Effects of a new lipid-based drug delivery system on the absorption of low molecular weight heparin (Fragmin) through monolayers of human intestinal epithelial Caco-2 cells and after rectal administration to rabbits

The effects of a novel drug delivery system, consisting of a lipid matrix and a drug, on the permeability, morphology and drug transport across monolayers of human intestinal epithelial cells were investigated. A 1:3 mixture (w/w) of chromatographically purified soybean phosphatidylcholine and medium chain monoacylglycerol was chosen as lipid matrix (PC:MG) and mannitol (mol. wt. 182) and Fragmin (low molecular weight heparin; mean mol. wt. 5000) were chosen as hydrophilic model drugs. PC:MG had an immediate and dose-dependent effect on the permeability of the cell monolayers, and on epithelial morphology (as seen under transmission electron microscopy). PC:MG (4–10 mM) dose-dependently enhanced the transport rate of mannitol and Fragmin, causing an approximately 10-fold increase in the transport rate of Fragmin at concentrations of 6–8 mM. The increase was independent of the dose of Fragmin and was reversible in concentrations up to 6 mM. At higher doses, clear effects on the apical cell membranes were observed although the tight junctions remained intact. PC:MG also enhanced Fragmin absorption in vivo after rectal administration to New Zealand White rabbits. Co-administration of Fragmin with PC:MG (7 mM) resulted in an increase in the relative bioavailability (compared with s.c. administration) from < 1% (without PC:MG) to 21 ± 12%. A maximal increase in relative bioavailability to 90 ± 19% was obtained at a PC:MG concentration of 35 mM. Thus, PC:MG functions as an absorption enhancer both in the cell monolayer model and in vivo, in the same concentration range. The results indicate that as well as providing mechanistic information, studies of absorption enhancers in Caco-2 monolayers also provide information on suitable dosage regimens for in vivo studies.     

国产与进口低分子量肝素钠注射液治疗不稳定性心绞痛的比较

目的：比较国产与进口低分子量肝素钠注射液（LMWH）在治疗不稳定性心绞痛方面的临床疗效。方法：治疗组与对照组各30例,腹壁皮下脂肪内注射,剂量为100抗XaIU／（kg·12h）,连续7d。结果：国产LMWH治疗不稳定性心绞痛显效率及有效率分别为33．3％和83．3％,与进口低分子量肝素钠注射液（法安明）的30．0％和80．0％无显著差异。结论：国产LMWH对不稳定性心绞痛的治疗安全有效,且与进口同类产品相一致。     

Relative contribution of phosphatidylcholine and monoglyceride to absorption enhancement of low molecular weight heparin (Fragmin) by a new lipid-based drug delivery system in monolayers of human intestinal epithelial Caco-2 cells and after rectal administration to rabbits

The relative contribution of the constituents of a novel drug delivery system based on a lipid matrix to its absorption-enhancing properties was studied in monolayers of human intestinal epithelial Caco-2 cells and after rectal administration to New Zealand White rabbits. Chromatographically purified soybean phosphatidylcholine and medium chain monoacylglycerol were chosen as lipid matrix (PC:MG). Five different compositions of PC:MG ranging from pure MG through 1:3, 1:1 and 3:1 (w/w) mixtures to pure PC were investigated for their effects on cell toxicity, epithelial permeability and transport of low molecular weight heparin (Fragmin) and mannitol in Caco-2 monolayers. The results indicate that MG enhances and PC inhibits all of these effects in the monolayers. Similar results were obtained after rectal administration to New Zealand White rabbits, suggesting that the effects of PC:MG can be controlled in vivo by varying the relative proportions of MG and PC in the mixtures.     

Heparin-induced thrombocytopenia: cross-reactivity between standard heparin, low molecular weight heparin, dalteparin (Fragmin) and heparinoid, danaparoid (Orgaran)

Summary. The incidence of cross-reactivity between unfractionated heparin and LMWH, fragmin, in patients with HIT is significantly lower (6/15, 40%) than hitherto reported in the literature. 7/9 patients with a negative cross-reactivity test were treated with dalteparin sodium (Fragmin) without any untoward events.     

