Use of the low-molecular-weight heparin nadroparin during pregnancy. A review

Summary

Antithrombotic therapy is often used during pregnancy for the treatment and prevention of venous thromboembolism, the prevention of systemic embolism in patients with heart valve prostheses and the prevention of foetal loss in patients with antiphospholipid syndrome. Low-molecular-weight heparins (LMWHs), including nadroparin, have largely replaced unfractionated heparin as the anticoagulant of choice. The use of the LMWH nadroparin in pregnant women at an increased risk of thromboembolism or foetal loss is discussed in this review. Deep vein thrombosis can be effectively treated or prevented with nadroparin without any serious adverse events. Nadroparin 0.1?ml/10?kg sc once daily prevents thromboembolic complications in pregnant women with heart valve prostheses. Nadroparin is also effective in preventing foetal loss, through contributing to normal placental development and in decreasing the risk of premature delivery in pregnant women with antiphospholipid syndrome or women with herpes and antiphospholipid syndrome. These results demonstrate nadroparin is effective, easy to administer and associated with a low incidence of foetal and maternal complications. The use of nadroparin at a prophylactic dose of 0.3?ml (2850IU AXa, 95?IU/kg) (for high-risk patients, 0.3–0.6?ml) sc once daily, and a therapeutic dose of 0.1?ml/10kg (95?IU/kg) sc twice daily, is in line with the latest international guidelines of the American College of Chest Physicians.     

Use of the low-molecular-weight heparin nadroparin during pregnancy. A review

Antithrombotic therapy is often used during pregnancy for the treatment and prevention of venous thromboembolism, the prevention of systemic embolism in patients with heart valve prostheses and the prevention of foetal loss in patients with antiphospholipid syndrome. Low-molecular-weight heparins (LMWHs), including nadroparin, have largely replaced unfractionated heparin as the anticoagulant of choice. The use of the LMWH nadroparin in pregnant women at an increased risk of thromboembolism or foetal loss is discussed in this review. Deep vein thrombosis can be effectively treated or prevented with nadroparin without any serious adverse events. Nadroparin 0.1 ml/10 kg s.c. once daily prevents thromboembolic complications in pregnant women with heart valve prostheses. Nadroparin is also effective in preventing foetal loss, through contributing to normal placental development and in decreasing the risk of premature delivery in pregnant women with antiphospholipid syndrome or women with herpes and antiphospholipid syndrome. These results demonstrate nadroparin is effective, easy to administer and associated with a low incidence of foetal and maternal complications. The use of nadroparin at a prophylactic dose of 0.3 ml (2850 IU AXa, 95 IU/kg) (for high-risk patients, 0.3-0.6 ml) s.c. once daily, and a therapeutic dose of 0.1 ml/10 kg (95 IU/kg) s.c. twice daily, is in line with the latest international guidelines of the American College of Chest Physicans.     

Tinzaparin sodium: a low-molecular-weight heparin.

The chemistry, pharmacokinetics, pharmacodynamics, clinical efficacy, dosage and administration, adverse effects, and therapeutic role of tinzaparin are reviewed. Tinzaparin is a low-molecular-weight heparin (LMWH) with antithrombotic properties. It has FDA-approved labeling for use in the treatment of acute symptomatic deep-vein thrombosis (DVT) with or without pulmonary embolism (PE) when administered in conjunction with warfarin sodium. Tinzaparin works by inhibiting reactions that lead to the clotting of blood. The much-improved pharmacokinetics of tinzaparin compared with unfractionated heparin (UFH) are due to its lower affinity for heparin-binding proteins and endothelial cells, shorter fractionated heparin chain (which allows for better bioavailability), and unsaturable renal elimination. Clinical trials have demonstrated that tinzaparin is at least as safe and effective as UFH for the treatment of DVT. Tinzaparin may also be effective for unlabeled uses, such as prophylaxis of venous thromboembolism (VTE) after orthopedic, general, and abdominal surgery, although more data are needed to define the optimal dose for this indication. The recommended dosage of tinzaparin for the treatment of established DVT with or without PE is 175 anti-factor Xa IU per kilogram of body weight administered subcutaneously once daily for at least six days until the patient achieves adequate anticoagulation with warfarin. As with other LMWHs, the most common complication of tinzaparin therapy is bleeding. Tinzaparin offers an additional treatment option for VTE.     

