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At least 19 recordsLinked to original sources
PubMed1994

The EC randomised controlled trial of prophylactic ethamsylate for very preterm neonates: early mortality and morbidity. The EC Ethamsylate Trial Group.

Immature infants are at increased risk of death and disability, often related to haemorrhagic and ischaemic brain damage. Two controlled trials have suggested that a policy of prophylactic ethamsylate may reduce this damage. The aim of the trial reported here was to assess the effects of such a policy in respect of death, disability, and the use of health service resources up to 2 years of age. Short term findings are reported here. Three hundred and thirty four immature (< or = 32 weeks' gestation) infants were recruited into the trial within four hours of birth from four centres in France and six in Greece. Almost all 165 infants allocated to the ethamsylate group received the drug, compared with one of the 169 infants in the control group. By about 3 months of age the trial groups were similar in terms of death (20% in the two groups), any diagnosis of periventricular or intraventricular haemorrhage (35% in the ethamsylate v 37% in the control group), or major cerebral abnormality assessed by ultrasound (13% v 12%). The trial provides little evidence to support the use of ethamsylate for routine prophylaxis. The confidence intervals are wide, however, and so these results alone cannot rule out a clinically useful benefit or a harmful effect. A follow up study of the surviving children at the age of 2 years is in progress.

Cerebral Hemorrhage↗
PubMed2003

Vascular permeabilization by intravenous arachidonate in the rat peritoneal cavity: antagonism by ethamsylate.

The hemostatic agent, ethamsylate, inhibits arachidonic acid metabolism by a mechanism independent of cyclooxygenase activity and blocks carrageenan-induced rat paw edema. Here, ethamsylate was investigated for (i) in vivo actions on the free radical-dependent, permeabilizing responses to arachidonic acid and (ii) its antioxidant potential in vitro. Vascular permeability was equated to the extravasation rate of Evans blue from plasma into the rat peritoneal cavity. Antioxidant potential was investigated by classical in vitro tests for superoxide radicals, hydroxyl radicals (OH(.)), and nitric oxide. Intravenous ethamsylate induced a very important and significant reduction of permeability responses to arachidonate, both when given preventively and cumulatively. Thus, (i) ethamsylate significantly reversed arachidonate-induced permeabilization, even at the lowest dose tested (44+/-5% at 10 mg/kg) and (ii) a maximal reversal (about 70%) was reached between 50 and 200 mg/kg ethamsylate. In contrast, ethamsylate (100 mg/kg) was unable to antagonize the vascular permeabilization induced by serotonin (5-HT). In antioxidant assays, ethamsylate showed scavenging properties against hydroxyl radicals generated by the Fenton reaction (H(2)O(2)/Fe(2+)) even at 0.1 microM (-20+/-3%). OH(.) scavenging by ethamsylate reached 42+/-8% at 10 microM and 57+/-7% at 1 mM and was comparable to that of reference compounds (vitamin E, troxerutin, and mannitol). Conversely, ethamsylate was a poor scavenger of superoxide and nitric oxide radicals. In conclusion, intravenous ethamsylate potently antagonized the peritoneal vascular permeabilization induced by arachidonate, an action likely due to its antioxidant properties, particularly against hydroxyl radical. Such a mechanism can explain previous observations that ethamsylate inhibits carrageenan-induced rat paw edema. Whether it also participates in the hemostatic action of ethamsylate deserves further investigation.

Animals↗
PubMed2004

The hemostatic agent ethamsylate promotes platelet/leukocyte aggregate formation in a model of vascular injury.

