Complementary new approaches enable repositioning of failed drug candidates

Until recently, safe drug candidates that failed in clinical trials were shelved as drug developers channelled resources to the next candidates in the pipeline. In the past few years, new technologies, improved genomic information and high-throughput methods have made it possible to quickly and economically re-examine advanced drug candidates for therapeutic activity against other diseases. This development arrives at an opportune time, as pharmaceutical companies strive to fill sparse late-stage pipelines at the same time as keeping costs down. Specialised companies are emerging with new methods and a fresh point of view to assist pharmaceutical developers in turning failed drug candidates from one therapeutic area into successful treatments in another. This editorial introduces a series of papers to be published in Expert Opinion on Investigational Drugs, discussing discontinued drugs from 2005.     

雌激素治疗绝经后骨质疏松的Meta-分析

目的 系统评价雌激素类药物治疗绝经后骨质疏松的疗效及安全性。方法 检索PubMed、EMbase、CochraneLibrary、中国生物医学文献数据库（CBM）、中国学术期刊全文数据库（CNKI）、维普中文期刊全文数据库（VIP）和万方数据库中关于雌激素治疗绝经后骨质疏松的临床随机对照研究（RCT），依据纳排标准纳入文献，运用软件ReviewManager 5.0和Stata 14.0进行疗效和安全性的系统评价。结果 共纳入15篇RCTs，包括13 280例患者。结果表明雌激素类药物对改变绝经后骨质疏松患者的腰椎骨密度［MD=1.08，95% CI（0.75，1.40），P<0.001］、椎体骨折发生率［OR=0.61，95% CI（0.52，0.71），P<0.001］、血清骨钙素［MD=-16.03，95% CI（-18.68，-13.67），P<0.001］等指标具有特异性。网状Meta-结果表明雌激素中巴多昔芬对于提高腰椎BMD的效果最好。雌激素治疗极少发生严重不良反应，普通不良反应发生率（潮热、肌肉痉挛等）较低。结论 雌激素类药物对绝经后骨质疏松的治疗具有积极意义，显著减低了椎体骨折发生率并改善了患者的骨密度；雌激素类药物治疗的不良反应发生率较低，安全性高。     

Effects of UGT1A1*28 polymorphism on raloxifene pharmacokinetics and pharmacodynamics

AIMS

Raloxifene concentrations were reported to correlate approximately with serum bilirubin levels. Bilirubin is a typical UGT1A1 substrate. Based on these facts, we postulated a hypothesis that UGT1A1 is the key enzyme for metabolic clearance of raloxifene and that the common UGT1A1*28 polymorphism significantly contributes to the large pharmacokinetic variability of raloxifene.

METHODS

Serum samples from postmenopausal osteoporotic patients treated with raloxifene were assayed for the concentrations of raloxifene and its glucuronides by liquid chromatography–mass spectrometry–mass spectrometry. The same samples were also genotyped for the presence of UGT1A1*28 polymorphism by the single-strand conformation polymorphism method. The pharmacodynamic effect was evaluated by measuring the change in bone mineral density (BMD) in femoral neck, hip and lumbar spine after 12 months'' raloxifene therapy.

RESULTS

Patients homozygous for the *28 allele showed significantly, twofold higher raloxifene glucuronide concentrations compared with the hetero- and homozygotes for the wild-type allele: 558 ± 115 nmol l⁻¹ compared with 295 ± 43 nmol l⁻¹, respectively (P = 0.012). This indicates a higher raloxifene exposure in the *28/*28 group. Consequently, a significantly greater increase in hip BMD was observed in subjects homozygous for the *28 allele compared with the group carrying at least one copy of the wild-type allele: 4.4 ± 2.4% compared with 0.3 ± 1.4% (P = 0.035).

CONCLUSIONS

In this study it is shown that a relatively common UGT1A1*28 polymorphism may considerably influence raloxifene pharmacokinetics and pharmacodynamics. Underlying mechanisms and clinical implications of our findings are also discussed.     

Alendronate and Raloxifene Therapy in the Early Period after Hip Fracture

Objective: The purpose of the present study was to clarify the efficacy of alendronate and raloxifene for preventing bone loss in patients with hip fracture by monitoring bone mineral densities (BMDs) and biochemical markers during the 9-month period after fracture.Patients and Methods: Eighty-two female hip fracture patients from 50 to 99 years old (mean ± SD: 81.6 ± 9.5) were randomly divided into two groups; there were 46 patients in the alendronate-treated group (group ALN) and 36 patients in the raloxifene-treated group (group RLX). Drugs were administered to patients six weeks after their operations. Lumbar spine BMD and neck, trochanter, Ward’s and total BMDs of the contralateral proximal femur, serum intact osteocalcin (intact OC), bone-specific alkaline phosphatase (BAP) and urinary N-terminal telopeptide of type I collagen (NTX) were measured just before the start of drug administration and at 9 months thereafter.Results: Twenty-two out of 46 patients in group ALN and 23 out of 36 patients in group RLX completed the study. The most common reason for dropping out was the patient’s failure to visit the outpatient clinic. Trochanter BMD in group ALN tended to increase by 8.4% compared with the baseline, and total hip BMD in group RLX showed a significant increase (5.7%), although neck BMD in both groups decreased during the 9 months of treatment (−8.7% for group ALN and −4.2% for group RLX compared with the baseline). Spine BMD did not change significantly in eithr group. Serum BAP and urinary NTX decreased significantly in both groups. Serum intact OC did not change significantly.Conclusions: Both alendronate and raloxifene have a favorable effect on trochanter and total BMDs of the contralateral proximal femur in the short period after hip fracture. However, both drugs could not prevent bone loss in the femoral neck during the 9 months of treatment.     

