Drug Targeting to the Lung: Chemical and Biochemical Considerations
Anthony J. Hickey, Sandro R.P. da Rocha in Pharmaceutical Inhalation Aerosol Technology, 2019
Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by an increase in blood pressure in the small arterioles that supply blood to the lungs. The underlying molecular and cellular mechanisms involved in PAH appear to be complex, with the pathophysiology suggesting a multifaceted disease in which cellular proliferation and vascular remodeling occurs, along with several other additional cellular mechanisms (Vaidya and Gupta 2015, Gaine and McLaughlin 2017). Combination therapy is now commonly used as the standard of care approach, with therapies that target three different pathogenic pathways. These therapies involve the use of drugs that target the endothelin and nitric oxide pathways, as well as the prostacyclin pathway (Malenfant et al. 2013, Lang and Gaine 2015). In recent studies (Bertero et al. 2016), it has been shown that in PAH-diseased lung tissue, dysregulation of vascular stiffness and cellular metabolism mechanoactivates the transcriptional coactivators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ)-dependent glutaminolysis, to drive PAH. These studies indicate that targeting this pathology with drugs such as the glutaminase inhibitor, CB-839 (Gross et al. 2014) or the YAP inhibitor, verteporfin (King et al. 2014) may prove beneficial in this disease. CB-839 is currently undergoing active clinical development in early clinical trials for cancer therapy, and verteporfin is already approved by the FDA for treatment of age-related macular degeneration (Kent 2014).
Pulmonary hypertension induced by drugs and toxins
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, characterized by intense remodelling resulting in a progressive increase in pulmonary vascular resistance.1 PAH is a progressive condition that can occur in an idiopathic form or in association with other disease states or exposures and is believed to result from environmental or disease-inciting factors coupled with genetically determined susceptibilities.1 By definition, PAH patients do not have significant left heart disease, lung disease, or acute or chronic thromboembolic disease.2 A diagnosis of PAH requires invasive haemodynamic criteria including a mean pulmonary artery pressure above 25 mmHg at rest and a normal pulmonary capillary wedge or left ventricular end-diastolic pressure under 15 mmHg.1
Cardiology
Kristen Davies, Shadaba Ahmed in Core Conditions for Medical and Surgical Finals, 2020
Also exacerbated by activity, e.g. raising legs a few times off the bed, with an opening snap and tapping apex beat. Loudest at the apex. Causes: (1) Rheumatic fever, (2) congenital.Symptoms: Palpitations, dyspnoea, fatigue, haemoptysis (from pulmonary hypertension), chest pain.O/E: Malar flush (CO2 retention), mid-diastolic murmur, opening snap, tapping apex beat (not displaced). A Graham-Steell murmur may occur (high-pitched early diastolic murmur heard at left sternal edge. Caused by pulmonary regurgitation secondary to mitral stenosis). JVP may be raised.Investigations: ECG (AF, p-mitrale, RVH, RAD), CXR (left atrial enlargement, pulmonary oedema), echocardiogram (diastolic).Management: In AF rate control + anticoagulation. Diuretics to reduce fluid and preload. Surgery (balloon valvuloplasty or valve replacement).
