Cardiotropic medicinal products of plant origin. Prospects for use in modern clinical practice

Nadezhda V. Nesterova¹, Natalia D. Bunatyan², Irina A. Samylina³, Vladimir A. Evteev²

1 Plekhanov Russian University of Economics, 36 Stremyanny Pereulok, Moscow 115054 Russia

2 Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’), 8/2 Petrovsky Boulevard, Moscow 127051 Russia

3 I. M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 2 Bolshaya Pirogovskaya St., Bldg 4, Moscow 119991 Russia

Corresponding author: Nadezhda V. Nesterova (nestero-nadezhda@yandex.ru)

Abstract

Introduction: The aim of the research was to study the current state of use and improvement of the prospects for the using cardiological medicinal products obtained on the basis of medicinal plant raw materials.

Materials and Methods: The work used content analysis, monitoring of scientific articles using the databases PubMed, Scopus, Google Scholar, ResearchGate, analysis of the nomenclature of the State Register of Medicines of the Russian Federation (2024) and the Register of Medicines of Russia (2024).

 Results and Discussion: The study revealed that diseases of the cardiovascular system are some of the most common causes of death among the population, with at least 37.7 million people suffering from varying degrees of heart failure alone. Despite the constant growth of the range of medicines for the treatment of cardiovascular diseases, medicinal plants and preparations based on them, which are more often used in complex therapy, still play an important role in their therapy. In this review, we consider drugs derived from medicinal plant raw materials used for the treatment of heart failure and arrhythmia of various etiologies, as the most serious cardiovascular pathologies.

Conclusion: Preparations based on herbal remedies with cardiotropic and antiarrhythmic effects are relevant in the treatment of cardiovascular diseases. Cardiotropic action is characteristic of the group of cardiac glycosides, and antiarrhythmic activity is more pronounced in alkaloids and flavonoid substances. Taking into account the prospects for the use of herbal preparations with cardiotropic effects in the complex therapy of cardiovascular diseases, an important and unsolved problem today remains the problem of their interaction with other drugs, which in the future can be solved by creating artificial intelligence programs that contribute to the formation of optimal prescriptions for a particular patient.

Graphical abstract

Keywords: cardiotropic effect; antiarrhythmic effect; cardiac glycosides; alkaloids; side effects; polypharmacotherapy

Introduction

Currently, diseases of the cardiovascular system are widespread in the world and are the leading cause of death in the population, with at least 37.7 million people suffering from heart failure alone (Shah et al. 2017; Clark and Velasquez 2020).

The annual increase in the number of cases of diagnosed arrhythmia per 1 thousand people in patients aged 45-49 years is 0.4%, and in patients aged 60-64 it has already increasing by 2 times (Schnabel et al. 2015).

Currently, the main risk factors for the development of cardiovascular diseases are considered to be arterial hypertension, dyslipidemia, diabetes mellitus, smoking, inactivity, obesity, and non-changeable biological characteristics such as age, gender, and heredity.

Taking into account the duration of use of drugs used in the treatment of cardiovascular diseases in the presence of chronic conditions in patients, often complicated by combined pathologies in complex therapy, it is still rational to use herbal medicines (Samylina et al. 2012).

Taking into account all the above, the purpose of this review is to study the current state of use and improvement of the prospects for the use of cardiological drugs obtained on the basis of medicinal plant raw materials

Materials and Methods

The review used content analysis, monitoring of scientific articles using the databases PubMed, Scopus, Cyberleninka, Google Scholar, ResearchGate, analysis of the nomenclature of the State Register of Medicines of the Russian Federation (2024) and the Register of Medicines of Russia (2024).

Results and Discussions

The State Register of Medicinal Products currently includes more than 40 names of medicinal products of plant origin used in the treatment of cardiovascular diseases.

Figure 1. Classification of medicinal products of plant origin approved for use in medicine.

Taking into account the requirements of the accepted classification (Kaisheva and Gabrielyan 2016, presented in Figure 1, medicinal plant raw materials and plant-based products used in the treatment of cardiovascular diseases registered in the Russian Federation are presented in Tables 1-4.

Table 1.	Download as	_XLSX_	_CSV_
Medicinal plant raw materials approved for the production of cardiotropic products

Raw material name	Composition	Pharmacological effect	Indications for use	Dosage form
Hawthorn fruit – Fruсtus crataegi	Complex of biologically active substances of hawthorn fruits	Antiarrhythmic, improving blood circulation in the vessels of the heart and brain, increasing the contraction of the heart muscle, increasing the sensitivity of the heart to the action of cardiac glycosides	Functional disorders of cardiac activity, angioneuroses, atrial fibrillation, paroxysmal tachycardia, initial forms of hypertension	In packs and filter bags
Hawthorn Flowers –Flores Crataegi	Complex of biologically active substances of hawthorn flowers	Antiarrhythmic, improving blood circulation in the vessels of the heart and brain, increasing the contraction of the heart muscle, increasing the sensitivity of the heart to the action of cardiac glycosides	Functional disorders of cardiac activity, hypertension, angioneurosis, atrial fibrillation, paroxysmal tachycardia	In packs and briquettes
Spring heis – Herba Adonidis vernalis	A complex of biologically active substances of Adonis herb, including cardiac glycosides: cymarin, adonitoxin, K-strophanthin-β. 1 g of herb contains 50-66 ICE, 6.3-8.0 KED	Cardiotonic	Mild forms of chronic circulatory insufficiency	Raw materials for obtaining infusion in pharmacies

