COPD所致肺动脉高压与同型半胱氨酸相关性研究

目的：探讨慢性阻塞性肺疾病（COPD）所致不同程度肺动脉高压（PH）与血浆同型半胱氨酸（Hcy）的相关性。方法：应用反相高效液相色谱荧光检测法测定了COPD合并PH轻、中、重度患者以及COPD合并高血压及PH轻、中、重度患者的Hcy,采用SPSS 17.0软件对数据进行统计分析。结果：COPD合并PH轻、中、重度患者血浆Hcy差异无统计学意义（P〉0.05）,但COPD合并PH及高血压患者的Hcy明显高于未合并高血压患者（P〈0.05）。结论：检测血浆Hcy对于高血压疾病的预防、诊断具有重要的临床应用价值,但对于COPD合并PH疾病无太大的临床应用价值。     

Cardiopulmonary indications for endothelin receptor antagonists: review of recent efficacy trials

Recent clinical and experimental animal trials indicate that endogenously produced endothelin-1 (ET-1) contributes to the abnormal systemic and pulmonary vascular resistance associated with congestive heart failure (CHF) and pulmonary hypertension (PH). In experimental CHF, the chronic blockade of ET-1 actions by ET receptor antagonists clearly improves haemodynamic status, and improves cardiac structure and survival. The latter is based on limited results. In experimental PH there are consistent reports of prevention and reversal of PH, pulmonary vascular remodelling and right ventricular hypertrophy, independent of the inciting mechanisms. These results in experimental animals illustrate the potential efficacy of the ET receptor antagonists in future clinical trials. With five ET receptor antagonists in clinical development, and more on the way, their potential will soon be realised.     

慢性阻塞性肺疾病肺动脉高压与气流受限的相关性研究

目的探讨慢性阻塞性肺疾病（COPD）相关性肺动脉高压的发生率、及其与气流受限的相关性。方法对82例稳定期的COPD患者及26例健康对照者进行静态肺功能、血气分析及超声心动图检测。COPD患者依据肺功能指标进一步分级;根据超声心动图检测的肺动脉收缩压（PSAP）值,将COPD患者分为COPD并肺动脉高压组（PASP≥40mmHg）和单纯COPD组（PASP〈40mmHg）。结果 COPD患者肺动脉高压的发生率为22%,进一步分层发现轻,中、重、极重度COPD患者肺动脉高压发生率分别为5%、27%、29%和54%（χ2=9.04,P〈0.05）,两两比较仅极重度COPD组与轻度COPD组肺动脉高压发生率有显著性差异,其他组间比较差异无统计学意义。COPD并肺动脉高压组及单纯COPD组第一秒用力呼气容积占预计值的百分比（FEV1占预计值%）、FEV11/用力肺活量（FVC）（FEV1/FVC）、动脉血氧分压（PaO）2均较健康对照组降低（P〈0.01）。COPD并肺动脉高压组与单纯COPD组比较FEV1占预计值%、FEV1/FVC、一氧化碳弥散量占预计值的百分比（DLCO占预计值%）、动脉血二氧化碳分压（PaCO）2差异均无统计学意义（P均〉0.05）;两组间PaO2比较差异有统计学意义（P〈0.01）。COPD并肺动脉高压组、单纯COPD组及健康对照组3组间年龄及性别相比差异均无统计学意义（P均〉0.05）。PASP与FEV1占预计值%、FEV1/FVC、DLCO占预计值%呈显著负相关（分别为：r=-0.42,r=-0.52,r=-0.38,均P〈0.01）,PASP与PaO2相关性更强（r=-0.61,P〈0.01）。结论随着COPD病情的加重,肺动脉高压的发生率随之增加。气流受限在肺动脉高压的形成中并非单一因素,部分COPD患者存在与气流受限＂不成比例＂的肺动脉高压。     

