Dalteparin Research Articles

The effect of VEGF antisense oligonucleotides combined with low molecular weight heparin on the growth and metastasis of mice Lewis lung cancer

To investigate the inhibitory effect of vascular endothelial growth factor (VEGF) antisense oligonucleotides or/and dalteparin sodium (fragmin) on tumor growth and metastasis of mice Lewis lung cancer. 40 mice with Lewis lung cancer were randomizedly divided into five groups: control group, VEGF antisense oligonucleotides (ASODN) group, VEGF mismatch sense oligonucleotides (MSODN) group, low molecular weight heparin (LMWH) group, and combined group. Sodium chloride, VEGF-ASODN, VEGF -MSODN, fragmin, and VEGF-ASODN plus fragmin were given respectively (once every two days, 15 times altogether). The volume and weight of subcutaneous tumors were measured, and the rates of lung metastasis were detected by HE staining. The microvessel density (MVD) in tumor mass were measured by immunohistochemistry staining. VEGF protein level in tumor tissue were detected by Western blot assay. After treatment, the tumor growth inhibitory rates were 47.34%, 27.31% and 59.03%, and the rates of lung metastasis were 37.5%, 37.5% and 25% in ASODN, LMWH, and the combined group, respectively. Tumor MVD and VEGF protein expression of the above three groups were lower than those of the control group. There was a significant difference in regard to the tumor growth inhibitory rates and MVD between the above three treated groups and the control group as well as the MSODN group (P < 0.05). VEGF-ASODN and fragmin may down-regulate VEGF gene expression and inhibit angiogenesis, Combined use of fragmin can enhance anti- tumor effect of VEGF-ASODN.

Effect of low-molecular-weight heparin on the commitment of bone marrow cells to liver sinusoidal endothelial cells in CCl4-induced liver injury

Recently liver regeneration by bone marrow transplantation has been proposed as an alternative source of functional liver cells. We investigate commitment of bone marrow cells (BMCs) to liver regeneration and the effect of dalteparin sodium (DS) on regeneration of the damaged liver caused by carbon tetrachloride (CCl(4)) administration in the mice. Liver injury was produced in 8-week-old mice by treating with CCl(4) for 4 weeks. Thereafter, mice received a lethal dose of irradiation (10Gy) to whole body, followed by injection of 1x10(7) green fluorescent protein (GFP)-positive BMCs via the tail vein. DS (50IU/kg, intraperitoneally) was administered daily for 28 consecutive days starting at 1 day post-BMC transplantation. Lineage marker analysis of GFP-positive liver cells was performed immunostaining with a CD31 antibody. Four weeks after BMC transplantation, GFP-positive cells in the CCl(4)-damaged liver could be detected in the lobule displaying a meshwork architecture extending from the periportal to pericentral regions, a pattern simulating sinusoidal lining. This localization of GFP-positive cells suggested that these cells were closely associated with sinusoidal endothelial cells. By staining the GFP-positive cells for CD31, it was confirmed that the majority of the GFP-positive cells are also positive for CD31. The GFP(+)CD31(+) cells were barely detected in the control group (1.0+/-1.2 per field). In marked contrast, a numerous number of GFP(+)CD31(+) cells were detected in the liver section obtained from the CCl(4)-induced liver damage group (3.8+/-1.3 per field, P<0.05 versus control). The number of GFP(+)CD31(+) cells in CCl(4) plus DS-treated group was further increased to 8.3+/-1.3 per field (P<0.05 versus CCl(4)-induced liver damage group). The majority of GFP-positive BMCs was committed to sinusoidal endothelial cells. DS promoted BMC differentiation into sinusoidal endothelial cells in the CCl(4)-damaged liver.

