Possibility and prospects of using the drug dipyridamole in patients with COVID-19

| 05.12.2019

"Dipyridamole" is a drug that is prescribed to expectant mothers for placental insufficiency, increased blood pressure and various circulatory disorders. With the help of this medicine, many problems that can affect normal pregnancy are eliminated. The use of this medicine while expecting a child is recommended only after a doctor's prescription.

Thanks to this medicine:

Introduction

Dipyridamole (ATC code: B01AC07) is a vasodilator. It is an antagonist of the endogenous adenosine diphosphate (ADP) aggregant, inhibits phosphodiesterase, thereby reducing the release of aggregation activators from platelets - thromboxane, ADP, serotonin, etc., increases the synthesis of prostacyclin PgI2 by the endothelium of vascular tissue, which prevents platelet aggregation. Registered in the Russian Federation for the treatment and prevention of cerebral circulatory disorders (ischemic type), discirculatory encephalopathy, prevention of arterial and venous thrombosis and their complications; prevention of placental insufficiency; thromboembolism after heart valve replacement, in complex therapy of microcirculation disorders of any origin [1], as well as for the prevention and treatment of influenza and other acute respiratory viral infections. In other countries, for example, Belarus [2], the USA [3], the indication for the treatment and prevention of viral infections is not registered.

Pleiotropic effects of dipyridamole: clinical perspectives

Dipyridamole, which has an antithrombotic effect, has been successfully used for the secondary prevention of ischemic stroke. The progression of cerebrovascular disease is facilitated by atherosclerosis and thrombosis, in the development of which inflammation and oxidative stress play an important role. Research results indicate that dipyridamole has anti-inflammatory, antioxidant and antiproliferative properties. These potential effects can minimize the risk of progression of cerebrovascular disease and improve treatment results.

Dipyridamole was introduced to the world market in the 1960s. as a coronary vasodilator. And for more than half a century it has been successfully used as a vasodilator and antiplatelet agent.

Currently, the effectiveness of several antiplatelet drugs and their combinations has been proven in reducing the risk of recurrent cerebral ischemic events in patients who have suffered an ischemic stroke or transient ischemic attack of a non-cardioembolic nature [1]. However, the most widely used are acetylsalicylic acid (ASA), clopidogrel and the combination of dipyridamole with ASA.

The advantage of antiplatelet drugs is to minimize the risk of disease progression in the long term in stroke survivors. It is believed that this is due to the additional effects of antiplatelet agents.

The pleiotropic effects of dipyridamole have continued to be the subject of both clinical and experimental studies over the past decades.

Antiplatelet effect

Dipyridamole is a classic representative of antiplatelet drugs, differing from classic aspirin in its lesser ability to induce bleeding. Other advantages of dipyridamole over ASA include the absence of gastrotoxicity and the ability to control the antithrombotic effect by adjusting the dose.

The main indication for the prescription of dipyridamole is the primary and secondary prevention of ischemic events, including stroke. With age, the benefit of antiplatelet therapy increases, but its risk increases significantly. Therefore, it is older people who need the safest drugs, such as dipyridamole. Dipyridamole is also indicated for intolerance to ASA, concomitant treatment with angiotensin-converting enzyme inhibitors. In addition, dipyridamole is an important component of dual antiplatelet therapy (simultaneous use of low doses of ASA and dipyridamole).

The preventive and therapeutic effect of dipyridamole is realized through its antiplatelet and neuroprotective effect. The antiplatelet effect is associated with inhibition of platelet phosphodiesterase. It is phosphodiesterase inhibition that reversibly affects platelet aggregation. At the same time, most studies demonstrate the polyvalent effect of dipyridamole. In addition to suppressing the activity of platelet phosphodiesterase, it is a competitive inhibitor of adenosine deaminase.

In 1967, HJ Aledort and LM Aledort found that the antiplatelet effect of aspirin can be neutralized by adenosine diphosphate, which is released from activated platelet cells and takes part in the formation of a blood clot [2]. Dipyridamole disrupts platelet aggregation by inhibiting the production of adenosine diphosphate. Dipyridamole is primarily seen as an inhibitor of adenosine uptake into red blood cells and endothelial cells, thereby increasing plasma adenosine concentrations. Acting through transmembrane receptors, adenosine stimulates adenylate cyclase in platelets, which leads to increased levels of cyclic adenosine monophosphate and inhibition of cyclic guanosine monophosphate phosphodiesterase. As a result, the effects of nitric oxide, a potential vasodilator and inhibitor of platelet activation, are enhanced.

