Bioequivalence and safety evaluation of domestic Nadroparin calcium injection in Chinese healthy volunteers / 中国药房

OBJECTIVE To evaluate the bioequivalence and safety of two k inds of Nadroparin calcium injection in healthy Chinese volunteers by subcutaneous injection. METHODS According to the block randomization method ，24 Chinese healthy adult volunteers were included and divided into TR （test preparation-reference preparation ）group and RT （reference preparation-test preparation）group at a ratio of 1∶1. A randomized ，open-labelled，single-dose and two-cycle crossover study was designed ，the fasting subjects of two groups were given test or reference preparation 6 150 AⅩaIU subcutaneously on the first day of each cycle and exchanged in the second cycle ，and the wash-out period was 7 days. The blood samples were collected at different time points before and after administration. The activity of anti-coagulant factor Ⅹa（Anti-Ⅹa）and Anti- Ⅱa in human plasma were determined by chromogenic substrate method ，and the pharmacodynamic parameters were calculated according to the non-atrioventricular model and the bioequivalence was evaluated. The occurrence of adverse events （AEs）was recorded. RESULTS After administration ，the main pharmacodynamic parameters for Anti- Ⅹa activity of test preparation and reference preparation were as follows ：t1/2 were（4.87±1.06） and（4.03±1.00）h，tmax were 4.50（2.00，8.00）and 5.50（2.50，8.00）h，Anti-Ⅹamax were（0.66±0.12）and（0.56±0.11）IU/mL；main pharmacodynamic parameters of Anti- Ⅱa activity of two preparations were as follows ：t1/2 were（3.64±1.60）and（5.74±7.23）h，tmax were 4.00（2.50，8.00）and 4.00（2.00，8.00）h，Anti-Ⅱamax were both （0.10±0.03）IU/mL. The values of 90％confidence interval of geometric mean ratio of Anti- Ⅹamax，AUEC0－t and AUEC 0－∞ were 110.98％-123.50％，112.11％-121.24％and 111.57％-120.00％， respectively. During experiment ，14 subjects reported 19 cases of mild AEs ，among which hematoma ，purpura and maculopapular rash may be related to drugs ；no serious AEs were observed. CONCLUSIONS The domestic Nadroparin calcium injection is bioequivalent to the reference preparation ，and both of them show good safety.

Technical analysis of low molecule weight heparins patents and R&D suggestions / 中国药科大学学报

@#An analysis of low molecule weight heparins(LMWH)patents throughout China and aroud the world is made. The suggestion, in terms of patent technical solution, is given to the R&D of LMWH, especially the enoxaparin, dalteprin and nadroparin.

Safety of early nadroparin for prevention deep vein thrombosis in patients with intracerebral hemorrhage / 国际脑血管病杂志

Objective To assess the safety of early subcutaneous injection of a low-dose low molecular weight heparin (LMWH) nadroparin for prevention of deep vein thrombosis (DVT) in patients with spontaneous intracerebral hemorrhage (sICH).Methods The patients with sICH who early using nadroparin or lower limb intermittent pneumatic compression (IPC) for prevention of DVT were enrolled.A nadroparin group continuously injected nadroparin 0.4 ml/d subcutaneously for 10 days at day 4 after admission and an IPC group used lower limb IPC.Head CT was reexamined and hematoma volume changes were evaluated at day 3,5,and 14 after admission.The hemorrhagic events during the course of treatment were documented,and the lower limb DVT was examined by color Doppler sonography.Results A total of 94 patients with acute sICH (n =41 in the nadroparin group,n =53 in the IPC group) who early use of nadroparin or IPC for prevention of DVT were enrolled.Fourteen patients had lower limb DVT,5 (12.2％) of them were in the nadroparin group and 9 (17.0％) of them were in the IPC group.However,there was no significant difference in the incidence of DVT between the two groups (x2 =0.418; P =0.518).During the treatment,no patient experienced increased intracranial hematoma and rebleeding.Conclusion Early subcutaneous injection of low-dose nadroparin for the prevention of DVT in patients with sICH is safe.