肾乐和法安明防治大鼠肾小球硬化机制的探讨

目的：观察肾乐和法安明（达肝素钠）对5/6肾切除大鼠残肾组织中Ⅳ型胶原和基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9)/组织金属蛋白梅抑制物-1（tissue inhibitors of metalloproteinase-1,TIMP-1）基因表达的影响，旨在探讨两种药物对细胞外基质降解酶系MMP-9/TIMP-1的影响，从而进一步提示其减轻肾小球硬化的机制。方法：用5/6肾切除的方法诱导大鼠局灶节段性肾小球硬化模型并给予肾乐（4g·kg^-1·d^-1)及法安明（1000IU·kg^-1·d^-1）治疗20周，观察大鼠血压、蛋白尿、血肌肝、血脂和残余肾组织的病理改变程度，以及残肾组织Ⅳ型胶原、MMP-9的沉积和TIMP-1基因的表达。结果：肾乐及法安明治疗组显著降低5/6肾切除大鼠血压、蛋白尿、血肌肝、血脂和减轻肾组织的病理改变程度，并且显著减少残肾组织中Ⅳ型胶原、MMP-9沉积以及下调Ⅳ型胶原、MMP-9/TIMP-1的基因表达；定量分析结果显示，与5/6Nx组比较，肾乐组和法安明组MMP-9的表达量分析下调了30.0%、28.5%TIMP-1的表达量分别下调了59.3%、55.0%。结论：肾乐和法安明可能通过调节MMP-9/TIMP-1的基因表达，减轻肾小球重塑过程中细胞外基质的异常代谢和积聚，促进了细胞外基质的降解，这可能是肾乐和法安明防治肾小球硬化的重要作用机制之一。     

The Adequacy of Fragmin as a Single Bolus Dose with Reused Dialyzers

Abstract: Thirty-four hemodialysis patients were studied in a crossover fashion to compare the effectiveness of bolus-dose Fragmin (a low molecular weight heparin) with regular heparin usage in hemodialysis. For each anticoagulant, 3 dialyzes were studied for each patient; the first sessions involved a new dialyzer, and the subsequent sessions involved dialyzers reprocessed with peracetic acid. To assess the effectiveness of the anticoagulation regimens, the following were measured: the dialyzer fiber bundle volume and the instantaneous dialyzer clearances for urea (1 h into the second session). In addition, factor Xa levels were measured in 5 patients during the first and second sessions at 0 min, 30 min, and 4 h. Fiber bundle volumes were (in ml) 75.4 ± 8.8, 73.0 ± 8.9, and 73.5 ± 7.6 on first, second, and third uses with Fragmin (p = ns); and 77.8 ± 9.0, 73.4 ± 8.1, and 73.8 ± 8.1 with heparin (p < 0.001 second and third vs. first). Thus, there were no significant differences between Fragmin and heparin. Instantaneous dialyzer clearances were 165.8 ± 12.6ml/min with Fragmin and 163.8 ± 9.8 with heparin (p = ns). Factor Xa levels were 0 predialysis, 0.81 ± 0.17 U/ml at 30 min on first use, and 0.92 ± 0.09 U/ml on second use (p = ns); they were 0.51 ± 0.21 U/ml at 4 h on first use and 0.61 ± 0.16 U/ml on second use (p = ns). Thus, bolus-dose Fragmin provided similar results to constant infusion heparin and is not deleteriously influenced by reprocessing dialyzers with peracetic acid.     

Measurement of whole blood factor Xa-activated clotting time during hemodialysis with low-molecular-weight heparin

Purpose To determine whole blood factor Xa-activated clotting time (XaACT), a test for monitoring low-molecular-weight heparins (LMWHs). Methods Blood was obtained from six healthy volunteers. Dalteparin, a LMWH, was mixed with the blood to concentrations of 0,05 and 1.0IU·ml⁻¹. XaACT, activated clotting time (ACT), and activated partial thromboplastin time (APTT) were measured at each dalteparin concentration. XaACT of blood from the outflow and inflow sides of the blood circuit in seven hemodialysis patients was measured before and after bolus administration of 1000 IU of dalteparin, followed by continuous infusion at a rate of 500IU·h⁻¹. Results XaACT, ACT, and APTT in dalteparin-containing blood from volunteers were correlated with dalteparin concentration (y=312.8x+86.4;r ²=0.88;P<0.001,y=41.8x +113.5;r ²=0.83;P<0.001, andy=59.5x+38.8;r ²=0.80;P<0.001, respectively). The regression slope of XaACT was steeper than those of ACT and APTT (P<0.001). In hemodialysis patients, dalteparin increased XaACT on the outflow and inflow sides of the circuit (P<0.001,P<0.05, respectively). Conclusion The measurement of XaACT can be employed to monitor LMWHs in clinical settings.     

低分子肝素钠治疗急性脑梗死的临床分析

目的探讨低分子肝素钠(法安明)在急性脑梗死(AIS)治疗中的有效性和安全性.方法对入选的98例AIS病人随机对照研究,法安明组56例,对照组42例.根据CSS对两组AIS病人治疗前后的神经功能状况进行分析比较,同时对比观察两组病人出血性合并症及病死率发生情况.结果法安明组总体疗效优于对照组(P＜0.05).在椎基底动脉(VBA)系统中法安明组优于对照组,疗效有显著差异(P＜0.025).在安全性方面,法安明与出血性合并症及病死率与对照组无显著差异.结论法安明治疗VBA系统AIS安全、有效.