The hemostatic agent ethamsylate enhances membrane expression of P-selectin in human platelets, but whether this promotes platelet-leukocyte aggregate formation is unknown. Here we investigated this point by flow cytometry determination of human platelet-leukocyte aggregates under basal conditions and after whole-blood perfusion through a damaged rabbit aorta segment. Actions of ethamsylate on adhesive molecules of platelets and leukocytes were investigated in parallel. Under basal conditions, ethamsylate was unable to modify whole-blood platelet-leukocyte aggregation, but following whole-blood perfusion through a damaged vessel, ethamsylate produced a modest, but significant increase in platelet-leukocyte aggregates (48+/-21 and 45+/-26% above control levels at ethamsylate 20 and 40 microm respectively). In isolated leukocyte plasma membranes, 14C-ethamsylate specifically bound up to an amount of 660 pmol/mg protein. Moreover, at concentrations > or =1 microm, ethamsylate induced an important (100-200%) and significant increase in the P-selectin glycoprotein ligand 1 (PSGL-1) fluorescence signal in isolated leukocytes and was unable to significantly modify the percentage of CD11b-positive cells. However, no significant changes in aggregate formation were found when ethamsylate was incubated with isolated leukocytes and blood was reconstituted and perfused. In isolated platelet cell membranes, anti-P-selectin antibody and the anti-integrin RGD-containing pentapeptide (GRDGS) were unable to displace 14C-ethamsylate binding. In conclusion, ethamsylate specifically binds to plasma membranes of leukocytes, enhances membrane PSGL-1 expression and promotes leukocyte-platelet aggregation in whole-blood perfused through a damaged vascular segment. These results together with the previously observed enhancement of platelet P-selectin membrane expression [Thromb. Res. (2002)107:329-335] confirms and extends the view that ethamsylate acts on the first step of hemostasis, by improving platelet homo- and heterotypic adhesiveness.

Animals↗
PubMed2002

The hemostatic agent ethamsylate enhances P-selectin membrane expression in human platelets and cultured endothelial cells.

Ethamsylate possesses antihemorrhagic properties, but whether or not it directly activates blood platelets is unclear. Here we investigated the platelet activation potential of ethamsylate, by measuring membrane P-selectin expression with flow cytometry in human whole blood and also by immunofluorescence imaging of isolated human platelets. Moreover, we measured membrane P-selectin expression in the SV40-transformed aortic rat endothelial cell line (SVAREC) and 14C-ethamsylate membrane binding and/or uptake in platelets and endothelial cells. Whole blood flow cytometry showed a modest, but statistically significant increase by ethamsylate in the percentage of platelets expressing P-selectin (from 2% to 4-5%, p < 0.05). Immunofluorescence showed a sizable (39%) and significant (p < 0.01) enhancement of P-selectin expression at the lowest concentration of ethamsylate tested (1 microM), with maximal enhancement of P-selectin expression (75-90%) at 10 microM ethamsylate. Similar results were obtained in SVAREC endothelial cells. 14C-ethamsylate specifically bound to platelets and endothelial cell membranes, without significant uptake into the cell interior. In conclusion, ethamsylate enhances membrane P-selectin expression in human platelets and in cultured endothelial cells. Ethamsylate specifically binds to some protein receptor in platelet and endothelial cell membranes, receptor which can signal for membrane P-selectin expression. These results support the view that ethamsylate acts on the first step of hemostasis, by improving platelet adhesiveness and restoring capillary resistance.

Animals↗
PubMedDate not supplied

Therapeutic efficacy and mechanism of action of ethamsylate, a long-standing hemostatic agent.

Ethamsylate (2,5-dihydroxy-benzene-sulfonate diethylammonium salt) is a synthetic hemostatic drug indicated in cases of capillary bleeding. This review covers more than 40 years of intensive clinical and fundamental research with ethamsylate. First, we summarize the large medical literature concerning its clinical efficacy. Of these, well-controlled clinical trials clearly showed the therapeutic efficacy of ethamsylate in dysfunctional uterine bleeding, with the magnitude of blood-loss reduction being directly proportional to the severity of the menorrhagia. Other well-controlled clinical trials showed therapeutic efficacy of ethamsylate in periventricular hemorrhage in very low birth weight babies and surgical or postsurgical capillary bleeding. Second, we review the numerous investigations performed to elucidate the mechanism of action of ethamsylate. Ethamsylate acts on the first step of hemostasis by improving platelet adhesiveness and restoring capillary resistance. Recent studies showed that ethamsylate promotes P-selectin-dependent, platelet adhesive mechanisms. Finally, we compare ethamsylate with other recent hemostatic agents. It is suggested that the place of ethamsylate as a hemostatic agent is that of a mild but well-tolerated drug, particularly useful in dysfunctional uterine bleeding when contraception is not needed.