Practical considerations for the pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension is a devastating disease. Before the 1990s, when pharmacologic treatment was finally approved, only supportive therapy was available, consisting of anticoagulation, digoxin, diuretics, and supplemental oxygen. Calcium channel blocker therapy was also an option, but only a small percentage of patients respond to it. However, starting with epoprostenol in 1996, the number of drugs approved to treat pulmonary arterial hypertension increased. Three distinct classes of drugs were developed based on the pathophysiology of the disease: the prostanoids, endothelin-1 receptor antagonists, and phosphodiesterase type 5 inhibitors. The prostanoids are administered either parenterally or by inhalation to replace the lack of prostacyclin within the pulmonary arterial vasculature. The endothelin-1 receptor antagonists were the first class of oral drugs to be developed, but drug interactions and adverse effects are prominent with this class. The phosphodiesterase type 5 inhibitors increase the second messenger cyclic guanosine monophosphate (GMP) that is induced by nitric oxide stimulation. All of the drugs within these three classes are distinct in and of themselves, and their clinical use requires in-depth knowledge of pulmonary arterial hypertension and its pathophysiology. Because these drugs have different mechanisms of action, combination therapy has shown promise in patients with severe disease, although data are still lacking. This article should serve as a practical guide for clinicians who encounter patients with pulmonary arterial hypertension and the drugs used for the treatment of this devastating disease.     

血浆B型利尿钠肽在COPD伴肺动脉高压患者中的应用研究

目的研究血浆B型利尿钠肽(BNP)在COPD伴肺动脉高压患者中的应用价值。方法 2008年4月～2010年12月收集稳定期COPD患者85例,应用心脏超声测定肺动脉压力,采用免疫荧光法测定血浆BNP水平,并根据肺动脉压力水平分为正常、轻度、中度、重度肺动脉高压组,同时选择10例健康体检者测定其肺动脉压力及血浆BNP水平,比较各组BNP水平。结果健康体检者与肺动脉压力正常的COPD患者之间血浆BNP水平差异无统计学意义,与轻度、中度、重度肺动脉高压的COPD患者差异有统计学意义;各组COPD患者之间血浆BNP水平差异均有统计学意义;肺动脉压力与BNP水平有较强的正相关性。结论血浆BNP水平在稳定期COPD患者中随着肺动脉压力的增高而升高,血浆BNP水平反映了COPD患者肺动脉高压的程度。     

Drug treatment of primary pulmonary hypertension

Primary pulmonary hypertension is a rare but difficult-to-manage condition. Adequate clinical trials of agents used in its treatment have not been performed. A variety of drugs have been reported to provide benefit in patients with primary pulmonary hypertension, including beta-adrenoceptor agonists, alpha-adrenoceptor antagonists, and vasodilators such as isosorbide dinitrate, diazoxide, hydralazine, angiotensin converting enzyme inhibitors, prostaglandins and calcium antagonists. Calcium antagonists appear to offer the most promise, although treatment failures have occurred with them as well as with all other drugs used in this condition. In the absence of a specific treatment for primary pulmonary hypertension, several of the agents listed above should be tried before accepting therapeutic failure. Invasive investigation is necessary to adequately monitor the acute response to therapy. Whether combination therapy with 2 or more drugs might improve the response to treatment is an area worthy of further research.     

Rho-kinase as a potential therapeutic target for the treatment of pulmonary hypertension

Pulmonary hypertension (PH) is a cardiovascular disorder characterized by vasoconstriction and vascular remodeling. Recently, rapidly increasing evidence from various rat models of PH and patients with PH suggest that small GTPase Rho and its downstream effector, Rho-kinase, play a key role in the pathogenesis of PH. Activation of the Rho/Rho-kinase pathway is important for pulmonary endothelial dysfunction, pulmonary vascular smooth muscle cell contractility, proliferation and apoptosis in PH. A greater Rho-kinase expression and an enhanced Rho-kinase activity have been observed in pulmonary arteries of PH rats, such as hypoxia-induced, monocrotaline-induced and genetic spontaneous PH rats. Moreover, Y-27632 or fasudil, the selective Rho-kinase inhibitors, significantly attenuated PH in various pulmonary hypertensive model rats and patients with PH, but did not reduce systemic blood pressure. Therefore, Rho-kinase inhibitors may have therapeutic potential for the treatment of PH.     

Comparative pharmacology of the angiotensin II receptor antagonists

The non-peptide angiotensin II (AII) receptor antagonists are a new class of compounds that are continuing to be developed as therapeutic agents for the treatment of hypertension, heart failure (HF) and chronic renal disease (CRD). Several of these compounds are currently available for therapeutic use in the USA and the European community with several more in clinical trials and in development. Compounds in this new class are as effective as angiotensin converting enzyme (ACE) inhibitors in treating hypertensive patients and appeared to have a similar therapeutic profile to ACE inhibitors in patients with HF and CRD. One clinical advantage of the AII receptor antagonists over ACE inhibitors is an improved side-effect profile with the absence of the persistent dry cough associated with ACE inhibitor therapy. To date, it is clear that the AII receptor antagonists are effective antihypertensive agents. Clinical trials are currently in progress to determine the therapeutic efficacy of these drugs in the treatment of HF and progressive renal disease.     

