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T. KNUDSEN A. T. KRISTENSEN T. C. NICHOLS H. AGERSØ A. L. JENSEN M. KJALKE M. EZBAN M. TRANHOLM 《Haemophilia》2011,17(6):962-970
Summary. Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti‐human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over‐expressed by gene transfer in haemophilia dogs, has provided long‐term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg?1 to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half‐life (FVIIa activity: 1.2–1.8 h; FVIIa antigen 2.8–3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin‐activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans. 相似文献
94.
目的:探讨华夏小葱制剂对大鼠脂肪肝的防治作用及其机制。方法:SD大鼠分为空白对照组,模型对照组,华夏小葱制剂低、中、高剂量组,东宝肝泰片组共6个组。空白对照组大鼠用普通饮食及普通水喂养;其他组用高脂饮食及酒精水喂养,并且每周一次行后肢皮下注射四氯化碳色拉油溶液建立大鼠脂肪肝模型。华夏小葱制剂低、中、高剂量组及东宝肝泰片组大鼠分别给予相应剂量的华夏小葱制剂或东宝肝泰片混悬液。8周后处死各组大鼠。采用全自动生化分析仪测定血浆中总胆固醇(TC)、甘油三酯(TG)含量,一氧化氮(NO),一氧化氮合酶(NOS),RT-PCR法测血管内皮生长因子(VEGF)mRNA的含量。结果:大鼠血浆TC、TG值,肝组织NO、NOS值及VEGF值各组比较,模型对照组显著高于空白对照组(P〈0.01),华夏小葱制剂低、中、高剂量组及东宝肝泰片组均显著低于模型对照组(P〈0.05或P〈0.01)。结论:华夏小葱制剂具有降低TG、TC,改善活性氮的作用,其治疗脂肪肝的机制可能与减少细胞因子损伤有关。 相似文献
95.
目的:观察小麦胚芽油(wheat germ oil,WGO)对动脉粥样硬化(atherosclerosis,AS)大鼠的治疗效果,并探讨其抗 AS 的可能作用机制。方法连续高脂乳剂灌胃4周,制作 AS 大鼠模型,分别给予各组大鼠连续灌胃不同剂量 WGO 8周;HE 染色光镜下观察大鼠主动脉弓病理形态的改变;酶联免疫吸附试验(ELISA)法检测各组大鼠血清中前列环素(Prostacyclin 2, PGI2)、血栓素 A2(Thromboxane 2,TXA2)及内皮素-1(Endothelin-1,ET-1)的含量。结果2.0 g·kg -1的 WGO 能明显改善 AS大鼠主动脉弓的病理状态,基本恢复正常状态;与模型组比较,1.0、2.0 g·kg -1 WGO 均可显著提高 AS 大鼠血清中 PGI2含量,明显降低 TXA2、ET-1水平(P <0.05)。结论WGO 能明显改善 AS 大鼠的动脉粥样硬化状态。其作用机制可能为小麦胚芽油具有良好的调节 PGI2、TXA2平衡,抑制血栓形成,修复内皮损伤以及较强的抗氧化作用。 相似文献
96.
With the growing integration of non–vitamin K antagonist oral anticoagulants (NOACs) into clinical practice, questions have arisen regarding their use in special populations, including groups that may have been underrepresented in clinical trials. Patients with renal impairment, particularly in the lower echelons of renal function, are one such group. In an effort to elucidate the current evidence regarding the use of NOACs in patients with renal impairment, a systematic assessment of the literature was performed. The MEDLINE database was interrogated for studies and analyses evaluating the influence of renal function on the pharmacokinetics, pharmacodynamics, efficacy, and safety of NOACs published from January 1, 2000, through August 2, 2017. The 82 relevant publications retrieved highlight the diversity in the NOAC class regarding the impact of renal function on drug clearance, drug exposures, and clinical trial outcomes. In several large clinical trials, subgroup analyses revealed no significant differences when patients were stratified by creatinine clearance as a measure of renal function. Efficacy findings, in particular, were largely aligned with the overall population in the included studies. However, relative risks of bleeding were shown to vary, sometimes driven by changes in bleeding event rates in the comparator arm (eg, warfarin, enoxaparin). With few exceptions, minimal influence of mild renal impairment was observed on the relative efficacy and safety of NOACs. Taken together, the evidence suggests that the presence of renal impairment merits careful consideration of anticoagulant choice but should not deter physicians from appropriate use of NOACs. 相似文献
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98.