Genistein aglycone improves skin repair in an incisional model of wound healing: a comparison with raloxifene and oestradiol in ovariectomized rats

Background and purpose:

Oestrogen loss at menopause is frequently related to poor wound healing. Genistein has been tested in anti-ageing cosmetic preparations with interesting results on skin health. Here, we investigated the effects of the genistein aglycones, given systemically, in an incisional model of wound healing, compared to systemic oestradiol and raloxifene.

Experimental approach:

Six months after ovariectomy (OVX), rats were randomly assigned to groups of 12 animals each and treated daily with genistein aglycone (1 and 10 mg·kg⁻¹ s.c.), raloxifene hydrochloride (0.05 and 0.5 mg·kg⁻¹ s.c.) or 17-α-ethinyl oestradiol (0.003 and 0.03 mg·kg⁻¹ s.c.) for 12 weeks. Untreated OVX and sham OVX rats were used as controls. Then, 14 or 7 days before the end of the experiment, an incisional wound healing procedure was performed and skin specimens were collected to evaluate molecular, histological and functional measurements.

Key results:

Seven and fourteen days after wounding, samples from OVX rats showed a decrease in transforming growth factor-β1, tissue transglutaminase 2 and vascular endothelial growth factor compared to samples from sham OVX rats. Oestradiol, raloxifene and genistein all significantly modified this decrease, but the lowest genistein dose exerted a greater effect than the other treatments. Moreover, the lowest dose of genistein was the most effective in improving skin healing and wound tensile strength.

Conclusions and implications:

Genistein aglycone might be an alternative therapy for the management of skin wound healing.     

利塞膦酸钠联合雷洛昔芬治疗绝经后骨质疏松症疗效分析

目的观察利塞膦酸钠联合雷洛昔芬治疗绝经后女性骨质疏松症的效果。方法将148例绝经后女性骨质疏松症患者随机分为治疗组和对照组,治疗组给予利塞膦酸钠联合雷洛昔芬治疗,对照组给予利塞膦酸钠治疗。在治疗前及治疗后12个月分别检测两组受试者腰椎及髋部骨密度、血清骨代谢指标、激素水平及研究期间药物不良反应和VAS评分的变化。结果药物治疗后12个月,两组腰椎(L1～4)及左侧股骨颈的骨密度明显增加,治疗组的骨密度显著高于对照组(P0. 05);血清雌激素和孕酮水平均明显下降,皮质醇水平明显上升,与治疗前相比差异有统计学意义(P0. 05),而对照组与治疗前相比差异无统计学意义(P0. 05);治疗后两组血清P1NP及β-CTX较治疗前明显下降、BAP和BGP较治疗前明显上升,比较差异有统计学意义(P0. 05),治疗组较对照组的改善更为明显(P0. 05);治疗后两组患者VAS评分较治疗前显著降低,比较差异有统计学意义(P0. 05),治疗组较对照组降低得更为明显(P0. 05);两组患者在研究期间的药物不良反应无统计学意义(P0. 05)。结论利塞膦酸钠联合雷洛昔芬治疗骨质疏松症较单独使用利塞膦酸钠治疗的效果更为显著,且不增加药物副作用。     

Selective Estrogen Receptor Modulators

Reviews in Endocrine and Metabolic Disorders -     

Jumping exercises with and without raloxifene treatment in healthy elderly women

Several meta-analyses confirm that physical exercise can slow down postmenopausal bone loss, but it is not clear whether physical exercise alone can increase bone mass. Our intent was to evaluate high-impact exercises (including jumping) and combined balance and leg-strength training, with and without raloxifene treatment, in three healthy elderly women, age 68-71 years. The 40-week study period consisted of two 17-week exercise periods with a 6-week rest period in between. The jumping exercises were performed both vertically and in different directions. Effects were measured in bone mineral density (BMD), balance, maximal gait speed, and leg extensor strength. BMD (g/cm(2)) was measured with dual-energy X-ray photon absorptiometry (DXA) at the proximal femur, lumbar spine, and total body. After the first exercise period, large losses of trochanteric BMD (8.1%-10.8%) were seen in all subjects. After both 6 weeks of rest and the second exercise period, which included both exercise and raloxifene, BMD increased in all subjects. During both exercise periods, the balance, gait speed, and leg extensor strength increased in all subjects. The results show that this kind of high-impact exercise had limited effects on BMD, but had large positive effects on balance, gait speed, and leg extensor strength. In conclusion, high-impact exercise in elderly women improves their fall risk factors, but, at least without raloxifene treatment, the trochanteric fracture risk might even increase because of reduction in the regional bone mass.     

Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in Chinese postmenopausal women with osteoporosis: a multi-center, randomized, placebo-controlled clinical trial

Thereducedproductionofestrogenfollowingmenopauseleadstoacceleratedbonelossinpostmenopausalwomen Inseverecases ,thismayleadtoosteoporosisincreasingriskoffractures Whileestrogenreplacementtherapy (ERT)andhormonereplacementtherapy (HRT )canpreventpostmenopausalboneloss ,1,2 estrogenusemayproduceundesirablesideeffectssuchasvaginalbleedingandbreasttenderness Long termestrogenuse (withoutconcurrentuseofprogestin)hasbeenreportedtocauseanincreasedriskofendometrialcancer 3　Inaddition ,ithasbeenrepo…