 

Table 2.	Download as	_XLSX_	_CSV_
Galenic and new galenic preparations

Name	Composition	Pharmacological effect	Indications for use	Dosage form
Adonisid –Adonisidum	New galenic preparation from the herb Adonis vernalis (Ranunculaceae). 1 ml contains 23_27 LED or 2.7-3.5 KED	Cardiotonic	Chronic circulatory insufficiency of the I and II degrees, autonomic neuroses	In flasks of 15 mL
Dry Adonizide – Adonisidum siccum	Extract from sping herb Adonis. 1 g contains 20000 LED or 2083 ED, which corresponds to 670 mL of liquid adoniside.	Cardiotonic	Chronic circulatory insufficiency of the I and II degrees, autonomic neuroses	Tablets of 0.00075 g, in a package of 30 pcs.
Hawthorn fruit tincture	Alcoholic extract from the fruits of blood-red hawthorn (Crataegus sanguinea Pall.), prickly hawthorn (C.oxyacantha Pojark.) and other species of hawthorn of the Rosaceae family	Antiarrhythmic, improving blood circulation in the vessels of the heart and brain, increasing the contraction of the heart muscle, increasing the sensitivity of the heart to the action of cardiac glycosides	Functional disorders of cardiac activity, hypertension, angioneuroses, atrial fibrillation, paroxysmal tachycardia	in bottles of 10,15,20,25 mL
Hawthorn tincture – Tinctura Crataegi	Alcoholic extract from the flowers of blood-red hawthorn (Crataegus sanguinea Pall.), prickly hawthorn (C. oxyacantha Pojark.) and other species of hawthorn of the Rosaceae family	Antiarrhythmic, improving blood circulation in the vessels of the heart and brain, increasing the contraction of the heart muscle, increasing the sensitivity of the heart to the action of cardiac glycosides	Functional disorders of cardiac activity, hypertension, angioneuroses, atrial fibrillation, paroxysmal tachycardia	In bottles of 25, 50 and 100 mL
Hawthorn extract liquid	Extract from the fruits of blood-red hawthorn (Crataegus sanguinea Pall.), prickly hawthorn (C. oxyacantha Pojark.) and other species of hawthorn of the Rosaceae family	Antiarrhythmic, improving blood circulation in the vessels of the heart and brain, increasing the contraction of the heart muscle, increasing the sensitivity of the heart to the action of cardiac glycosides	Functional disorders of cardiac activity, hypertension, angioneurosis, atrial fibrillation, paroxysmal tachycardia	In bottles of 25 mL
Corglycone Lily-of-the-Valley Leaf Glycoside	Preparation containing the sum of cardiac glycosides from the flowers, leaves and herbs of lily-of-the-valley, lily-of-the- valley of Transcaucasia or Lily-of-the-Convallaria keiskei (Liliaceae)	Cardiotonic	Acute and chronic circulatory failure, cardiac decompensation, paroxysmal tachycardia attacks	Solution in ampoules
Lily-of-the-valley tincture	Tincture of lily-of- the-valley herb sem. Lily and other species containing cardiac glycosides	Cardiotonic	Cardioneurosis, cardiac disorders (without signs of decompensation)	Bottles of 25 mL
— Erysimum diffusum liquid extract	Liquid extract from Erysimi herb Sam. Cruciferous	Cardiotonic	Cardioneurosis, cardiac disorders (without signs of decompensation)	Bottles of 25 mL

 

Table 3.	Download as	_XLSX_	_CSV_
Complex preparations

Name	Composition	Pharmacological effect	Indications for use	Dosage form
Adonis-bromine	Dry redflower extract 0.25, potassium bromide 0.25	Cardiotonic, sedative	Neuroses and mild forms of circulatory insufficiency	Coated blets
Valocordin	Combined preparation containing ethylbromoisovalerianate 2.00 g, phenobarbital 2.00, mint oil 0.14, hop oil 0.02 55 vol% ethanol up to 100 ml	Sedative, antispasmodic	Neuroses, spasms of coronary vessels, tachycardia, early stages of hypertension	In dropper bottles of 15 and 25 mL
Valocormid	A combined drug containing 10 mL of valerian and lily-of-the-valley tinctures, 5 mL of sodium bromide 4 g. belladonna tinctures. menthol 0.25 g, water distilled to 30 mL	Sedative, antispasmodic	Cardioneuroses accompanied by bradycardia	In bottles of 30 mL
Valoserdin	100 g of the drug includes ethyl ester of a-bromoisovaleric acid 2 g, phenobarital 2 g, peppermint oil 0.14 g, oregano oil 0.02 g	Sedative, antispasmodic	Neuroses, cardialgia, arterial hypertension, spasms of coronary vessels, tachycardia	In dropper bottles of 15 mL
Green drops - Guttae Zelenini	Lily-of-the-valley tinctures and valerian tinctures 10 mL each, belladonna tinctures 5 mL, menthol 0.2 g.	Sedative, antispasmodic	Cardioneurosis accompanied by bradycardia	In bottles of 25 mL
Cardiovalenum	Complex preparation containing jaundice juice 17.2 mL, concentrated adonizide 30.3 mL, tincture of fresh rhizomes with valerian roots 48.6 mL, hawthorn extract 2.2 mL, camphor 0.4 g, sodium bromide 2 g, ethyl alcohol 95% 1.6 mL, chlorobutpnol hydrate 0.25 g.	Cardiotonic, sedative	Rheumatic heart defects, cardiosclerosis with heart failure and circulatory disorders I IIA	In bottles of 15, 20, 25 mL
Cardiplant	1 capsule contains 80 mg of dry extracts of hawthorn leaves and flowers, 15 mg of procyanidin oligomer	Cardiotonic, adaptogenic	Heart failure (initial stage)	Capsules
Corvalol	Combined preparation containing ethyl ester of a-bromoisovaleric acid 20 g, phenobarbital 18.26 g, caustic soda 3.15 g, peppermint oil 1.42 g, ethyl alcohol 580 ml, purified water 420 ml	Sedative, antispasmodic	Spasms of coronary vessels, tachycardia, early stages of hypertension.	In dropper bottles of 15 and 25 mL
Lily-of-the-valley drops -Tinctura Convallariae et Tinctura Valerianae	Lily-of-the-valley tinctures and valerian tinctures in equal proportions	Cardiotonic	Cardioneurosis, cardiac disorders (without signs of decompensation)	In bottles of 30 mL
Lily-of-the-valley motherwort drops -Tinctura Convallariae et Tinctura Leonuri	Lily-of-the-valley tinctures and motherwort tinctures in equal proportions	Cardiotonic, Sedative	Cardioneurosis, cardiac disorders (without signs of decompensation)	In bottles of 25 mL
Lily-of-the-valley drops with adoniside-Tinctura Convallariae et Tinctura Valerianae Adonisido	Lily-of-the-valley tinctures. tinctures of valerian and adoniside in equal proportions	Cardiotonic	Cardioneurosis, cardiac disorders (without signs of decompensation)	In bottles of 30 mL