小剂量阿奇霉素联用辛伐他汀治疗慢性阻塞性肺病合并肺动脉高压的系统评价

目的:系统评价小剂量阿奇霉素联用辛伐他汀治疗慢性阻塞性肺病(COPD)合并肺动脉高压(HP)的临床疗效和安全性。方法：计算机检索PubMed、Medline、CNKI、VIP、万方等数据库,手动检索相关杂志、会议论文及学术论文,收集小剂量阿奇霉素联用辛伐他汀治疗COPD合并HP的临床随机对照研究,检索年限为2000年1月至2016年10月。由2名研究者独立提取数据、评价质量,并交叉核对。采用RevMan 5.2 软件进行Meta分析。结果：共纳入11项研究,943例患者。Meta分析结果显示,剂量阿奇霉素联用辛伐他汀能显著提高COPD合并HP患者FVC [MD=0.50,95%CI(0.40,0.61),P<0.01]、FEV1 [MD=0.31,95%CI(0.24,0.38),P<0.01]、PaO₂ [MD=7.68,95%CI(7.10,8.26),P<0.01]、SaO₂(%) [MD=3.89,95%CI(3.29,4.50),P<0.01]、6MWT[MD= 77.01, 95%CI(72.88 , 81.14),P<0.01],显著降低平均肺动脉压[MD= -1.82,95%CI(- 2.27,- 1.36),P<0.01]和CRP[MD= -8.91, 95%CI(-10.42 , -7.39),P<0.01]。两组均未发生严重不良反应。倒漏斗图提示发表偏倚性较小。结论：现有证据表明,小剂量阿奇霉素联用辛伐他汀能显著改善COPD合并肺动脉高压患者肺功能、血氧饱和度和提高活动耐受力,同时显著降低肺动脉压和CRP,且安全可靠。     

转化生长因子β1血清水平与左向右分流型先天性心脏病肺动脉压力的相关性探讨

目的 通过对先天性心脏病及先天性心脏病伴肺动脉高压（PH）患者血清中转化生长因子β1（TGF-β1）水平的检测,进一步明确其与先天性心脏病伴肺动脉高压的关系.方法 采用实验研究策略,利用酶联免疫吸附测定（ELISA）方法测定48例先天性心脏病患儿（4组分为无PH组、轻度PH组、中度PH组、重度PH组各12例）静脉血清中TGF-β1的水平变化.结果 TGF-β1在重度PH组（2.01±0.26）μg/L明显高于中度PH组（1.80±0.56）μg/L、轻度PH组（1.34±0.11）μg/L及无PH组（0.82e±0.11）ug/L（P＜0.01）,尤以重度与无PH之间较为明显,差异具有统计学意义（P＜0.01）.结论 左向右分流型先天性心脏病患儿TFG-β1参与先天性心脏病伴肺动脉高压的形成,可能对先天性心脏病伴肺动脉高压程度的评价、手术指征及预后起着重要作用.     

N-端脑钠肽前体与慢性阻塞性肺疾病的相关性分析

目的探讨N-端脑钠肽前体在慢性阻塞性肺疾病（COPD）中的变化及其意义。方法117例确诊为COPD患者,分为单纯COPD组和COPD合并肺心病组,用电化学发光法测定血浆NT-ProB-NP并比较其差异。结果COPD合并肺心病组NT-ProBNP水平明显高于单纯COPD组,且NT-ProBNP水平在轻、中、重度肺动脉高压组间差异有统计学意义（P〈0.05）;NT-ProBNP与肺动脉收缩压、主肺动脉宽度、右心室前壁厚度、右心室舒张末内径有良好的相关性。结论血浆NT-ProBNP浓度能较好地反映COPD患者的肺动脉高压情况及右心室功能状态。     