Leukocytapheresis for Ulcerative Colitis: A Comparative Study of Anticoagulant (Nafamostat Mesilate vs. Dalteparin Sodium) for Reducing Clinical Complications

Leukocytapheresis (LCAP) is a therapeutic strategy for extra corporeal immunomodulation that has been used to treat several immunological disorders, including ulcerative colitis (UC), with encouraging results, inducing remission in steroid-resistant patients. However, we have experienced some complications during or after LCAP therapy. Common adverse effects include fever, chills, nausea, vomiting, and hypotension. One of the reasons for these adverse effects might be the use of nafamostat mesilate (NM) as an anticoagulant. In the present study, 75 patients with UC were divided into two groups, an NM group and a dalteparin sodium (DS) group. The clinical efficacy of these treatments, improvement after treatment, changes in leukocyte differential count, and adverse effects after LCAP therapy were then compared. The clinical efficacy, improvement after treatment, and changes in leukocyte classification were not significantly different between the two groups, while some adverse effects were observed in the NM group but not in the DS group. In conclusion, LCAP therapy is a useful therapy for patients with moderate to severe UC who fail to respond to glucocorticoid therapy, however, a safe anticoagulant should be used to avoid its related adverse effects.

Dalteparin sodium "feasible" option during PCI

Dalteparin sodium "feasible" option during PCI

Is antithrombotic prophylaxis required in cancer patients with central venous catheters? Yes for special patient groups.

Is antithrombotic prophylaxis required in cancer patients with central venous catheters? Yes for special patient groups.

Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin: Assessment of a Standardized Periprocedural Anticoagulation Regimen

The safety and efficacy of a standardized periprocedural anticoagulation regimen with low -rnolecular-weight (LIH) heparin vvas studied n 650 cat-ients who hao eumbolic stroke, chronic atria! fibrillation, or a mechanical neart valve and required interrup ton of warfarin therapy because of an nvasive procedure. Warfarin was stopped 5 or 6 days before the procedure and NIH hepadin (subcutaneous dalteparin sodium' was begun 3 days before the procedure, Patients who had a procedure considered at low risk of bleeding and whose postprocedural hemostas:s was adequate resumed warfarin on the everrng of the procedure and dalteparin was resumed the Fext itay. Dalteparin was delayed if hemostasis was unstab e. Patients wino underwent a procedure at high risk of bleeding resurned warfarin or, the evening of the procedure but dalteparin was not given after the procedure. In 542 patients who underwernt a procedure at low risk for bleeding, 2 thromboermiulic events, 4 mrajor bleeding episodes, and 32 episodes of rncrea...

A Randomized Trial Comparing 2 Low-Molecular-Weight Heparins for the Outpatient Treatment of Deep Vein Thrombosis and Pulmonary Embolism

Low-molecular-weight heparins (LMWHs) are now standard therapy for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE). No published trials have compared LMWHs, and few studies have examined outpatient therapy for PE. Only tinzaparin sodium has demonstrated superiority to unfractionated heparin in a clinical trial. We compared 2 LMWH products, tinzaparin and dalteparin sodium, for the treatment of acute DVT and PE in a randomized, controlled clinical trial of consecutive outpatients presenting to a venous thromboembolism service at 4 tertiary-care hospitals. Patients were treated with subcutaneous tinzaparin sodium, 175 IU/kg every 24 hours, or subcutaneous dalteparin sodium, 200 IU/kg every 24 hours, for at least 5 days. Warfarin sodium therapy was started simultaneously and continued for 90 days. The primary end point was efficacy (recurrence of venous thromboembolism); safety (bleeding) was a composite end point. Two hundred fifty-four patients received tinzaparin (39 with PE and 215 with DVT) and 251 received dalteparin (51 with PE and 200 with DVT). Most patients had an active malignancy or idiopathic DVT/PE. The outcome events occurred in 11 (4.4%; 95% confidence interval [CI], 2.2%-7.7%) and 15 patients (5.9%; 95% CI, 3.3%-9.5%) in the dalteparin and tinzaparin groups, respectively, including 9 and 10 recurrences, respectively, and 2 and 5 major hemorrhages, respectively (P = .44). The 95% CI on the difference of -1.5% was -5.3% to 2.4%. Tinzaparin and dalteparin are safe and effective for the outpatient treatment of DVT or PE. Our finding of no differences between the LMWHs based on major clinical end points means that practical issues can be the deciding factor on which drug to use.