Adult↗
PubMed1984

Beagle puppy model of intraventricular hemorrhage: ethamsylate studies.

Intraventricular hemorrhage (IVH) remains a major problem of preterm neonates, and ethamsylate, an inhibitor of specific prostaglandin-synthetic enzymes has been demonstrated to prevent IVH in these patients. We have examined the effects of ethamsylate on newborn beagle pups who were, by randomized computerized design, assigned to four cells consisting of (a) either ethamsylate or saline pretreatment and (b) either insulted or not insulted with hemorrhagic hypovolemia/volume re-expansion. Prostaglandin levels were obtained prior to and thirty minutes following administration of the solutions and 14C iodoantipyrine autoradiography was performed for cerebral blood flow (CBF) determinations. Ethamsylate produced a significant decrease in the incidence of IVH in this model (p less than 0.05). Following drug administration, ethamsylate-pretreated pups had significant declines in thromboxane B2 and 6-keto PGF1 alpha levels, the major breakdown products of thromboxane A2 and prostacyclin. Although ethamsylate significantly lowered baseline CBF in all brain regions examined in insulted and non-insulted pups (p less than 0.05), in the drug-treated group it did not prevent the changes seen in CBF to the germinal matrix region which were detected in the saline-pretreated pups. Nor did it significantly blunt the blood pressure changes in response to the hemorrhagic hypovolemia/volume re-expansion insult found in the latter group of animals. In addition, only ethamsylate pretreated pups had marked hypotensive responses to the reperfusion phase of the insult. Although the diminution of baseline CBF may contribute to the prevention of neonatal IVH which this drug has been demonstrated to exhibit, ethamsylate may also act as a capillary stabilizing agent.

Animals↗
PubMed1994

Ethamsylate and lung permeability in ventilated immature newborn rabbits.

The leakage of proteins in the immature neonatal lung can reduce the effect of exogenous surfactant. The effect of ethamsylate, a more specific prostaglandin inhibitor than indomethacin and aspirin-like drugs, on alveolar albumin leak was studied in a group of 27 immature newborn rabbits (gestational age 27 days). A pilot study was carried out using 4 animals and low-dose ethamsylate (10 mg/kg). A second group of animals (n = 12) received at birth, by intravenous injection, ethamsylate (50 mg/kg) and 10% human albumin (7 ml/kg). Animals not receiving ethamsylate (n = 11) served as control group. After 30 min of artificial ventilation with standard tidal volume (10 ml/kg) the lungs were lavaged and the amount of human albumin in lung lavage fluid was determined by immunodiffusion. No statistically significant differences were found in lung-thorax compliance and vascular to alveolar albumin leak between ethamsylate-treated animals and controls (p > 0.5). However, there was a statistically significant negative correlation between protein leak and lung compliance (r = -0.41; p < 0.04). These results suggest no direct influence of early ethamsylate administration on neonatal lung permeability in the immature neonate confirming that lung permeability is inversely related to compliance.

Animals↗
PubMed1993

Ethamsylate in the prevention of periventricular-intraventricular hemorrhage in premature infants.

