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Blue lips are one of the important clinical manifestations of pulmonary hypertension (PH), and PH is a serious and dangerous severe disease that affects the quality of life
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(PS: The “8-year-old girl buying **” on the hot search is talking about this disease
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) Recently, the CDE official website released the "Technical Guidelines for Clinical Trials of Drugs for the Treatment of Arterial Pulmonary Hypertension" & "Treatment of Pediatric Pulmonary Arterial Hypertension" Technical Guidelines for Drug Clinical Trials
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In this way, the author introduces the "disease-drug" of PH, and focuses on the characteristics and key points of this guideline, so as to hope that more people can pay attention to this patient group and that more R&D investment can be injected into this field.

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01 What is pulmonary hypertension? Before introducing the disease professionally, the author will first talk about this disease based on my own experience.
Except for blue lips, going up and downstairs, running, and activities that have some normal requirements for cardiopulmonary function may all be fatal
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The following is a professional introduction
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Pulmonary hypertension (PH) refers to a clinical and pathophysiological syndrome in which pulmonary vascular resistance and pulmonary arterial pressure are increased due to changes in pulmonary vascular structure or function caused by a variety of heterologous diseases (causes) and different pathogenic mechanisms, and then develop Right heart failure and even death
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Pulmonary arterial hypertension (PAH), which is the first category, refers to the increased pulmonary vascular resistance and pulmonary artery pressure caused by lesions of the pulmonary arteries (mainly pulmonary arterioles), while the pulmonary arteriolar wedge pressure is normal
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For children, PAH patients differ from adults in terms of pulmonary vascular structure, function, clinical course, right ventricular adaptation, and responsiveness to targeted therapy, and are more susceptible to genetic and developmental factors
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European epidemiological studies have shown that the incidence and prevalence of PAH are 5-10/million person-years and 15-60/million, respectively
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Among the PAHs, congenital heart disease-related PAHs, hereditary PAHs, drug- and poison-related PAHs are common, and among the disease-related PAHs, connective tissue disease-related PAHs are the most common.

