Thorough cardiac QTc interval conductance assessment of a novel oral tranexamic acid treatment for heavy menstrual bleeding

Objective: To assess the effect of a novel oral tranexamic acid treatment on cardiac repolarization in a randomized, double-blind, positive- and placebo-controlled, four-treatment single-dose cross-over inpatient study.

Methods: QTc interval and drug exposure relationship analyses were performed using triplicate digital electrocardiographs (ECGs) collected from 12-lead Holter monitors from healthy females (n = 48) with plasma drug concentrations and pharmacokinetics simultaneously evaluated over 24 h post-dose. Therapeutic (1.3 g) and supratherapeutic (3.9 g) tranexamic acid modified immediate-release doses, a positive-control 0.4 g moxifloxacin dose, and a placebo-control were administered at each period.

Results: All post-dose, time-matched, baseline-adjusted, mean QTcF (Fridericia's heart rate correction, QT/RR^1/3) treatment-placebo differences (ΔΔQTcF), were less than 5 milliseconds (ms) for the 1.3 g and 3.9 g tranexamic acid doses. Upper limits of the 95% confidence interval (CI) for all tranexamic acid-placebo ΔΔQTcF doses were < 10 ms for all time points. Lower limits of the 95% CI for the positive-control (moxifloxacin-placebo) ΔΔQTcF were > 5 ms at multiple time points demonstrating assay sensitivity. No correlation between tranexamic acid plasma concentrations and adjusted QTc intervals was observed. A positive linear relationship was observed for moxifloxacin (p < 0.01).

Conclusion: Cardiac repolarization is not influenced by tranexamic acid at the doses studied.     

Retrospective analysis of variation in heavy menstrual bleeding treatments by age and underlying cause

Abstract

Objective:

To describe treatment patterns associated with heavy menstrual bleeding (HMB) in US practice.     

氨甲环酸治疗月经过多的研究进展

月经过多严重影响患者健康及正常生活,可致缺铁性贫血和生活质量下降。氨甲环酸是一种抗纤溶蛋白溶解剂,通过可逆性阻断血纤维蛋白溶酶原分子上的赖氨酸结合位点,发挥抗纤维蛋白溶解的作用。氨甲环酸主要通过肾脏消除,胃肠道内的食物不影响其药动学性质。与安慰剂、非甾体抗炎药、周期性黄体期口服孕激素或酚磺乙胺相比,氨甲环酸能更为有效地减少月经失血,安全性好。     

Tranexamic acid in gynecologic surgery

Abstract

Objective: To review the mechanism of action, pharmacology, dosing, and complications of tranexamic acid (TXA) and consolidate current evidence for TXA in gynecologic surgery.

Methods: A literature search of PubMed, Ovid (MEDLINE), Google Scholar, and Elsevier was performed, in addition to a targeted search of cited references involving TXA and gynecologic surgery. Preference was given to systematic reviews and randomized control trials (RCTs).

Results: TXA reversibly binds to plasminogen, preventing clot degradation. RCTs on hysterectomy, myomectomy, cervical conisation, hysteroscopy, and surgery for cervical and ovarian cancer were identified, as were case reports on TXA use for ectopic pregnancy. During hysterectomy, TXA reduces blood loss (two RCTs, n?=?432, mean difference –66.0?mL and 180?mL), blood transfusion (1 RCT, n?=?100, 12% vs. 42%, p?<?.00001). For myomectomy, a systematic review and meta-analysis showed a statistically significant decrease in blood loss with TXA (two RCTs, mean difference –213.1?mL, 95% CI: –242.4?mL to –183.7?mL). Following cervical conisation, TXA decreased the risk of delayed hemorrhage (four RCTs, RR 0.23, 95% CI: 0.11–0.50). A single RCT for cervical and ovarian cancer surgery demonstrated a decrease mean blood loss of 120?mL–135?mL and 210?mL, respectively, and fewer blood transfusions for the latter (OR 0.44, upper 95% CI: 0.97, p?=?.02). Less robust data suggest a possible benefit from TXA during hysteroscopy and surgery for ectopic pregnancies. Most commonly, 1?g of intravenous TXA is given intraoperatively.

Conclusion: TXA is a safe adjunct that can be considered in a variety of gynecologic surgeries to decrease blood loss and risk of blood transfusion.     

Management of heavy menstrual bleeding in general practice

Abstract

Background:

Heavy menstrual bleeding (HMB) is a common symptom that leads women to seek medical treatment. Sources of HMB are variable; patients may present with obvious uterine pathology, systemic disease, or even localized hemostatic dysregulation that defies clinical measurement. Whereas surgical intervention even in the absence of overt pathology had historically been the most common route of treatment for HMB, an expanding therapeutic armamentarium provides greater options and the possibility of maintaining fertility in affected women.     

