Method for reducing risk of adverse events in patients with pulmonary arterial hypertension while taking pulmonary vasodilators

Abstract

FIELD: cardiology.SUBSTANCE: used to reduce the risk of adverse events in patients with pulmonary arterial hypertension while taking pulmonary vasodilators. The method involves taking a drug containing diosmin and hesperidin. If an adverse event in the form of a headache occurs, the patient takes a medicinal product containing 900 mg of diosmin and 100 mg of hesperidin in one dosage form, or a medicinal product containing 1000 mg of purified micronized flavonoid fraction, consisting of 900 mg of diosmin and flavonoids, calculated as 100 mg of hesperidin.EFFECT: use of the invention makes it possible to reduce the risk of adverse events from taking pulmonary vasodilators by increasing the tone of the venous wall, reducing venous distensibility and venous congestion, normalizing microcirculation, reducing capillary permeability, improving trophism and lymphatic drainage, reducing tissue swelling, reducing venous pressure, facilitating outflow from the venous system, resulting in a decrease in venous hypertension, improving blood outflow from the cerebral venous sinuses and reducing the severity of cephalgic syndrome.1 cl, 3 ex

Description

[0001] The invention relates to medicine, in particular to cardiology, and can be used to reduce the risk of adverse events in patients with pulmonary arterial hypertension (PAH) while taking pulmonary vasodilators.

[0002] Pulmonary arterial hypertension is a rare, incurable disease that develops as a result of progressive remodeling of small and medium-sized pulmonary vessels due to inflammation and endothelial damage. This leads to an imbalance between proliferative mediators (such as thromboxane A2 and endothelial-1) and antiproliferative vasodilators (nitric oxide and prostacyclin) localized within the endothelium. Endothelial dysfunction leads to rapid constriction of pulmonary arterioles and cellular proliferation. At the same time, sympathetic stimulation increases, hypoxemia and reperfusion injury of the endothelium progress, leading to additional cytokine production, contributing to further vascular wall remodeling, fibrosis, and local microthrombosis.Ultimately, the above-described changes lead to a progressive increase in pulmonary vascular resistance, elevated pulmonary pressure, and right heart overload. As the disease progresses, chronic right ventricular failure develops, leading to cardiac decompensation and subsequent death.

[0003] According to the classification of pulmonary hypertension revised in 2022 at the European Congress of Cardiology, PAH belongs to the 1st classification group, which includes idiopathic pulmonary hypertension with a subdivision into a positive vasoreactive test and a negative vasoreactive test; familial / hereditary pulmonary arterial hypertension; pulmonary arterial hypertension associated with HIV; portal arterial hypertension, pulmonary arterial hypertension associated with congenital heart defects; pulmonary arterial hypertension associated with schistosomiasis and persistent pulmonary arterial hypertension of the newborn.

[0004] Without specific treatment, patients with PAH are characterized by an extremely poor prognosis, short survival (usually about 2-5 years after diagnosis), and a significant decrease in quality of life. The use of maximal PAH-specific therapy increases patient survival from an average of 2.8 to 10.8 years, according to data from the 6th World Symposium on Pulmonary Hypertension (2018).

[0005] Modern approaches to treating patients with PAH include the use of specific pulmonary vasodilators, whose mechanism of action targets one of the disease's pathogenesis pathways. Their efficacy and positive impact on prognosis have been demonstrated in numerous international randomized clinical trials (RCTs) conducted with a group of drugs related to the nitric oxide signaling pathway—PDE-5 inhibitors (sildenafil, tadalafil) and the soluble guanylate cyclase stimulator riociguat—as well as the prostacyclin pathway (sildenafil, tadalafil, riociguat, iloprost, and selexipag). Despite their proven efficacy, these drugs are often discontinued due to adverse events, often without the possibility of replacement, as the range of drugs used for this condition is extremely limited.

[0006] The most common adverse reaction leading to discontinuation of pulmonary vasodilators is headache (cephalgia), which develops due to venous dilation. For all vasodilator medications, the "adverse reactions" section of the package insert lists headaches as "Very common" (i.e., may occur in up to 1 in 10 people).

[0007] Vasodilator (phosphodiesterase type 5 inhibitor (PD-5), soluble guanylate cyclase stimulator, prostacyclin IP receptor agonist, synthetic prostacyclin analogue) has inflammatory and hyperalgesic properties, the action of which is very similar to that of prostaglandin E1, which has long been known to cause vascular headaches. Patients may experience headaches of varying intensity, nature, frequency, and duration.

[0008] A method is known to reduce the risk of adverse events when using pulmonary vasodilators by slowing the rate of titration of the vasodilator dose or by premedication with acetaminophen or other pain relievers to prevent the occurrence of headache or reduce its intensity.

[0009] (Martha Kingman, Christine Archer-Chicko, Mary Bartlett, et. all. Management of prostacyclin side effects in adult patients with pulmonary arterial hypertension. - Pulmonary Circulation, Volume 7 Number 3, pp. 598-608).

[0010] The disadvantages of this method, described in the above article, consist of the use of drugs belonging to the class of analgesics without taking into account the vascular mechanism of the occurrence of headaches due to the use of pulmonary vasodilators, which relieves the headache for a short time, but does not eliminate the cause of its occurrence.