 

Table 4.	Download as	_XLSX_	_CSV_
Individual compounds used in the treatment of cardiovascular diseases

Name	Composition	Pharmacological effect	Indications for use	Dosage form
Allapinin –Allapininum	The alkaloid lappaconitin (with an admixture of concomitant alkaloids isolated from the herb aconite (Aconitum leucostonum Worosch.) Ranunculaceae Family	Antiarrhythmic	Supraventricular and ventricular extrasystoles, atrial fibrillation and flutter, paroxysmal tachycardia, arrhythmias secondary to myocardial infarction	Tablets of 0.025 g, 0.5% solution in ampoules of 2 mL
Digoxin	Cardiac glycoside isolated from the leaves of Digitalis lanata Ehrh. fam. Scrophulariaceae	Cardiotonic	Chronic heart failure, supraventicular tachyarrhythmias (especially atrial fibrillation)	Tablets of 0.25 and 0.1 mg, 0.025% solution in ampoules
Raunatin	Sum of alkaloids from the roots of Rauwolfia serpentine of the Apocynaceae Family	Hypotensive. Antiarrhythmic. Sedative	Hypertension	Film-coated tablets

There is no doubt that the most important group of herbal remedies used in the treatment of cardiovascular diseases for many decades has been cardiac glycosides (cardiosteroids), which are still used today. In therapeutic doses, cardiac glycosides affect all myocardial functions, increasing excitability and contractility, reducing sinus automatism and conduction. The main indications for the prescription of cardiac glycosides are chronic heart failure, tachyarrhythmias – paroxysmal atrial fibrillation, and paroxysmal supraventricular tachycardia. The mechanism of action of cardiac glycosides (Gurevich and Gavrilin 2014) and their characteristic pharmacological effects are shown in the figures below.

Figure 2. Mechanism of action of cardiosteroids

These substances have a positive inotropic effect. It blocks the t-transport Na/K-ATPASE, resulting in an increase in the Na content in the cardiomyocyte, which leads to the opening of Ca channels and the entry of Ca-into cardiomyocytes. Excess Na causes activation of sodium/calcium metabolism, which accelerates the release of Ca from the SPR and increases the content of calcium ions, which, in turn, increases the strength of myocardial contraction. An increase in the strength and speed of myocardial contraction occurs by a mechanism other than the Frank-Starling mechanism (it does not depend on a degree of pre-stretching of the myocardium). Systole becomes shorter and more energy-efficient.

Figure 3. Main pharmacological effects of cardiac glycosides (Gurevich and Gavrilin 2014).

Despite the fact that the basic principles of therapy using cardiac glycosides have been known for a long time, some features are still revealed in the course of clinical observation of patients. Thus, it was found that when digoxin is prescribed in low doses (0.25, mg/day) in patients with synapse rhythm, the drug develops mainly a neuromodulatory effect, causing a decrease in the activity of the sympathoadrenal system (Hood et al. 2014). Currently, clinicians are ambivalent about prescribing cardiosteroids, for example, concerns are raised about the safety of using digoxin in atrial fibrillation (AF) (Moiseev 2011; Elayi et al. 2020).

Dr. Chris J. Kapelios found that digoxin use is statistically characterized by lower mortality/morbidity rates in patients with atrial fibrillation, but higher rates in patients without AF.

According to the literature, the group of cardiovascular diseases, the treatment of which is considered difficult, includes cardiac arrhythmias.

It should be noted that the improvement of treatment standards in this area, as well as the growth in the range of antiarrhythmic drugs, paradoxically leads to a noticeable increase in complicated conditions (Nedostup 2008).