Health Canada has approved Pfizer's dalteparin sodium [Fragmin

Health Canada has approved Pfizer's dalteparin sodium [Fragmin

Efficacy and Safety of Fixed Low-Dose Dalteparin in Preventing Venous Thromboembolism Among Obese or Elderly Hospitalized Patients

We were concerned that a fixed rather than a weight-based dosing regimen of dalteparin sodium to prevent venous thromboembolism (VTE) might result in decreased efficacy in obese patients and decreased safety in elderly patients. We retrospectively performed subgroup analyses using the database from the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients (PREVENT) Trial, a study of 3706 hospitalized, medically ill patients randomized to receive either dalteparin sodium, 5000 U/d, or placebo. The primary end point was a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal deep venous thrombosis by day 21. Obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 30 or greater for men and 28.6 or greater for women. Overall, 1118 patients (30.4%) were obese and 1226 (33.3%) were 75 years or older. In obese patients, the primary end point occurred in 2.8% of the dalteparin and in 4.3% of the placebo groups (relative risk, 0.64; 95% confidence interval [CI], 0.32-1.28). In patients 75 years or older, the primary end point was reported in 4.2% of the dalteparin and in 8.0% of the placebo groups (relative risk, 0.52; 95% CI, 0.31-0.87). The dalteparin effect for the primary end point (odds ratio, 0.51; 95% CI, 0.32-0.82) was not attenuated when adjusted for age, sex, obesity, history of VTE, and varicose veins. Dalteparin was not associated with an increase in major hemorrhage by day 21 in obese (0% vs 0.7% placebo; P>.99) and in elderly (1.1% vs 0.7%; P=.12) patients. Our findings suggest that a fixed low dose of dalteparin sodium of 5000 U/d is effective and safe in preventing VTE in obese and elderly hospitalized medical patients.

Interventional Cardiovascular Pharmacotherapy

In the last decade, a variety of novel anticoagulant and antiplatelet agents that improve outcomes in patients undergoing percutaneous coronary revascularization have emerged. During the next decade, continued refinements in catheter-based device technology should lead to further increases in the number of interventional procedures. The use of optimal antithrombotic strategies is pivotal in reducing adverse events among patients undergoing percutaneous coronary intervention (PCI). Our purpose is to review the current evidence regarding the efficacy of available adjunctive anticoagulant and antiplatelet agents in treating patients undergoing percutaneous coronary revascularization. It should be borne in mind that patients undergoing PCI in the midst of an acute coronary event require a different level of coagulation and platelet aggregation inhibition than low-risk patients undergoing elective PCI for stable angina pectoris. Similarly, generalizing antithrombotic regimen safety data to a wide spectrum of catheter-based therapeutic devices should be avoided. A level of anticoagulation that is safe and effective for angioplasty and stent placement may not be sufficient for devices with longer intracoronary dwell times such as brachytherapy catheters. In light of current evidence, activated clotting times should be targeted in the 200- to 250-second range during elective PCI and in the 250- to 300-second range when intervening on a higher-risk lesion, such as one with an angiographically visible thrombus or in patients presenting with an acute coronary syndrome (ACS).Low-dose enoxaparin sodium is an attractive antithrombin strategy in PCI because it is intrinsically adjusted for renal function, age, and concomitant glycoprotein (GP) IIb/IIIa antagonist use. Other low-molecular weight heparins have also been studied as adjunctive anticoagulants during cardiac catheterization. For example, in pilot studies, dalteparin sodium was shown to have a good safety profile when used alone or in combination with abciximab during PCI.A wealth of data supports the use of a GP IIb/IIIa antagonist in patients presenting with ACS, especially those with high-risk features such as elevated cardiac markers; the systematic use of GP IIb/IIIa inhibitors in this population is therefore encouraged. Overall, the use of GP IIb/IIIa inhibitors reduces the incidence of thrombotic complications following PCI, is associated with a mortality benefit, but has no impact on the risk of restenosis.

Cost Effectiveness of Dalteparin for Preventing Venous Thromboembolism in Abdominal Surgery