The effect on platelet activation is the main point of application of dipyridamole. Changing the dynamics of platelet activity and vascular reactivity helps improve cerebral perfusion [3]. This is confirmed by the results of studies in animal models. Thus, using a model of embolic occlusion of the rabbit middle cerebral artery, it was found that better perfusion rates in the acute period of stroke were observed in animals that received dipyridamole 24 hours before the event, compared with untreated animals [4]. This model simulates a clinical situation where a patient suffers a stroke while receiving dipyridamole for secondary stroke prevention. Consequently, treatment with dipyridamole reduces the severity and consequences of acute dyshemia.

In the 1980s another antithrombotic mechanism of action of dipyridamole was discovered - an increase in the release of plasminogen activator, the most important enzyme of fibrinolysis [5]. It was subsequently revealed that plasminogen activator in the endothelium of brain capillaries increases when dipyridamole is added to tissue culture. In the experiment, in animals receiving dipyridamole during euthanasia, a reduction in the size of the injected blood clot was also observed.

Thus, the antithrombotic effect of dipyridamole is realized through two complementary mechanisms: an antiplatelet effect, which prevents the formation of a blood clot, and an action associated with the activation of plasmin, leading to a reduction of the formed blood clot.

More than 30 years of use of dipyridamole confirms its role in stroke prevention. In the large-scale randomized ESPS2 trial, which included 6602 patients who had suffered a transient ischemic attack or ischemic stroke, the effectiveness of dipyridamole monotherapy at a dose of 400 mg/day was comparable to the effectiveness of ASA monotherapy [6]. In the clinical studies ESPS2 [6] and ESPRIT [7], the effectiveness of combination therapy with dipyridamole at a dose of 400 mg/day and ASA at a dose of 50 mg/day was significantly higher than that of ASA monotherapy at a dose of 50 mg/day. Thus, in the ESPS2 study, combination therapy reduced the risk of recurrent stroke compared with placebo by 37%, compared with ASA by 18%. The incidence of hemorrhagic complications was the same in all groups [6]. In addition, according to a meta-analysis of these studies [8], the relative risk for the composite endpoint of stroke, myocardial infarction and death from vascular events was significantly lower in the combination therapy groups.

Dipyridamole and endothelial function

The endothelium controls the growth of smooth muscle cells and angiogenesis, thrombus formation, fibrinolysis and many other processes, regulates vascular tone through the release of vasodilators (nitric monoxide, prostacyclin I2, natriuretic peptide C, kinins) and vasoconstrictors (endothelin 1, thromboxane A2, angiotensin 2) factors and modulates contractile activity of smooth muscle cells.

Under physiological conditions, the release of relaxing factors predominates, which ensures normal dilatation of the vessel. In various vascular diseases, the ability of endothelial cells to release relaxing factors is reduced, but the release of vasoconstrictor factors remains or increases, that is, endothelial dysfunction develops. Impairment of endothelium-dependent vasodilation, primarily due to a decrease in the bioavailability of nitric oxide, leads to vasoconstriction, local immunological inflammatory reactions, platelet aggregation, and blood clot formation.

Several studies have demonstrated that dipyridamole enhances the nitric oxide-mediated vasodilatory effect [9]. In addition, at therapeutic concentrations, dipyridamole suppresses the formation of endothelial cells that release reactive oxygen species, which improves the redox balance of the endothelium. Thus, dipyridamole simultaneously regulates both nitric oxide-mediated vasodilation and superoxide release from the endothelium [10]. The combined antiplatelet and vasodilator effect of dipyridamole improves tissue perfusion.

Antioxidant effect

In recent years, a large body of evidence has emerged that late-life diseases and oxidative stress are associated with significant cerebrovascular changes. Peroxidation is considered one of the significant links in the activation of gene reactions encoding apoptosis. Focal oxidative stress can lead to endothelial cell dysfunction and increase thrombus formation. Endothelial dysfunction can significantly influence the degree of damage to brain tissue during ischemia.

Oxidative stress, as the main mechanism of cell damage, is the cause of both acute and chronic cerebrovascular accidents. An acute ischemic process triggers a cascade of reactions, including oxidative stress. Some of them end in the acute period, some persist for a certain period and contribute to the aggravation of cell apoptosis. As a result, signs of chronic cerebral circulatory failure increase [11]. Under conditions of chronic hypoperfusion, the energy supply to the brain is reduced, and the compensatory capabilities of antioxidant systems are depleted.

Ischemic stroke in most cases develops against the background of pathological changes that have occurred. As a rule, such patients have morphofunctional and histochemical changes that are caused by the previous dyscirculatory process. Its symptoms increase significantly in the post-stroke period.