Historically, one of the first drugs for the treatment of arrhythmia was the alkaloid quinine isolated from the bark of the quinine tree and its right-rotating isomer quinidine, whose antiarrhythmic activity is associated with the blockade of sodium channels and slowing the rate of depolarization of the action potential. Despite the rejection of the drug in many countries due to the risk of ventricular arrhythmias and a number of other side effects, there is evidence that quinidine can be considered as the only oral drug that consistently shows effectiveness in preventing arrhythmias and reducing storms in patients with Brugada syndrome (Stelios et al. 2013). Later, the alkaloid Rauvólfia serpentína aimalin was introduced into medical practice, which is active in relieving paroxysms of AF, supraventricular tachycardia, ventricular tachycardia, as well as in the complex therapy of extrasystole. Aimalin is used in a pharmacological test to diagnose Brugada syndrome (BrS) and identify patients at higher risk of developing life-threatening arrhythmias and sudden death as a result of cardiac arrest. (Monasky et al. 2021a, 2021b).

For the prevention of tachyarrhythmias in patients with Wolff-Parkinson-White syndrome syndrome (WPW), as well as with moderate bradycardia, allapinin is prescribed, which is a hydrobromide of lappaconitine, and an alkaloid contained in the grass of white Aconite (Aconitum leucostomum Worosch.), Ranunculaceae (Buttercup) Family. The antiarrhythmic effect of allapinin is realized by inhibiting potential-dependent sodium channels sensitive to tetrodotoxin (Chuikin and Shtanko 2013). Relatively few non-randomized studies of allapinin have demonstrated its effectiveness in the prevention of AF paroxysms (Syrkin et al. 2010).

Unfortunately, this drug is registered only in the Russian Federation and is not included in international recommendations, which makes it a reserve drug. In order to assess the safety of using lappaconitine preparations, further full-fledged study of its pharmacokinetics is necessary, and research in this area is underway (Archakova et al. 2021). To correct a number of drawbacks of the drug, such as high toxicity (Gutser et al. 1997; Archakova et al. 2021), problems with calculating the therapeutic dose due to its possible accumulation in organs and tissues, nonlinear pharmacokinetics (Mishra et al. 2022), and a number of side effects (Liu et al. 2022), studies are being conducted aimed at immobilizing allapinin in order to prolong its release process (Sun et al. 2016; Salikhov et al. 2024).

Salikhov et al. (2024) showed that the complex of allapinin with monoammonium salt of glycyrrhizic acid is characterized by reduced toxicity and improved antiarrhythmic activity. Prolonging the release of the alkaloid, which reduces the residual side effects, is achieved by encapsulating the allapinin complex with a monoammonium salt of glycyrizzic acid in polyelectrolyte microcapsules based on polyallylamine and polystyrene sulfonate.

Figure 4. Alkaloids with antiarrhythmic activity.

Antiarrhythmic action is characteristic of hawthorn flowers and fruits, which also exhibit coronary-expanding and hypotensive effects (Wang et al. 2013; Kurkin et al. 2017; Orha 2018; Nazhand et al. 2020).

The antiarrhythmic effect of extracts from hawthorn raw materials, which manifests itself in the form of shortening the duration of arrhythmia and reducing its severity in comparison with the control group, as well as the presence of antifibrillator activity, has been repeatedly experimentally proven both on the aconitin and calcium chloride models (Trofimova et al. 2011).

The data of clinical observation in dynamics showed that the addition of dry hawthorn extract to the standard therapy of chronic heart failure, which was standardized according to hyperoside, has a positive effect on the rhythmic activity of the heart, suppressing initially increased ventricular ectopic activity and preventing the persistence and development of new ventricular extrasystoles of high gradations, which significantly optimizes therapeutic measures and improves the prognosis in patients with chronic heart failure, especially in cases where the use of antiarrhythmic drugs recommended by the standard treatment is contraindicated for some reason (Trofimova et al. 2011; Miller et al. 2019; Elayi et al. 2020; Doschitsin and Tarzimanova 2022).

The antiarrhythmic activity of hawthorn raw materials is associated with the presence of flavonoids quercitin and hyperoside in the raw material (Orhan 2018). It was experimentally established that quercitin, rutin, and (+)-catechin have an antiarrhythmic effect on aconitin-induced arrhythmia, while the pharmacological effect, according to the researchers, may be due to the modulation of the activity of Na+and CaCa2+channels in cardiomyocytes (Lazuko et al. 2009; Trofimova et al. 2011; Chuikin and Shtanko 2013; Khushmatov et al. 2015).

Further search for medicinal plants with cardiotropic effects is associated with the study of promising sources of flavonoids. Thus, embinin, a flavone C-glycoside, was isolated from the aboveground part of Iris lactea, the inotropic effect of which was compared with digoxin in a Langendorff model of perfusion of an isolated rat heart. (Ivkin et al. 2018).

There is also experimental evidence in the scientific literature of the use of “non-traditional” antiarrhythmic drugs, such as omega-3-polyunsaturated fatty acids in the prevention and complex therapy of arrhythmias (Moiseev 2011). When studying the Omacor preparation, as well as a number of vegetable oils, the effect of polyunsaturated fatty acids on the transport of sodium and calcium ions was established by blocking fast potential-dependent sodium channels and reducing the intake of calcium ions. The effect of omega-3 polyunsaturated fatty acids on the expression of connexins in the myocardium has also been revealed, which contributes to the achievement of an antiarrhythmic effect. (Gaikova 2010).

Thus, there is a significant potential for obtaining drugs for treatment and prevention based on medicinal plant raw materials for use in the complex therapy of cardiovascular diseases.