A random and controlled trial was conducted to evaluate the efficacy and safety of ethamsylate in the prevention of periventricular-intraventricular hemorrhage (PIVH) in premature infants. Between January 1990 and July 1992, 171 premature infants with a birth weight of < 1,751 g who displayed no PIVH on initial cranial ultrasound scan, performed within an hour of delivery, were randomly divided into two groups. Group 1 consisted of 86 premature infants with a mean birth weight of 1.4 +/- 0.5 kg and a mean gestational age of 30.1 +/- 2.4 weeks. The first dose of ethamsylate 12.5 mg/kg (0.1 mL/kg from 250 mg/2mL ampoules) was given to group 1 intravenously within an hour of delivery and was followed by doses at six-hourly intervals for four days (total dose 200 mg/kg). Group 2 consisted of 85 premature infants with mean birth weight of 1.4 +/- 0.3 kg and mean gestational age of 30.4 +/- 2.2 weeks. Group 2 received 0.1 mL/kg normal saline intravenously in a similar fashion as the ethamsylate-treated group. Cranial ultrasound examinations were performed on postnatal days one, two, three, five, seven and 14. The incidence of PIVH in the ethamsylate-treated group was 24/86 (27.9%) and 39/85 (45.9%) in the control group (p < 0.02). In addition, the incidence of severe PIVH in the ethamsylate-treated group was 9/86 (10.5%) and 20/85 (23.5%) in the control group (p < 0.05). No adverse effects were attributed to ethamsylate therapy in this study.

Cerebral Hemorrhage↗
PubMed1976

A double-blind trial of ethamsylate in the treatment of primary and intrauterine-device menorrhagia.

22 patients complaining of primary menorrhagia or menorrhagia associated with an intrauterine device (I.U.C.D.) were studied in a double blind trial with crossover of ethamsylate and placebo. Acutal menstrual blood-losses were calculated from the iron content of used sanitary material during one pre-trail menstrual period and four trial menstrual periods, during which patients received ethamsylate ("Dicynene") treatment during two menstrual cycles and placebo during two cycles. During ethamsylate treatment the mean menstrual blood-loss was reduced by 50% in patients with primary menorrhagia and by 19% in patients with an I.U.C.D. This difference between the two groups is probably accounted for by the differing values of initial blood-loss which was significantly higher in the group with primary menorrhagia. Tampon usage and the duration of bleeding were not significantly altered by ethamsylate treatment. Reported side-effects, which were not serious, were equally common during ethamsylate and placebo treatment.

Adolescent↗
PubMed1986

Multicentre trial of ethamsylate for prevention of periventricular haemorrhage in very low birthweight infants.

The effectiveness of ethamsylate in the prevention of periventricular haemorrhage (PVH) in very low birthweight infants was evaluated by means of a multicentre, placebo-controlled, double-blind trial. In 330 infants without evidence of PVH on initial cranial ultrasound examination there was little difference between ethamsylate and placebo groups with respect to subependymal haemorrhage, but intraventricular and parenchymal haemorrhages developed in 30/162 infants (18.5%) in the treated group, compared with 50/168 (29.8%) in the control group (p less than 0.02). The incidence of intraventricular and parenchymal haemorrhage in survivors was 20/137 (14.6%) in the ethamsylate group and 37/146 (25.3%) in the controls (p less than 0.05). In 30 infants with evidence of PVH on the initial scan, ethamsylate treatment seemed to limit parenchymal extension. Analysis of the total cohort of 360 infants showed that the proportion of infants in whom an increase of two or more grades of severity of PVH was recorded during the trial was lower in the treated than in the placebo group (p less than 0.01). No adverse effects were attributed to ethamsylate therapy. The reported incidence of patent ductus arterious was lower in the treated than in the placebo group (p less than 0.02). Mortality was similar in the two groups.

Benzenesulfonates↗
PubMed1991

Synergistic shortening of the bleeding time by desmopressin and ethamsylate in patients with various constitutional bleeding disorders.

