What is pulmonary hypertension?

Pulmonary arterial hypertension is a clinical pathophysiological syndrome characterized by a progressive increase in pulmonary vascular resistance. Its hemodynamic definition is: the average pulmonary artery pressure measured by the right heart catheterization at rest is ≥ 20mmHg (normal value is 11-15mmHg). According to the latest classification at the 2022 World Conference on Pulmonary Hypertension, PH is divided into five clinical types, with the first type being pulmonary arterial hypertension (PAH), which is the most representative subtype characterized by vascular remodeling and stenosis caused by lesions in the pulmonary arterioles themselves.

What is the epidemiological study of pulmonary hypertension?

Epidemiological data show that the global prevalence of PAH is about 15-50 cases/million people, and the annual incidence rate is about 5-10 cases/million people. Although it is a rare disease, its disability and mortality rates are extremely high, and the median survival time without targeted drug treatment is only 2.8 years, making it a "malignant tumor of the cardiovascular system". The latest registered research in China shows that the median age of diagnosis for PAH patients is 36 years old, with female patients accounting for about 76%, highlighting its significant impact on the social labor force.
 

What is the pathophysiological mechanism of pulmonary arterial hypertension?

The pathophysiological mechanism of pulmonary hypertension is a complex process involving vasoconstriction, vascular remodeling, inflammatory reaction and in-situ thrombosis. Its core is the progressive increase of pulmonary vascular resistance, which leads to the increase of right ventricular afterload and eventually leads to right heart failure. The following is a detailed mechanism analysis based on the latest medical consensus:

First, the core mechanism: pulmonary vascular remodeling Pulmonary vascular remodeling is the most fundamental pathological change of pulmonary hypertension, which is mainly manifested by thickening of the middle layer, intimal hyperplasia and fibrosis of pulmonary arterioles, leading to stenosis or even occlusion of vascular lumen.

1. Endothelial cell dysfunction: Under normal circumstances, vascular relaxing factor secreted by endothelial cells is in equilibrium with vasoconstrictor. When the internal environment is unstable, this balance is often reduced due to the contraction factor, which will lead to the continuous abnormal contraction of blood vessels. In this process, the continuous decrease of cGMP and cAMP messengers as signal pathways also directly weakened the vasodilation ability.

2. Abnormal proliferation of smooth muscle cells: Potassium channel dysfunction: The function of voltage-gated potassium channel (Kv) on pulmonary artery smooth muscle cells (PASMC) is down-regulated, which leads to the decrease of intracellular potassium ion outflow and depolarization of cell membrane, thus activating voltage-gated calcium channel and increasing calcium ion inflow. Elevated intracellular calcium concentration (Ca2+i) is the key signal to drive the proliferation and contraction of smooth muscle cells. Metabolic reprogramming: Smooth muscle cells with PH show similar metabolic characteristics to cancer cells, that is, "Warburg effect", which gives priority to glycolysis even under aerobic conditions, which provides energy and biosynthetic precursors for their rapid proliferation.

Second, the auxiliary mechanism According to the latest research

in addition to the above core mechanisms, the following factors will also aggravate the latest progress of this disease:

Inflammation and immunity: A variety of inflammatory cells infiltrate the pulmonary vascular wall, release inflammatory factors and promote vascular remodeling. In situ thrombosis: due to vascular endothelial injury and blood stasis, microthrombosis is easy to form in pulmonary microcirculation, further blocking blood vessels. Genetic factors: some patients have mutation of bone morphogenetic protein receptor 2 gene, which leads to damage of BMP/Smad signal pathway, inhibition of cell apoptosis and uncontrolled proliferation.

The comprehensive change of the above mechanisms leads to the continuous increase of pulmonary vascular resistance and the increase of right ventricular afterload, which leads to compensatory hypertrophy of right ventricle and eventually develops into right heart failure. With the progress of the disease, the decrease of cardiac output will lead to insufficient perfusion of the whole body organs, forming a vicious circle of "right heart failure-low cardiac output-multiple organ failure".

What is the mechanism of Riociguat API Powder in treating pulmonary hypertension?

1. Targeting the core pathological pathway: NO-sGC-cGMP.
There is serious endothelial dysfunction in patients with pulmonary hypertension, which leads to the decrease of NO synthesis. NO is the key messenger to activate sGC, and its lack makes the downstream cGMP insufficient. CGMP is the core second messenger to regulate vascular smooth muscle relaxation and inhibit cell proliferation, and the decrease of CGMP level directly leads to the continuous contraction and abnormal remodeling of pulmonary vessels.
2. Unique dual activation mode
The mechanism of action of Riociguat powder is different from that of the traditional PDE-5 inhibitor. It does not inhibit the degradation of cGMP, but directly promotes its production:
NO- Synergism: When there is a small amount of NO in the body, Riociguat raw powder can enhance the sensitivity of sGC to NO and amplify the signal.
NO- independent direct activation: This is the most unique function of Riociguat API Powder. It can directly bind to the heme binding site of sGC, and can strongly activate sGC and catalyze GTP to cGMP even in the absence of NO or extremely low NO level.
3. Downstream therapeutic effect
By increasing the intracellular cGMP level, Riociguat plays the following key therapeutic roles:
Vasodilation: cGMP activates protein kinase G(PKG), which leads to the opening of potassium channels and the decrease of calcium influx, which leads to the relaxation of pulmonary artery smooth muscle and significantly reduces pulmonary vascular resistance (PVR).
Anti-remodeling: High-level cGMP can inhibit the abnormal proliferation and migration of smooth muscle cells and reduce the fibrosis of vascular wall, thus reversing or delaying pulmonary vascular remodeling and fundamentally improving the pathological process.
4. Clinical advantages
Based on the above mechanism, high purity Riociguat can effectively make up for the deficiency of NO in patients with pulmonary hypertension, especially for patients with poor response or intolerance to PDE-5 inhibitors, which provides a new treatment option for severe PAH.

Why did you choose our Riociguat API Powder?

Riociguat API Powder of Xi'an Faithful BioTech Co., Ltd is selected because it has the comprehensive advantages of quality, compliance, supply and service: in terms of quality, the product purity is stable ≥99.5%, and the impurity spectrum is strictly controlled (single impurity ≤ 0.5%); In compliance, it has a complete DMF/EDMF filing and GMP system certification; In terms of supply, it can achieve stable delivery from kilogram to ton, and provide customized specifications; In terms of service, it can provide full-cycle collaboration from technical document support to registration and declaration, thus ensuring the safety and consistency of APIs and the reliability of supply chain for downstream customers.

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