[0011] The objective of the invention is to create a method for reducing the risk of adverse events in patients with pulmonary arterial hypertension while taking pulmonary vasodilators, which makes it possible to influence the cause of headaches, which will make it possible to continue the prescribed course of treatment without discontinuing or replacing drugs and will improve the prognosis for the duration and quality of life of a patient with PAH.

[0012] The technical result consists in reducing the risk of adverse events from taking pulmonary vasodilators.

[0013] This is achieved by the fact that in the claimed method for reducing the risk of occurrence of adverse events in patients with pulmonary arterial hypertension while taking pulmonary vasodilators, according to the invention, when an adverse event in the form of a headache occurs, the patient is additionally prescribed a drug containing in one dosage form diosmin 900 mg and hesperidin 100 mg, or a drug containing 1000 mg of purified micronized flavonoid fraction consisting of diosmin 900 mg and flavonoids, calculated as hesperidin 100 mg.

[0014] The technical result is achieved through the use of preparations containing 900 mg of diosmin and 100 mg of hesperidin in a single dosage form, or a preparation containing 1000 mg of a purified micronized flavonoid fraction consisting of 900 mg of diosmin and flavonoids, equivalent to 100 mg of hesperidin, in the treatment of patients with pulmonary arterial hypertension (PAH) who experience headaches while taking vasodilators. Diosmin and hesperidin (or flavonoids) increase venous wall tone, reduce venous distensibility and venous congestion, normalize microcirculation, decrease capillary permeability, improve trophism and lymphatic drainage, and reduce tissue edema. They also reduce venous pressure, facilitating outflow from the venous system. As a result, venous hypertension is reduced, blood flow from the cerebral venous sinuses is improved, and the severity of cephalgic syndrome is reduced. Implementation of the method.

[0015] Venous dilation triggers a cascade of pathological hemodynamic changes that ultimately lead to the development of so-called venous headaches. This venous dyscirculation leads to obstructed venous outflow from the cranial cavity, which in turn leads to venous congestion, increased intracranial pressure, distension of the venous sinuses, and irritation of pain receptors. Impaired venous outflow also leads to ischemia due to venous blood stagnation, decreased tissue perfusion, and increased tissue hypoxia. This results in pathophysiological phenomena such as plasmorrhea and diapedetic hemorrhages. This poses a serious risk to patients' health. Therefore, it is crucial to treat this pathological condition as early as possible.

[0016] Therefore, the use of drugs with a direct venotonic effect, including those containing diosmin and hesperidin in a single dosage form, is pathogenetically justified. Currently, the drugs used in clinical practice are tablets with a fixed dose of 900 mg diosmin and 100 mg hesperidin, or tablets containing 1000 mg of purified micronized flavonoid fraction, consisting of 900 mg diosmin (90%) and 100 mg hesperidin (10%).

[0017] Based on the above, for a patient with PAH who has experienced adverse events in the form of headache while taking vasodilators, it is advisable to additionally prescribe a drug containing diosmin and hesperidin (or flavonoids in terms of hesperidin), depending on the severity of the headache.

[0018] Clinical example No. 1.

[0019] Patient S., 48, has been suffering from PAH associated with systemic sclerosis since 2020. Since 2022, she has been receiving dual PAH-specific therapy with macitentan 10 mg / day in a single dose and selexipag 1600 mcg / day in two divided doses of 800 mcg. Further drug titration was not possible due to the development of severe headaches. The patient was monitored via telemedicine during the titration period.

[0020] Below are the 3 conclusions in chronological order.

[0021] Medical report

[0022] Clinic name: Federal State Budgetary Institution "NMITsK named after Academician E.I. Chazov"

[0023] Doctor's specialty: Cardiologist, E.I. Chazov National Medical Research Center of Cardiology

[0024] Consultation date: September 17, 2024

[0025] Recommendations: For the prevention of headaches with a probable mechanism of their occurrence in the form of a violation of venous outflow, it is recommended to take Detralex 1000 mg 1 time per day.

[0026] Case History: Complaints of moderate-intensity, wave-like headaches. The pain occurs in the morning, 2 hours after taking Selexipag (taken at 7 a.m.). The pain subsides after lunch. Headaches do not recur after taking Selexipag in the evening.

[0027] Doctor's response: The attending physician's active role is required

[0028] Medical Report (2)

[0029] Clinic name: Federal State Budgetary Institution "NMITsK named after Academician E.I. Chazov"

[0030] Doctor's specialty: Cardiologist, E.I. Chazov National Medical Research Center of Cardiology

[0031] Consultation date: September 30, 2024

[0032] Recommendations: Given the positive trend in headache resolution, a decision was made to increase the selexipag dose to 1200 mcg twice daily. A follow-up assessment will be performed after 7 days.

[0033] Medical History: No complaints at the time of consultation. According to the patient, she began taking Detralex Retard 1000 mg in the morning on September 18, 2024, to improve cerebral venous outflow. Daytime headaches after taking Selexipag ceased on September 20, 2024.