Desmopressin and ethamsylate were evaluated for possible synergistic effects on the bleeding time. The drugs were administered individually and together to 12 patients with markedly prolonged bleeding times known to be relatively or absolutely unresponsive to desmopressin alone. The bleeding disorders studied included Glanzmann's thrombasthenia (one), other disorders of platelet function (four), pseudo-von Willebrand disease (one), and von Willebrand disease type I (three), type II (two), and type III (one). Desmopressin alone shortened the bleeding time from 23.9 +/- 1.5 to 19.5 +/- 2.3 min (p = 0.03). Ethamsylate alone was without effect. Desmopressin and ethamsylate together shortened the bleeding time to 11.2 +/- 1.4 min (p less than 0.01 compared to baseline, p = 0.02 compared to desmopressin alone). The combination was ineffective in three patients, with Glanzmann's thrombasthenia (one), and von Willebrand disease type I (one) and type III (one). Toxic effects of the drugs were not observed. Five patients received desmopressin and ethamsylate prior to dental work with mandibular block (one), heart surgery requiring cardiopulmonary bypass (two), and adenotonsillectomy surgery (two). Normal hemostasis was achieved in each case. A synergistic shortening of the bleeding time was observed with the combination of desmopressin and ethamsylate in a wide range of bleeding disorders.

Adolescent↗
PubMed1991

A comparative study of ethamsylate and mefenamic acid in dysfunctional uterine bleeding.

The effects of ethamsylate and mefenamic acid on menstrual blood loss were compared in a double-blind trial in 34 women with menorrhagia. Both drugs produced statistically significant reductions in blood loss during the 3 months of treatment; the overall reduction was 20% in the ethamsylate group and 24% in the mefenamic acid group. Compared with pretreatment values, blood loss was significantly less in each of the 3 treatment months in the mefenamic acid group, but only in the second and third months of treatment in the ethamsylate group. However, more women had a clinically useful reduction in blood loss (greater than 40%) in the ethamsylate group. The onset of effect of mefenamic acid was rapid but ethamsylate showed a comparatively greater effect as the trial progressed. Cessation of treatment was followed by an increase in blood loss, more pronounced in mefenamic acid group who reverted to pre-treatment levels. A greater number of side-effects were reported with mefenamic acid.

Adolescent↗
PubMed1986

Studies on the action of ethamsylate (Dicynene) on haemostasis.

Twelve healthy subjects received ethamsylate or a placebo by mouth over a 48 h period in a randomized double-blind trial. The template bleeding time (including estimation of amount of blood loss), platelet aggregation studies, and plasma levels of plasminogen, alpha 2-antiplasmin and fibronectin were carried out before and during treatment. The effect of a single dose (600 mg) of aspirin, given 24 h after commencement of treatment, was also determined. Neither ethamsylate nor placebo caused a significant change in the basal values of any of the variables monitored but both the prolongation of the bleeding time and the amount of blood loss induced by aspirin were significantly less during ethamsylate treatment than with placebo. Ethamsylate failed to prevent the aspirin-induced elimination of the secondary wave of platelet aggregation. We conclude that ethamsylate may reduce the haemorrhagic symptoms associated with mild functional platelet defects.

Adult↗
PubMed2006

Simultaneous determination of ethamsylate, tramadol and lidocaine in human urine by capillary electrophoresis with electrochemiluminescence detection.

