Clinical pharmacokinetics and pharmacogenetics of tamoxifen and endoxifen

Introduction: Tamoxifen dominates the anti-estrogenic therapy in the early and metastatic breast cancer setting. Tamoxifen has a complex metabolism, being mainly metabolized by CYP2D6 into its 30–100 times more potent metabolite, endoxifen. Recently, a phase I study in which endoxifen as an orally z-endoxifen hydrochloride has been successfully evaluated.

Areas covered: the principal pharmacogenetic and non-genetic differences in the pharmacology of tamoxifen and endoxifen are evaluated. To this end, references from PubMed, Embase or Web of Science, among others, were reviewed As non-genetic factors, important differences and similarities such age, or adherence to tamoxifen therapy are comprehensively illustrated. Additionally, since CYP2D6 genotypes are considered the main limitation of tamoxifen, many studies have investigated the association between the worsened clinical outcomes in patients with non-functional CYP2D6 genotypes. In this review, an overview of the research on this field is presented. Also, a summary describing the literature about individualizing tamoxifen therapy with endoxifen concentrations and its limitations is listed.

Expert opinion: z-endoxifen hydrochloride is only investigated in the metastatic setting, still more research is required before its place in therapeutics is known. Similarly, monitoring tamoxifen efficacy based on endoxifen concentrations might not be overall recommended due to the limited evidence available.     

肾损伤的治疗进展

轻度、中度的肾损伤可行保守治疗。严重的肾损伤出血应首选超选择性肾动脉栓塞术,因该技术定位准确,止血迅速,创伤小,恢复快,并发症少,能最大限度地保护肾脏功能,是一种安全可靠治疗肾损伤出血的有效方法。     

Multi-detector CT angiography for lower gastrointestinal bleeding: Can it select patients for endovascular intervention?

This is a retrospective review of the results at our institution of using multi-detector CT angiography (CTA) to localise lower gastrointestinal (GI) bleeding. We hypothesised that in our patient population: (i) CTA was unlikely to demonstrate bleeding in patients who were haemodynamically stable; (ii) in haemodynamically unstable patients in whom CTA was undertaken, the results could be used to select patients who would benefit from catheter angiography; and (iii) in haemodynamically unstable patients in whom CTA was undertaken, a subgroup of patients could be identified who would benefit from primary surgical treatment, avoiding invasive angiography completely. A retrospective review was conducted of the clinical records of all patients undergoing CTA for lower GI haemorrhage at our institution between 1 January 2005 and 30 June 2007. Out of the 20 patients examined, 10 had positive CTAs demonstrating the bleeding site. Nine were haemodynamically unstable at the time of the study. Four patients with positive CT angiograms were able to be treated directly with surgery and avoided invasive angiography. Ten patients had negative CTAs. Four of these were haemodynamically unstable, six haemodynamically stable. Only one required intervention to secure haemostasis, the rest stopped spontaneously. No haemodynamically stable patient who had a negative CTA required intervention. CTA is a useful non-invasive technique for localising the site of lower GI bleeding. In our patient population, in the absence of haemodynamic instability, the diagnostic yield of CTA was low and bleeding was likely to stop spontaneously. In haemodynamically unstable patients, a positive CTA allowed patients to be triaged to surgery or angiography, whereas there was a strong association between a negative CTA and spontaneous cessation of bleeding.     

Individualized Mycophenolate Mofetil Dosing Based on Drug Exposure Significantly Improves Patient Outcomes After Renal Transplantation

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12-month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration-controlled doses or fixed-dose MMF. A novel Bayesian estimator of MPA AUC based on three-point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration-controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration-controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg*h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg*h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.     

子宫动脉栓塞治疗子宫肌瘤89例报告

目的 评价子宫动脉栓塞术治疗子宫肌瘤的近期疗效。方法 89例子宫肌瘤患者，采用Seldinger技术分别作左右子宫动脉主干插管检查和栓塞治疗，栓塞剂采用聚乙稀醇颗粒(PVA)或白芨混合颗粒。结果 72例(80．9％)完成随访，随访时间1～28个月。有94．1％(64／68)的患者月经复常；治疗后瘤体缩小25．2％～76．8％(M=41．3％)。除了术中术后疼痛(65例)和发热(16例)外，有2例因肌瘤坏死行子宫切除术，1例出现卵巢早衰。结论 子宫动脉栓塞术治疗子宫肌瘤的近期疗效满意，远期疗效尚待进一步观察。     

特异性荧光偏振免疫法监测521例肾移植后环孢素A全血浓度3275次

目的通过监测肾移植后病人环孢素A(CsA)全血浓度 ,提出CsA在三联免疫抑制用药方案中的理想治疗窗。方法用特异性荧光偏振免疫法测定CsA全血浓度 ,对521例病人监测3275次 ,按术后时间及临床表现分组比较。结果肾移植后<1 ,、1～3、3～6、6～12个月、1～2和>2年的CsA全血谷浓度的理想治疗窗应分别为250～450、200～400、150～300、100～250、100～200和100～180μg/L。结论CsA全血浓度在上述范围内 ,中毒反应和排异反应明显减少     

复方强的松龙治疗混合型血管瘤

复方强的松龙液局部注射治疗混合型血管瘤70例,治愈60例。本法操作简便,值得推广。     

中医对干燥综合征治法和用药初探

干燥综合是一种全身性自身免疫病,目前西医对本病无疗法。因此探讨中医对本病的治法和用药,提高临床有效率是十分必要的。本文在中医辯证理论的指导下,提出了:益气养阴、养阴清热、琉风清热、养血活血、清热化湿、痹通络等六种治疗方法和用药初探,以供临床参考应用。     

Relative bioavailability of four controlled-release nifedipine products

Four controlled-release nifedipine products were investigated in two clinical studies. In study 1, 22 healthy male volunteers took part in an open, multiple-dose, randomized, crossover study to determine the relative bioavailablity of two 10 mg controlled-release nifedipine tablet (Adalat® Retard, Bayer), administered 12 hourly, and one 20 mg controlled-release nifedipine tablet (Adalat® Retard, Bayer) administered 12 hourly. In study 2, 24 healthy male volunteers took part in an open, multiple-dose, randomized, three-period, crossover study to determine the relative bioavailability of (i) two 30 mg nifedipine gastro-intestinal therapeutic system (GITS) tablets (Adalat® XL, Bayer) administered once daily; (ii) one 60 mg nifedipine GITS tablet (Adalat® XL, Bayer) administered once daily; and (iii) one 20 mg plus one 10 mg nifedipine controlled-release tablet (Adalat® Retard, Bayer), administered 12 hourly. In both studies detailed pharmacokinetic data, in particular with respect to the controlled-release characteristics of the different formulations, were collected. Results of both studies indicate that all nifedipine products investigated are bioequivalent with respect to the extent of absorption of nifedipine. The nifedipine GITS products (Adalat® XL) have better controlled-release properties than the Adalat® Retard product, and are suitable for once-a-day administration.     

十二烷氮酮氟尿嘧啶凝胶治疗疣及银屑病150例

443例(男225例,女218例;年龄36±14a)皮肤病患者,其中150例(扁平疣52例、寻常疣55例、银屑病43例)外用含1.8％十二烷氮(艹卓)酮的1％氟尿嘧啶(5-FU)凝胶作为治疗组,148例外用1％5-FU凝胶及145例外用2.5％5-FU霜作为2个对照组。经双盲对照临床试验,结果表明含1.8％十二烷氮(艹卓)酮的1％5-FU凝胶的疗效明显优于2个对照组(P<0.01及P<0.005)。证明氮(艹卓)酮对5-FU确有渗透促进作用。