Establishment of the First National Reference Material for Low Molecular Weight Heparin / 中国药学杂志

OBJECTIVE: In June 2017, the National Pharmacopoeia Committee published on the internet the draft of national standards for dalteparin sodiumenoxaparin sodium and nadroparin calcium. As the new monographs to be added to the Chinese Pharmacopoeia in 2020. To establish the first batch national standards of low molecular weight calirantdalteparin sodiumenoxaparin sodium and nadroparin calcium for system suitability. METHODS: A national collaborative study involving thirteen laboratories had taken place, organized by National Institutes for Food and Drug Control(NIFDC)to provide supporting data for the establishment of the 1st national standards of low molecular weight heparin for molecular weight calibrantdalteparin sodium enoxaparin sodium and nadroparin calcium for system suitability of molecular weight determinations. The molecular weight determination methods in draft standards were used in the national collaborative study. The 2nd international standard low molecular weight heparin for molecular weight calibration(05/112) were used as molecular weight calibrant. The candidate national standards of low molecular weight heparin for molecular weight calibration (140820-201801) and the candidate dalteparin sodium(140811-201801) enoxaparin sodium(140810-201801) nadroparin calcium(140812-201801)for system suitability of molecular weight determination were tested in the study. RESULTS: The cumulative percent of peak area at the 18 molecular points from 600-18 000 of the candidate national standard of low molecular weight heparin for molecular weight calibration (140820-201801) were calculated. Based on the statistical analysis, the candidate gave low intra- and inter-laboratories variations.Of all 13 laboratories, standard deviations (SD) of two laboratories ranged from 1% to 2%,the others were less than 1%.Between laboratories, SD were all less than 1%,relative standard deviation(RSD) were all less than 5% except two points of the small molecular. The intra-lab SD of the test to determine the molecular weight of the candidate dalteparin sodium(140811-201801) enoxaparin sodium(140810-201801) nadroparin calcium(140812-201801)for system suitability of molecular weight determination was between 4 and 110,RSD was less than 2.5%. The inter-lab SD were less than 30, RSD was less than 1.0%. CONCLUSION: After the examination of the expert committee on pharmaceutical standardization, the candidate (140820-201801) was approved as the first national standard of low molecular weight heparin for molecular weight calibration, the broad standard table is also provided the broad standard table. The candidate(140811-201801) is approved as the first national standard of dalteparin sodium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 6 268. The candidate(140810-201801) is approved as the first national standard of enoxaparin sodium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 4 435. The candidate(140812-201801) was approved as the first national standard of nadroparin calcium for system suitability of molecular weight determination, with an assigned molecular weight (Mw) of 4 832.

Comparison of rivaroxaban and dalteparin for the long-term treatment of venous thromboembolism in patients with gynecologic cancers / 부인종양

Comparisons of Bleeding Risks between Rivaroxaban and Dalteparin for Treatment of Venous Thromboembolism in Cancer Patients

BACKGROUND: Venous thromboembolism (VTE) is a common and life-threating condition in cancer patients. Low molecular weight heparins (LMWH), such as dalteparin, are recommended in the treatment of VTE. Also, rivaroxaban, an orally administered direct factor Xa inhibitor, was approved for the treatment of VTE. It showed similar efficacy to standard therapy (LMWH or warfarin) and was associated with significantly lower rates of major bleedings. However, in the real world, bleeding has been reported to occur frequently in cancer patient receiving rivaroxaban. The goal of this research was to analyze bleeding risks between rivaroxaban and dalteparin for treatment of VTE in cancer patients. METHODS: Medical records of oncology patients who were treated with rivaroxaban or dalteparin for VTE from July 2012 to June 2014 were retrospectively reviewed. Data collected were as follows: age, sex, weight, height, cancer types and stages, ECOG (eastern cooperative oncology group) PS (performance score), VTE types, concurrently used medications, study drug information (dose and duration of therapy), INR (international normalized ratio), PT (prothrombin time), and platelet counts. Bleeding was classified into major bleedings, clinically relevant non-major bleedings, and minor bleedings. RESULTS: A total of 399 patients were included in the study. Of these patients, 246 were treated with rivaroxaban and 153 with dalteparin. Bleeding rates were significantly higher in the rivaroxaban group than in the dalteparin group (adjusted odds ratio (AOR) 2.09, 95% CI 1.22-3.60) after adjusting for confounders. In addition, rivaroxaban remained independently associated with 1.78-fold (95% CI 1.14-2.76) shorter time to bleeding compared to dalteparin after adjusting other factors known to be associated with poor outcomes. CONCLUSION: This study suggested that rivaroxaban was associated with an increased risk of bleedings in cancer patients.