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The etiology of idiopathic pulmonary arterial hypertension (IPAH) is currently unknown.
Foreign registration studies have reported that the lowest prevalence of IPAH is about 5.
9/million, which is a rare disease
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Figure 1.
1 PAH registration data from different countries and periods Guidelines are officially issued
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In fact, CDE has been paying attention to PAH for nearly 15 years
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For example, as early as 2007, CDE published an electronic publication, which disclosed that "FDA announced to revise the instructions of ED treatment drugs Cialis, Aileda and Viagra", which mentioned that "Viagra can reduce pulmonary hypertension because of its ability to reduce arteriovenous shunt and pulmonary artery.
pressure, FDA-approved for the treatment of pulmonary arterial hypertension
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" After that, the FDA and EMA-related information on pulmonary arterial hypertension was introduced at intervals until 2018, when the National Health and Medical Commission released the first batch of rare disease lists, of which the 54th was "idiopathic pulmonary arterial hypertension"
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The real breakthrough in pulmonary arterial hypertension is the two drafts released in August 2021.
Technical Guidelines for Clinical Trials of Drugs for Pulmonary Arterial Hypertension (Draft for Comment)
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On January 12, 2022, CDE finally officially released relevant technical guidelines for clinical trials
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Figure 2.
1 Important guidelines for pulmonary arterial hypertension recently released by CDE
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?"Technical Guidelines for Clinical Trials of Drugs for the Treatment of Arterial Pulmonary Hypertension" This guiding principle focuses on "overall considerations of clinical development" and "key elements of clinical trial design"; Clinical trials and confirmatory clinical trials were described in detail; the key elements of the design were discussed in seven aspects: study population, background treatment, control selection, dose selection, study period, efficacy evaluation, and safety evaluation
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Based on the author's personal understanding of this aspect, the key contents that can be further divided are as follows: This guideline is also applicable to chronic thromboembolic pulmonary hypertension; Pharmacokinetic studies in patients with hepatic impairment and/or renal impairment; non-inferiority trial designs may be used in confirmatory clinical trials; calcium channel blockers are not allowed as routine background therapy; study duration usually requires at least 6 months ; The effect on mortality can be achieved through an open extension study; The main efficacy indicator is 6MWD; Only based on the results of long-term controlled studies with death as the main efficacy indicator, the conclusion of the drug's effect on mortality can be made
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Figure 2.
2 CDE "Technical Guidelines for Clinical Trials of Drugs for the Treatment of Arterial Pulmonary Hypertension" ? "Technical Guidelines for Clinical Trials of Drugs for the Treatment of Pediatric Arterial Pulmonary Hypertension" This guiding principle technically focuses on "overall considerations for clinical development", " Pharmacodynamics and dose-finding studies", and "Key elements of confirmatory clinical trial design"; the overall consideration is divided into "drugs whose benefits outweigh risks for adults with PAH" and "no safety and efficacy for adults with PAH" The key elements of confirmatory clinical trials mainly include "study population, background treatment, selection of control, dose selection, study period, efficacy evaluation, and safety evaluation"
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Based on the author’s personal understanding of this aspect, the key contents that can be further divided into the following are: Children-related PH is mainly idiopathic pulmonary hypertension, hereditary pulmonary hypertension and disease-related arterial hypertension; PVRI is used for hemodynamic criteria; Randomized controlled trials of the proposed dose in specific pediatric populations, with further dose exploration if necessary; the age group included in pediatric patients should be adequately representative; drug rescue therapy may be considered in rapidly deteriorating conditions; blood flow When kinetic parameters are used as primary efficacy indicators, the study period can be 12 weeks; neonates with PPHN should be followed for at least 24 months
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Figure 2.
3 CDE "Technical Guidelines for Clinical Trials of Drugs for the Treatment of Pediatric Arterial Pulmonary Hypertension" (PS: For the above specific content, readers can study the relevant guidelines according to their own needs, website: https:// main/news/listpage/3cc45b396497b598341ce3af000490e5) 03 Overview of current drug therapy This guideline introduces: There are currently a variety of targeted therapy drugs for PAH, including: endothelin receptor antagonists, phosphodiesterase type 5 inhibitors , soluble guanylate cyclase agonists, prostacyclin analogs and prostacyclin receptor agonists
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(PS: Conventional calcium channel blockers are not recommended in this guideline
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) The endothelin receptor antagonist endothelin-1 (endothelin 1) binds to endothelin receptors A and B, and endothelin receptor A ( Activation of endothelin A, ETA) leads to pulmonary vasoconstriction and smooth muscle cell proliferation, while endothelin receptor B (endothelin B) clears ET1, mediates endothelial vasodilation and the release of nitric oxide and prostacyclin
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ERA has obvious therapeutic effect on PAH
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Bosentan is a non-selective ERA and may cause abnormal liver function when administered, in addition to anemia and peripheral edema
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Ambrisentan selectively acts on ETA, but there are still adverse drug reactions such as anemia, peripheral edema, headache, and abnormal liver function during treatment
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Compared with bosentan, macitentan is more tissue permeable and produces longer-lasting receptor blockade with relatively fewer adverse effects
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In general, this class of drugs is a very important class of current treatment of pulmonary hypertension
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Representative drugs: bosentan, ambrisentan, macitentan
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? Type 5 phosphodiesterase inhibitor Nitric oxide combines with soluble guanylate cyclase (sGC) to generate cGMP, which leads to vasodilation of small arteries, inhibits cell proliferation, and promotes vascular remodeling; PDE5i can prevent the degradation of cGMP
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Sildenafil is the first PDE5i on the market, which is prone to rapid failure and can improve hemodynamics, but cannot delay the progression of the disease; Tadalafil is a dose-dependent drug, and 40 mg daily can safely and effectively treat PAH; Udenafil has better efficacy in patients who have previously used ERA, and has higher safety and tolerability
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This type of drug is also an important means of current patient curve treatment
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Representative drugs: Sildenafil, Tadalafil, Udenafil
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? Soluble guanylate cyclase agonist sGC stimulator can directly activate sGC, enhance the sensitivity of sGC to NO, and mimic the effect of NO when endogenous NO is deficient.
When NO is deficient, PDE5i will lose its effect and can be stimulated by sGC.
agent instead of PDE5i
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Riociguat is an sGC stimulator indicated for the treatment of inoperable or persistent PAH patients with chronic thromboembolic PAH after percutaneous pulmonary angiography, which improves patient activity tolerance, symptoms, pulmonary hemodynamics, and cardiac function
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PDE5i is ineffective for patients with insufficient endogenous NO production, and riociguat is used instead, and its effect is better than PDE5i
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Representative drug: Riociguat
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? Prostacyclin analogs and prostacyclin receptor agonists Prostacyclin is released by endothelial cells, promotes pulmonary vasodilation, and has antithrombotic and antiproliferative effects
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Prostacyclins can be taken orally (treprostinil or beprostin), inhaled (iloprost), subcutaneously (treprostinil) and intravenously (epoprostenol or treprostinil), side effects larger
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Epoprostenol, as the first listed prostacyclin drug, has a very short half-life (<5min) and is unstable at room temperature, which can cause a variety of adverse reactions, such as headache, facial flushing, and abdominal pain
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Treprostinil has various dosage forms.
Inhalation and intravenous injection can improve exercise capacity and hemodynamics, delay disease progression, and have good safety and tolerance
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The efficacy of beprostacycline is unstable
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As an inhaled formulation, iloprost may be an effective drug for the treatment of patients with severe PAH
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Celecipa is a non-prostacyclin drug that targets the prostacyclin receptor and is not prone to tachyphylaxis.
It can delay disease progression, but cannot reduce mortality
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Representative drugs: epoprostenol, treprostinil, beprostinil, iloprost, xelocipa
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04 Summary In conclusion, this is the current status of the "disease-clinical trial guidelines-drug" of pulmonary hypertension, especially arterial pulmonary hypertension
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Although there are many types of drugs for the treatment of pulmonary hypertension, but no drugs can eradicate it, there are still many unmet clinical needs, but few resources are invested.
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At the same time, this paper also hopes to take this CDE It is an opportunity to issue guidelines to further introduce the disease and the current drugs for treatment to the public.
I hope this group can get more attention and help.

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Advances in drug treatment of pulmonary arterial hypertension.
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Research progress in anti-pulmonary hypertension drugs.
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Research progress of anti-pulmonary hypertension drugs and their mechanism of action.
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