氨甲环酸对冠状动脉旁路移植术后出血疗效观察

目的：观察冠状动脉旁路移植术（coronary artery bypass graft,CABG）后应用氨甲环酸（tranexamic acid,TA）对术后出血的治疗效果。方法：选择2006年6月～2009年10月在本院接受CABG的60例患者,将其随机分为氨甲环酸组（31例）和对照组（29例）,在CABG术前和术中分别静脉注射氨甲环酸和等量的0.9%氯化钠溶液,观察TA在CABG后24h对总失血量和输血量的影响及术前和术后3h D-dimer水平的变化。结果：CABG术后24h氨甲环酸组的总失血量（450±205）ml显著少于对照组（863±343）ml,且术中输血量TA组显著少于对照组。术后对照组的血浆D-dimer水平显著增加,而TA组的D-dimer水平无显著变化。结论：与对照组相比,氨甲环酸可以发挥抗纤溶作用,并能够有效地降低CABG术后出血。     

荟萃分析氨甲环酸治疗特发性月经过多的疗效

目的系统评价氨甲环酸治疗特发性月经过多文献的质量,荟萃分析氨甲环酸治疗特发性月经过多的疗效。方法全面收集关于氨甲环酸治疗月经过多的相关文献,并根据改良Jadad量表严格评价文献质量,用Rev Man 4.2荟萃分析软件分析比较氨甲环酸与安慰剂、孕激素类药物及非甾体类药物治疗月经过多的有效性与安全性。结果根据纳入与排除标准对收集到的文献进行筛选,共有8篇文献纳入本次研究,其中英文文献7篇,中文文献1篇。优质文献的比例为87.5%。氨甲环酸与孕激素、非甾体类等止血药物均可在某种程度上减少特发性月经过多患者的月经量。但在月经量减少程度、治疗有效率、患者自我感觉改善的比例上,氨甲环酸的效果均显著高于安慰剂及其他药物组。氨甲环酸并不改变患者的经期长度,且引起不良反应的比例显著低于孕激素类药物。结论氨甲环酸是一种用于治疗特发性月经过多的安全有效的药物,值得临床推广。但由于纳入本次研究的文献数量偏少,且中文只有1篇,结论存在一定的偏倚,有待更大样本量研究的验证。     

Evaluation of a new estradiol oral contraceptive: estradiol valerate and dienogest

Importance of the field: Since ethinyl estradiol is a potent activator of hepatic enzymes, the use of natural estradiol (E2) has been studied; but, until recently, bleeding control has hampered development of an E2 pill.

Areas covered in this review: A historical review of oral contraceptive development leading to the successful design of an estradiol pill. Pharmacology, mechanism of action and clinical trials of contraceptive efficacy and bleeding profile of the estradiol valerate/dienogest (E2V/DNG) pill are reviewed. Details of two placebo-controlled treatment trials of the E2V/DNG pill in women with heavy menstrual bleeding are discussed. All available literature was searched using pubMed and additional data were obtained from published abstracts.

What the reader will gain: Information on the novel features and indications for the E2V/DNG pill.

Take home message: The dynamic-dosing E2V/DNG oral contraceptive pill provides a highly effective contraceptive option with an adjusted Pearl Index (method failure) of 0.51 (upper limit of 95% CI 0.97) and unadjusted Pearl Index (user failure) of 1.01 (1.59) for women aged 18 – 35 years. In addition, two large randomized controlled trials have demonstrated that E2V/DNG provides effective treatment for women with heavy menstrual bleeding.     

Menorrhagia Impact Questionnaire: assessing the influence of heavy menstrual bleeding on quality of life

Abstract

Objective:

Menorrhagia, or heavy menstrual bleeding (HMB), has a negative impact on women’s quality of life (QOL). The objective was to develop, validate, and assess the performance of a disease-specific patient-reported outcome (PRO) measurement instrument for HMB (the Menorrhagia Impact Questionnaire [MIQ]).     

氨甲环酸中顺式异构体的高效液相色谱法测定

本文采用高效液相色谱法测定氨甲环酸中的顺式异构体含量。先用衍生化试剂３，５－二硝基苯酰氯预处理氨甲环酸，然后通过ＨＰＬＣ，以喹啉为内标，ＹＭＣ－ＰａｃｋＡＭ－３０２ＯＤＳ为色谱柱，甲醇－０．０２ｍｏｌ／Ｌ醋酸铵溶液（４：７）为流动相，在２５４ｎｍ波长处检测，顺式异构体在１～２．５μｇ／ｍｌ范围内线性关系良好（ｒ＝０．９９６１），最低检测限为０．０２％。     