Despite its universality, the damaging effect of oxidative stress is always individual. Its features are determined by the background state of brain metabolism, as well as the status and reactivity of antioxidant systems.

Limiting oxidative stress in the acute phase of ischemia and preventing increased permeability of the blood-brain barrier (blocking free oxidative radicals and peroxide substances that are produced during ischemia) can improve clinical outcome. Therefore, we can assume a therapeutic benefit of antioxidants in the acute and chronic stages of cerebral ischemia. Currently, stratification of patients with a high risk of unfavorable course of oxidative stress and indications for antioxidant and neuroprotective therapy in patients with discirculatory encephalopathy are not sufficiently developed. However, the collected data allows us to identify target groups of patients with dyscirculatory encephalopathy depending on their pro/antioxidant state.

Among the main clinical factors contributing to the development of oxidative stress in patients suffering from chronic cerebral ischemia are:

• age over 60 years;
• arterial hypertension;
• arterial hypertension in combination with atherosclerosis;
• coronary heart disease with changes in the geometric parameters of the heart;
• dyslipidemia; hyperhomocysteinemia;
• type 2 diabetes mellitus;
• excess body weight.

As a potential oxidizing agent that transfers electrons from hydrophilic and hydrophobic molecules, dipyridamole eliminates free radical oxidation products, resulting in increased vascular protection. The protective effect of dipyridamole is observed mainly in relation to peroxidation of membranes and mitochondrial lipids of erythrocytes and other blood cells [12]. In addition, dipyridamole inhibits the formation of free radicals in platelets and endothelial cells. This leads to improved redox cellular reactions. Many experimental studies have demonstrated that neutralization of free radicals prevents the development of pathological vasoreactivity and disruption of the permeability of the blood-brain barrier [13, 14]. In experimental models of diabetes mellitus, low doses of dipyridamole were effective in preventing induced angiopathy and nephropathy by reducing renovascular oxidative stress [15].

The antioxidant properties of dipyridamole, discovered more than 20 years ago, continue to be actively studied both in experiments on animal models and in clinical practice [16].

Anti-inflammatory effect

According to the modern understanding of the pathogenesis of cerebrovascular disease, inflammatory reactions play a major role in the formation of a blood clot and, accordingly, the severity of a stroke.

Atherothrombotic genesis of acute dyshemia is the most common mechanism for the development of ischemic stroke. This process is characterized by thrombus formation and inflammation caused by the interaction of platelets and leukocytes in the area of ​​vascular damage [17]. Clinically significant symptoms of cerebral ischemia are rarely the result of vessel occlusion by growing atherosclerotic plaque. Much more often - the result of embolization of a vessel with fragments of a damaged plaque or blood clots. Reperfusion of a thrombosed vessel leads to an acute inflammatory response, which serves as an additional factor in damage to endothelial, microglial and neuronal cells [18].

There is a post-reperfusion inflammatory transient response, which is induced by cytokines, interleukin 1-beta, tumor necrosis factor, and a chronic response associated with interleukin 6 or 8. The latter is involved in the regulation of the release of fibrinogen and adhesion molecules [19].

In addition, inflammatory reactions themselves may be an additional cause of oxidative stress, leading to endothelial dysfunction and platelet activation.

Currently, antiplatelet agents are considered as potential modulators of the inflammatory response during ischemic stroke. Experimental models have shown that dipyridamole reduces the expression of intercellular adhesion molecules and matrix metalloproteinases in brain endothelial cells [20]. Dipyridamole also inhibits the action of tumor necrosis factor. At the same time, the blocking of interleukin 6 and tumor necrosis factor is enhanced when using a combination of dipyridamole with ASA [10]. Intercellular adhesion molecules are ligands for leukocytes. They can control the migration of inflammatory cells across the blood-brain barrier. In turn, matrices of metalloproteinases destabilize the atherosclerotic plaque, break through the blood-brain barrier, support edema, microhemorrhages, and promote apoptosis.

Animal models have shown that animals treated with dipyridamole have a smaller volume of the area damaged by ischemia and less microhemorrhages in the tissues surrounding the infarction area. These facts correlate with better survival rates.

Increased adenosine levels induced by dipyridamole contribute to the inhibition of neutrophil activation by reducing the expression of neutrophil adhesion molecules. Neutrophils are among the first blood cells to infiltrate the ischemic zone of injury based on chemotaxis. A local increase in neutrophil concentration can contribute to the formation of atherosclerotic plaques in the capillary bed and increased microvascular permeability. In turn, the expression of neutrophil mediators, including the activation of oxidative substances and cytokines, can lead to disruption of the blood-brain barrier.