The effect of small-molecular-weight heparin added to chemotherapy on survival in small-cell lung cancer - A retrospective analysis.

Aims and Background: Small cell lung cancer (SCLC) is a chemotherapy-responsive tumor and associated with alterations in the coagulation system. Addition of low-molecular-weight heparin (LMWH) to combination chemotherapy (CT) had resulted in increase in survival. The present retrospective trial was designed to determine whether the duration of dalteparin usage has an effect on progression and survival. Materials and Methods: The medical records of 67 patients with SCLC who were given cisplatin-etoposide and concomitant LMWH (dalteparin) was evaluated retrospectively. Results: Median follow-up of patients was 11.3 months. Outcome: 10.6% complete response, 3.0% good partial response, 36.4% partial response, 10.6% stable disease, and 39.4% progressive disease. Side-effects were seen in 40.3% of the patients. Median dalteparin duration was 6,1 months. According the duration of dalteparin patients were grouped in three: who took dalteparin less than 4 months (Group A), 4-6 months (Group B) and more than 6 months (Group C). Mean overall survival (OS) in Group A was 6.5 months, in Group B 11.8 months, and Group C 14.6 months. Mean OS in Group B and C were statistically significantly (P < 0.001) longer than Group A, between Group B and C there was not any significant difference (P = 0.037). Mean progression free survival (PFS) was 9 months. Conclusions: The CT plus LMWH minimum 4 months long is well-tolerable, and may improve PFS and OS in patients with SCLC. For treatment of patients with SCLC CT plus LMWH may be considered as effective future-therapy, and further multi-centre randomised prospective clinical trials must be done to determine the new standard treatment approach for SCLC.

Catéter subcutáneo para la administración de heparina de bajo peso molecular en pediatría / Subcutaneous catheter used for administration of low-molecular-weight-heparin in pediatrics

Introduction: Subcutaneous catheter is a device easy to assemble, which was created for the administration of insulin in diabetic patients, especially in children, aiming to reduce the number of punctures, pain and anxiety of patients and their parents. Objective: To describe the experience using the catheter for subcutaneous administration of low molecular weight heparin (LMWH) in hospitalized pediatric patients. Patients and Method: A prospective descriptive study in 28 patients who used 87 subcutaneous catheters for the administration of LMWH in the Pediatric Service of the Universidad Catolica de Chile between July, 2010 and November, 2011. Results: Complications associated with the catheter had an incidence of 33 percentin total catheters evaluated; the most frequent complication was the presence of hematoma at the site of insertion (26 percent). These complications occurred more frequently in male (38 percent versus 31 percent in females) and younger patients (9 months versus 12 months), who received dalteparin (54 percent versus 30 percent of other types of heparin) administered every 24 hours (41percent versus 30 percent, administered every 12 hours), and when the catheter was located on both thighs (36 percent versus 32 percent in both arms); however, these differences were not statistically confirmed. Conclusion: The subcutaneous catheter is a good technique to be considered for LMWH in children as it presents minor complications for drug administration.

Introducción: El catéter subcutáneo es un dispositivo de fácil instalación, el cual fue ideado para la administración de insulinas en pacientes diabéticos, especialmente en pediatría, con el fin de disminuir el número de punciones, el dolor y la ansiedad de los pacientes y sus padres. Objetivo: Describir la experiencia del uso del catéter subcutáneo para la administración de heparina de bajo peso molecular (HBPM) en pacientes pediátricos hospitalizados. Pacientes y Método: Estudio descriptivo prospectivo en 28 pacientes que utilizaron 87 catéteres subcutáneos instalados para la administración de HBPM, en el Servicio de Pediatría de la Pontificia Universidad Católica de Chile en el período comprendido entre los meses de julio de 2010 y noviembre de 2011. Resultados: Las complicaciones asociadas al catéter presentaron una incidencia de 33 por ciento en el total de catéteres evaluados, siendo la más frecuente la presencia de hematoma en el sitio de inserción (26 por ciento). Estas complicaciones se presentaron con mayor frecuencia en pacientes de sexo masculino (38 por ciento versus 31 por ciento en sexo femenino) de menor edad (9 meses versus 12 meses), con indicación de dalteparina (54 por ciento versus 30 por ciento con otros tipos de heparina) administrada cada 24 h (41 por ciento versus 30 por ciento cuando fue administrada cada 12 h), y cuando el catéter estuvo ubicado en ambos muslos (36 por ciento versus 32 por ciento en ambos brazos); sin embargo, estas diferencias no fueron confirmadas estadísticamente. Conclusión: El catéter subcutáneo es una buena técnica a considerar para la administración de HBPM en la edad pediátrica, ya que permite la administración del medicamento con complicaciones leves asociadas a su uso.

