The Effect of Riociguat on Gas Exchange, Exercise Performance, and Pulmonary Artery Pressure During Acute Altitude Exposure
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Mean Pulmonary Artery Pressure
研究概览
简要总结
During ascent to high altitude there is a physiologic response to hypoxia that results in an elevated pulmonary arterial pressure associated with decreased exercise performance, altitude-induced pulmonary hypertension, and high altitude pulmonary edema (HAPE). Riociguat is a novel agent from Bayer Pharmaceuticals that has already demonstrated effectiveness in the treatment of pulmonary hypertension, and it may prove to be beneficial in cases of altitude-induced pulmonary hypertension or HAPE. This research study, composed of 20 healthy volunteers ages 18-40 years, will attempt to mimic the decreased oxygen supply and elevated pulmonary artery pressures found in conditions of high altitude, allowing observation of the effects of riociguat and exercise on pulmonary arterial pressure, arterial oxygenation, and exercise performance. Prior to entering the hypobaric chamber, subjects will have radial arterial lines and pulmonary artery catheters placed to obtain arterial and pulmonary artery pressure measurements. Subjects will then enter the hypobaric chamber and perform exercise tolerance tests at a simulated altitude of 15,000 feet on an electrically braked ergometer (exercise bike) before and after administration of riociguat. If, after administration of riociguat and exposure to a simulated altitude of 15,000 feet, the exercise performance is improved and observed pulmonary artery pressures are lower than those measurements seen prior to administration of riociguat, this could lead to development of a prophylactic and/or treatment strategy for HAPE and high-altitude pulmonary hypertension. Statistical analysis will compare the variables of pulmonary artery pressure, radial arterial pressure, ventilation rate, cardiac output, PaO2, and work rate at exhaustion before and after administration of the drug riociguat. The investigator's hypothesis is that riociguat will decrease pulmonary artery pressure and improve gas exchange and exercise performance at altitude.
详细描述
Background and Significance:
Impairment of exercise performance during hypoxemia due to altitude exposure or lung disease is caused primarily by reduced oxygen delivery to the exercising muscles, due to the reduction in arterial oxygen content. This reduction in arterial oxygen content is due to reduced alveolar PO2 and ventilation/perfusion (VA/Q) mismatch, and to some extent alveolar to end-capillary diffusion impairment. Ultimately, hypoxemia results in secondary diffuse pulmonary vasoconstriction (hypoxic pulmonary vasoconstriction, HPV), which in turn causes pulmonary hypertension. This secondary pulmonary hypertension is believed to worsen VA/Q mismatch, further reducing the PO2, suggesting that pharmacologic blockade of HPV could increase PO2 (e.g. during altitude exposure) and thus improve exercise performance. Reduction in pulmonary artery pressure (PAP) in individuals susceptible to high altitude pulmonary edema (HAPE) could also facilitate both prevention and treatment of HAPE.
Sildenafil is commonly used to treat pulmonary hypertension, including pulmonary hypertension that occurs due to altitude exposure, with variable success in treating cases of altitude-induced pulmonary hypertension and HAPE. Sildenafil works via blockade of blocks phosphodiesterase-5 (PDE-5) in pulmonary arterioles, causing an increase in cGMP. When cGMP is activated by nitric oxide (NO) it induces vasodilatation, and indeed, sildenafil administration during altitude exposure does increase arterial oxygenation slightly. However, attempting to block HPV with sildenafil by using a pathway that requires NO can only be realized if there is sufficient NO available to produce cGMP. During hypoxia endogenous levels of NO are depleted due to impaired endothelial NO synthesis. This may explain the inconsistent effects of sildenafil when used to improve oxygenation and performance at altitude.