A study of the effects of dipyridamole showed that samples of ischemic tissue from animals treated with the drug are stained with neutrophil dyes to a minimal extent. Neutrophils are usually associated with acute inflammation; their presence in the subacute stage of stroke indicates prolongation of inflammatory processes. Dipyridamole may minimize inflammatory processes initiated by neutrophils during the subacute phase.

The most important property of dipyridamole is its ability to increase the formation of endothelial growth factor and stimulate the development of the capillary network due to the action of adenosine on adenosine receptors in capillaries. This effect is important for patients with coronary heart disease - exercise tolerance increases, and in patients with left ventricular dysfunction, the ejection fraction increases.

Conclusion

The neuroprotective effects of dipyridamole are associated with the suppression of inflammatory processes, which directly and indirectly affect thrombus formation and vascular endothelium.

Current research results have proven that dipyridamole has additional benefits. First of all, it directly and indirectly affects the endothelium and inhibits proliferation. In addition, dipyridamole is characterized by antioxidant and anti-inflammatory effects. These properties require further study.

These effects of dipyridamole complement the mechanisms of action of ASA, which serves as an argument in favor of using their combination for secondary prevention of stroke. Primary prevention can be carried out only with dipyridamole 25 or 75 mg three times a day. Indications for prescribing a high dose are the long course of the disease and the presence of repeated episodes of acute dyshemia [21].

Additional indications for the prescription of dipyridamole are factors that can lead to the development of severe oxidative stress: age over 60 years, instability of systemic hemodynamics (arterial hypertension, coronary heart disease, with changes in the geometric parameters of the heart), dysmetabolic conditions (dyslipidemia, hyperhomocysteinemia, type 2 diabetes mellitus , overweight).

Despite numerous studies and many years of experience with the use of dipyridamole, the identification of clinical targets for its pleiotropic effects is still relevant.

Possibility of use in patients with COVID-19

The prerequisites for the use of dipyridamole for COVID-19, in the pathogenesis of which endothelial damage and hypercoagulation [4], as well as the so-called “thrombus inflammation” [5], play a large role, are its antithrombotic, anti-inflammatory, antioxidant and vasodilator activity [6][7] [8][9][10], immunomodulatory [1][11], antifibrotic [12], cardioprotective effect [13], the ability to improve renal function [14][15], as well as antiviral activity against the influenza A virus [ 16][17], mengovirus [18], herpes simplex virus [19], HIV [20], ARVI [21][23], demonstrated both in the laboratory and in the clinic, including in children [24] .

A possible mechanism of antiviral action against SARS-CoV-2 is nonspecific immunity (induction of IFN-α and -γ) [1], binding of the SARS-CoV-2 Mpro protease with subsequent suppression of virus replication, stimulation of the response to type I IFN in vitro [ 25].

We found one clinical trial (CT) on the effectiveness of dipyridamole in the treatment of COVID-19. A multicenter, parallel, randomized controlled trial involving 31 patients with COVID-19 [26] used dipyridamole versus control. The addition of dipyridamole at a dose of 150 mg/day for 14 days to standard therapy (ribavirin 500 mg every 12 hours, methylprednisolone sodium succinate 40 mg 4 times a day) did not statistically significantly affect the rate of clinical cure and remission in patients with mild and severe course of the disease (odds ratio 23.75; p=0.06). 7 out of 8 (87.5%) patients with severe disease who received dipyridamole were cured and discharged, 1 patient (12.5%) was in clinical remission. In the control group, 4 out of 12 (33.3%) seriously ill patients were discharged, 2 (16.7%) patients were in remission, and 2 (16.7%) patients died. The average time for detection of viral RNA (by qualitative method) was reduced by 1.6 days compared to the control. D-dimer levels were initially elevated in 50% of severely ill patients in the dipyridamole group and in 42% of the control group. Over time, the level of D dimer decreased in the dipyridamole group, while increasing in the control group (p<0.05), and the level of lymphocytes and platelets (ns) increased. All patients in the treatment group showed an improvement in the CT scan; in the control group, 1 patient out of 12 showed progression. Of the two critically ill patients receiving dipyridamole, one was a 70-year-old man with hypoxia and multiple organ dysfunction on admission, a high D-dimer level of 16.2 mg/l, lymphopenia 0.37 × 109/l, and persistently low oxygen saturation died after 5 days after starting treatment. The second patient, also with low oxygen saturation and high D-dimer levels (8.83 mg/l), was in remission in the hospital at the time of submission of the manuscript. The authors believe that dipyridamole should be prescribed before progression to critical illness.