Microparticles as a strategy for low-molecular-weight heparin delivery

The aims of this work were preparation and physical-chemical characterization of a microparticulate release system for delivery of enoxaparin sodium (ENX), a low-molecular-weight heparin, as a potential vehicle for optimization of deep venous thrombosis therapy. Microparticles (MPs) containing ENX were prepared from polylactide-co-glycolic acid [PLGA; (50:50)] by a double emulsification/solvent evaporation method. The preparation parameters, such as proportion ENX/PLGA, surfactant concentration, type, time, and speed of stirring, were evaluated. The encapsulation efficiency and yield process were determined and optimized, and the in vitro release profile was analysed at 35 days. The MPs showed a spherical shape with smooth and regular surfaces. The size distribution showed a unimodal profile with an average size of 2.0 ± 0.9 μ m. The low encapsulation efficiency (<30%), characteristic of hydrophilic macromolecules was improved, reaching 50.2% with a procedure yield of 71.3%. The in vitro profile of ENX release from the MPs was evaluated and showed pseudo-zero-order kinetics. This indicated that diffusion was the main drug release mechanism.     

Standardisation of unfractionated and low-molecular-weight heparin

Unfractionated and low-molecular-weight heparins are complex biologicals. Standardisation and global harmonisation of units and methods of measurement are essential for safety and efficacy of this important class of anticoagulants. This chapter describes the traceability of the international unit and current status of the relationship between the international and pharmacopoeial standards, together with a review on current pharmacopoeial assay methods.     

Use of low-molecular-weight heparin to bridge therapy in obese patients and in patients with renal dysfunction

OBJECTIVE: To recommend strategies to bridge therapy with low-molecular-weight heparin (LMWH) in obese patients and in patients with renal dysfunction. METHODS: A MEDLINE search was performed of the literature from January 1966-November 2005. Published material dealing with bridging of anticoagulation therapy or short-term use of LMWH therapy in patients with renal dysfunction or obesity was reviewed. The manufacturers of enoxaparin, dalteparin, and tinzaparin were contacted for the references used to determine dosing recommendations. RESULTS: Although LMWH has been commonly used to bridge therapy, our search revealed no trials that specifically examined LMWH bridge therapy in obese patients or in patients with renal dysfunction. However, nine trials using LMWH in obese patients and 14 trials using LMWH in patients with renal dysfunction were identified. When compared with normal-weight individuals, obese patients receiving enoxaparin and dalteparin based on total body weight did not demonstrate higher hemorrhage rates or antifactor Xa levels. Subtherapeutic antifactor Xa levels were more common with once-daily dosing of enoxaparin than with dosing every 12 hours. Enoxaparin accumulates in patients with a creatinine clearance of 30 ml/minute or less; in this population, enoxaparin dosage adjustments have been attempted. Tinzaparin does not accumulate in patients with a creatinine clearance of 20 ml/minute or greater after at least 10 days of dosing. CONCLUSION: Obese patients, weighing 90-150 kg, receiving LMWH for bridge therapy should receive dosages based on total body weight. Unfractionated heparin is recommended in patients weighing more than 150 kg; however, if LMWH is used, antifactor Xa levels should be monitored. Bridging with enoxaparin should be limited to patients with a creatinine clearance greater than 30 ml/minute. The use of enoxaparin 1 mg/kg once/day for patients with a creatinine clearance of 30 ml/minute or less is not recommended for anticoagulation bridge therapy. Tinzaparin may be considered for cross-coverage of high-risk patients with recent or recurrent venous thromboembolism who have a creatinine clearance of at least 20 ml/minute.     

