Low Molecular Weight Heparin Drugs Research Articles

Development and attestation of a standard sample of calcium nadroparin

Introduction. The widespread use of heparin preparations for the treatment and prevention of venous thromboembolic complications is known. One of the low molecular weight heparin drugs successfully used in clinical practice is calcium nadroparin. The modern approach to assessing the quality of medicines involves the use of standards, in comparison with which the quality control of the drug is carried out – standard samples (SS). The most important specific parameter in assessing the authenticity of low molecular weight heparins is the characteristic of the fractional composition.Aim. The aim of the work was to develop, attestation and determine the stability during the shelf life of a secondary standard sample to determine the authenticity of calcium nadroparin as part of improving the quality control system of the enterprise with the prospect of creating a domestic pharmacopoeia standard sample.Materials and methods. The object of development and attestation was the standard sample of the enterprise – low molecular weight heparin, obtained on the basis of the Technology implementation center of Siberian state medical university. The certified standard sample was obtained by purification of calcium nadroparin by solid-phase extraction. The completeness of the purification was confirmed by comparing the chromatograms of the purified samples with the chromatograms of the international standard sample. The characteristics of the molecular weight distribution were determined chromatographically. The stability of the certified SSE (the standard sample of the enterprise) was studied under two storage conditions – at a temperature below 8 °C in a dry state for 16 months and in solution at –40 °C for 6 months by evaluating trends in molecular weight distribution.Results and discussion. For each batch of the certified standard sample, the molecular weight and molecular weight characteristics are calculated in 2 parallel definitions, and a representative chromatogram is presented. The values of the relative standard deviation of the molecular weight of the samples and the content of the controlled fractions did not exceed 2.5 %. A detailed analysis of the molecular weight distribution showed the "classical" dependence of RSD (relative standard deviation) from the average value with a significant increase up to 30 % for small fraction values (less than 0.5 %). It was found that during 16 months at a storage temperature below 8 ºC, the molecular weight and molecular weight characteristics of standard samples of low molecular weight heparin did not significantly change. However, in the SSE solution at a storage temperature of minus 40 °C for 6 months, they degraded by more than 10 %.Conclusion. According to the results of the study, a protocol has been developed for obtaining a standard sample of low-molecular-weight heparin for the standardization of the calcium nadroparin substance according to the indicator "molecular weight distribution". The established shelf life of the sample is at least 16 months at temperatures below 8 °C. The stability of solutions of the standard sample at a storage temperature of –40 °C for 3 months is shown.

Electronic Prescribing Systems as Tools to Improve Patient Care: A Learning Health Systems Approach to Increase Guideline Concordant Prescribing for Venous Thromboembolism Prevention

Background: Venous thromboembolism (VTE) causes significant mortality and morbidity in hospitalised patients. In England, reporting the percentage of patients with a VTE risk assessment is mandated, but this does not include whether that risk assessment resulted in appropriate prescribing. Full guideline compliance (defined as an assessment and an appropriate action) is rarely reported. Education, audit and feedback enhance guideline compliance but electronic prescribing systems (EPS) can mandate guideline-compliant actions. We hypothesised that EPS-based interventions would increase full VTE guideline compliance more than other interventions. Methods: All admitted patients within University Hospitals Birmingham NHS Foundation Trust were included for analysis between 2011-2020. The proportion of patients who received a fully compliant risk assessment with the recommended action (prophylaxis or not, depending on the risk score) was assessed over time. Interventions included face-to-face feedback based on measured performance (an individual approach) and mandatory risk assessment and prescribing rules into an EPS (a systems approach). Findings: Data from all 235,005 admissions and all 5503 prescribers were included in the analysis. Face-to-face feedback gradually improved full VTE guideline concordance from 70% to 77% (p=<0.001). Changes to the EPS to mandate assessment with prescribing rules increased full VTE compliance to 95% (p=<0.001). Further amendments to the EPS system to reduce erroneous VTE assessments slightly reduced full compliance to 92% (p<0.001), but this was then maintained during two changes to the low molecular weight heparin drug used for VTE prophylaxis. Interpretation: While both feedback and a rules-based EPS intervention improved guideline-compliant VTE management, a systems approach was more effective and benefits were sustained even during changes to formulary drugs. Non-compliance (an assessment without appropriate action or no assessment) was not eradicated despite this mandated system. Further work is needed to understand this and to ensure software changes enhance full guideline compliance. Funding Statement: This work was supported by PIONEER, the Health Data Research Hub in acute care and the HDR-UK Better Care programme. Declaration of Interests: S Gallier, P Nightingale, T Pankhurst, I Woolhouse, MA Berry, M Garrick report no conflicts of interest. S Ball reports funding support from the HDRUK. E Sapey reports funding support from HDRUK, MRC, Wellcome Trust, NIHR, Alpha 1 Foundation, EPSRC and British Lung Foundation. All other authors have nothing to declare. Ethics Approval Statement: This research was conducted under the ethical approvals of PIONEER, a Health data research hub in acute care (East Midlands – Derby Research ethics committee, reference 20/EM/0158).

