Curantyl® N 25 (Curantyl® N 25)
Dipyridamole inhibits platelet aggregation and adhesion, improves microcirculation, and has a mild vasodilator effect. The mechanism by which dipyridamole has an inhibitory effect on platelet aggregation is associated with the suppression of the reuptake of adenosine (an inhibitor of platelet reactivity) by endothelial cells, erythrocytes and platelets; activation of adenylate cyclase and inhibition of platelet phosphodiesterases. Thus, dipyridamole prevents the release of aggregation activators from platelets - thromboxane (TxA2), ADP, serotonin, etc. Dipyridamole increases the synthesis of prostacyclin PgI2 by the endothelium of the vascular wall, normalizes the ratio of PgI2 and TxA2, preventing platelet aggregation; enhances the synthesis of endothelial nitric oxide (NO). Dipyridamole reduces platelet adhesiveness, prevents the formation of blood clots in blood vessels and stabilizes blood flow in the ischemic area.
Dipyridamole dose-dependently prolongs the pathologically shortened platelet life time.
Dipyridamole, due to its vasodilating properties, helps reduce total peripheral vascular resistance, improves microcirculation, and has an angioprotective effect. These effects are due to increased activity of endogenous adenosine (adenosine affects vascular smooth muscle and prevents the release of norepinephrine). Dipyridamole has both angiogenic and arteriogenic activity, stimulating the formation of new capillaries and collateral arteries.
Dipyridamole normalizes venous outflow and reduces the incidence of deep vein thrombosis in the postoperative period. Improves microcirculation in the retina and renal glomeruli.
In neurological practice, the pharmacodynamic effects of dipyridamole are used, such as reducing cerebral vascular tone and improving cerebral circulation. According to angiographic studies, the use of dipyridamole in combination with acetylsalicylic acid (ASA) can slow down the progression of atherosclerosis.
In obstetric practice, dipyridamole is used to improve placental blood flow and prevent dystrophic changes in the placenta, eliminate hypoxia of fetal tissue and the accumulation of glycogen in them. Thus, it is advisable to use dipyridamole for early manifestations of placental insufficiency, in pregnant women with a high risk of placental insufficiency: intrauterine infection, gestosis (threat of preeclampsia and eclampsia), autoimmune pathology, extragenital diseases (diabetes mellitus, metabolic syndrome); as well as diseases with a tendency to thrombosis.
As a pyrimidine derivative, dipyridamole is an interferon inducer and has a modulating effect on the functional activity of the interferon system, in
vitro
increases the reduced production of interferon alpha (α) and gamma (γ) by blood leukocytes. Increases nonspecific antiviral resistance to viral infections.
How to reduce the risk of venous thromboembolism when taking COCs
In the previous article, I told you about the main risks of taking oral contraceptives - deep venous thrombosis and pulmonary embolism. This is a life-threatening condition, which, of course, is better not to reach. Today we will discuss the main risk factors in order and see how they should be taken into account.
It's not possible - it's not possible
First, do not allow women who have contraindications to take COCs in accordance with the National Medical Criteria for Contraceptive Methods and WHO criteria (5th revision, 2015).1
Consider combinations of various factors that require caution
The benefit/risk ratio is carefully assessed in patients with several conditions/diseases for which COCs are not contraindicated, but require caution (2nd class of acceptability).
For example, age over 40 years and obesity with a BMI = 30 kg/m2 are not contraindications, but the combination of these two factors is quite explosive. The large-scale cohort study European Active Surveillance Study on Oral Contraceptives (EURAS-OC), conducted in 2000–2005, demonstrated the association of the risk of venous thromboembolism with age and weight: the older the patient and the higher her weight, the higher the likelihood of developing venous thrombosis.
Don't do pointless tests
In most cases, before starting COC use, the likelihood of venous thromboembolism cannot be predicted using tests. No coagulogram or D-dimer will allow you to assess how the blood coagulation system will behave.
It has now become very fashionable to conduct genetic studies to identify mutations in the genes of the hemostatic system before prescribing COCs to everyone. This, of course, is very interesting and exciting, but it is only necessary for those who have had early strokes, heart attacks or thromboembolism among their close relatives. In fact, mutations are quite rare and are not a 100% indicator that trouble will definitely happen.