Quality specification study of low molecular weight heparin / 中国药学杂志

OBJECTIVE: To revise the national specification low molecular weight heparin for improving the quality and quality control level its domestic products as candidate new varieties Chinese Pharmacopoeia 2015 edition. METHODS: Domestic and imported original products and related information were collected, including 27 batches raw material from 11 manufacturers and 49 batches injections from 13 manufacturers. Domestic low molecular weight heparin products were classified according to the production process. The analysis focused on the verification structure, molecular weight and activity, process impurities, and degradation impurities. Various physical, chemical and biological methods were used, such as ion chromatography, size exclusion chromatography, reversed phase chromatography, gas chromatography, NMR, atomic absorption spectrometry, micro-chromogenic substrate methods, and so on. RESULTS: The domestic low molecular heparin products were divided into three categories; dalteparin sodium, enoxaparin sodium, and nadroparin calcium. Eight draft specifications the raw material and preparations have been made. In the draft specifications, eight items have been added: structure type, production, 1, 6-anhydro derivatives for enoxaparin sodium, free sulfate, nitrite, benzyl alcohol, ultraviolet absorption maximum specific absorption enoxaparin sodium, and residual solvent; 15 items have been revised. Chinese name, English name, definition, characters, pH value, molecular weight and molecular weight distribution, anti-FXa activity, the ratio between anti-FXa and anti-FIIa activity, the color the solution, sodium, sulfate and carboxylate ratio, loss on drying, volume injection, storage, preparation; one item has been deleted: light absorption at 260 and 280 nm. CONCLUSION: The current draft specifications low molecular weight heparin have been greatly improved than the national specifications established in 2005. The products are divided into three categories. A lot items have been added and the limits are more reasonable. The draft specifications are roughly equal with the Europe and the United States Pharmacopoeia. The drafts are more stringent than the foreign Pharmacopoeias in some items, such as free sulfate and residual solvent. Due to economic consideration, NMR identification, boron, and N-NO examination, which are included in the Europe and the United States Pharmacopoeia, are not introduced in the draft specifications at present.

A Case of Rectus Sheath Hematoma and Pelvic Cavity Hematoma Induced by Dalteparin Injection / 대한내과학회지

Rectus sheath hematoma (RSH) is an uncommon condition caused by hemorrhage into the rectus sheath. RSH is characterized by abdominal pain and an abdominal mass. This condition is associated with old age, childbirth, abdominal surgery, severe coughing, severe sneezing, anticoagulation therapy, and/or coagulation disorders. We report herein a case of RSH and pelvic cavity hematoma that was induced by dalteparin injection in a 77-year-old woman with pulmonary embolism and deep vein thrombosis, and who was successfully treated by conservative management.

A Case of Rectus Sheath Hematoma and Pelvic Cavity Hematoma Induced by Dalteparin Injection / 대한내과학회지

Rectus sheath hematoma (RSH) is an uncommon condition caused by hemorrhage into the rectus sheath. RSH is characterized by abdominal pain and an abdominal mass. This condition is associated with old age, childbirth, abdominal surgery, severe coughing, severe sneezing, anticoagulation therapy, and/or coagulation disorders. We report herein a case of RSH and pelvic cavity hematoma that was induced by dalteparin injection in a 77-year-old woman with pulmonary embolism and deep vein thrombosis, and who was successfully treated by conservative management.