When considering the role of herbal preparations in the treatment of cardiovascular diseases, it is necessary to strictly distinguish between drugs used in pure form (digoxin, lappaconitine) and those included in the list of vital and essential drugs (VED) and extracts, infusions, tinctures, etc. medicinal forms of various plants that are not always standardized by specific ingredients (Bhat and Bhat 2021; Dinan et al. 2021; Liu et al. 2022; Nawrot et al. 2022; Saqib et al. 2022; Xulu et al. 2022; Barratt et al. 2023; Joubert et al. 2023; Gorchakova et al. 2024; Macwan et al. 2024). Since many herbal medicines do not always have proven clinical benefits, even minor side effects may not be acceptable for patients with cardiovascular diseases (Boyko et al. 2017).

The solution of the problem of prescribing herbal cardiotonic drugs in the complex therapy of cardiovascular diseases, taking into account the factor of possible interaction with other drugs of complex therapy, is possible using artificial intelligence (Fersht et al. 2020; Chen et al. 2023; Garcia et al. 2024).

Conclusion

 Medicinal plant raw materials and drugs based on it, which have cardiotropic and antiarrhythmic effects, are still relevant tools in the treatment of cardiovascular diseases. Cardiotropic action is characteristic of the group of cardiac glycosides, and antiarrhythmic action is shown by the alkaloids quinidine, aimalin and allapinin, which exhibit a significant range of side effects, but are still used in medical practice for certain heart pathologies. A mild antiarrhythmic effect is characteristic of hawthorn raw materials of various types, whose biologically active substances, especially flavonoids, provide not only the main cardiotropic effect, but also such effects as anti-inflammatory, antispasmodic, diuretic, etc., which contributes to the optimal achievement of the therapeutic effect in complex therapy.

Considering the future prospects for the use of herbal preparations with cardiotropic effects in the complex therapy of cardiovascular diseases, an important and unsolved problem today remains the problem of their interaction with other drugs, which in the future can be solved by creating artificial intelligence programs that contribute to the formation of optimal prescriptions for a particular patient.

Additional information

Conflict of interest

The authors have declared that no competing interests exist.

Acknowledgements

This work was supported by the Russian Science Foundation grant, project # 23-75-30012.

Data availability

All of the data that support the findings of this study are available in the main text.

References

§     Archakova OA, Komarov TN, Rogov AV, Shchelgacheva DS, Aleshina, AA, Bagaeva NS, Shohin IE (2021) Determination of lappaconitine, a diterpene alkaloide obtained from the Aconitum leucostomum plants, and its active metabolite N-desacetyllappaconitin in human plasma and blood. Development and Registration of Medicines [Razrabotka i Registratsiya Lekarstvennykh Sredstv] 10: 105–113. [in Russian]

§     Archakova OA, Komarov TN, Rogov AV, Shchelgacheva DS, Alyoshina AV, Bagaeva NS, Shokhin IE (2021) Determination of lappaconitine, a diterpene alkaloid derived from Aconitum leucostomum plants, and its active metabolite N-deacetyllappaconitin in human plasma and whole blood. Development and Registration of Medicines [Razrabotka i Registratsiya Lekarstvennykh Sredstv] 10(3): 105–113. [in Russian]

§     Baklykova OB, Sizova ZhM, Shikh EV (2009) Possibilities of using standardized hawthorn extract in the correction of cardiac arrhythmias in patients with chronic heart failure. Antibiotics and Chemotherapy [Antibiotiki i Khimioterapiya] 6: 48–56. [in Russian]

§     Barratt AL, Li Y, Gooroovadoo I, Todd A, Dou Y, McAlister S, Semsarian C (2023) Environmental impact of cardiovascular healthcare. Open Heart 10(1): e002279. https://doi.org/10.1136/openhrt-2023-002279 [PubMed] [PMC]

§     Bhat IUH, Bhat R (2021) Quercetin: a bioactive compound imparting cardiovascular and neuroprotective benefits: scope for exploring fresh produce, their wastes, and by-products. Biology 10(7): 586. https://doi.org/10.3390/biology10070586 [PubMed] [PMC]

§     Boyko Nikolay Nikolaevich, Bondarev Alexander Vasilyevich, Zhilyakova Elena Theodorovna, Pisarev Dmitry Ivanovich, Novikov Oleg Olegovich Phytopreparations, analysis of the pharmaceutical market of the Russian Federation // Scientific results of biomedical research. 2017. №4.Podzolkov VI, Tarzimanova AI (2019) Antiarrhythmic therapy in the treatment of atrial fibrillation: yesterday, today, tomorrow. Cardiovascular Therapy and Prevention [Kardiovaskulyarnaya Terapiya i Profilaktika] 18(3): 81-87. [in Russian]

§     Bozic B, Uzelac TV, Kezic A, Bajcetic M (2018) The role of quinidine in the pharmacological therapy of ventricular arrhythmias 'quinidine'. Mini Reviews in Medicinal Chemistry 18(6): 468–475. https://doi.org/10.2174/1389557517666170707110450 [PubMed]

§     Chen RJ, Wang JJ, Williamson DFK, Chen TY, Lipkova J, Lu MY, Sahai S, Mahmood F (2023) Algorithmic fairness in artificial intelligence for medicine and healthcare. Nature Biomedical Engineering 7(6): 719–742. https://doi.org/10.1038/s41551-023-01056-8 [PubMed] [PMC]

§     Chuikin S. V., Shtanko M. I. Pathogenetic justification of the use of phytotherapy with polyextract of blood-red hawthorn leaves in elderly and senile patients // PM. 2013. No. 4 (72).