Characterization of Low-Molecular-Weight Heparins by Strong Anion-Exchange Chromatography.

Currently, detailed structural characterization of low-molecular-weight heparin (LMWH) products is an analytical subject of great interest. In this work, we carried out a comprehensive structural analysis of LMWHs and applied a modified pharmacopeial method, as well as methods developed by other researchers, to the analysis of novel biosimilar LMWH products; and, for the first time, compared the qualitative and quantitative composition of commercially available drugs (enoxaparin, nadroparin, and dalteparin). For this purpose, we used strong anion-exchange (SAX) chromatography with spectrophotometric detection because this method is more helpful, easier, and faster than other separation techniques for the detailed disaccharide analysis of new LMWH drugs. In addition, we subjected the obtained results to statistical analysis (factor analysis, t-test, and Newman-Keuls post hoc test).

Meta-analysis for clinical effects of Shuxuetong and low-molecular-weight heparin in patients with deep vein thrombosis in lower limbs

Objective To systematically review the clinical effects of Shuxuetong and Low-molecular-weight Heparin(LMWH)in patients with deep vein thrombosis(DVT)in lower limbs. Methods The CNKI, Wanfang, VIP, SinoMed, PubMed, EMBASE, and ISI Web of Science databases were electronically searched from inception to February 3th, 2017, to collect the randomized clinical trials on the clinical effects of Shuxuetong and LMWH on DVT in lower limbs.Two investigators independently screened the literatures, extracted data and assessed the quality of enrolled studies.All analyses were performed using the Stata 11.0 software. Results Twenty studies involving 1 515 patients were finally included.The meta-analysis results showed that the total effective rate was significantly higher in Shuxuetong group than in LMWH drug control group(RR = 1.22, 95%CI: 1.13-1.32, P < 0.001). The subgroup analysis showed that there was no significant difference in total effective rate between the Shuxuetong alone group and LMWH alone control group(RR = 1.05, 95%CI: 0.98-1.12, P = 0.136). However, the total effective rate was significantly higher in Shuxuetong combined with LMWH group than in LMWH alone control group(RR = 1.30, 95%CI: 1.18-1.44, P < 0.001). Conclusions Shuxuetong combined with LMWH has better clinical effects than do LMWH alone group in treating patients with DVT in lower limbs. Key words: Venous thrombosis; Heparin, low-molecular-weight; Meta-analysis

Role of low molecular weight heparin in preventing deep vein thrombosis in elderly patients with hip fracture

Background: Deep vein thrombosis is one of the most prevalent medical problems today, with an annual incidence of 80 cases per 100,000. Lower-extremity DVT is the most common venous thrombosis, with a prevalence of 1 case per 1000 population Objective: To study the role of low molecular weight heparin i.e. injection enoxaparin in preventing deep vein thrombosis in elderly hip fracture patients. Methodology: The present study was conducted in department of orthopedics, yashoda super speciality hospital, malakpet, Hyderabad. Forty elderly Patients of hip fracture presenting to outpatient department and emergency department of orthopedics during the period from May 2010 to august 2011 was included in this study. Results: Out of 40 patients 23 (57.5%) had fracture neck femur and 17(42.5%) intertrochanteric fracture. The incidence of DVT in hip fracture patients with thromboprophylaxis by this study is 20%, of which 6(26.08%) patients had fracture neck femur and 2(11.76%) had intertrochanteric fracture. 1 patient had wound hematoma and 1 patient had minor wound bleeding. only 2(25%) out of 8 patients was symptomatic (leg pain, oedema) and remaining 6(75%) were asymptomatic. Conclusion: Low molecular weight Heparin drugs are better in preventing deep vein thrombosis with very less complications.