By the way, about “genetic risk”. In recent years, a number of publications have appeared in the scientific literature indicating that carriers of blood groups II, III and IV have 2 times higher chances of getting venous thrombosis than carriers of the first group. This phenomenon was even called “non-zero blood type.” So, a non-zero blood group is a stronger risk factor for thrombosis than heterozygous polymorphisms of the II and V factor genes. But we do not deny the opportunity to take COCs to all carriers of blood group II (A) (and they are the majority in our population)!
Consider the “travel syndrome” (or “economy class syndrome”)
The connection between venous thrombosis and travel was first noted on flights across the Atlantic Ocean. It is now known that the risk lies not on the plane, but in a long-term forced sedentary position during flights or transfers lasting more than 6 hours2. In such situations, it is advisable for all COC users to use compression knitwear of the 1st class, choose an aisle seat, walk frequently, and do exercises for the calf muscles.
If you have surgery
Surgery itself is a serious thrombogenic factor. That is why COCs should be discontinued at least 2 weeks before planned operations, resuming use no earlier than 3 weeks after complete restoration of physical activity. Minor surgeries lasting up to 30 minutes do not increase the risk of thrombotic complications, but it is best to discuss this issue with your doctor3. Surgical treatment of varicose veins is not associated with a high risk of venous thromboembolism.
Avoid unnecessary “breaks”
It is absolutely no secret that the risk of thromboembolic complications is highest in the first months of taking COCs - during the period of adaptation to the drug. After just 3 months, the risk decreases significantly and by the end of the first year it becomes even lower than the population average.
I have always been terribly perplexed by the mysterious love for “rest breaks” while taking COCs. As soon as the body adapted to the drug, the risk of dangerous events decreased significantly. It would seem, take your pills and enjoy life. But no! It is imperative to take a break for 1-3 months, either after 6 months, or after 9, or after a year, forcing the body to go through the most difficult period of adaptation again and raise the risk of thrombosis to new heights4.
How the risk of venous thrombosis is reduced5
Incidence of venous thromboembolism vs duration of COC use. EURAS study.
Note The increased risk is mainly concentrated in the first year (more precisely, in the first 3 months) after starting use.
A “rest” from contraceptives for a woman in need of contraception is fraught not only with the onset of an unwanted pregnancy, but also with quite serious complications. In the end, it is absolutely unclear why the body, which is in a monotonous dormant state while regularly taking COCs, is so “tired” of it.
For the vast majority of healthy women of reproductive age, the well-established benefits of COCs outweigh the very low absolute risk of venous thromboembolism, but awareness of this and the use of appropriate precautions is certainly necessary.
1. World Health Organization. Medical Eligibility Criteria for Contraceptive Use, 4th edition. Geneva: WHO, 2009. WHO. Medical eligibility criteria for contraceptive use. Fifth edition. Geneva: WHO August 2015. https://www.who.int/reproductivehealth/publications/family_planning/MEC-5/en/ 2. Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications (VTEC) // Phlebology. - 2015. - No. 4, issue 2. - P. 1–52. 3. Contraception and thrombosis. Ways to reduce thrombotic risk in women using COCs: information bulletin / G. B. Dicke, A. V. Solovyova; edited by V. E. Radzinsky. - M.: Editorial office of the magazine StatusPraesens, 2016. - 16 p. 4. Dinger JC, et al. The risk of venous thromboembolism in OC users: time patterns after initiation of treatment // Pharmacoepidemiol Drug Saf 2010; 19 (S1); S214-5. 5. Figure adapted from Suissa, et al. //Hum Reprod 2000; 15:817–21.
Oksana Bogdashevskaya
Photo istockphoto.com
Up to 20% of clinically diagnosed pregnancies end in spontaneous termination, with the first trimester accounting for up to 75-80% of cases [4]. Among the causes of spontaneous abortion, especially in the early stages, there is the so-called “uterine factor”, which can be represented by hypoplasia and “immaturity of the endometrium”, hemodynamic disorders in the vascular bed of the uterus. These changes, often combined with endocrinopathies, infectious diseases, immunological and hemostasiological disorders both at the systemic and local levels, result in inferiority of the processes of implantation and placentation [2]. The morphological basis of the “uterine factor” is most often represented by chronic endometritis [1].