Antidepressant prescribing patterns: a comparison of blacks and whites in a medicaid population

OBJECTIVE: This paper reports results stemming from a retrospective inquiry designed to determine the prescribing pattern of tricyclic antidepressants (TCAs) relative to selective serotonin reuptake inhibitors (SSRIs), and the subsequent effect on regimen adherence among African American (Black) and White beneficiaries enrolled in the state of South Carolina Medicaid programme. PATIENTS AND METHODS: Adjudicated patient-level paid-claims data for the time-frame 1 January 1990 to 31 December 1994 were abstracted resulting in a statewide cohort of 8596 ambulatory beneficiaries, 18 to 64 years of age, without receipt of antidepressant pharmacotherapy in the 1-year time-frame prior to initiating a regimen of either a TCA or SSRI, and remaining Medicaid-eligible for 1 year thereafter. RESULTS: Black race [odds ratio (OR) = 1.56, 95% confidence interval (CI) = 1.43 to 1.70], age 40 to 64 years (OR = 1.15, 95% CI = 1.06 to 1.26), and male gender (OR = 1.27, 95% CI = 1.14 to 1.41) were significant predictors of initiating antidepressant pharmacotherapy with a TCA. Relative to Whites, Blacks were found to be less likely to have obtained at least a 3-month (>/=90 days) supply of a TCA (22.1 vs 31.7%) or an SSRI (30.7 vs 36.1%), or to have obtained a 6-month (>/=180 days) supply of a TCA (6.4 vs 10.9%) or an SSRI (8.1 vs 13.2%). CONCLUSION: Further prospective research is required to discern the reasons for observed differences in prescribing and adherence patterns for antidepressant pharmacotherapy by age, gender and race, and to foster the development of educational programming designed to ensure clinically rational and equitable access to pharmacotherapeutic innovation.     

低分子肝素治疗脓毒症的效果探讨

目的分析低分子肝素治疗脓毒症的临床效果。方法80例脓毒症患者,采取随机数字表法分为对照组与观察组,每组40例。对照组给予常规治疗,观察组在对照组基础上加用低分子肝素治疗。对比两组治疗前后凝血功能指标[凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、血小板计数(PLT)、C反应蛋白(CRP)]、急性生理学及慢性健康状况评分系统Ⅱ(APACHEⅡ)评分、随访28 d生存率及不良反应发生率。结果治疗后第7天,观察组PT、APTT短于对照组、PLT高于对照组、CRP水平低于对照组,差异有统计学意义(P<0.05)。治疗后第7天,观察组APACHEⅡ评分(12.60±4.36)分低于对照组的(18.75±9.11)分,差异有统计学意义(P<0.05)。观察组随访28 d生存率95.00%高于对照组的77.50%,差异有统计学意义(P<0.05)。两组不良反应发生率对比差异无统计学意义(P>0.05)。结论低分子肝素治疗脓毒症可有效改善凝血功能指标,患者生存率较高,同时未增加不良反应发生率,保证了用药的安全性。     

低分子肝素在治疗原因不明性复发性流产中的应用

目的探讨低分子肝素治疗原因不明性复发性流产的疗效和安全性。方法选取57例未查明原因的复发性流产患者,将其分为3组。治疗组25例,皮下注射低分子肝素钙4 100 IU,q12 h,至妊娠17周后改为4 100 IU,qd,停药时间视胎儿成熟情况,一般为孕34³6周;对照组25例,口服泼尼松5 mg,qd+阿司匹林75 mg,qd,直至妊娠结束;空白组7例,常规给予黄体酮、人绒毛膜促性腺激素、维生素E、叶酸治疗。观察3组的妊娠结局与活产率。结果治疗组足月产22例,早产2例,活产率为96%;对照组足月产9例,早产6例,活产率为60%;空白组7例全部流产,组间比较有非常显著差异(P<0.01)。所有病例均未发生严重不良反应。结论低分子肝素治疗原因不明性复发性流产的疗效显著,可大幅提高妊娠成功率,且安全性较好。     