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.

Nadroparina cálcica: una revisión de su farmacología básica y clínica / Nadroparin calcium: a review of its basic and clinical pharmacology

Objetivo. Evaluar críticamente la información sobre la farmacología básica y clínica de la nadroparina cálcica. Fuente de datos. Se hizo una búsqueda en la literatura científica de octubre de 1985 a septiembre de 2010, en las bases de datos electrónicas: Pubmed, Cochrane, MDConsult,Scielo y Medscape, y en el Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA).Selección de estudios. Se incluyeron los estudios publicados en inglés, español o francés, realizados en humanos y animales de experimentación, en los que se revisarala farmacología básica y clínica de la nadroparina cálcica. Extracción y síntesis de datos. Se revisaron 792 resúmenes y se seleccionaron 60artículos que cumplieron los criterios de inclusión, de acuerdo con un método se resolvieron todas las discrepancias por discusión y consenso.Conclusión. En algunos estudios la nadroparina cálcica ha mostrado una eficacia igual o superior a la de la heparina no fraccionada y la de un placebo. Sin embargo, la información evaluada no es lo suficientemente sólida para considerar superior lanadroparina frente a las otras heparinas de bajo peso molecular. La literatura científica muestra que, en general, el tratamiento con estas últimas es más seguro y costo-efectivo que con heparina no fraccionada. No existen pruebas suficientes, fuertes y concluyentes para calificar la nadroparina cálcica como superior aotras heparinas de bajo peso molecular en el tratamiento antitrombótico. Las de bajo peso molecular han demostrado una reducción significativaen la angiogénesis tumoral y un aumento en la supervivencia de pacientes con enfermedades oncológicas. Sin embargo, se requieren más investigaciones para caracterizar y comprender mejor este nuevo hallazgo...

Objective: To evaluate critically the evidence on the basic and clinical pharmacology of nadroparin calcium.Data source: We conducted a literature review from October 1985 to September 2010 in the electronic databases: Pubmed, Cochrane,MD Cosult, Medscape, Scielo and Instituto Nacional de Vigilancia de Medicamentos y Alimentos (INVIMA).Study selection: Studies published in English, Spanish or French made in humans and animals for experimentation which reviewed the basic and clinical pharmacology of nadroparin calcium wereincluded. Data extraction and synthesis: 792 abstracts were reviewed by authors and 60 papers were selected that met inclusion criteria according to a standardized method All discrepancies were resolved by discussion and consensus. Conclusion: Some studies have shown that the efficacy of nadroparin calcium is equal or superior to unfractionated heparin (UFH) and placebo, however, the strength of assessed evidencehas been insufficient for considering nadroparin calcium superior to other low molecular weight heparins (LMWH). Literature shows that LMWHstherapy is more cost-effective and safer than UFH therapy in general. It does not exist enough, strong and conclusive evidence for considering antithrombotic nadroparin calcium therapy greater to other LMWHs. LMWHs have shown a significantreduction in tumor angiogenesis and increased survival in oncology patients. To conduct further research is necessary to characterize and understand better this new finding...

Clinical efficacy and safety evaluation of fibrinolytic, anticoagulant and antiplatelet drug combination treatment in patients with progressive ischemic stroke / 中国综合临床