Dipyridamole is included in the COVID-19 Treatment Protocol of the Moscow State University Medical Center in the basic treatment regimen for hospitalized patients of moderate and severe severity, as well as outpatients of mild and moderate severity in complex therapy. The regimen for prescribing dipyridamole is 75 mg 2 times a day on the 1st day, then 150 mg 2 times a day [27].

Consequences of treatment with dipyridamole

The effect of the combination of dipyridamole and ASA on the human body was revealed in a study involving 36 people (18 males and 18 females). The study of the effects of these two drugs took place in an outpatient setting. Participants in the experiment took the drugs in the morning (under the supervision of medical personnel) and in the evening. Blood was also drawn in the morning. The morning dose on the 5th day was the last. Then the “washing” period began. 72 hours after the last dose, the 5-day course was repeated. The purpose of this study was to identify how these medications interact when taken together and how they affect the body. Scientists were interested in what causes severe headaches.

Analysis of indicators

Throughout the experiment, participants answered a question daily about their well-being. It was necessary to identify adverse events and assess the extent of their manifestation. All this was done according to the WHO classification. One such event in the functioning of the central nervous system was headache. 1 case was not recorded due to the etiology of the symptom - influenza.

To identify the reasons why a headache begins, several factors were identified, each of which could in one way or another affect the well-being of the study participant. Among them:

• Concentration of the drug in the body;
• Treatment with one of the medications used;
• Further treatment period;
• Patient cohort.

To understand how headaches are related to each of these factors, scientists conducted an analysis. The dependent variable was the severity and duration of pain. It is these indicators that fully reflect the discomfort of each participant. There were also independent variables. Logistic units were used to assess headache severity. The scale consisted of 4 categories: “none”, “mild”, “moderate”, “severe”. Data had to be entered daily. Patients did this for the first 4 days.

results

The desired symptom was reported by 72% of participants. The nature of the pain was mild, transient and did not require the use of special medications to eliminate it. 2 people experienced severe discomfort, which forced them to interrupt the experiment and leave it. An additional 1 participant left the study due to other adverse events that occurred as a result of taking dipyridamole and ASA.

As it became known as a result of the analysis of the final indicators of the experiment, the headache disappeared in the first days of therapy. The symptom was less pronounced not only towards the end of taking the drugs, but also during the “wash-out” period. Most often, the headache began to hurt in the morning, 2-3 hours after taking it. Approximately the same thing was observed in the evening hours after the next dose, although the pain was mild. By the way, it was at this time that the concentration of the active components of the drug was maximum.

Conclusion

The 36 people who participated in the study became a clear example of how dipyridamole therapy can lead to such negative consequences. Scientists believe that the final indicators obtained as a result of the experiment will be different if the volunteers were not young and healthy adults, but elderly patients who had suffered a stroke.

Most often, headaches occurred on the first day, while discomfort decreased over the subsequent days.
It is difficult to determine how much the drug intake affected these changes, since a number of other factors also affected the patient’s well-being. For example, volunteers who stopped taking caffeine experienced headaches 52% of the time. In this case, it is associated with withdrawal syndrome. But, as the experiment showed, such a symptom is exclusively a side effect of taking dipyridamole. It decreases during therapy, both in duration of manifestation and in its intensity. Author: K.M.N., Academician of the Russian Academy of Medical Sciences M.A. Bobyr

Safety of dipyridamole

According to the instructions for medical use, when using therapeutic doses, side effects are usually not pronounced and are transient in nature, disappearing with long-term use of the drug [1]. Possible tachycardia, bradycardia, “flushing” of blood to the face, hypotension; coronary steal syndrome (at a dose of more than 225 mg/day), dyspepsia; thrombocytopenia, bleeding, weakness, dizziness, noise in the head, headache, migraine, ear fullness, arthritis, myalgia, rhinitis, allergic reactions. Dipyridamole is contraindicated in severe cardiovascular pathology, severe heart rhythm disturbances; severe arterial hypertension; arterial hypotension, collapse; COPD; bleeding tendency; liver and/or kidney failure; hypersensitivity to the components of the drug; intolerance to fructose, lactose, deficiency of sucrase/isomaltase, lactase, glucose-galactose malabsorption; in children under 12 years of age. The use of the drug during pregnancy and lactation is possible if the expected benefit to the mother outweighs the possible risk to the fetus and child.