Screening enoxaparin tetrasaccharide SEC fractions for 3-O-sulfo-N-sulfoglucosamine residues using [(1)H,(15)N] HSQC NMR.

Heparin and heparan sulfate (HS) are important in mediating a variety of biological processes through binding to myriad different proteins. Specific structural elements along the polysaccharide chains are essential for high affinity protein binding, such as the 3-O-sulfated N-sulfoglucosamine (GlcNS3S) residue, a relatively rare modification essential for heparin's anticoagulant activity. The isolation of 3-O-sulfated oligosaccharides from complex mixtures is challenging because of their low abundance. Although methods such as affinity chromatography are useful in isolating oligosaccharides that bind specific proteins with high affinity, other important 3-O-sulfated oligosaccharides may easily be overlooked. Screening preparative-scale size-exclusion chromatography (SEC) fractions of heparin or HS digests using [(1)H,(15)N] HSQC NMR allows the identification of fractions containing 3-O-sulfated oligosaccharides through the unique (1)H and (15)N chemical shifts of the GlcNS3S residue. Those SEC fractions containing 3-O-sulfated oligosaccharides can then be isolated using strong anion-exchange (SAX)-HPLC. Compared with the results obtained by pooling the fractions comprising a given SEC peak, SAX-HPLC analysis of individual SEC fractions produces a less complicated chromatogram in which the 3-O-sulfated oligosaccharides are enriched relative to more abundant components. The utility of this approach is demonstrated for tetrasaccharide SEC fractions of the low molecular weight heparin drug enoxaparin facilitating the isolation and characterization of an unsaturated 3-O-sulfated tetrasaccharide containing a portion of the antithrombin-III binding sequence.

ANTITHROMBOTIC THERAPY IN CANCER PATIENTS

The article describes the main anticoagulant drugs used in cancer patients, taking into consideration pathogenetic aspects of hypercoagulation status in cancer patients: oral anticoagulants, heparin drugs, selective inhibitors of Xa factor. The basic advantages of low molecular weight heparin compared with unfractioned heparin. The comparison of low-molecular weight heparin drugs, their generics and biosimilar drugs is surveyed. Reviewed recommendations for the prevention of thrombotic complications in cancer patients. Overviewed the possible complications of heparin therapy and methods of prevention.

The interaction of enoxaparin and fondaparinux with calcium

The main sites of calcium binding were determined for the low molecular weight heparin drug enoxaparin and the synthetic pentasaccharide Arixtra (fondaparinux). [1H,13C] HSQC pH titrations were carried out to characterize the acid–base properties of these samples both in the presence and absence of calcium. The differences in the titration curves were used to determine the structural components of enoxaparin and fondaparinux responsible for Ca2+ binding. In enoxaparin both unsubstituted and 2-O-sulfated iduronic acid residues are important in calcium binding and the presence of the 2-O-sulfo group does not seem to influence the Ca2+ binding capability of the iduronate ring. In fondaparinux changes in chemical shifts upon Ca2+ binding were smaller than observed for enoxaparin, and were observed for both the glucuronic acid and 2-O-sulfated iduronic acid residues. In enoxaparin significant perturbations of the chemical shift of the N-sulfoglucosamine anomeric carbon in residues connected to 2-O-sulfated iduronic acid were detected on Ca2+ binding, however it was not possible to determine whether these changes reflect direct involvement in calcium complexation or result from through space interactions or conformational changes.

Experimental study of low molecular weight heparin drug delivery system for prevention of posterior capsular opacification in rabbit eyes