[0034] Doctor's response: The attending physician's active is required

[0035] Medical Report (3)

[0036] Name of the clinic: Federal State Budgetary Institution "NMITsK named after Academician E.I. Chazov"

[0037] Doctor's specialty: Cardiologist, E.I. Chazov National Medical Research Center of Cardiology

[0038] Consultation date: 12 / 12 / 2024

[0039] Recommendations: To prevent headaches while titrating Selexipag from 800 mcg to 1600 mcg, the patient took Detralex 1000 mg twice daily, followed by a single dose of 500 mg, with good results. Severe headaches completely disappeared. Therefore, she switched to 500 mg of Detralex. Since November 4, 2024, the patient has been taking Selexipag 1600 mcg twice daily. Headaches no longer occur every day, are mild in intensity, and do not require additional analgesics.

[0040] Amnesis of the disease: complaints of shortness of breath during moderate physical exertion or when climbing a hill, which goes away at rest.

[0041] Doctor's response: No assistance required.

[0042] Clinical example No. 3.

[0043] Patient E., 52 years old, diagnosed with idiopathic pulmonary hypertension, WHO class 3 FC. History of high pulmonary arterial hypertension since 2022 (SPPA 90 mmHg). In August 2024, the diagnosis of idiopathic pulmonary hypertension was verified. Therapy with sildenafil 20 mg 3 times a day was prescribed. In March 2025, disease progression occurred. As part of a readmission in May 2025, dual PAH-specific therapy was initiated: selexipag at a dose of 200 mcg twice a day was added to sildenafil 20 mg 3 times a day, with the need for further dose titration in accordance with the algorithm until a dose of 1600 mcg twice a day is reached. Monitoring of selexipag titration via telemedicine is recommended.

[0044] The first request was on 10 / 03 / 2025.

[0045] Below are the 2 conclusions in chronological order.

[0046] Medical report P)

[0047] Patient E. 52 years old.

[0048] Clinic name: Federal State Budgetary Institution "NMITsK named after Academician E.I. Chazov"

[0049] Doctor's specialty: Cardiologist, E.I. Chazov National Medical Research Center of Cardiology

[0050] Consultation date: 10 / 03 / 2025

[0051] History of the disease.

[0052] Complaints: Moderate shortness of breath when walking up to 400 m at a moderate pace, which resolves with rest. A moderate-intensity headache that occurs after taking 800 mcg of selexipag in the morning and resolves spontaneously by lunchtime.

[0053] Recommendations: In order to attempt to relieve headaches associated with taking Selexipag, it is recommended to add Detralex 1000 mg once in the morning to the ongoing therapy.

[0054] Medical Report (2)

[0055] Patient E. 52 years old.

[0056] Clinic name: Federal State Budgetary Institution "NMITsK named after Academician E.I. Chazov"

[0057] Doctor's specialty: Cardiologist Cardiologist of the E.I. Chazov National Medical Research Center of Cardiology Consultation date: 10.10.2025 Medical history Diseases

[0058] Complaints: moderate shortness of breath when walking up to 400 m at a moderate pace, passing at rest. History: After the appointment of selexipag 200 mcg 2 times a day, the main complaint was a headache of moderate intensity. The dynamics of headaches during titration were as follows: 1. 200 mcg 2 times a day - headache for 3 days, then passed on its own. 2.400 mcg 2 times a day - headache for 3 days, then passed on its own. 3. 600 mcg 2 times a day - headache for 7 days, then passed on its own. 4. 800 mcg 2 times a day A severe headache has persisted for 7 days, occurring after the morning dose of selexipag, lasting until lunch, and then resolving spontaneously. The patient has been taking the medication for one month and does not risk titrating it further due to persistent headaches. To attempt to relieve headaches associated with selexipag, Detralex 1000 mg was added to her current therapy. The first dose was given on April 4.October 2025 - The headache remained unchanged in intensity and duration. October 5, 2025 - After taking 1000 mg of Detralex, the headache intensity significantly decreased. Since October 6, 2025, headaches have been absent.

[0059] Recommendations. Given the absence of headaches, it is recommended to continue titrating selexipag at a dose of 1000 mcg in the evening and 800 mcg in the morning. A follow-up consultation is scheduled on October 13, 2025, to assess the patient's tolerability at the new dose.

[0060] Thus, prescribing diosmin and hesperidin (or flavonoids), including the micronized form, to patients with PAH taking pulmonary vasodilators (prostacyclin) to reduce the risk of headaches allows us to address the key pathogenetic mechanisms underlying headache development. Continuing treatment with pulmonary vasodilators in PAH patients will, in turn, have a positive impact on the long-term prognosis and quality of life of this group of patients.

Claims

A method for reducing the risk of adverse events in patients with pulmonary arterial hypertension while taking pulmonary vasodilators, characterized in that when an adverse event in the form of a headache occurs, the patient additionally takes a drug containing 900 mg of diosmin and 100 mg of hesperidin in a single dosage form, or a drug containing 1000 mg of purified micronized flavonoid fraction consisting of 900 mg of diosmin and flavonoids, calculated as 100 mg of hesperidin.