Patients undergoing abdominal surgeries face substantial risk of experiencing venous thromboembolic events in the perioperative period. The low-molecular-weight heparin dalteparin sodium is clinically effective in reducing the incidence of venous thromboembolism (VTE) in these patients. Dalteparin may be used in low (2500 units [U]) and high (5000 U) once-daily doses for this indication. However, the cost effectiveness of dalteparin 5000 U compared with dalteparin 2500 U and unfractionated heparin (UFH) for this indication has not been studied. To conduct a cost-utility analysis to evaluate the cost effectiveness of dalteparin compared with UFH for preventing VTE in patients undergoing elective abdominal surgery. A Markov model, from a healthcare perspective, was constructed to evaluate the cost effectiveness of dalteparin 5000 U and dalteparin 2500 U compared with UFH. A 69-year-old mixed sex patient population was studied using pooled probabilities of clinical outcomes from randomised, controlled trials. Cost data were mostly derived from Medicare reimbursement, in year 2002-03 values. Cost effectiveness was measured as cost per QALY gained over the patient's lifetime. Total costs for patients given UFH, dalteparin 2500 U and dalteparin 5000 U were US45,855 dollars, US45,882 dollars and US46,308 dollars, respectively, while QALYs were 9.5603, 9.5632 and 9.5811, respectively. Hence, the incremental cost effectiveness of dalteparin 5000 U over dalteparin 2500 U and UFH was US23,799 dollars/QALY and US21,779 dollars/QALY gained, respectively. Similarly, cost effectiveness for dalteparin 2500 U over UFH was US9310 dollars/QALY gained. Univariate sensitivity analysis showed that dalteparin 5000 U maintained its cost effectiveness (incremental cost-effectiveness ratio [ICER] <US50 000 dollars/QALY gained) over the other two regimens for a wide range of cost and effectiveness estimates. Acceptability curves based on the results of Monte Carlo simulation (50,000 patients) showed that dalteparin 5000 U would achieve cost effectiveness for 90% of patients at values close to US230,000 dollars/QALY. Dalteparin 2500 U was less effective than UFH for patients aged <63 years. Even though our base-case analysis seems to show that dalteparin 5000 U is cost effective compared with dalteparin 2500 U and UFH for prophylaxis of VTE in patients undergoing abdominal surgery, Monte Carlo simulation demonstrated that this was the case for only about 50% of the patients if the threshold for cost effectiveness is set at US50,000 dollars per QALY gained. Furthermore, there was substantial uncertainty in the cost-effectiveness results. To ensure that > or =90% patients receive the benefit of the medication, policy makers would need to commit substantially more resources than suggested by the baseline ICERs.

Inhibition of Breast Cancer and Leukemia Cell-Induced Endothelial Angiogenesis by Low Molecular Weight Heparins (LMWH).

Background: Clinical studies have suggested a survival advantage associated with LMWH administration in cancer patients. Angiogenesis is an important step in tumor progression and it has been demonstrated that LMWH can affect in-vitro vessel growth induced by purified proangiogenic factors.Objective: In this study we investigated whether two different LMWHs, enoxaparin (ENX) and dalteparin (DLT), and unfractionated heparin (UFH), were able to counteract the tube formation capacity of human microvascular endothelial cells (HMEC-1) induced by tumor cell conditioned media (TCM) or by purified factors (i.e. VEGF, bFGF, TNF-alpha and IL-1beta).Methods: TCM were obtained after a 24h growth from three breast cancer cell lines, i.e. MCF-7, ZR75.1 and MDA.MB.231, and one human promyelocytic leukemia cell line, i.e. NB4 cells. HMEC-1 cells were resuspended in TCM or purified cytokine solutions in the presence or absence of 10 IU/ml heparins (DLT, ENX or UFH) and then seeded in a 96-well plate pre-coated with growth factor-reduced Matrigel. After 24h, tube formation was examined under phase-contrast microscopy and tube length determined by image analysis software. To characterize TCM cytokine contents, TCM were first screened for their VEGF, bFGF, TNF-alpha and IL-1beta levels by ELISA, and then inhibition studies were performed by pre-incubating TCM with specific neutralizing antibodies directed against each of these factors.Results: TCM from all 4 tumor cell lines induced a significant (p<0.05) increase in total tube length (60 to 95% mean increase) compared with control TCM. Purified proangiogenic factors significantly (p<0.05) promoted tube formation (46 to 68% mean increase), although to a lesser extent than TCM. Angiogenesis induced by each TCM was significantly affected (76 to 100% mean inhibition) by ENX and DLT, but was less sensitive to UFH. A similar pattern of inhibition was observed with tube formation induced by purified angiogenic factors, particularly the angiogenesis induced by VEGF, bFGF, TNF-alpha or IL-1b was 100% inhibited by ENX and 65–75% by DLT, whereas minor or no inhibition was observed with UFH (VEGF= 27%; bFGF = 0%; TNF-alpha= 53%; IL-1beta= 53%). Inhibition studies with neutralizing MoAbs against proangiogenic factors demonstrated that anti-VEGF MoAb was the most effective in inhibiting tube formation induced by both breast cancer and leukemic cells (77 to 84% mean inhibition).Conclusion: Our data indicate that heparins can inhibit the proangiogenic stimulus of both tumor cells and purified angiogenic factors on microvascular endothelium, and that the LMWHs are more effective than UFH in this experimental system.

