ACTUAL INFORMATIONDicinone (2,5-dihydroxybenzenesulfonate diethylammonium salt; ethamylate) is a synthetic hemostatic drug prescribed for capillary bleeding. It was discovered in 1959 by Estev et al. In clinical use as a hemostatic non-thrombogenic drug since 1964.
Appointment
It is prescribed for short courses to reduce menorrhagia, to eliminate surgical or postoperative capillary bleeding. In 1980, it was proved that etamzilate acts on platelet adhesion mechanisms and thus helps to reduce capillary bleeding.
One of the reviews covers more than 40 years of intensive clinical and fundamental research using etamsylate. Firstly, a large amount of medical literature is summarized regarding its clinical effectiveness. Of these, well-controlled clinical studies clearly showed the therapeutic efficacy of etamsylate in dysfunctional uterine bleeding, and the magnitude of the reduction in blood loss was directly proportional to the severity of menorrhagia (heavy menstruation). Other well-controlled clinical studies have shown the therapeutic efficacy of etamzilate in periventricular hemorrhage in children with very low birth weight and surgical or postoperative capillary bleeding. However, this fact in the future, unfortunately, was not used in the appointment. Secondly, numerous studies were conducted to determine the mechanism of action of etamzilate.
Dicinone (etamzilate) acts in the first stage of hemostasis, improving platelet adhesion and restoring capillary resistance. Recent studies have shown that etamsylate promotes the development of P-selectin-dependent platelet adhesion mechanisms. Finally, etamzilate was compared with other hemostatic agents. It is believed that etamzilate as a hemostatic agent is considered to be mild in its action, but well-tolerated, especially useful for dysfunctional uterine bleeding when contraception is not required (Garay R.P., 2006).
Research
In recent experimental studies, protein adhesion mechanisms have been well characterized using etamsylate as an example. In recent years, new hemostatic agents have appeared with a certain number of studies published in scientific journals, and already comprehensively reviewed. Animal studies have clearly demonstrated the efficacy of etamsylate as a hemostatic agent, while clinical efficacy has been clearly shown in certain, but not all, blood clotting disorders. In 1964, a double-blind, placebo-controlled study of the effect of oral and intramuscular administration of etamsylate was conducted in 60 patients, most of whom were diagnosed with tuberculosis. Ethamsylate reduced mean bleeding time by 33.8 and 32.9%. Assigned (250 mg every 6 hours for 2 days) and intramuscularly (500 mg), respectively; whereas the placebo values were 8.1 and 4.5%.
Further studies confirmed such hemostatic reactions in patients with various coagulation disorders, while the effects were less noticeable or tended to zero in healthy subjects under normal conditions. In healthy people, oral dicinone (etamzilate) (1 tablet of 500 mg, 4 times a day for 2 days) noticeably reduces the increase in bleeding and blood loss caused by acetylsalicylic acid. Finally, the magnitude of the reduction in etamzilate blood loss was proportional to the severity of the bleeding. Four double-blind studies were conducted to study the therapeutic efficacy of etamsylate in dysfunctional uterine bleeding. Positive results were obtained in all 4 studies. It was found that etamsylate reduces menstruation (blood loss) more in patients with primary menorrhagia (50%) than in women using intrauterine devices (19%). Dicinone (etamsylate) was prescribed 2 tablets of 250 mg 4 times a day, starting from the 5th day before the expected start of menstruation and continued for 10 days. Interestingly, the difference between the two groups is explained by different values of the initial blood loss, which were significantly higher in the group with primary amenorrhea.