Endogenous concentration of unbound NO is actually quite low, and most of the biological effects of NO are mediated through formation of S-nitrosothiols (SNOs) such as S-nitrosohemoglobin (SNO-Hb). NO binds to hemoglobin in a PO2-dependent manner, forming SNO-Hb so that when PO2 is low, NO-Hb binding is less avid and SNO-Hb is depleted. Depletion of SNO-Hb during hypoxia has been proposed as a mechanism that augments HPV, and indeed hypoxia has been shown to induce low levels of SNO-Hb. It is quite possible that the reduction in available endogenous NO and depletion of SNO-Hb during hypoxia limits the effect of the cGMP mechanism by which sildenafil works. Thus, an agent which can activate cGMP during periods of hypoxia when NO and SNO-Hb are depleted should be more effective in treating altitude-induced pulmonary hypertension.
Riociguat is a stimulator of soluble guanylate cyclase that bypasses the NO pathway and is currently approved by the FDA for treatment of pulmonary hypertension. Riociguat exhibits a dual mode of action that i.) stabilizes the reduced form of the nitrosyl-heme complex, enhancing the NO-cGMP signaling pathway in the absence of endogenous NO and ii.) acts in synergy with endogenous NO by increasing sGC sensitivity to NO. Essentially, riociguat stimulates sGC to produce cGMP in the absence of NO, and it is a mechanism by which pulmonary vascular resistance could be attenuated during altitude-induced pulmonary hypertension. It has recently been shown to augment exercise performance and decrease pulmonary artery pressure in both primary pulmonary hypertension and pulmonary arterial hypertension (PAH) due to chronic thromboembolic disease. Lowering pulmonary artery pressure could improve pulmonary gas exchange and performance at altitude, which has significant implications for those living at altitude, conducting military operations, altitude trekkers and high-altitude rescue teams. Direct stimulation of sGC also represents a promising alternative therapeutic strategy for those susceptible to high altitude pulmonary edema (HAPE) when current treatment modalities of nifedipine and sildenafil are ineffective and oxygen is unavailable. By itself or in combination with sildenafil, riociguat could produce a significant advance in exercise performance during altitude exposure and provide a substantial improvement over the current therapeutic options in the prevention and treatment of HAPE.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Other
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 40 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy males and females
- •Non-smoking
- •Non-pregnant females
- •Ages 18 - 40 years old
排除标准
- •Serious pulmonary or cardiovascular comorbidities
- •Pregnant women
- •VO2max < 35 mL/kg per minute
- •Sickle cell trait or disease
- •Lung disease
- •Hypertension
- •Cardiac disease and left bundle branch block
- •Taking nitrates, nitric oxide donors (such as amyl nitrite), and phosphodiesterase (PDE) inhibitors (including specific PDE-5 inhibitors, such as sildenafil, tadalafil, or vardenafil, or non-specific PDE inhibitors, such as dipyridamole or theophylline).
研究组 & 干预措施
Riociguat 0.5 mg
Riociguat 0.5 mg tablets, one-time oral dose of 0.5 mg
干预措施: Riociguat (Drug)
Riociguat 1.0 mg
Riociguat 0.5 mg tablets, one-time oral dose of 1.0 mg
干预措施: Riociguat (Drug)
结局指标
主要结局
Mean Pulmonary Artery Pressure
时间窗: At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test
Subject pulmonary artery pressures will be continuously monitored during the VO2max exercise test in the hypobaric chamber at a simulated altitude of 15,000 feet. Exercise level will be increased every 3 minutes until test termination criteria are achieved. Measurements will be obtained at rest, every 3 minutes during the exercise test (referred to as a stage below) and at 5 minutes post exercise. Results will be reported as a 30 second average. Subjects in the Riociguat cohorts will be tested prior to receiving drug and 90 minutes after receiving drug (midway through a three hour rest period between altitude exposures).
次要结局
- Mean Radial Arterial Pressure(At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test)
- Mean Arterial Oxygen Saturation (SaO2)(At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test)
- Mean Ventilation Rate(At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test)
- Mean Work Rate at Exhaustion(At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test)
- Cardiac Output(At rest, every 3 minutes during the exercise test and 5 minutes after each exercise test)
研究者
Richard Moon
Medical Director, Duke Center for Hyperbaric Medicine and Environmental Physiology, Professor of Anesthesiology, Professor of Medicine
Duke University