats. Fecal microbiota analysis showed that DAT treatment can significantly change the intestinal microflora of rats, the dose of 125 mg/kg/day has the most significant effect on the diversity of intestinal microbiota. In daily application, the side effects caused by DAT might be gastrointestinal irritation, weight loss, liver or kidney injury, and blood sugar elevation. Based on our study, the no-observed-adverse-effect level (NOAEL) of DAT is 125 mg/kg BW/day for rats.

Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases.

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.

Oral therapies for the treatment of pulmonary arterial hypertension: a population-based cost-minimization analysis.

BACKGROUND AND OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare but life-threatening condition that is characterized by progressive elevation of pulmonary artery pressure and pulmonary vascular resistance, leading to right-sided heart failure and frequently death. Orally administered agents used for the treatment of symptomatic, moderate-to-severe PAH include sildenafil and the endothelin (ET) receptor antagonists (ERAs), bosentan and sitaxentan (sitaxsentan). Ambrisentan is a new oral ET(A) receptor-selective ERA, with higher ET receptor affinity than bosentan. Placebo-controlled, randomized clinical trials (RCTs) have demonstrated that ambrisentan (5 or 10 mg/day) is safe and effective. To provide health economic data on the multiple oral PAH therapies currently available, a population-based cost-minimization analysis (CMA) was conducted for Canada. METHODS: The primary requirement for a CMA is that all clinical outcomes be equivalent between comparator treatments. To provide such supporting data, a literature search was conducted for RCTs of oral agents used to treat symptomatic PAH. This was followed by application of direct and indirect statistical methods to support the hypothesis of clinical equivalence between the oral agents. Estimates for PAH prevalence, incidence and death rates were then used to build a population-based CMA model. The base-case analysis considered costs for drug therapy, outpatient pharmacy costs, medical consultations and visits, laboratory and diagnostic procedures and other healthcare-related resources. In addition, costs for secondary pharmacotherapy in cases where the primary agent had to be discontinued because of adverse effects were also included. The time horizon for evaluating pharmacotherapy was 3 years, all costs were in 2008 Canadian dollars ($Can) and the costs were discounted at a rate of 3% annually. The study perspective was the Canadian healthcare system. RESULTS: There were no double-blind RCTs comparing ambrisentan with any of the other oral agents. Therefore, an indirect comparison of placebo-controlled trials of PAH drugs had to be used to support the clinical equivalence. This included a calculation of standardized mean differences (SMD) between agents (vs placebo) and a meta-regression analysis on the primary and secondary trial endpoints. Keeping in mind the caveats associated with indirect trial comparisons, the data suggested similar clinical efficacy over 12-16 weeks between agents, as indicated by the identical magnitude of the SMD between the active agent and placebo and the non-significant differences between drugs as determined by the meta-regression analysis. The population-based model projected that the number of PAH patients clinically suitable for these drugs in Canada would be 931 in the first full-budget year (i.e. 2009) with an increase to 1114 by the third full year. The CMA revealed the following rank order of the least to most costly agent; sildenafil, ambrisentan, sitaxentan and bosentan. Sildenafil was the least costly, primarily because of the lower daily drug-acquisition cost. Of the three ERAs, ambrisentan would be associated with annual cost savings of $Can3.4 and $Can5.6 million when used as an alternative to sitaxentan or bosentan, respectively. CONCLUSIONS: Ambrisentan is less costly than other available ERAs, including bosentan and sitaxentan, but is more costly than sildenafil. In PAH patients in whom an ERA is the preferred agent, ambrisentan may be the drug of choice because of its economic advantages and improved safety profile.

Role of ambrisentan in the management of pulmonary hypertension.