§     Dinan L, Dioh W, Veillet S, Lafont R (2021) 20-Hydroxyecdysone, from plant extracts to clinical use: therapeutic potential for the treatment of neuromuscular, cardio-metabolic and respiratory diseases. Biomedicines 9(5): 492. https://doi.org/10.3390/biomedicines9050492 [PubMed] [PMC]

§     Dolginina SI, Duplyakov DV (2016) The role of allapinin in the treatment of cardiac arrhythmias. Cardiology: News, Opinions, Discussions [Kardiologiya: Novosti, Mneniya, Obuchenie] 2: 25–29. [in Russian]

§     Doschitsin VL, Tarzimanova AI (2022) Historical aspects of the use of antiarrhythmic drugs in clinical practice. Rational Pharmacotherapy in Cardiology [Ratsional'naya Farmakoterapiya v Kardiologii] 18(3): 350–358. [in Russian]

§     Elayi CS, Shohoudi A, Moodie E, Etaee F, Guglin M, Roy D, Khairy P, AF-CHF Investigators (2020) Digoxin, mortality, and cardiac hospitalizations in patients with atrial fibrillation and heart failure with reduced ejection fraction and atrial fibrillation: An AF-CHF analysis. International Journal of Cardiology 313: 48–54. https://doi.org/10.1016/j.ijcard.2020.04.047 [PubMed]

§     Fersht Viktor Mikhailovich, Latkin Alexander Pavlovich, Ivanova Valentina Nikolaevna Modern approaches to the use of artificial intelligence in medicine // Territory of new opportunities. 2020. №1

§     Gaikova LB (2010) Omega-3-polyunsaturated fatty acids: laboratory methods in assessing their multifactorial action. Reviews of Сlinical Pharmacology and Drug Therapy [Obzory po Klinicheskoi Farmakologii i Lekarstvennoi Terapii] 4(8): 3–11. [in Russian]

§     Garcia MB, Arif YuM, Khlaif ZN (2024) Effective integration of artificial intelligence in medical education: Practical tips and actionable insights. In: Transformative Approaches to Patient Literacy and Healthcare Innovation. IGI Global, pp. 1-19. http://dx.doi.org/10.2139/ssrn.4770043

§     Gurevich MA, Gavrilin AA (2014) Cardiac glycosides in modern clinical practice. Almanac of Clinical Medicine [Al'manakh Klinicheskoi Meditsiny] 35: 101–105. [in Russian]

§     Gutser UT, Friese J, Heubach JF, Matthiesen T, Selve N, Wilffert B, Gleitz J (1997) Mode of antinociceptive and toxic action of alkaloids of Aconitum spec. Naunyn-Schmiedeberg's Archives of Pharmacology 357: 39–48. [PubMed]

§     Hood WB Jr, Dans AL, Guyatt GH, Jaeschke R, McMurray JJ (2014) Digitalis for treatment of congestive heart failure in patients in sinus rhythm: systematic review and meta-analysis. Journal of Cardiac Failure 10(2): 155–164. https://doi.org/10.1016/j.cardfail.2003.12.005 [PubMed]

§     Ivkin DYu, Luzhanin VG, Karpov AA, Minasyan SM, Poleshchenko YaI, Mamedov AE, Povydysh MN, Poroykov VV, Narkevich IA (2018) Embinin is a promising cardiotonic agent of natural origin. Development and Registration of Medicines [Razrabotka i Registratsiya Lekarstvennykh Sredstv] 3: 166–170. [in Russian]

§     Ivkin DYu, Luzhanin VG, Karpov AA, Minasyan SM, Poleshchenko YaI, Mamedov AE, Povydysh MN, Poroykov VV, Narkevich IA (2018) Embinin is a promising cardiotonic agent of natural origin. Development and Registration of Medicines [Razrabotka i Registraciya Lekarstvennyh Sredstv] 3: 166–170. [in Russian]

§     Joubert JPJ (2023) Cardiac glycosides. Toxicants of plant origin. CRC Press, pp. 61-96.

§     Kaisheva NS, Gabrielyan NV (2016) Trends and structure of demand for phytopreparations used in the treatment of cardiovascular diseases. Medical Bulletin of the North Caucasus 3: 51-54. [in Russian]

§     Kapelios CJ, Lund LH, Benson L, Dahlström U, Rosano GMC, Hauptman PJ, Savarese G (2022) Digoxin use in contemporary heart failure with reduced ejection fraction: an analysis from the Swedish Heart Failure Registry. European Heart Journal. Cardiovascular Pharmacotherapy 8(8): 756–767. https://doi.org/10.1093/ehjcvp/pvab079 [PubMed] [PMC]

§     Khushmatov ShS, Mfkhmudov RR, Mavlyanov SM (2015) Comparative study of inotropic and antiarrhythmic activity of flavonoids – quercitin, rutin and (+)-catechin. Russian Journal of Cardiology [Rossijskii Kardiologicheskij Zhurnal] 11(127): 35–41. [in Russian]

§     Kurkin VA, Morozova TV, Pravdivtseva OE (2017) Research on the development of methods for standardization of blood-red hawthorn leaves. Chemistry of Plant Raw Materials [Khimiya Rastitel'nogo Syr'ya] 3: 169–173. [in Russian]

§     Lazuko SS, Krasilnikov AA, Utkina GA, Kugach VV, Sokolovsky AV, Shugrina ES (2009) Comparative assessment of the antiarrhythmic activity of hawthorn tinctures obtained by various methods. Bulletin of Pharmacy 44(2): 22–28.