To investigate the safety and efficacy of low-molecular-weight heparin drug delivery system (LMWH DDS) for prevention of posterior capsular opacification (PCO) in rabbit eyes. (1) To prepare the LMWH DDS by freeze-drying way with Polylactic-co-glycolic acid (PLGA) as the carrier, and evaluate its release properties in vitro. (2) Fifty New Zealand albino rabbits (50 eyes) undergoing phacoemulsification were equally divided into five groups: receiving normal saline eye drops (group A), 3 different dose (1 mg, 0.5 mg and 0.25 mg) of LMWH DDS respectively implanted into the posterior chamber (group B, C and D), and a carrier DDS implanted into the posterior chamber (group E). All the 50 eyes were examined by slit-lamp microscopy. The low-molecular-weight heparin levels in aqueous humor were measured, and the wet posterior capsules were weighed. The LMWH DDS prepared with a freeze-dried way has high encapsulation efficiency, and the equation of 49-day release curve fitting in vitro were were similar to zero order. The fibrin exudation in group B, C and D were lower than in Group A and E during the first postoperative day. There were 10, 2, 3, 9 and 10 eyes that developing PCO in the group A, B, C, D and E, respectively. The mean wet-weight of the posterior capsule were (114.59 +/- 14.58) mg, (24.14 +/- 6.08) mg, (39.23 +/- 17.13) mg, (99.35 +/- 29.37) mg, (115.29 +/- 19.87) mg respectively in 5 trial groups. There were stable and high concentration of low molecular weight heparin in aqueous of group B and C during the 4 weeks (> 20 mg/L), while a instable and lower concentrations in group D. The result of optical microscopy and electron microscopy examination indicated that fibroblast proliferation was quite active in groups A, D and E, but inactive in group B and C. Neither infiltration of inflammatory cells at the cornea, iris, trabecular meshwork and ciliary body nor retinal degeneration or necrosis was found in any group at 12 weeks. There was no intraocular bleeding in all the five groups in the following 12 weeks. The LMWH DDS prepared by freeze-drying way with PLGA as the carrier has good slow-release and biological tolerance. Implantation of LMWH DDS into the posterior chamber of experimental animals can significantly reduce postoperative fibrin exudation, and can safe and effective prevent the occurrence of PCO, and also there were some dose-effect relationship.

Correlation between Antifactor Xa Activity and Thrombin Generation Time, Platelet Contractile Force and Clot Elastic Modulus Following Enoxaparin Exposure in Patients with and without Renal Dysfunction.

Patients with renal dysfunction that receive hemodialysis (HD) are highly sensitive to low molecular weight heparin (LMWH) drugs such as Enoxaparin. There have been numerous reports of hemorrhagic effects with these drugs in this population. Although current guidelines recommend judicious monitoring of antifactor Xa activity in HD patients to prevent adverse events, this parameter is poorly correlated to efficacy and toxicity. Newer, more specific parameters such as thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) may play a role in monitoring LMWH drugs in high-risk populations such as those with renal dysfunction. To determine the utility of monitoring TGT, PCF and CEM for this purpose, we conducted a prospective clinical trial in 8 non-thrombosed HD and 8 control subjects. All subjects received escalating doses of Enoxaparin 0.25, 0.50 and 1.0 mg/kg subcutaneously during this study. Blood samples were obtained four hours post-dose to capture the peak effect of Enoxaparin on antifactor Xa activity, TGT, PCF and CEM. Pearson's correlation was used to determine the relationships between antifactor Xa activity and TGT, PCF and CEM at each dose, respectively. Repeated measures analysis of covariance was used to assess for intergroup differences in the slopes of each regression line using the group status and antifactor Xa concentration as the covariates. The correlation coefficient (r), coefficient of determination (r2) and p-value for each parameter in each group are listed in the Tables. The figure illustrates the relationship between antifactor Xa and TGT in both controls and ESRD patients. These findings suggest that TGT, PCF and CEM are highly correlated to antifactor Xa activity in patients with and without renal dysfunction. There were no differences in the slopes of the regression lines between groups. Further studies are needed to determine if TGT, PCF and CEM provide more useful clinical information regarding the level of anticoagulation in high-risk patients receiving low-molecular weight heparin therapy. [Display omitted] Correlation Parameters for Antifactor Xa and TGT, PCF and CEM for Control SubjectsModelrr2P-valueAntifactor Xa vs. TGT0.880.770.001Antifactor Xa vs.PCF0.850.730.0003Antifactor Xa vs. CEM0.800.630.02Correlation Parameters for Antifactor Xa and TGT, PCF and CEM for HD subjectsModelrr2P-valueAntifactor Xa vs. TGT0.910.820.0002Antifactor Xa vs. PCF0.900.800.0004Antifactor Xa vs. CEM0.900.800.0005

Neuraxial Anesthesia and Low-Molecular-Weight Heparin Prophylaxis in Major Orthopedic Surgery in the Wake of the Latest American Society of Regional Anesthesia Guidelines