氯沙坦治疗肺动脉高压的初步探讨

目的：探讨氯沙坦在治疗肺动脉高压中的作用，以评价其对慢性肺源性心脏病（肺心病）的疗效。方法：60例慢性阻塞性肺疾病同时伴有肺动脉高压病人分成两组，均给予常规吸氧、抗感染、祛痰、平喘等治疗。治疗组加服氯沙坦，50mg/次，每日一次。疗程2周。治疗前和2周时测定肺动脉压。结果：两组治疗后肺动脉压均有显著下降（P＜0．01）；治疗组肺动脉压的下降与对照组比较有极显著的差异（P＜0．001），动脉血氧分压的上升与对照组比较有明显差异（P＜0．05）。结论：慢性阻塞性肺疾病急性加重期病人通过常规吸氧、抗感染、祛痰、平喘等治疗可使肺动脉压降低，加用氯沙坦可使肺动脉压下降更为明显，并使动脉血氧分压上升，提示氯沙坦可用于肺心病的治疗。     

Corticosteroid resistance and novel anti-inflammatory therapies in chronic obstructive pulmonary disease: current evidence and future direction

Corticosteroids are widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, in contrast to their use in mild-to-moderate asthma, they are much less effective in enhancing lung function and have little or no effect on controlling the underlying chronic inflammation. In most clinical trials in COPD patients, corticosteroids have shown little benefit as monotherapy, but have shown a greater clinical effect in combination with long-acting bronchodilators. Several mechanisms of corticosteroid resistance have been postulated, including a reduction in histone deacetylase (HDAC)-2 activity and expression, impaired corticosteroid activation of the glucocorticoid receptor (GR) and increased pro-inflammatory signalling pathways. Reversal of corticosteroid resistance in COPD patients by restoring HDAC2 levels has proved effective in a small study, and long-term studies are needed to determine whether novel HDAC2 activators or theophylline improve disease progression, exacerbations or mortality. Advances in the understanding of the cellular and molecular mechanisms of corticosteroid resistance in COPD pathophysiology have supported the development of new emerging classes of anti-inflammatory drugs in COPD treatment. These include treatments such as inhibitors of phosphoinositide-3-kinase-delta (PI3Kδ), phosphodiesterase-4 (PDE4), p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB), and therapeutic agents such as chemokine receptor antagonists. Of these, PI3Kδ, PDE4, p38 MAPK inhibitors and chemokine receptor antagonists are in clinical patient trials. Of importance, patient adverse effects associated with oral administration of these novel agents needs to be addressed in order to optimize therapy and patient compliance. Combinations of these drugs with corticosteroids may have additional benefits.     

当归注射液对低氧性肺动脉高压血管收缩肽的影响

目的 :探讨当归注射液对低氧性肺动脉高压病人内皮素 1(ET 1)、血管紧张肽Ⅱ (AT Ⅱ )、内源性洋地黄 (EDF)和肺血流动力学的影响。方法 :慢性阻塞性肺疾病 (COPD)伴肺动脉高压 60例 ,随机分成 2组 ,每组 30例。当归组 [男性 2 1例 ,女性9例 ;年龄 ( 60±s 7)a]给予 2 5%当归注射液 2 50mL静脉滴注 ,qd× 10d ;对照组 [男性 2 0例 ,女性10例 ;年龄 ( 60± 8)a]给予静脉滴注 5%葡萄糖注射液 2 50mL ,qd× 10d。结果 :当归治疗后ET 1,ATⅡ和EDF分别降低 ( 2 0± 6) % ,( 36± 9) %和 ( 38± 11) % ,平均肺动脉压和肺血管阻力也降低 ( 17±5) %和 ( 2 7± 8) % ,与对照组相比均差异有显著意义或非常显著意义 (P <0 .0 5或P <0 .0 1)。结论 :当归能减少COPD伴肺动脉高压病人机体ET 1,AT Ⅱ和EDF的合成和释放 ,使肺动脉压降低 ,改善肺循环。     

Recent developments of small molecule endothelin modulators

Endothelin (ET) receptor antagonists, in particular endothelin ET_A-selective or ET_A/ET_B balanced antagonists, represent a novel new class of therapeutic agents. They have demonstrated utility or promise for unmet medical needs such as pulmonary hypertension, resistant hypertension, heart failure, diabetic nephropathy and subarachnoid haemorrhage. Oral endothelin antagonist-based treatments, either as monotherapy or in combination with agents of other mechanisms of action, should afford benefits to those patients. The importance of this field is evidenced by the number of compounds in clinical trials (i.e., 8) and by the number of patents filed in recent years. Between January 2002 and September 2005, there were 46 endothelin patents, of which 38 are concerned with endothelin receptor antagonists (ETRAs) and 8 with endothelin-converting enzyme (ECE) inhibitors/ET secretion inhibitors. Of the 38 ETRA patents, 12 disclose new chemical structures, 5 disclose processes, 11 disclose new uses and 10 disclose combination therapies. This article first discusses small-molecule endothelin antagonists presently in the clinic and then focuses on the 20 novel composition-of-matter patents in the area of ETRA, ECE inhibitors and ET secretion inhibitors.     