Ethamsylate, tramadol and lidocaine, partly excreted by the kidney, are generally used as hemostatic, analgesic and local anesthetic in surgery. We developed a simple and sensitive method for their simultaneous monitoring in human urine based on CE coupled with electrochemiluminescence detection by end-column mode. Under optimized conditions the proposed method yielded linear ranges from 5.0 x 10(-8) to 5.0 x 10(-5), 1.0 x 10(-7) to 1.0 x 10(-4) and 1.0 x 10(-7) to 1.0 x 10(-4) M with LODs of 8.0 x 10(-9) M (36 amol), 1.6 x 10(-8) M (72 amol) and 1.0 x 10(-8) M (45 amol) (S/N = 3) for ethamsylate, tramadol and lidocaine, respectively. The RSD for their simultaneous detection at 1.0 x 10(-6) M was 2.1, 2.8 and 3.2% (n = 7), respectively. For practical application an extraction step with ethyl acetate at pH 11 was performed to eliminate the influence of the sample ionic strength. The recoveries of ethamsylate, tramadol and lidocaine at different levels in human urine were between 87 and 95%. This method was used for simultaneous detection of ethamsylate, tramadol and lidocaine in clinic urine samples from two medicated patients. It was valuable in clinical and biochemical laboratories for monitoring these drugs for various purposes.

Electrophoresis, Capillary↗
PubMed1981

Ethamsylate in the treatment of climacteric flushing.

Ethamsylate, a non-hormonal agent acting at the capillary level, was compared with a placebo in a double-blind trial of 12 wk duration in 20 post-menopausal patients with hot flushes. Both ethamsylate and placebo patients showed fluctuations in the frequency of flushes during the trial, but there was a significant downward trend in the ethamsylate group. Capillary strength was measured but was not found to be low or to alter during the trial except in 1 patient in the placebo group. No side-effects attributable to trial medication were reported. Other symptoms recorded during the trial were probably climacteric and occurred more frequently during placebo treatment than during treatment with ethamsylate.

Adult↗
PubMed2006

Electrochemical parameters of ethamsylate at multi-walled carbon nanotube modified glassy carbon electrodes.

In this paper, some electrochemical parameters of ethamsylate at a multi-walled carbon nanotube modified glassy carbon electrode, such as the charge number, exchange current density, standard heterogeneous rate constant and diffusion coefficient, were measured by cyclic voltammetry, chronoamperometry and chronocoulometry. The modified electrode exhibits good promotion of the electrochemical reaction of ethamsylate and increases the standard heterogeneous rate constant of ethamsylate greatly. The differential pulse voltammetry responses of ethamsylate were linearly dependent on its concentrations in a range from 2.0 x 10(-6) to 6.0 x 10(-5) mol L(-1), with a detection limit of 4.0 x 10(-7) mol L(-1).

Biosensing Techniques↗
PubMed2002

Determination of ethamsylate in pharmaceutical preparations based on an auto-oxidation chemiluminescence reaction.

Strong chemiluminescence emission has been observed by mixing alkaline hydrolytic products of ethamsylate with Tween 80 in acidic rhodamine 6G solution. This phenomenon has been utilized to design a flow-injection chemiluminescence method for the determination of ethamsylate in a pharmaceutical preparation. Under the optimum conditions, the proposed procedure has a linear range between 0.05 and 2.0 microg ml(-1), with a detection limit of 0.02 microg ml(-1) for ethamsylate. The method was applied to the determination of ethamsylate in pharmaceutical preparations. The possible mechanism of this chemiluminescence reaction was proposed.

Ethamsylate↗
PubMed1989

Failure of ethamsylate to reduce aspirin-induced gastric mucosal bleeding in humans.

1. We investigated the effect of the haemostatic agent ethamsylate on aspirin-induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with each dose preceded by ethamsylate 500 mg. 3. At the end of each treatment period gastric mucosal bleeding into timed gastric washings was quantified using the orthotolidine reaction. 4. Aspirin increased bleeding from a rate on placebo of 1.2 microliters 10 min-1 geometric mean (95% confidence limits) (0.7-1.8) microliters 10 min-1 to 20.0 (11.6-34.2) microliters 10 min-1, (P less than 0.01). The rate of bleeding after aspirin preceded by ethamsylate [14.1 (8.5-23.4) microliters 10 min-1] was not significantly different from that after aspirin alone. 5. We conclude that ethamsylate does not reduce acute aspirin-induced gastric mucosal bleeding in healthy humans.

Adult↗