In May 2003, the Second American Society of Regional Anesthesia Consensus Conference statement was issued partly in response to continued safety concerns over the use of regional anesthesia--in particular, neuraxial techniques--with low-molecular-weight heparin (LMWH) prophylaxis in major orthopedic surgery. As the 2003 Consensus statement makes clear, regional anesthesia may be used safely with LMWH prophylaxis. The key to optimizing patient safety, however, depends on a careful calibration of the total daily dose and the timing of the first and subsequent doses of the LMWH drug with the timing and management of the regional anesthetic procedure. Because the challenge of successfully providing regional anesthesia in the presence of LMWH thromboprophylaxis is a clinical one, anesthesiologists should do what they can to ensure that every member of the surgical team has an understanding of current literature and practice guidelines such as those recently published by the American Society of Regional Anesthesia.

Favourable influence of low molecular weight heparin in mitigating the peroxidative membrane damage induced by a cytotoxic agent and an atherogenic diet.

The present study is aimed to demonstrate the protective effect of a heparin derivative, low molecular weight heparin (LMWH) against erythrocyte membrane injury. Two models serve to induce membrane lipid peroxidative damage, namely a potent cytotoxic agent, adriamycin and a hypercholesterolemic atherogenic diet. Two groups of male Wistar rats (140 +/- 10 g) received a single intravenous injection of adriamycin (ADR, 7.5 mg/kg), while two other groups were fed an atherogenic diet comprising a supplementation of 4% cholesterol, 1% cholic acid and 0.5% thiouracil (CCT diet) for 2 weeks. For each of the above two groups, LMWH (Troparin; 300 microg/day per rat subcutaneously) treatment commenced on day 8 and continued for a week. One group was maintained as the normal control group, and another group that received only LMWH treatment was designated as the LMWH drug control group. Erythrocyte membrane was isolated and assayed for its cholesterol levels, lipid peroxidation and ATPases activity. The activities of antioxidant enzymes were assessed in the haemolysate. The findings of the study were that both adriamycin and the atherogenic diet produced elevated membrane cholesterol levels and lipid peroxidation. The membrane ATPases suffered loss in activity. Accentuated oxidative stress was marked by rise in the activities of antioxidant enzymes (SOD, catalase and GPx). LMWH intervention reverted these changes thereby normalizing the membrane composition and function. The membrane protective effect of LMWH is illuminated by this work.

Low molecular weight heparin versus unfractionated heparin in the colonoscopy peri-procedure period: a cost modeling study

OBJECTIVE: The aim of this study was to compare the economic outcomes of peri-procedure anticoagulation approaches for elective colonoscopy. METHODS: Decision analysis was used to model the economic outcomes of five peri-procedure anticoagulation options: outpatient low molecular weight heparin (LMWH), inpatient unfractionated heparin infusion (UFHi), continuous warfarin (with probability of a repeat procedure using LMWH or UFHi), and discontinuation of anticoagulation therapy. The model’s base-case scenario assumed drug therapy options for high-risk patients were equally effective in preventing a thromboembolic event (0.1% risk), with a higher probability for the no anticoagulation strategy (0.4%); event costs were based on published data and adjusted to 1997 dollars. Drug costs reflected 1997 average wholesale price. Medical costs for other variables were estimated based on local hospital charges. Indirect costs were not considered. Risk probabilities and LMWH drug cost were tested in sensitivity analysis. RESULTS: In the base-case scenario, costs for the options evaluated were $1436/patient, $1792/patient, $1848/patient, $2629/patient, and $5196/patient for no anticoagulation, continuous warfarin/repeat LMWH, LMWH as outpatient, continuous warfarin/repeat UFHi, and UFHi as inpatient respectively ($1997). Discontinuing anticoagulation was the least costly approach but involved the greatest thromboembolic risk. The cost of continued warfarin anticoagulation/repeat LMWH was minimally less than the LMWH option, but assumes 25% of patients would require a second procedure. The traditional approach (UFHi) requires an extended hospitalization and is the most costly option. Varying risk category or LMWH cost in sensitivity analysis had a negligible impact on overall costs. CONCLUSION: Within the model’s assumptions, LMWH offers a novel, convenient, and economical solution to the problem of peri-procedure anticoagulation for elective colonoscopy.

Neurotrauma &amp; Deep Vein Thrombosis

Neurotrauma &amp; Deep Vein Thrombosis

Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management.

Low molecular weight heparin: biochemistry, pharmacology, perioperative prophylaxis regimens, and guidelines for regional anesthetic management.