Perinatal changes in estradiol and Ang II concentrations in pregnant women with pulmonary arterial hypertension and their correlation
Published in Hypertension in Pregnancy, 2019
Yanshuang Wang, Hao Che, Kai Kang, Guosheng Zhao, Xiaoguang Li, Xiangming Che, Mingjun Xu, Liyun Zhao
Pulmonary arterial hypertension (PAH) is a rare and progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs and may lead to right heart failure and death. Typical pathological changes of PAH include pulmonary vasoconstriction, intimal hyperplasia and remodeling, and thrombosis. PAH is usually considered refractory, and there is still a lack of effective treatment (1). Pregnancy with PAH is even more dangerous. As observed in clinical practice, deterioration usually occurs at an early stage after delivery in women with congenital heart disease plus severe PAH (2). It remains unclear whether the changes in hormone levels before and after delivery play a role. As more knowledge is gained with respect to PAH, it has been found that perinatal sex hormones in pregnant women regulate neurotransmitters and cell receptor expressions, hence further influencing hemodynamic changes. Renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of PAH (3). Renin, Ang I, Ang II and renin-angiotensin-aldosterone system (RAAS) play a role in the pathogenesis of PAH. Based on the literature review, PAH is associated with the changes in estradiol E2 levels (4,5). However, it has been rarely reported whether estradiol E2 is related to Ang II, especially in pregnant women with PAH. We reviewed the clinical data of 21 pregnant women with PAH who were treated at Beijing Anzhen Hospital Affiliated to Capital Medical University from March 2015 to March 2016, and assessed the perinatal changes in plasma concentrations of E2 and Ang II and the potential correlation between the two.
Effect of ambrisentan on echocardiographic and Doppler measures from patients in China with pulmonary arterial hypertension
Published in Expert Review of Cardiovascular Therapy, 2020
Qin-Hua Zhao, Fu-Hua Peng, Zai-Xin Yu, Gang-Cheng Zhang, Qiu-Shang Ji, Yong Wang, Jin-Ming Liu, Yong Huo, Xiao-Feng Zeng, Jian-Hui Li, Lu Zi, Zhi-Cheng Jing
Pulmonary arterial hypertension (PAH) is a condition defined by a mean pulmonary artery pressure (mPAP) ≥ 25 mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and a pulmonary vascular resistance of ≥3. Wood Units that leads to a restricted flow through the pulmonary arteries [1]. This complex, multifactorial disorder typically results in an overload of the right ventricle (RV), progressive right-sided heart failure, and premature death [2]. PAH can occur in multiple clinical conditions, including connective tissue disease (CTD)-PAH and idiopathic pulmonary arterial hypertension (IPAH) [3]. According to a retrospective cohort study conducted in China, 1- and 3-year survival estimates were 92.1% and 75.1%, respectively, in patients with IPAH, and 85.4% and 53.6%, respectively, in patients with CTD-PAH. The data points to the fact that PAH imposes a considerable disease burden in the Chinese population [4].
Two patients with mixed connective tissue disease complicated by pulmonary arterial hypertension showing contrasting responses to pulmonary vasodilators
Published in Modern Rheumatology Case Reports, 2020
Katsuhide Kusaka, Kazuhisa Nakano, Shigeru Iwata, Satoshi Kubo, Tomoya Nishida, Yoshiya Tanaka
Mixed connective tissue disease (MCTD) was proposed by Sharp et al. [1] in 1972. It clinically involves at least 2 of the following 3 manifestations: systemic lupus erythematosus (SLE)-like manifestation, systemic sclerosis (SSc)-like manifestation, and polymyositis/dermatomyositis (PM/DM)-like manifestation. Serologically, it is characterised by positivity for only high-titer anti-U1-ribonucleoprotein (U1-RNP) antibody. This disease is associated with a wide range of organ dysfunctions. Raynaud’s phenomenon and finger swelling are physical findings that aid in its diagnosis. In this disease, pulmonary arterial hypertension (PAH) is the most important organ dysfunction that defines prognosis. PAH is a prognostic factor for not only MCTD but also SLE and SSc. On comparing PAH with idiopathic pulmonary arterial hypertension (IPAH) without any underlying diseases, such as connective tissue diseases (CTDs), PAH might be more responsive to immunosuppressive therapy as well as pulmonary vasodilators. PAH is one of the disease types of broadly defined pulmonary hypertension (PH), and its recommended therapies differ from those for other types of PH. CTDs, such as MCTD, are complicated by multiple organ dysfunctions because of their various clinical pathological conditions. Thus, it is necessary to appropriately diagnose the disease type of PH, classify the severity, and select treatment accordingly. Here, we present 2 cases of MCTD complicated by PH that had contrasting clinical courses.
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