As one of the main components of preconception preparation for the “uterine factor” of recurrent pregnancy loss (RPL), drugs that improve microcirculatory and hemorheological parameters have proven themselves to be effective [5].
In this aspect, the use of dipyridamole (Curantil Berlin-Chemie AG, Germany), which has anticoagulant and antiplatelet effects, is particularly relevant. The antithrombotic effect of dipyridamole is associated with the release of prostaglandin precursor from the vascular endothelium. By influencing the metabolism of arachidonic acid, dipyridamole increases the synthesis of prostacyclin in the vascular wall and reduces the synthesis of thromboxane A2 in platelets by inhibiting thromboxane synthetase. As a result, the adhesion of platelets to the endothelium, subendothelium and collagen of the damaged vascular wall is reduced, which leads to an increase in the life expectancy of platelets and a slowdown in their aggregation. Dipyridamole also potentiates the antiplatelet and vasodilatory effects of endothelial factor and inhibits erythrocyte aggregation. As a result of the release of plasminogen from the vascular wall, the drug has a fibrinolytic effect [7].
The effect of the drug Curantil is aimed at improving microcirculation, inhibiting thrombus formation, reducing total peripheral vascular resistance, improving oxygen delivery to tissues, and preventing hypoxia. The drug Curantil activates microcirculatory processes caused by changes in the aggregation properties of blood, increases the number of actively functioning capillaries and the speed of blood flow, which helps restore normal tissue structure [6].
The absence of teratogenic and embryotoxic effects, the “controllability” of the action of dipyridamole allows it to be used not only during pregestational preparation, but also during pregnancy. At the same time, the greatest effectiveness of dipyridamole is observed in the early stages of pregnancy, i.e. during the period of the most active formation of the chorion and placenta. Thus, in the studies of A.P. Milovanova and P.A. Kiryushchenkov [3], performed on the basis of a pathomorphological study of chorionic villi at 6-10 weeks of pregnancy with PPB syndrome, showed a lag in the rate of maturation and vascularization of the villi by 2-3 weeks compared with those during physiological pregnancy. In addition, there was a slowdown in erythropoiesis, which was expressed in the predominance of nuclear forms (erythroblasts) in relation to typical forms (erythrocytes). After using the drug Curantil at a dose of 25 mg 3 times a day for 7-10 days, activation of angiogenesis in the chorionic villi was established, which was expressed in the formation of a branched capillary network with a wide lumen. Activation of erythropoiesis was indicated by an increase in the content of erythrocytes relative to erythroblasts in the chorionic vessels.
These data served as the basis for a non-invasive (ultrasound) assessment of the effectiveness of Curantil in the early stages of gestation for PPB syndrome.
The purpose of the study was to evaluate the effectiveness of the use of dipyridamole in the first trimester of pregnancy in the “uterine form” of PPB syndrome based on dynamic hemostasiological studies and ultrasound using the Doppler method.
Material and methods
The main group consisted of 41 pregnant women (average age 32.3±0.5 years) with PPB syndrome. The average period of unsuccessful pregnancy outcomes was 7.8±0.2 weeks. The control group consisted of 38 healthy primigravida women (average age 28.5±0.4 years).
The hemostasiological study included determination of the concentration of fibrinogen, activated partial thromboplastin time (aPTT), prothrombin index (PI), chronometric and structural coagulation, according to thromboelastogram (TEG), assessment of the functional properties of platelets, levels of thrombinemia - soluble fibrin-monomer complexes in plasma (RSFM) ), D-dimer. The natural anticoagulant link was assessed by the level of antithrombin III (ATIII) activity.
Ultrasound was performed at 7-8 weeks and 13-14 weeks of pregnancy. Along with the traditional assessment of the state of the embryo (fetus), chorion (placenta), a Doppler assessment of the state of hemodynamics in the vascular system of the uterus was carried out.
To simplify the study, a carbon-independent indicator, the resistance index (IR), was used. The distribution of vascular color signals in the myometrium was also taken into account. Ultrasound examination of blood flow was performed at the level of the uterine, arcuate, radial, and basal arteries. The absence or presence of chorionic blood flow was also assessed.