Gregory Y. H. Lip Lars H. Rasmussen S. Bertil Olsson Eva Jensen Bengt Hamrén Ulf G. Eriksson Karin W?hlander 《British journal of clinical pharmacology》2015,80(6):1362-1373
AimsAZD0837 is a novel oral anticoagulant investigated in clinical studies for stroke prevention in patients with atrial fibrillation (AF). It is bioconverted to its active form, AR‐H067637, a potent, specific and reversible thrombin inhibitor. The effects on coagulation biomarkers were correlated with the pharmacokinetic (PK) exposure of AR‐H067637 to guide selection of the effective dose regimen for a confirmatory efficacy study in AF patients.MethodsBlood samples were obtained from 601 AF patients randomized to one of four doses of AZD0837 (blinded treatment) or dose‐adjusted vitamin K antagonists (VKA, open treatment) for 3–9 months. A pharmacodynamic model was developed to describe the time course of the AR‐H067637 exposure dependent effects and the effect of VKA on fibrin D‐dimer. The thrombin generation measured ex vivo in venous plasma was also investigated.ResultsThe PK exposure of AR‐H067637 was stable with an interindividual variability of 33% and no or minor influence of patient demographics or comedications. For AZD0837, D‐dimer levels decreased with more rapid onset than for VKA. The decrease in D‐dimer levels correlated with steady‐state plasma concentrations (C
ss) of AR‐H067637, with a maximum decrease of baseline D‐dimer levels estimated to approximately 60% for both AZD0837 and VKA therapy. The effect on thrombin generation correlated closely with the plasma concentration of AR‐H067637.ConclusionsThe effects on thrombin generation and fibrin D‐dimer levels correlated with the plasma concentration of its active form and provided comparable effects to well‐controlled VKA therapy at an exposure at least corresponding to the 300 mg once daily dose of AZD0837. 相似文献
99.
Azrin N Abd Rahman Susan E Tett Halim A Abdul Gafor Brett C McWhinney Christine E Staatz 《British journal of clinical pharmacology》2015,80(5):1064-1075
Aims
The aim was to examine relationships between total and unbound mycophenolic acid (MPA) and prednisolone exposure and clinical outcomes in patients with lupus nephritis.Methods
Six blood samples were drawn pre- and at 1, 2, 4, 6 and 8 h post-dose and total and unbound MPA and prednisolone pre-dose (C0), maximum concentration (Cmax) and area under the concentration–time curve (AUC) were determined using non-compartmental analysis in 25 patients. The analyses evaluated drug exposures in relation to treatment response since starting MPA and drug-related adverse events.Results
Dose-normalized AUC varied 10-, 8-, 7- and 19-fold for total MPA, unbound MPA, total prednisolone and unbound prednisolone, respectively. Median values (95% CI) of total MPA AUC(0,8 h) (21.5 [15.0, 42.0] vs. 11.2 [4.8, 30.0] mg l–1 h, P= 0.048) and Cmax (11.9 [6.7, 26.3] vs. 6.1 [1.6, 9.2] mg l–1, P = 0.016) were significantly higher in responders than non-responders. Anaemia was significantly associated with higher total (37.8 [14.1, 77.5] vs. 18.5 [11.7, 32.7] mg l–1 h, P = 0.038) and unbound MPA AUC(0,12 h) (751 [214, 830] vs. 227 [151, 389] mg l–1 h, P = 0.004). Unbound prednisolone AUC(0,24 h) was significantly higher in patients with Cushingoid appearance (unbound: 1372 [1242, 1774] vs. 846 [528, 1049] nmol l–1 h, P = 0.019) than in those without. Poorer treatment response was observed in patients with lowest tertile exposure to both total MPA and prednisolone as compared with patients with middle and higher tertile exposure (17% vs. 74%, P = 0.023).Conclusions
This study suggests a potential role for therapeutic drug monitoring in individualizing immunosuppressant therapy in patients with lupus nephritis. 相似文献100.
目的了解神经外科术后患者静脉输注替考拉宁时脑脊液药物浓度,探讨神经外科手术破坏血脑屏障后是否可增加脑脊液药物浓度,以及药物持续泵入对脑脊液药物浓度的影响。方法选择神经外科术后留置术区/脑室引流管的患者,分为常规给药组(替考拉宁400 mg,30 min泵入,1次/12 h重复给药)和持续给药组(替考拉宁400 mg,30 min泵入,再以200 mg,1次/6 h持续泵入),于给药后相应时间点采集脑脊液标本检测替考拉宁浓度。结果常规给药组脑脊液替考拉宁浓度泵入后即刻浓度为(0.004±0.0123)mg/L,泵入后1 h达峰值(0.712±1.028)mg/L,后逐渐下降,泵入后12、18、24 h分别为(0.254±0.222)、(0.173±0.152)、(0.355±0.207)mg/L。持续给药组脑脊液替考拉宁泵入后即刻浓度为(0.017±0.020)mg/L,4 h后达峰值(0.587±0.255)mg/L,泵入后6、12、18、24 h分别为(0.429±0.416)、(0.325±0.254)、(0.476±0.686)、(0.318±0.464)mg/L,6 h后药物浓度相对稳定,介于(0.318±0.464)~(0.476±0.686)mg/L。常规给药组、持续给药组的AUC0—24 h分别为5.590 mg/L·h、9.082 mg/L·h。两组患者仅峰值附近区域替考拉宁浓度达到凝固酶阴性葡萄球菌(CNS)MIC50,但其浓度高于CNS MIC50的时间占整个给药时间的比例远小于50%;两组患者脑脊液替考拉宁浓度均未能达到金黄色葡萄球菌MIC50。结论持续输注替考拉宁后,患者脑脊液药物浓度较常规给药组有所增加,但仍未能达所要求的MIC;结合血药浓度的实验,血液浓度增高有利于脑脊液药物浓度增加,可考虑适当增加剂量以达到临床治疗目的。 相似文献