OBJECTIVE: To review the role of ambrisentan in the treatment of pulmonary arterial hypertension (PAH). DATA SOURCES: Literature was accessed through MEDLINE (1950-June 2008), Iowa Drug Information Service (1966-March 2008), EMBASE (1966-June 2008), bibliographies of pertinent articles, and unpublished data provided by the manufacturer and the Food and Drug Administration (FDA). Search terms included ambrisentan, endothelin antagonist, pulmonary hypertension, and pulmonary arterial hypertension. Due to limited literature available, additional criteria to limit searches were not used. STUDY SELECTION AND DATA EXTRACTION: Abstracts and original preclinical and clinical research reports available in the English language were identified for review. All manufacturer-provided data were also evaluated. Literature related to ambrisentan, endothelin antagonists, pulmonary hypertension, and pulmonary arterial hypertension were included. Four clinical trials evaluated the efficacy of ambrisentan in adults with symptomatic PAH. DATA SYNTHESIS: Ambrisentan is the latest endothelin-receptor antagonist (ERA) to obtain FDA approval for the treatment of PAH. It joins the first FDA-approved ERA, bosentan. Like bosentan, ambrisentan is available orally (with once-daily dosing compared with bosentan's twice-daily dosing) and has been shown to improve exercise capacity and delay clinical worsening. As with bosentan, the most significant safety concerns with ambrisentan relate to potential liver injury and a contraindication in pregnancy. Although ambrisentan has higher affinity for the endothelin type A receptor than for the endothelin type B receptor, specific advantages of this selectivity, in terms of efficacy compared with bosentan, a nonselective agent, have not been demonstrated. CONCLUSIONS: Ambrisentan has been shown to be an effective ERA in patients with PAH. A significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH.

Ambrisentan for the management of pulmonary arterial hypertension.

BACKGROUND: Approved by the US Food and Drug Administration in 2007, ambrisentan is the second oral endothelin A-receptor antagonist available for the management of pulmonary arterial hypertension (PAH) in patients with World Health Organization class II or III symptoms. OBJECTIVE: This article examines the clinical pharmacology of ambrisentan, its efficacy and adverse effects, and future directions for research. METHODS: Pertinent articles and abstracts were identified through searches of MEDLINE and Current Contents from 1966 to January 15, 2008, using the term ambrisentan. The reference lists of identified articles were searched for additional publications. Abstracts presented at professional meetings from 2005 through 2007 were also reviewed. RESULTS: The literature review identified 3 studies of ambrisentan in PAH: 1 dose-ranging study; 2 randomized, double-blind, placebo-controlled studies; and 1 drug-conversion study. In the dose-ranging study, ambrisentan at doses of 1 to 10 mg was associated with significant improvements from baseline in the 6-minute walk distance at 12 weeks that ranged from 33.9 m with ambrisentan 1 mg (P = 0.003) to 38.1 m with ambrisentan 5 mg (P = 0.001). In the placebo-controlled studies, ambrisentan at doses of 2.5 to 10 mg/d was associated with significant improvements versus placebo in the 6-minute walk distance at 12 weeks that ranged from 22 m with ambrisentan 2.5 mg (P = 0.022) to 59 m with ambrisentan 5 mg (P

[The analysis of prescription frequency and the factors on adverse reactions of NSAIDs for post-operative pain in orthopedic patients].

Recently, adverse reaction of non-steroidal anti-inflammatory drugs (NSAIDs) is the critical problem, although NSAIDs are one of the most commonly used classes of medications worldwide. Therefore, it is worthwhile to investigate the prescription frequency and the factors on adverse reactions of NSAIDs for post-operative pain in orthopedic patients of our hospital. In orthopedic field, loxoprofen was most prescribed in various kinds of NSAIDs. Logistic regression analysis strongly indicated that previous adverse reaction or allergy caused by drugs (not NSAIDs) or food is the important role in the adverse reaction of NSAIDs. In addition, significant correlation was observed between previous illness of gastrointestinal ulcer and gastrointestinal complication of NSAIDs. Moreover, the present study point out that pharmacist clinical intervention against the adverse reaction of NSAIDs may be saved on medical costs. Although further investigation may be needed, these present studies provide the good information for our medication management and instruction tasks (i.e. pharmaceutical care and counseling for inpatients) for post-operative pain of orthopedic patients.