Objective To investigate the clinical efficacy and safety evaluation of fibrinolytic,anticoagulant and antiplatelet drug combination treatment in patients with progressive ischemic stroke (PIS). Methods Ninety cases with PIS were randomly divided into the treatment group (47 cases) and the control group (43 cases). The patients in the control group were given combination therapy of Diemailing, Nadroparin calcium and Ozagrel,while the combination therapy of Defibrase, Diemailing, Nadroparin Calcium and Ozagrel were given in the treatment group. The plasma fibrinogen (Fib), prothrombin time (PT), part enabled prothrombin time (APTT), liver and kidney function were observed. The clinical efficacy was evaluated after 14 days treatment. Results After treatment,the total effective rate of the treatment group was 89.4% ,which was significantly higher than that of the control group (67.4%) (P ＜ 0.05). After treatment, the PT and APTT levels of the treatment group were respectively (19.76± 5.53)s and (35.43 ± 6.03)s,the control group were respectively(17.26 ± 1.49)s and (35.71±5.64) s, the PT and APTT increased significantly compared with the pre-treatment condition in both groups (P ＜ 0.05), while the difference between the two groups was not statistically significant (P ＞ 0.05). The Fib level was (1.51 ±0.42)g/L in the treatment group,and (3.10 ±0.69)g/L in the control group. In the treatment group the Fib level was significantly lower than the control group and the condition before treatment(P ＜0.05). We found no significant difference between conditions before or after the treatment in the control group (P ＞ 0.05). The incidence of adverse clinical events showed no significantly difference between the treatment group and control (P ＞0.05). Conclusions Applying of fibrinolytic, anticoagulant and antiplatelet drug combination treatment in patients with PIS has a good efficacy and safety,which is good for clinical application.

Nadroparin and percutaneous transluminal coronary angioplasty in elderly Thais with unstable angina.

Objective: Unstable angina (UA) is one of the leading problems in healthcare management in developing countries where facilities of catheterization laboratory are scarce and well-trained operators who are able to manage acute coronary syndrome often unavailable. In this scenario, strategy to arrive at optimal management to stabilize the condition medically is always a controversy. There is still controversy concerning the optimal management strategy during medical stabilization at places with inadequate catheterization laboratory facilities and a lack of well-trained operators who are able to manage acute coronary syndrome. Furthermore, the choices of medical and invasive management, including the use of percutaneous transluminal coronary angioplasty (PTCA) are still debatable. Curious by the challenge, we launch this prospective randomized controlled study to compare the efficacy of nadroparin with percutaneous transluminal coronary angioplasty (PTCA) in elderly patients with UA or non ST-elevation myocardial infarction (NSTEMI). Methods: Ninety-three elderly patients with UA, whose clinical manifestations were classified according to Braunwald’s classification, were recruited. All patients underwent coronary angiography within 96 hours after hospitalization; those who had angiographic coronary arterial stenosis that was feasible for PTCA were randomized to receive either nadroparin 7,500 IU subcutaneously twice daily for 5 days or PTCA. All clinical events in hospital and post-discharge up to 12 months, including death, composite end point [myocardial infarction (MI), recurrent angina/or ischemia], re-intervention (either PTCA or coronary artery bypass surgery) and rehospitalization, were recorded. Results: Only Forty-six patients were randomized equally into NAD group (n =23) and PTCA group (n =23). There were no statistically significant differences between NAD vs. PTCA regarding their baseline clinical characteristics, ECG, number of diseased vessels involved and outcomes (death and MI). The composite end point occurred more frequently in the NAD group [(34.5% vs. 4.3%); p = 0.01]. After a 12-month follow-up there was no difference in death rate or MI between the two groups but there was a clinically significant difference with regard to post-discharge outcomes in the NAD group, i.e, higher recurrent angina in NAD vs. PTCA (43.5% vs. 23.7%; p = 0.012), requiring additional PTCA (39.1% vs. 21.7%; p = 0.012), rehospitalization (47.8% vs. 30.4%; p = 0.015) and composite endpoint (47.8% vs. 30.4%; p = 0.015). Conclusions: PTCA achieve less composite endpoint than conservative management while nadroparin was easy to administer, but one-third of the patients still experienced recurrent angina or ischemia. PTCA is another option and could be performed safely, resulting in a less recurrent angina and shorter hospital stay. It is suggested that in the elderly with UA, nadroparin may be considered is the initial optimal management where PTCA facility is not available; those with recurrent angina symptoms should be referred afterwards for PTCA.