Methods of treating and preventing endothelial dysfunction using bardoxolone methyl or analogs thereof
一种肾病、用途的技术，应用在药物组合、医药配方、呼吸系统疾病等方向
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Embodiment 1
[0405] Example 1 - Bardoxolone Methyl Alleviates Endothelial Dysfunction
[0406] In a clinical trial of bardoxolone methyl (BARD) in patients with stage 3b or 4 chronic kidney disease and type 2 diabetes, a significant improvement in the content of circulating endothelial cells was noted ( figure 2 ). An improvement was also noted in the number of CECs that tested positive for inducible nitric oxide synthase (iNOS), an inflammation-promoting enzyme. Nonclinical studies have shown that BARD and other AIMs can reduce ROS content and increase NO bioavailability in endothelial cells (Figure 3).
[0407] Nonclinical studies have also shown that BARD reduces the expression of endothelin-1 (ET-1) in mesangial cells (found in the kidney) and endothelial cells (Table 22). In this study, BARD also reduced vasoconstriction ET A Receptor expression, while increasing vasodilation ET B Expression of receptors (Table 22). ET-1 (natural peptide) is the most potent endogenous vasoconstr...
Embodiment 2
[0413] Example 2 - Effect of RTA dh404 on lung histology in a rat model of monocrotaline-induced pulmonary hypertension
[0414] The effect of oral administration of the bardoxolone-methyl analog RTA dh404 was evaluated in a rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). MCTs are macrolytic pyrrolizidine alkaloids and are activated in the liver by cytochrome P450 enzymes to toxic metabolites (i.e., dehydromonocrotaline), which then induce PAH, pulmonary mononuclear A syndrome characterized by cellular vasculitis and right ventricular hypertrophy (Gomez-Arroyo et al., 2012).
[0415] To evaluate RTA dh404, male Sprague-Dawley rats received a single injection of MCT on day 1 and then received vehicle (sesame oil), RTA dh404 (2, 10 or 30 mg / kg / day) or positive control Sildenafil (60mg / kg / day) for 21 days. The arterial hypertrophy, cell infiltration and pulmonary edema of the lung tissue were then analyzed by histopathology. The carrier lung app...
Embodiment 3
[0418] Example 3 - Dose Range Study of the Efficacy and Safety of Bardoxolone Methyl in Patients with Pulmonary Arterial Hypertension
[0419] This two-part phase 2 trial will investigate the safety, tolerability and efficacy of bardoxolone methyl in patients with WHO group 1 PAH. Part 1 will be a double-blind, randomized, dose-ranging, placebo-controlled treatment period and Part 2 will be an extension period. Eligible patients must have been receiving oral, disease-specific PAH therapy consisting of an endothelin-receptor antagonist (ERA) and / or a phosphodiesterase type 5 inhibitor (PDE5i). The dose of prior therapy must have been stable for at least 90 days prior to Day 1.
[0420] Part 1: Part 1 of the study will include both dose escalation and expansion groups. Dose escalation cohorts will be recruited, one at a time. Each cohort will include the next 8 eligible patients randomized in a 3:1 assignment ratio to receive bardoxolone methyl or matching placebo to be admin...
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