§     Liu XY, Ke BW, Qin Y, Wang FP (2022) The diterpenoid alkaloids. Chemistry and Biology 87: 1–360. https://doi.org/10.1016/bs.alkal.2021.08.001 [PubMed]

§     Lu L, Yue-Ming Yu, Fan-Zhi B, Yan-Tuan L, Cui-Wei Ya, Zhi-Yong W (2022) The first cocrystallization of milrinone with nutraceuticals: The adjusting effects of hydrophilicity/hydrophobicity in cavities on the in vitro/in vivo properties of the cocrystals. Crystal Growth and Design 22(3): 1623–1637. https://pubs.acs.org/doi/10.1021/acs.cgd.1c01143

§     Macwan CP, Suhagia BN, Soni T, Ahmed SS, Patel J (2024) Evaluation of cardioprotective activity of Corchorus aestuans L. leaves. Journal of Natural Remedies 24(10): 2287–2293. https://doi.org/10.18311/jnr/2024/44997

§     McCabe DJ (2022) Clinical effects from ingestion of lappaconitine, an aconitum alkaloid with sodium channel blocking effects. Journal of Medical Toxicology 18(3): 243–247. https://doi.org/10.1007/s13181-022-00896-1 [PubMed] [PMC]

§     Miller ON, Syrov AV, Doshchitsin VL, Pavlova TV, Tarasov AV (2019) Clinical recommendations and expert opinion on the use of antiarrhythmic drugs in real practice. Consilium Medicum 21(5): 43–49. [in Russian]

§     Mishra G, Singh P, Molla M, Shumet Yimer Y, Ewunetie A, Yimer Tadesse T, Mengie Ayele T, Kefale B (2022) Nutraceuticals: A source of benefaction for neuropathic pain and fibromyalgia. Journal of Functional Foods 97: 105260. https://doi.org/10.1016/j.jff.2022.105260

§     Moiseev SV (2011) Possibilities of using omega-3-polyunsaturated fatty acids in cardiac arrhythmias. Pharmateka [Farmateka] 8(221): 14–20. [in Russian]

§     Monasky MM, Micaglio E, D'Imperio S and Pappone C (2021) The mechanism of ajmaline and thus brugada syndrome: Not only the sodium channel!. Frontiers in Cardiovascular Medicine 8: 782596. https://doi.org/10.3389/fcvm.2021.782596 [PubMed] [PMC]

§     Monasky MM, Micaglio E, D'Imperio S, Pappone C (2021) The mechanism of ajmaline and thus brugada syndrome: not only the sodium channel! Frontiers in Cardiovascular Medicine 8: 782596. https://doi.org/10.3389/fcvm.2021.782596 [PubMed] [PMC]

§     Nawrot J, Gornowicz-Porowska J, Budzianowski J, Nowak G, Schroeder G, Kurczewska J (2022) Medicinal herbs in the relief of neurological, cardiovascular, and respiratory symptoms after COVID-19 infection a literature review. Cells 11(12): 1897. https://doi.org/10.3390/cells11121897 [PubMed] [PMC]

§     Nazhand A, Lucarini M, Durazzo A, Zaccardelli M, Cristarella S, Souto SB, Silva AM, Severino P, Souto EB, Santini A (2020) Hawthorn (Crataegus spp.): An updated overview on its beneficial properties. Forests 11(5): 564. https://doi.org/10.3390/f11050564 [in Russian]

§     Nedostup AV (2008) Strategy of therapy of cardiac arrhythmias. Russian Medical Journal [Rossijskii Meditsinskii Zhurnal] 16(6): 431–435. [in Russian]

§     Orhan IE (2018) Phytochemical and pharmacological activity profile of Crataegus oxyacantha L. (Hawthorn) – a cardiotonic Herb. Current Medicinal Chemistry 25(37): 4854–4865. https://doi.org/10.2174/0929867323666160919095519 [PubMed]

§     Paraskevaidis S, Theofilogiannakos EK, Kamperidis V, Chatzizisis YS, Tsilonis K, Vassilikos VP, Dakos G, Stavropoulos G, Ziakas A, Hadjimiltiades S, Styliadis IH (2013) Quinidine: an “endangered species” drug appropriate for management of electrical storm in brugada syndrome. Indian Pacing and Electrophysiology Journal 13(5): 178–180. https://doi.org/10.1016/s0972-6292(16)30670-2 [PubMed] [PMC]

§     Parikh RR, Patel KR, Pergolizzi JV Jr, Breve F, Magnusson P (2022) Effects of digoxin in heart failure (HF) with reduced ejection fraction (EF). Cureus 14(3): e22778. https://doi.org/10.7759/cureus.22778 [PubMed] [PMC]

§     Salikhov SI, Musin EV, Kim AL, Oshchepkova YI, Tikhonenko SA (2024) Polyelectrolyte microcapsules: An extended release system for the antiarrhythmic complex of allapinin with glycyrrhizic acid salt. International Journal of Molecular Sciences 25(5): 2652. https://doi.org/10.3390/ijms25052652 [PubMed] [PMC]

§     Samylina IA, Pyatigorskaya NV, Morokhina SL (2011) Herbal medicine for angina pectoris and other cardiovascular diseases. Remedium 5: 42-47. [in Russian]