The effects of etamsylate and mefenamic acid on menstrual blood loss were compared in a double-blind study in 34 women with menorrhagia. Both drugs caused a statistically significant reduction in blood loss within 3 months of treatment; the overall decrease was 20% in the etamsylate group and 24% in the mefenamic acid group. Compared with the values before treatment, blood loss was significantly less in each of the 3 months of treatment in the mefenamic acid group, but only in the 2nd and 3rd months of treatment in the etamsylate group. Nevertheless, if we consider the overall result, then a greater number of women noted a clinically useful decrease in blood loss (more than 40%) in the etamsylate group. The onset of mefenamic acid was rapid, but ethamylate showed a relatively greater effect during the studies. Discontinuation of treatment was accompanied by an increase in blood loss, more pronounced in the mefenamic acid group, which returned to the level before treatment. More side effects have been reported with mefenamic acid (Chamberlain G., 2006).
However, other researchers, by contrast, have shown superiority of mefenamic acid (as well as tranexamic acid) over ethamylate. Indeed, a study negative for etamsylate was conducted in women who use intrauterine devices. It was found that in this condition, etamzilate reduces menstrual blood loss less than in patients with primary menorrhagia. Unfortunately, no placebo group was included in these comparative studies.
Experience in treating menorrhagia with Dicinon
It is interesting to note that 30 years of experience in treating menorrhagia with etamzilate has been confirmed by doctors around the world. They expressed their satisfactory opinion and demonstrated results.
The estimate of the amount of blood loss during surgery is very variable due to various technical factors (occurring during the operation), propensities to diseases (diabetes mellitus, arterial hypertension) and a number of other reasons. In the 1960-1970s, experimental studies were conducted on the use of etamsylate in surgical or postoperative bleeding. The results were favorable. The effectiveness of the drug was observed in a number of surgical interventions. These included cataract surgery, 32 major intra-abdominal, 33 prosthetic (piezotraumatic) surgeries, 34 surgical interventions on the vessels and middle ear. These positive findings were prerequisites for more well-controlled clinical trials. In the 1950s and 1960s, several attempts were made to control surgical bleeding, reducing blood pressure and blood flow. Therefore, it was a natural decision to study the effect of etamsylate on the bloodstream.
In patients receiving a single oral dose of 500 mg of ethamsylate, the maximum concentration of ethamsylate in the blood plasma was 60 mmol / l after 4 hours; 95% of the drug binds to plasma proteins. Ethamylate is excreted from the body mainly unchanged by the kidneys. The plasma half-life is about 8 hours after oral administration and 2 hours after intravenous administration.
Animal studies have shown that dogs and cats tolerate intravenous injection of etamsylate at a dose of up to 200 mg / kg body weight. In mice and rats, the lethal dose of intravenous administration of etamsylate (LD50) is 800 and 1350 mg / kg body weight, respectively.
In conditions of endothelial damage, etamzilate can act as a hemostatic agent, increasing cross-talk between platelets, white blood cells and endothelium through membrane interactions (American Journal of Therapeutics, 13/2006).
Excellent tolerance of dicinone
In patients, most researchers have confirmed the excellent tolerance of etamzilate. However, etamzilate can sometimes cause nausea, headache, and a rash. A convincing connection between etamsylate therapy and deep vein thrombosis has not been established. A double-blind study was performed on 76 patients with no clinical signs of deep vein thrombosis. No differences were found between the etamzilate group and the placebo group.
Well-controlled clinical studies have shown the therapeutic efficacy of etamsylate in dysfunctional uterine bleeding with reduced blood loss without directly proportional to the severity of menorrhagia (Garay R.P., 2006).
Other studies examine benign but debilitating conditions of menorrhagia, dysmenorrhea, and irregular menstrual bleeding. In the literature there are reports of these common ailments that can worsen the quality of life of women in the reproductive period. Both dysmenorrhea and menorrhagia are subjective complaints, but, despite the exact means of measuring menstrual blood loss, such a quantitative determination is rarely carried out. It is the lack of diagnostic accuracy that is cause for concern, especially since the conduct of medical and surgical treatment is not without risk. Therapeutic alternatives that are usually prescribed in an attempt to correct such menstrual irregularities are discussed. These include non-steroidal anti-inflammatory drugs, combined oral contraceptives, danazole, progestogens, antifibrinolytics, hemostatics, analogues of luteinizing hormone, releasing hormone and clomiphene. The results of clinical studies in which these agents were studied are considered in terms of both the effectiveness of the treatment and its potential side effects (Higham J.M., Shaw R.W., 2014).