Observation of the effect of first trimester use of low molecular weight heparin in prevention intrauterine growth restriction / 中国基层医药

Objective To study the clinical effect of low molecular weight heparin on fetal growth restriction (FGR) prevention in early pregnancy.Methods 100 pregnant women had been employed in our study,they were divided into two groups,observation( n =60) and control( n =40) group.Both groups were given the natural vitamin E 0.1g,and folie acid 0.4mg daily oral administration,continuing to 12 weeks of gestation.5000 u of subcutaneous dalteparin sodium was added to pregnant women with notmal level of D-dimer in the observation group until 12 weeks of pregnancy,while the dose of Fragmin was adjusted in pregnant women with abnormal level of D-dimer until retuned to normal level.The pregnacy outcome of two groups were compared.Results The gestational age,birth weight,placental weight of the obseruation group was signiticantly higher than thal of the control group ( t =4.55,2.79,11.91,all P ＜ 0.05 ),while FGR,oligohydramnies,fetal distress and the incidence of hypertensive disorters of the obseruation group were significantly lower than that of control group ( x2 =6.50,20.55,7.87,3.76,all P ＜ 0.05 ) ; Compared to the control group,the observation group didn't have higher incidence of intrauterine fetal death,neonatal asphyxia and perinatal death ( P ＞ 0.05).Conclusion Low molecular weight heparin using in early pregnancy was effective in preventing FGR in pregnant women with FGR risk factors.

Safety and efficacy of dalteparin in percutaneous coronary intervention in Chinese patients with non-ST-elevation acute coronary artery syndromes: comparison with unfractionated heparin / 老年心脏病学杂志（英文版）

Objective To prospectively evaluate the safety and therapeutic efficacy ofdalteparin in patients with high risk non-ST-elevation acute coronary syndromes (ACS) during percutaneous coronary intervention (PCI). Methods Atotal of 175 patients with high risk non-ST-elevation ACS were randomly assigned to 2 groups [dalteparin group and unfractionated heparin (UFH) group]. The patients in dalteparin group were given dalteparin at a dose of 5,000U subcutaneously soon after diagnosis and then an additional 60U/ kg intravenous bolus ofdalteparin before emergent PCI. Vascular access sheaths were removed immediately after PCI or coronary artery angiography; the patients in UFH group were given UFH intravenously at a dose of 25mgjust before PCI and an additional 65mg bolus was administered if angiographic findings showed that the patients were suitable for percutaneous transluminai coronary angioplasty (PTCA). Sheaths were removed at 4-6 hours after PCI; Results Eighty-three patients in dalteparin group underwent PCI while 82 patients in UFH group underwent PCI; anti-Xa activities of 52 patients in dalteparin group were measured. The average anti-Xa activity was (0.83±0.26) U/ml at 15 minutes after intravenous injection of dalteparin and anti-Xa>0.5U/ml was obtained in 96.1% of the patients; hematomas at puncture sites were significantly fewer in dalteparin group as compared with UFH group (2.3% vs 9. 2%, P < 0.05); none of the patients in 2 groups suffered major bleeding events. No death, acute arterial reocclusion or emergent revascularization events occurred at 30 days after PCI. Conclusions Our study demonstrated that early subcutaneous injection of dalteparin at a dose 5,000U after diagnosis and an additional 60U/kg intravenous bolus ofdalteparin before PCI is safe and efficacious for patients with high risk non-ST-elevation ACS undergoing emergent PCI

Dalteparin sodium-associated retroperitoneal hematoma in a patient with diabetic nephropathy / 대한내과학회지

Retroperitoneal Hematoma is a rare intraabdominal bleeding occurring in patients with low- molecular weight heparin anti-coagulant therapy. We report a case of dalteparin sodium-associated retroperitoneal hematoma in a 70-year-old man with diabetic nephropathy with review of this condition in the literature. He had been suffered from type 2 diabetes mellitus and hypertension for 15 years. In July 2002, he was admitted to our hospital because of unstble angina and left pleural effusion. He was treated with dalteparin sodium and aspirin for unstable angina. On the second hospital day, he was refered to division of nephrology for diabetic nephropathy. Laboratory data on admission included white blood cell count of 4,500/mm3, hemoglobin 9.6 g/dL, platelet count 294,000/mm3, BUN 58.1 mg/dL, serum creatinine 4.1 mg/dL, blood glucose 178 mg/dL, hemoglobin A1c 5.9%, PT 13.9 sec (INR: 1.09), and aPTT 50 sec. On days 6 through 8, he had lower back pain, lower extremity pain and neuropathy, anemia and hypotension. Abdominal ultrasound showed 6 x 6 cm-sized well marginated mixed echogenic lesion in psoas muscle and fluid collection in retroperitoneal cavity. Magnetic resonance imaging (MRI) showed increased signal intensity and thickening of the right psoas muscle including 4.7 x 2.3 x 2.1 cm-sized cytic lesion and 6.2X5.3X3.7 cm-sized cystic lesion on the lateral portion of right psoas muscle in T2-weighted images. Percutaneous drainage of cystic lesion was performed by right lateral approach. Hemodialysis was begun without heparinization. Abdominal CT showed 5.5X5 cm-sized high attenuated lesion in right psoas muscle and 5X3 cm, 3X2 cm, 4.5 x 2.5 cm, 4 x 2.5 cm-sized heterogenous, slightly high attenuated lesions in the right lower abdomen and cul-de-sac in the scans with no enhancement. He was treated by conservative therapy. He recovered gradually. Patients with kidney diseases receiving low molecular weight heparin (dalteparin, enoxaparin, etc.) should be closely monitored to prevent serious bleeding complications. The possibility of retroperitoneal hematoma should be considered, whenever symptoms including lower back pain, inguinal pain, leg pain, anemia, or hypotension occured during the lower molecular weight heparin anticoagulant therapy. To our knowledge, this is the first reported case of retroperitoneal hematoma in a patient during dalteparin sodium (Fragmin(R)) anticoagulant therapy.