Muscarinic antagonists in early stage clinical development for the treatment of asthma

Introduction: Parasympathetic neurons utilize the neurotransmitter acetylcholine to modulate and constrict airway smooth muscles at the muscarinic acetylcholine receptor. Inhaled agents that antagonize the muscarinic (M) acetylcholine receptor, particularly airway M3 receptors, have increasing data supporting use in persistent asthma.

Areas covered: Use of inhaled long-acting muscarinic antagonists (LAMA) in asthma is explored. The LAMA tiotropium is approved for maintenance in symptomatic asthma patients despite the use of inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA) and/or long-acting beta₂ agonists (LABA). LAMA agents currently approved for chronic obstructive pulmonary disease (COPD) include tiotropium, glycopyrrolate/glycopyrronium, umeclidinium and aclidinium. These agents are reviewed for their pharmacological differences and clinical trials in asthma.

Expert opinion: Current guidelines place inhaled LAMAs as adjunctive maintenance therapy in symptomatic asthma not controlled by an ICS and/or a LTRA. LAMA agents will play an increasing role in moderate to severe symptomatic asthma patients. Additional LAMA agents are likely to seek a maintenance indication perhaps as a combined inhaler with an ICS or with an ICS and a LABA. These fixed-dose combination inhalers are being tested in COPD and asthma patients. Once-a-day dosing of inhaled LAMA agents in severe asthma patients will likely become the future standard.     

Vascular endothelin in hypertension

Endothelins are powerful vasoconstrictor peptides that also play numerous other functions in many different organs. Endothelin-1 (ET-1) is the most abundant and important of this family of peptides in blood vessels. Production of ET-1 is increased in the endothelium and the kidney in salt-dependent models of hypertension (e.g.: DOCA-salt rats and Dahl salt-sensitive rats, in salt-loaded SHR-SP, in angiotensin II-infused and in diabetic rats). ET-1 elicits an inflammatory response by increasing oxidant stress in the vascular wall, which induces vascular remodeling and endothelial dysfunction found in the hypertensive models that exhibit an endothelin-mediated component. Endothelin receptor antagonism reduces blood pressure and vascular hypertrophic remodeling present in these hypertensive models. Patients with stage 2 hypertension have enhanced vascular expression of ET-1. Endothelin receptor antagonists lower blood pressure in hypertensive patients. They could become therapeutic agents for prevention of target organ damage in hypertension and in type 2 diabetes, chronic renal failure and congestive heart failure. Side effects of endothelin receptor blockers have prevented up to the present their development for these indications. New endothelin antagonists devoid of these side effects, or alternatively inhibitors of the endothelin converting enzymes that generate ET-1 may in the future become available to block the endothelin system. However, to date endothelin antagonists have been approved only for the treatment of primary pulmonary hypertension, a rapidly fatal condition in which the endothelin system plays an important role and endothelin antagonists exert favorable effects.     

Discontinued drug projects in the respiratory therapeutic area during 2012

During 2012, a number of respiratory drug projects and individual agents were discontinued, for a variety of reasons, including toxicity, lack of efficacy, commercial re-evaluation and change in corporate focus. These included three antagonists of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2), which had been evaluated in allergic respiratory disease and (in one case) chronic obstructive pulmonary disease (COPD), and other agents intended for the treatment of asthma, COPD, pulmonary hypertension and lung fibrosis. These have been reviewed against the background of a general reduction in respiratory research by the pharmaceutical industry.     

The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension

Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90mmHg for uncomplicated hypertension and <130/80 mmHg for patients with diabetes mellitus or renal disease. For those with uncontrolled hypertension, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of hypertension include several major classes of drugs: diuretics, ß-adrenoceptor antagonists (ß-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of ARBs in combination with amlodipine for the treatment of hypertension, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with ARBs revealed six publications, which are included in this review.