Endometrial endothelin: regulator of uterine bleeding and endometrial repair

1. Endothelin (ET) and its mRNA are present in endometrium. Expression of ET varies across the menstrual cycle, reaching maximal levels in the premenstrual phase, suggesting a paracrine role in endometrial bleeding and/or repair. 2. The major cellular source of ET is the epithelium, although endothelium and decidualized stroma are additional sites of production. Epithelial ET is the ET-1 isoform and this is able to contract rat thoracic aortic rings ex vivo. 3. Endothelin-1 production by cultured endometrial epithelial cells is markedly increased by serum and, to a lesser extent, by transforming growth factor-beta and interleukin-1 alpha, but not by epidermal growth factor, oxytocin, arginine vasopressin, thrombin or angiotensin II, which stimulate ET production in other tissues. 4. Endothelin-1 has mitogenic actions on endometrial stromal cells; it stimulates the uptake of [3H]-thymidine, acting via the AP-1 cis element c-jun. 5. Neutral endopeptidase (NEP), a membrane-bound ectoenzyme that is capable of degrading ET, is localized principally in endometrial stroma and immunoreactivity is maximal in the secretory phase of the cycle. 6. A potential role for ET in regulating endometrial bleeding is suggested by studies on endometrium from two groups of women who were experiencing abnormal uterine bleeding: users of the contraceptive Norplant (Leiras Co., Turku, Finland) and subjects with documented menorrhagia. In both groups, ET-1 immunoreactivity in endometrial epithelium was markedly reduced compared with the normal menstrual cycle and did not vary cyclically, while NEP immunoreactivity, particularly in the epithelium, was increased. Thus, ET may be involved in endometrial bleeding, as a vasoconstrictor before the onset of menstruation when vasoconstriction is intense and, subsequently, when it may be required in the cessation of menstrual bleeding. Furthermore, the mitogenic actions of ET may play a role in endometrial regeneration and remodelling during the menstrual cycle, particularly following menstruation.     

Estimating a meaningful reduction in menstrual blood loss for women with heavy menstrual bleeding

Abstract

Objective:

A dichotomy exists within the treatment of heavy menstrual bleeding (HMB); guidelines and expert opinion recommend that clinical management be guided by subjective, patient-centered measures, yet clinical trials often describe treatment efficacy in terms of objective reductions in menstrual blood loss (MBL). The purpose of this investigation was to correlate subjective and objective aspects of HMB treatment by identifying the minimum change in MBL that would be considered meaningful to women.     

氨甲环酸分析测试方法的研究进展

目的 介绍氨甲环酸分析测试方法的研究进展,供药品质控、新药开发、药动学以及生物等效性研究参考,确保药品质量和临床用药安全。方法 查阅近20年的国内外文献,对氨甲环酸分析测试方法进行概述。结果 氨甲环酸制剂以及体液的分析测试方法主要有容量分析法、光谱分析法、色谱分析法、核磁共振波谱法等。结论 氨甲环酸的检测方法在不断提高,为促进临床安全合理用药及进一步开发新型的氨甲环酸药物制剂提供依据与参考。     

氨甲环酸制剂开发的研究进展

目的为氨甲环酸的制剂开发、临床应用和新药研发提供依据。方法检索PubMed,Medline,EMBASE／EM,IPA及CNKI等数据库中2013年5月前有关氨甲环酸制剂开发及临床应用的相关文献及专利,并进行分析。结果研制开发的氨甲环酸制剂有普通及缓释片剂、胶囊剂、糖浆剂、注射剂、吸收性止血海绵、含漱液、复方制剂及乳剂、溶液剂、脂质体等外用制剂,氨甲环酸对治疗纤维蛋白溶解亢进所致的各种出血、月经过多、黄褐斑等具有良好的疗效和耐受性。结论应促进临床安全、合理用药,进一步开发新型的氨甲环酸药物制剂。     

中药及针灸在青春期功血调整月经周期方面的应用

目的观察中药及针灸在青春期功血调整月经周期方面的临床疗效。方法选择我院2009年1月～2013年6月青春期功血患者92例,根据治疗方法不同分为两组,观察组46例在中药治疗基础上结合针灸,对照组46例患者给予雌孕激素人工周期,观察停药后两组月经恢复情况。结果观察组总有效率为91．30％;对照组总有效率为78．26％,观察组治疗效果明显好于对照组（P〈0．05）。两组不良反应比较差异无显著性（P〉0．05）。结论中药及针灸联合治疗可调整机体生殖内分泌,使下丘脑一垂体一卵巢轴功能逐渐趋于键全,在青春期功血调整月经周期方面具有较好的治疗作用。     

HPLC法测定氨甲环酸胶囊中氨甲环酸的含量

目的 建立用于测定氨甲环酸胶囊中氨甲环酸含量的HPLC法.方法 采用Karomasil-C18ODS(250mm×4.6mm,5μm)色谱柱.流动相为磷酸盐缓冲液(pH值为2.5)-甲醇(60∶30,V/V);检测波长:220 nm,流速∶1.0 mL·min-1.结果 线性范围0.4～2.0 g·L-1,r=0.9994.回收率为100.7%,RSD=0.64%(n=6).结论 本方法简便,精确,重现性好,可用于控制氨甲环酸胶囊中氨甲环酸的内在质量.     