All women in the main group, in addition to standard therapy, received the drug Curantil at a dose of 25 mg 3 times a day 1 hour before meals for 6 weeks. Patients with hemorrhagic syndrome, severe arterial hypotension and tachycardia (BP below 90/60 mm Hg, heart rate more than 90 beats/min) were excluded from the study.
Results and discussion
When assessing hemostasiogram parameters before therapy, initial signs of activation of intravascular coagulation were noted, which was expressed in an increase in the functional activity of platelets (ADP, collagen aggregation) and moderate thrombinemia (RCFM).
During therapy, there was a decrease in platelet aggregation properties by 1.6-1.7 times (p<0.05), a decrease in the level of thrombinemia (the number of weakly positive RKFM samples decreased by 2.7 times, p<0.05). These features are reflected in the table.
In addition, the following features of uteroplacental blood flow in the early stages of gestation have been established. With Doppler ultrasound at 7-8 weeks in women of the main group, visualization of large vessels of the uterus was possible in all patients. The blood flow spectrum had a pronounced systolic wave, and diastolic blood flow was visualized. When studying the digital indicators of the blood flow spectrum curve (BCS), hemodynamic disturbances were revealed in the uterine arteries (IR 0.82±0.02; p<0.05), protodiastolic notches were present in the vast majority of women. The difference in the peripheral resistance of the right and left uterine arteries was insignificant and amounted to no more than 11.4%. In the arcuate arteries, the resistance index was 0.73±0.01, in the radial arteries - 0.71±0.02, and the measurement of this indicator was possible only in 19 (46.3%) women. In the basal arteries and in the subchorionic zone, vascular color signals were not detected in all cases (41 patients). 35 (85.4%) women had a pronounced asymmetry in the distribution of color signals in the myometrium (there was an avascular anterior or posterior wall, no lateralization was detected).
In women in the control group, hemodynamic indicators in the uterine arteries (IR 0.76±0.01), arcuate arteries (IR 0.69±0.01), radial arteries (IR 0.63±0.01) and basal arteries ( IR 0.53±0.02) corresponded to generally accepted standards for this stage of pregnancy in 33 (86.8%) patients.
Thus, the resistance index values in the uterine, arcuate and radial arteries before treatment with Curantil in patients of the main group were significantly higher (p<0.05) than in women in the control group. Uniform distribution of color signals in the myometrium in patients of the control group was observed in 100% of cases.
After therapy, a control ultrasound at the 13-14th week of pregnancy showed normalization of hemodynamic parameters in the myometrial vessels, as well as a normal diffuse distribution of color vascular signals (see the figure in the color insert).
Figure 1. Doppler dynamics of uterine blood flow during pregravid preparation (three-dimensional reconstruction of the uterus and its vascular bed). a — before treatment: hypovascularization of the posterior wall of the uterus, impaired hemodynamics in small vessels.
Figure 1. Doppler dynamics of uterine blood flow during pregravid preparation (three-dimensional reconstruction of the uterus and its vascular bed). a — before treatment: hypovascularization of the posterior wall of the uterus, impaired hemodynamics in small vessels.
Figure 1. Doppler dynamics of uterine blood flow during pregravid preparation (three-dimensional reconstruction of the uterus and its vascular bed). b — after treatment: enrichment of the vascular pattern, normalization of hemodynamic parameters in small vessels.
Figure 1. Doppler dynamics of uterine blood flow during pregravid preparation (three-dimensional reconstruction of the uterus and its vascular bed). b — after treatment: enrichment of the vascular pattern, normalization of hemodynamic parameters in small vessels. Visualization of chorionic blood flow using power Doppler mapping was possible in 29.3% (12 patients) of the main group, which was almost 2 times higher than this figure in the control group - 13.2% (5).
According to our data, the most optimal study of uterine hemodynamics to identify early rheological complications of pregnancy occurs during the period of 7-8 weeks, which corresponds to the first wave of cytotrophoblast invasion, since deterioration of hemodynamics in the uterus during these periods can significantly disrupt the formation of the uteroplacental system.
Conclusion
A study using hemostasiological and ultrasound methods confirmed the effectiveness of using the drug Curantil in the early stages of gestation in the “uterine form” of recurrent pregnancy loss syndrome, which is crucial for the normal functioning of the fetoplacental system in the future.