国产低分子肝素对阿霉素肾病大鼠尿蛋白的影响

目的探讨国产低分子肝素海普宁是否具有降低大鼠阿霉素肾病蛋白尿,减轻足突细胞损害的作用。方法健康雄性SD大鼠尾静脉一次性注射阿霉素6.5mg/kg建立肾病模型,按给药方法分3组:对照组(5只):静脉注射生理盐水的同时,腹腔注射生理盐水,每日1次,按2mL/kg给予;肾病组(25只):静脉注射阿霉素的同时,腹腔注射生理盐水,每日1次,按2mL/kg给予;治疗组(25只):静脉注射阿霉素的同时,腹腔注射海普宁,每日1次,按200IU/kg给予(海普宁按100IU/mL溶解)。各组均于0d、3d、7d、14d、21d、28d收集24h尿液,对照组于第28天,肾病组及治疗组于收集尿液结束当天各取大鼠5只,留取肾组织及血液标本进行检测。结果与对照组相比,肾病组0d、3d尿蛋白无增加(P>0.05),从第7天开始增加(P<0.05),随时间延长逐渐增多,21d、28d达高峰,28d与21d相比,尿蛋白稍增加,但无统计学意义(P>0.05);治疗组尿蛋白演变过程与肾病组相似,亦第7天开始增加(P<0.05),第21天、28天达高峰,但与等天数肾病组相比,尿蛋白明显减少(P<0.05)。与对照组相比,肾病组血清ALB于第7天开始下降(P<0.05),第14d天达最低值,第21天、第28天较14d稍升高,但仍处低水平状态,无统计学差异(P>0.05);治疗组ALB下降过程与肾病组相近,但比同等天数肾病组及治疗组下降的少(P<0.05)。肾病组TG、ChoL第14天开始升高(P<0.05),第21天达高峰,第28天较21d下降(P<0.05);治疗组与同等天数肾病组相比增高较少(P<0.05)。光镜:肾病组:于第7天可见蛋白管型,14d较易见到蛋白管型,第21天、28天肾小球出现轻度系膜增生性改变,可见大量蛋白管型及间质纤维化;治疗组与肾病组相比,蛋白管型明显减少,无间质纤维化。电镜:肾病组:于第3天可见到足突融合,第14天最明显,第21天、28天出现足突细胞变形,体积变大,胞质中微丝增多,毛细血管袢闭塞、充血,大量红细胞填塞,内皮细胞孔消失,基底膜正常;与肾病组相比,治疗组足突细胞融合明显减轻,无毛细血管袢闭塞及足突细胞变形和体积增大。结论国产低分子肝素海普宁具有降低大鼠阿霉素肾病蛋白尿的作用,而且这种作用可能通过稳定足突细胞结构实现。     

The cytoprotective role of a low-molecular-weight heparin fragment studied in an experimental model of glomerulotoxicity