The use of Low Molecular Weight Heparin to Predict Clinical Outcome in Patients with Unstable Angina That Had Undergone Percutaneous Coronary Intervention

BACKGROUND: Antithrombotic therapy with heparin reduces the rate of ischemic events in patients with acute coronary syndrome. Low-molecular-weight heparin, given subcutaneously twice daily, has a more predictable anticoagulant effect than standard unfractionated heparin. Moreover, it is easier to administer and does not require monitoring. METHODS: We prospectively analyzed 180 patients with unstable angina who had undergone percutaneous coronary intervention (PCI) between 1999 and 2001 at Chonnam National University Hospital and had received either 120 U/kg of dalteparin (Fragmin (R) ), administered subcutaneously twice daily (Group I; n=90, 61.8 +/- 8.9 years, male 67.8%), or had received continuous intravenous unfractionated heparin (Group II; n=90, 62.6 +/- 9.7 years, male 70.0%). During hospitalization and at 6 month after PCI, major adverse cardiac events such as acute myocardial infarction, target vessel revascularization, death, and restenosis were examined. RESULTS: During hospitalization, the incidence of acute myocardial infarction, target vessel revascularization and death were not different between the two groups. At follow-up coronary angiography 6 months after PCI, the incidence of restenosis was lower in group I than in group II (Group I; 26/90, 28.8% vs. Group II; 32/90, 35.6%, p=0.041) and the incidence of target vessel revascularization was lower in group I than in group II (Group I; 21/90, 23.3% vs. Group II; 27/90, 30.0%, p=0.039). No difference was found in the rates of major and minor hemorrhages, ischemic strokes or thrombocytopenia between two groups. By multivariate analysis, the factors related to restenosis were lesion length, postprocedural minimal luminal diameter, CRP on admission, diabetes mellitus, the type of heparin, and stent use. CONCLUSION: Dalteparin, a low molecular weight heparin, is superior to standard unfractionated heparin in terms of reducing the restenosis rate and target vessel revascularization without increasing bleeding complications.

Clinical Presentation of Adverse Drug Reaction of Dalteparin in Acute Coronary Syndrome

BACKGROUND AND OBJECTIVES: Heparin is crucial in the treatment of acute coronary syndrome. However, unfractionated heparin has pharmacokinetic, biophysical and biological limitations, but its low molecular weight has been used to overcome these limitations. The aim of this study was to find the optimal dose of dalteparin in Koreans. Instead, significant rises in the levels of aminotransferase were found in the liver during the study. SUBJECTS AND METHODS: A clinical investigation was conducted, at Seoul National University Hospital, between December 2000 and February 2001. The anti-Xa activity was checked just before the first, and 4 hours after, the second and ninth doses of dalteparin. Liver function tests were obtained on the first and follow-up day (day 6 or 7). RESULTS: Of the 17 patients who completed 10 doses of dalteparin, 13 showed significant rises in the levels of liver aminotransferase. In 5 cases, the levels of aminotransferase rose to 3 times, and in one case, to over 10 times the upper normal limit. All of the patients were asymptomatic, and the levels showed a decline one or two days later. The follow-up aminotransferase level was normalized in 8 out of 11 patients whose liver function tests were followed up. CONCLUSION: Previous studies have shown that 120 IU/kg of dalteparin was the optimal dose in Western countries. Whether this is the optimal dose for Koreans has not been proven, and there have been no studies to elucidate its adverse effects (e.g. hepatotoxicity) in Koreans. Therefore, large scale, randomized trials may be warranted to determine the pharmacodynamics and kinetics of dalteparin in Koreans.