§     Saqib S, Ullah F, Naeem M, Younas M, Ayaz A, Ali S, Zaman W (2022) Mentha: nutritional and health attributes to treat various ailments including cardiovascular diseases. Molecules 27(19): 6728. [PubMed] [PMC]

§     Schnabel RB, Yin X, Gona P, Larson MG, Beiser AS, McManus DD, Newton-Cheh C, Lubitz SA, Magnani JW, Ellinor PT, Seshadri S, Wolf PA, Vasan RS, Benjamin EJ, Levy D (2015) 50 year trends in atrial fibrillation prevalence, incidence, risk factors and mortality  in the Framingham Heart Study: A cohort study. Lancet 386(9989): 154–162. https://doi.org/10.1016/S0140-6736(14)61774-8 [PubMed] [PMC]

§     Serdoz VL, Rittger H, Furlanello F, Bastian D (2019) Quinidine – A legacy within the modern era of antiarrhythmic therapy. Pharmacological Research 144: 257–263. https://doi.org/10.1016/j.phrs.2019.04.028 [PubMed]

§     Shah KS, Xu H, Matsouaka RA, Bhatt DL, Heidenreich PA, Hernandez AF, Devore AD, Yancy CW, Fonarow GC (2017) Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. Journal of the American College of Cardiology 70(20): 2476–2486. https://doi.org/10.1016/j.jacc.2017.08.074 [PubMed]

§     Sun ML, Ao JP, Wang YR, Huang Q, Li TF, Li XY, Wang YX (2018) Lappaconitine, a C18-diterpenoid alkaloid, exhibits antihypersensitivity in chronic pain through stimulation of spinal dynorphin A expression. Psychopharmacology 235(9): 2559–2571. https://doi.org/10.1007/s00213-018-4948-y [PubMed]

§     Sun W, Saldaña MDA, Zhao Y, Wu L, Dong T, Jin Y, Zhang J (2016) Hydrophobic lappaconitine loaded into iota-carrageenan by one step self-assembly. Carbohydrate Polymers 137: 231–238. https://doi.org/10.1016/j.carbpol.2015.10.060 [PubMed]

§     Syrkin AL, Ivanov GG, Aksel'rod AS, Bulanova NA, Popov VV (2010) Prediction of the effectiveness of maintenance antiarrhythmic therapy in paroxysmal atrial fibrillation. Cardiology and Cardiovascular Surgery [Kardiologiya i Serdechno-Sosudistaya Khirurgiya] 4: 84–87. [in Russian]

§     Trofimova SV, Khasanova SR, Kudashkina NV, Baschenko NZh, Sapozhnikova TA, Khisamutdinova RYu (2011) Study of antiarrhythmic activity of Crataegus sanguinea (Rosaceae) leaves. Medical Bulletin of Bashkortostan [Meditsinskii Vestnik Bashkortostana] 4: 299–302. [in Russian]

§     Venskutonis P (2018) Phytochemical composition and bioactivities of hawthorn (Crataegus spp.): Review of recent research advances. Journal of Food Bioactives 4(2018): 69–87. https://doi.org/10.31665/JFB.2018.4163

§     Wang J, Xiong X, Feng B (2013) Effect of crataegus usage in cardiovascular disease prevention: An evidence-based approach. Evidence-Based Complementary and Alternative Medicine 2013: 149363. https://doi.org/10.1155/2013/149363 [PubMed] [PMC]

§     Xulu JH, Ndongwe T, Ezealisiji KM, Tembu VJ, Mncwangi NP, Witika BA, Siwe-Noundou X (2022) The use of medicinal plant-derived metallic nanoparticles in theranostics. Pharmaceutics 14(11): 2437. https://doi.org/10.3390/pharmaceutics14112437 [PubMed] [PMC]

Author Contribution

Nadezhda V. Nesterova, Ph. D., Senior Researcher, Plekhanov Russian University of Economics, Moscow, Russia; e-mail: nestero-nadezhda@yandex.ru; ORCID ID: https://orcid.org/0000-0002-9752-9757. Contribution to the article: collection and systematization of the material, formation of the design of the work, writing the text of the article.

Natalia D. Bunyatyan, Doctor Habil. of Pharmaceutical Sciences, Professor, Leading Researcher at the Scientific Department of Clinical Pharmacology at the Institute of Research and Development of the Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’) of the Ministry of Health of Russia, Moscow, Russia; e-mail: ndbun@mail.ru; ORCID ID: https://orcid.org/0000-0001-9466-1261. Contribution to the article: formation of the depth of literature search.

Irina A. Samylina, Doctor Habil. of Pharmacy, Professor, Professor of the Department of Pharmaceutical Natural Sciences, I.M. Sechenov First Moscow State Medical University, Moscow, Russia; e-mail: laznata@mail.ru; ORCID ID: https://orcid.org/0000-0002-4895-0203. Contribution to the article: general guidance on the work.

Vladimir A. Evteev, Senior Researcher at the Scientific Department of Clinical Pharmacology at the Institute of Research and Development of the Federal State Budgetary Institution Federal State Budgetary Institution ‘Scientific Centre for Expert Evaluation of Medicinal Products’ of the Ministry of Health of the Russian Federation (FSBI ‘SCEEMP’) of the Ministry of Health of Russia, Moscow, Russia’ of the Ministry of Health of Russia, Moscow, Russia; e-mail: pharmchemist@gmail.com; ORCID ID: https://orcid.org/0000-0002-6150-5796. Contribution to the article: selection and moderation of the content of scientific literature.