Abnormal glomerular glycosaminoglycan metabolism is involved in the onset of the morphological and functional aberrations of glomerulopathies. In the present study, a heparin derivative, low-molecular-weight heparin, was tested for its ability to afford renoprotection in an established model of experimental glomerulopathy. Two groups of male albino rats of the Wistar strain (140 +/- 10 g) received a single intravenous injection of adriamycin (7.5 mg/kg) to induce glomerulopathy, and one of them received low-molecular-weight heparin (Certoparin Sodium, Troparin; 300 microg/day/rat s.c.) treatment, commencing on day 8, for a week. Urinary protein/creatinine ratio, serum albumin, urea, uric acid and creatinine clearance were evaluated. Renal cell injury was assessed in terms of renal tissue lactate dehydrogenase, aminotransferases (aspartate and alanine transaminases) and alkaline phosphatase activities, as well as renal antioxidant status (superoxide dismutase, catalase and glutathione peroxidase, reduced glutathione, vitamins E and C). The kidney tissue was subjected to histopathologic examination. Low-molecular-weight heparin significantly reduced proteinuria and improved creatinine clearance and serum albumin levels in the rats with glomerulopathy. The significant rise in serum uric acid in the rats with glomerulopathy was reversed by low-molecular-weight heparin. Altered tissue enzyme activities in response to injury, oxidative stress challenged renal antioxidant system and abnormal renal histology were observed in the untreated nephrotic rats, while low-molecular-weight heparin treatment protected the nephrotic rats against these changes. Thus, in this study, low-molecular-weight heparin was evaluated for its role in combating glomerular injury, on the basis of some salient biochemical parameters, oxidative injury indices and histologic picture. The ability of low-molecular-weight heparin to restore glomerular anatamo-functional features in this nephrotoxic condition illuminates its multi-faceted renoprotective role.     

Prescribing of antipsychotic medication in a medicaid population: use of polytherapy and off-label dosages

OBJECTIVES: To describe the use of atypical antipsychotic medications in a Medicaid-enrolled population composed primarily of elderly and disabled patients. Our analyses focused upon the frequency of use of polytherapy with multiple antipsychotic medications and the prescribing of off-label dosages. METHODS: We conducted a cross-sectional retrospective analysis of oral antipsychotic medication use, as prescribed for this population in 2003. The unit of analysis was the patient. We determined the prevalence of use of each type of antipsychotic medication according to gender and age group and determined the extent of use of combination therapies with multiple oral antipsychotic medications. Using the dosage ranges described in the product labeling, we identified the percentage of patients prescribed in-range dosages, overall and for each atypical antipsychotic medication studied. Those identified as receiving out-of-range (off-label) dosages were further stratified by gender and age group. The statistical significance of differences between these proportions was assessed using the chi-square test. RESULTS: Of the 8,616 patients meeting our inclusion criteria, 7,748 (90%) received monotherapy with an oral antipsychotic medication and 868 patients (10%) received polytherapy with multiple oral antipsychotic medications. Approximately 2 of 3 patients receiving atypical antipsychotic medications were prescribed a dosage that was within the range recommended in the product labeling. Dosages lower than recommended in the product labeling were prescribed for 27% of patients receiving atypical antipsychotics, while 6% of patients received an above-range dosage. The frequency of patients receiving in-range dosages varied substantially among medications. Younger patients and male patients were more frequently prescribed above-range dosages while older patients and female patients were more frequently prescribed below-range dosages of these medications (P<0.001 for both findings). CONCLUSION: In this subpopulation of Medicaid enrollees who were prescribed antipsychotic medications, we found a 10% incidence of use of antipsychotic polytherapy and a 33% incidence of prescribing of dosages outside the range listed in the product labeling. These findings suggest that physicians commonly prescribe antipsychotic medications in a manner that differs from the recommendations described in the prescribing information. The off-label use of atypical antipsychotic medications raises important questions regarding the purpose and applicability of the product labeling and the role and ability of the pharmacist to provide information regarding the risks and benefits of therapy as commonly prescribed.     

几种不同实验设计在低分子肝素活性测定中的比较

目的:对低分子肝素(LMWH)生物活性测定中几种不同的实验设计进行比较。方法:对LMWH生物活性测定采用酶促反应的分光光度法,进行了量反应平行线实验设计中4.4法与4.3法、3.4法、3.3法的比较。结果:量反应平行线实验设计中4.4法与4.3法、3.4法、3.3法结果相似,其差异无统计学意义(P>0.05)。结论:采用酶促反应的分光光度法对LMWH的效价测定,应采用量反应平行线法实验设计;在符合标准规定前提下,4.4法与4.3法、3.4法、3.3法不同剂量组实验设计都可应用。