The majority of patients who receive dalteparin sodium during pregnancy require dose increases to maintain peak therapeutic levels,

The majority of patients who receive dalteparin sodium during pregnancy require dose increases to maintain peak therapeutic levels,

LOW MOLECULAR WEIGHT HEPARIN INDUCED PRIAPISM

A 52-year-old male had right lower extremity swelling following a long automobile ride. Venous duplex scan revealed a right popliteal deep venous thrombosis (DVT), and outpatient treatment with daily subcutaneous injection of 5,000 units dalteparin sodium, an LMWH, was instituted. Approximately 2 hours following the injection on the third day painful priapism developed without preceding trauma or sexual activity. The patient had no history of priapism and denied ingestion of alcohol or cocaine. The priapism was successfully treated with corporeal irrigation with saline and phenylephrine. Dark blood was irrigated from the corpora, which was suggestive of low flow priapism. Oral warfarin was started the next day and maintained for 6 months as DVT therapy. The patient responded well and suffered no further episodes of DVT or priapism.

Low-molecular-weight heparin as bridging anticoagulation during interruption of warfarin: assessment of a standardized periprocedural anticoagulation regimen.

The treatment of patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin sodium therapy is a common clinical problem. We investigated the efficacy and safety of a standardized periprocedural anticoagulation regimen with low-molecular-weight heparin. We studied 650 consecutive patients with a mechanical heart valve, chronic atrial fibrillation, or embolic stroke who required interruption of warfarin therapy because of an invasive procedure. Warfarin was stopped 5 or 6 days before the procedure, and patients received subcutaneous dalteparin sodium, 100 IU/kg twice daily, starting 3 days before the procedure. The risk of postprocedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non-high-bleeding-risk procedure who had adequate postprocedural hemostasis, warfarin was resumed on the evening of the procedure, and dalteparin sodium, 100 IU/kg twice daily, was resumed on the next day and continued until the international normalized ratio was 2.0 or more. If postprocedural hemostasis was not secured, the resumption of dalteparin was delayed. In patients undergoing a high-bleeding-risk procedure, warfarin was resumed on the evening of the procedure, but dalteparin was not given after the procedure. Patients were followed up during the preprocedural and postprocedural period for a mean of 13.8 days (range, 10-18 days). In 542 patients who underwent a non-high-bleeding-risk procedure, there were 2 thromboembolic events (0.4%), 4 major bleeding episodes (0.7%), and 32 episodes of increased wound-related blood loss that precluded postprocedural dalteparin administration (5.9%). In 108 patients who underwent a high-bleeding-risk procedure, there were 2 deaths (1.8%) possibly due to thromboembolism and 2 major bleeding episodes (1.8%). In patients at increased risk for arterial thromboembolism who require temporary interruption of warfarin therapy, a standardized periprocedural anticoagulant regimen with low-molecular-weight heparin is associated with a low risk of thromboembolic and major bleeding complications.

Serious adverse incidents with the usage of low molecular weight heparins in patients with chronic kidney disease