The potential role of elagolix for treating uterine bleeding associated to uterine myomas

ABSTRACT

Introduction

Uterine myomas represents a widespread gynecological disease of women in reproductive age. Although surgery remains the first choice for treating most patients, in the last years, new medical approaches have been considered in order to ameliorate heavy menstrual bleeding (HMB) related to their presence. Elagolix is a second-generation gonadotropin-releasing hormone (GnRH) antagonist under investigation for the long-term treatment of uterine myomas.     

Antifibrinolytic therapy with tranexamic acid in pregnancy and postpartum

Objective: The aim of this study is critically to review the available evidence regarding the use, efficacy and safety of tranexamic acid in the management of hemorrhage during pregnancy and for prevention and treatment of postpartum hemorrhage.

Research design and methods: We performed a systematic search of electronic literature (PubMed, Embase, CINAHL, Scopus, Cochrane, DARE) to review all studies looking at the use of tranexamic acid during pregnancy and puerperium. We did a metanalysis on three randomized controlled trials that evaluated reduction in blood loss in women undergoing cesarean sections with the use of tranexamic acid.

Results: An electronic search yielded 34 articles, the studies dating from 1976 to 2010, five randomized controlled trials, seven observational studies, and twenty-two case reports. Meta-analysis showed that the estimate of the combined effect of tranexamic acid compared with placebo was a difference of 32.5 ml reduction in blood loss (95% CI ?4.1 – 69.13; p = 0.08). Tranexamic acid was also used successfully to prevent and treat bleeding in observation studies and case reports. Pulmonary embolism was reported in two cases; however, the possible involvement of tranexamic acid in these thrombotic episodes could neither be confirmed nor excluded.

Conclusions: The clinical studies suggest that tranexamic acid reduces the amount of blood loss after delivery during cesarean sections and vaginal deliveries, and reduces the requirement for blood transfusion. Tranexamic acid seems to be safe and effective in the prevention and management of bleeding during pregnancy. Further investigation and larger clinical trials with better design and methodological quality are required to confirm these findings.     

氨甲环酸注射液细菌内毒素检查法的建立

目的：建立用于氨甲环酸注射液的细菌内毒素检查法,以保证其临床使用的安全性。方法：按照《中国药典》2005年版二部的有关规定,确定该注射剂的细菌内毒素限值和稀释倍数,并通过干扰试验和凝胶限量试验进一步确定样品的最大不干扰浓度和检查样品中内毒素含量。结果：本品最大不干扰浓度为12．5g·L^-1。在此浓度下,经鲎试验测得本品内毒系含量符合限值要求。结论：本法可用于氨甲环酸注射液中细菌内毒素的检查。     

术中氨甲环酸局部浸泡对人工全膝关节置换围手术期失血量的影响

目的:评价手术切口浸泡氨甲环酸对人工膝关节置换术围手术期失血量的影响。方法:采用随机的方法,将2010年8月至2011年4月符合收入标准的需行单侧全膝关节置换术的连续200例患者分为氨甲环酸组和对照组;其中氨甲环酸组97例患者在止血带释放前、假体植入后切口浸泡浓度为1%的氨甲环酸溶液100 m L共5 min,对照组103例患者局部浸润生理盐水100 m L,两组患者的年龄、性别、体质量指数、假体类型、止血带使用时间均无显著性差异(P>0.05)。观察记录两组患者的术前血红蛋白值和术后血红蛋白最低值、术前和术后HSS评分以及术后24 h引流量和总出血量。在术后必要时B超检查双下肢动静脉有无血栓形成。结果:随访率98%,在总出血量、引流量、术后血红蛋白最低值、术前血红蛋白与术后最低值之差方面,氨甲环酸组与对照组间均有显著性差异(P<0.01)。两组手术前后HSS改善值、下肢血管血栓发生率比较均无显著性意义。两组输血率无显著性意义,但是在输血量上两组有显著性差异(P<0.05)。结论:人工膝关节置换术中浸泡氨甲环酸可以减少失血量、引流量、手术前后血红蛋白丢失量,在改善术后血红蛋白最低值方面作用显著。可以减少输血量,但是对于对输血率改善不明显。本实验中氨甲环酸浸泡并未增加下肢深静脉血栓形成等风险。