Other well-controlled clinical trials have shown the therapeutic efficacy of etamzilate in preterm birth, in babies with very low birth weight and surgical or postoperative capillary bleeding. Ethamsylate acts on the first step of hemostasis by improving platelet adhesion and restoring capillary resistance.
Dicinon has been used in all births of preterm infants with a preventive purpose since 1987. The drug is taken before or during childbirth. A diagnosis of cerebral hemorrhage was made at autopsy, and cases were compared with previous periods when dicinone was not used. With the prophylactic use of dicinone, the risk of cerebral hemorrhage is significantly reduced in premature babies. It is well known that the etiology of cerebral hemorrhages is multifactorial. And favorable experience is confirmed by the literature, while the use of Dicinon may be one of the effective prophylactic against paralysis in premature babies (Györe F., 2009).
Premature babies are at risk of bleeding in the brain in the first few weeks of life. This is called intraventricular hemorrhage. Children born at less than 32 weeks of gestation are most at risk. Many potential treatments have been studied to determine if they can reduce the risk of this bleeding. One such treatment has been proposed drug called Dicinon (etamzilat). Before that, it was precisely known how it works - it reduces bleeding in other clinical situations, such as excessive menstrual bleeding and some types of surgical intervention.
A total of 7 studies with 1,410 premature babies were included in this review. Most of these initial studies were conducted between 1980 and 1990. Premature infants receiving ethamsilate had the same results for death and disability at the age of 2 years compared with infants treated with placebo. In children born after less than 35 weeks of pregnancy, intraventricular hemorrhage was less with etamsylate compared with the control group, but this did not lead to an improvement in later childhood. When using etamzilat side effects were not observed. Based on these results, unfortunately, the routine use of etamzilate in premature infants to prevent intraventricular hemorrhage cannot be recommended. It is unlikely that any further studies will be conducted to study this clinical issue (Hunt R., Hey E., 2010).
Synergism of Dicinon with other drugs
Desmopressin and etamsylate were evaluated for possible synergistic effects on bleeding time. The drugs were administered separately and concomitantly to 12 patients with a markedly increased bleeding time. Studied bleeding disorders included Glanzmann thrombasthenia (1), other platelet dysfunction (4), pseudo-von Willebrand disease (1) and von Willebrand disease type I (3), type II (2) and type III (1)). Desmopressin in the form of monotherapy reduced the bleeding time from 23.9 ± 1.5 to 19.5 ± 2.3 minutes (p = 0.03). Ethamsylate as monotherapy did not show effect. Desmopressin and etamsylate combined reduced bleeding time to 11.2 ± 1.4 minutes (p <0.01 compared to baseline, p = 0.02 compared to desmopressin alone). The combination was ineffective in 3 patients with Glanzmann thrombasthenia and von Willebrand disease type I (1) and type III (1). No toxic effects of drugs have been identified. 5 patients received desmopressin and etamsylate before dental work with blocking the lower jaw (1), heart surgery requiring cardiopulmonary bypass (2), and adenotonsillotomy surgery (2). Normal hemostasis was achieved in each case. A synergistic reduction in bleeding time was observed with a combination of desmopressin and etamsylate with a wide range of bleeding disorders (Kobrinsky N.L., 1991).
Recent studies have shown that etamzilate stimulates P-selectin-dependent thrombocyte-adhesion mechanisms. The use of etamzilate as a hemostatic agent is supposed - mild action, but well tolerated; especially useful for dysfunctional uterine bleeding when contraception is not required (Garay R.P., 2006).
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