Background: The aim of the study is to describe serious adverse events in patients with renal insufficiency administered low molecular weight heparins (LMWHs). Methods: Systematic case note review from July 2002 to March 2003, Hope Hospital, Salford, UK, was used. Results: Ten patients experienced an adverse incident on LMWH therapy. Five patients were on maintenance hemodialysis therapy, and 1 patient was on continuous ambulatory peritoneal dialysis therapy. Three patients had calculated creatinine clearances of 5, 11, and 33 mL/min (0.08, 0.18, and 0.55 mL/s), and 1 patient had an estimated glomerular filtration rate of 12 mL/min. Age range was 45 to 89 years. Indications for anticoagulation were suspected pulmonary embolism (1 patient), acute coronary syndrome (7 patients), severe nephrotic syndrome (1 patient), and postoperative venous thromboembolic prophylaxis (1 patient). Three patients also were administered aspirin; 1 patient, clopidogrel; and 3 patients, aspirin and clopidogrel. LMWHs used were enoxaparin (6 patients), tinzaparin (3 patients), and dalteparin sodium (1 patient). Bleeding sources were retroperitoneal (1 patient), spontaneous soft tissue (3 patients), gastrointestinal (2 patients), dialysis catheter and cannula sites (2 patients), hemorrhagic pericardial effusion (1 patient), and intracranial (1 patient). Activated partial thromboplastin time was prolonged in 7 of 10 patients, with no other identifiable cause found. Three patients died despite aggressive resuscitation, including packed red blood cell infusions and protamine sulfate administration. Eight of the 10 prescriptions for LMWHs were either started or continued within our directorate, giving an approximate incidence of major hemorrhagic events in patients with chronic kidney disease of 7.8%. Conclusion: LMWHs administered at fixed-weight doses and without monitoring show unpredictable anticoagulant effects in patients with chronic kidney disease stages 4 and 5, leading to serious and even fatal adverse incidents.

Ximelagatran/Melagatran

Ximelagatran (Exanta), the first available oral direct thrombin inhibitor, and its active form, melagatran, have been evaluated in the prevention of venous thromboembolism (VTE) in patients undergoing hip or knee replacement. After oral administration ximelagatran is rapidly bioconverted to melagatran. Melagatran inactivates both circulating and clot-bound thrombin by binding to the thrombin active site, thus, inhibiting platelet activation and/or aggregation and reducing fibrinolysis time. The efficacy of subcutaneous melagatran followed by oral ximelagatran has been investigated in four European trials and the efficacy of an all oral ximelagatran regimen has been investigated in five US trials. In a dose-ranging European study, preoperatively initiated subcutaneous melagatran 3 mg twice daily followed by oral ximelagatran 24 mg twice daily was significantly more effective than subcutaneous dalteparin sodium 5000IU once daily in preventing the occurrence of VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), in patients undergoing hip or knee replacement. In one study, there were no significant differences in VTE prevention between subcutaneous melagatran 3 mg administered after surgery followed by ximelagatran 24 mg twice daily and enoxaparin sodium (enoxaparin) 40 mg once daily. Compared with enoxaparin, significantly lower rates of proximal DVT and/or PE (major VTE) and total VTE were observed when melagatran was initiated preoperatively (2mg) then postoperatively (3mg) and followed by ximelagatran 24 mg twice daily. In the US, four studies showed that postoperatively initiated ximelagatran 24 mg twice daily was of similar efficacy to enoxaparin or warfarin in the prevention of VTE in patients undergoing hip or knee replacement. However, ximelagatran 36 mg twice daily was superior to warfarin (target international normalised ratio of 2.5) at preventing the incidence of VTE in patients undergoing total knee replacement in two studies.Ximelagatran alone or after melagatran was generally well tolerated. Overall, the incidence of bleeding events and transfusion rates were not markedly different from those documented for comparator anticoagulants. In a post-hoc analysis of one study, transfusion rates were lower in ximelagatran than enoxaparin recipients. Oral ximelagatran alone or in conjunction with subcutaneous melagatran has shown good efficacy and was generally well tolerated in the prevention of VTE in patients undergoing orthopaedic surgery. Furthermore, patients receiving ximelagatran/melagatran do not require anticoagulant monitoring. The drug has a low potential for drug interactions and can be administered either by subcutaneous injection or orally. Thus, on the basis of available evidence, ximelagatran/melagatran appears poised to play an important role in the prophylaxis of VTE in patients undergoing orthopaedic surgery.

Use of dalteparin sodium for thromboprophylaxis in high-risk pregnancies is effective and safe without anti-FXa* monitoring,

Use of dalteparin sodium for thromboprophylaxis in high-risk pregnancies is effective and safe without anti-FXa* monitoring,

Tinzaparin sodium: a review of its pharmacology and clinical use in the prophylaxis and treatment of thromboembolic disease.

Tinzaparin sodium (tinzaparin; innohep) is a low molecular weight heparin (LMWH) formed by the enzymatic degradation of porcine unfractionated heparin (UFH). In clinical trials, once-daily subcutaneous (SC) tinzaparin was effective and generally well tolerated in the prophylaxis and treatment of thromboembolic disease. SC tinzaparin 75 anti-Xa IU/kg/day showed similar thromboprophylactic efficacy to adjusted-dosage oral warfarin in patients undergoing total hip arthroplasty; in patients undergoing knee replacement, the incidence of deep vein thrombosis (DVT) was significantly lower with tinzaparin. The drug had similar efficacy to equivalent-dosage SC enoxaparin sodium in orthopaedic surgery. In patients undergoing general surgery, SC tinzaparin 3500 anti-Xa IU/day was of equivalent thromboprophylactic efficacy to SC UFH 5000IU twice daily. Encouraging preliminary results have been obtained with tinzaparin in the prevention of DVT in patients with complete motor paralysis. In the initial treatment of acute proximal DVT and pulmonary embolism, SC tinzaparin 175 anti-Xa IU/kg/day was at least as effective as adjusted-dosage intravenous (IV) UFH. In the outpatient treatment of venous thromboembolism, tinzaparin has demonstrated similar efficacy to dalteparin sodium (dalteparin) and warfarin. Tinzaparin was effective in preventing clotting in haemodialysis circuits; the anticoagulant efficacy of tinzaparin in patients undergoing haemodialysis was similar to that of SC dalteparin and similar to or less than (although in this case the tinzaparin dose was too low for sufficient anticoagulant efficacy) that of IV UFH. Advantages of tinzaparin over UFH and warfarin include ease of administration and lack of need for laboratory monitoring. Tinzaparin is more cost effective than UFH in the treatment of established thromboembolic disease, and home-based treatment with tinzaparin may offer greater cost benefits than hospital-based therapy. Tinzaparin is well tolerated, including in elderly patients and those with renal impairment receiving long-term treatment. Incidences of major bleeding complications were low and reports of heparin-induced thrombocytopenia were infrequent in clinical studies. In conclusion, tinzaparin is a valuable LMWH in the prophylaxis and management of thromboembolic disease.

Dalteparin sodium prevents liver injury due to lipopolysaccharide in rat through suppression of tumor necrosis factor-alpha production by Kupffer cells.

Sensitization of Kupffer cells (KC) to lipopolysaccharide (LPS) and overproduction of tumor necrosis factor (TNF)-alpha play important roles in the pathogenesis of alcoholic liver damage and sepsis-associated organ injury. Therefore, suppression of TNF-alpha should prove useful for treatment of LPS-induced liver injury. Recently, heparin has been reported to diminish TNF-alpha production from macrophages in response to LPS. Dalteparin sodium (DS) is a low-molecular-weight heparin with a mean molecular weight of 5,000. DS elicits an antithrombotic effect through a mechanism depending on anti-factor Xa activity but not on the antithrombin activity. DS is thus suitable for treatment of disseminated intravascular coagulation because it has a much smaller prohemorrhagic property. In this study, we evaluated whether DS could prevent LPS-induced liver injury. Female Wistar rats were administered DS (50 IU/kg intraperitoneally) followed by challenge with LPS (5 mg/kg intravenously) 2 hr later. Livers and sera were collected 24 hr later. KC from rats were isolated and cultured in RPMI 1640 supplemented with 10% fetal bovine serum. After the addition of LPS (10 microg/ml) to the culture media, intracellular Ca2+ was measured by using a fluorescent indicator, fura-2. LPS (5 mg/kg intravenously) caused focal necrosis and neutrophil infiltration in the control liver. The histological changes and increased alanine aminotransferase levels caused by LPS injection were diminished by treatment with DS. LPS increased intracellular Ca2+ of KC in control rats from the basal level (26 +/- 6 nmol/liter) to 280 +/- 18 nmol/liter. This increase was blunted by DS (126 +/- 28 nmol/liter). The DS treatment decreased the LPS-induced TNF-alpha production by KC from 911 +/- 78 pg/ml to 309 +/- 45 pg/ml (p < 0.05). These results indicate that DS reduces the LPS-induced liver injury through suppression of TNF-alpha production.