伊班膦酸钠合成工艺的改进

目的改进伊班膦酸钠的合成工艺。方法以N-甲基正戊胺为原料经加成、水解、成盐、膦酸化、水解、成盐得伊班膦酸钠。结果与结论改进的工艺明显提高了反应收率,工艺条件温和,合成步骤简洁,适合工业化生产。     

伊斑膦酸钠的合成

目的：合成伊斑膦酸钠,方法：以戊胺为原料,经缩合,甲基化,加成,水解,无溶剂膦酸化,中和反应合成。结果：合成了伊斑膦酸钠,总收率21．2％。结论：本方法提高了反应收率,降低了成本,简化了操作,是合成伊斑膦酸钠的有效途径之一。     

利塞膦酸钠的合成研究

目的合成新型抗骨质疏松药利塞膦酸钠。方法以烟酸为原料,经酯化、缩合、Willgerodt反应和水解等步骤得到关键中间体3-吡啶乙酸盐酸盐,3-吡啶乙酸盐酸盐与亚磷酸反应后得到利塞膦酸钠。结果在合成过程中,通过探讨Willgerodt反应的时间和反应条件以及产率,优化合成路线,提高总反应收率。结论此合成路线使利塞膦酸钠的合成方法能较好地适用于工业化生产。     

伊班膦酸钠单用与联合放疗及单纯放疗对骨恶性肿瘤的临床疗效评价

目的评价伊班膦酸钠、伊班膦酸钠联合骨肿瘤局部病灶的放射治疗及单纯放射治疗的临床疗效的优劣。方法回顾性分析本院近5年门诊及住院71例次各类恶性骨肿瘤患者,其中20例为以伊班膦酸钠为主体的综合治疗,26例次是以伊班膦酸钠联合骨肿瘤局部病灶放射治疗的综合治疗,25例次单纯对骨肿瘤病灶采取了姑息放射治疗;按WHO规定评价疗效及不良反应。结果病灶局部疼痛控制情况:3组总有效率依次为70.0%,88.5%,68.0%;骨肿瘤溶骨性病灶骨密度增加好转率依次为65.0%,80.8%,48.0%。结论尽管3组之间的疗效经统计学处理未见显著差异,但伊班膦酸钠联合放射治疗是在骨肿瘤病人疼痛反应的缓解率和增加溶骨性病灶骨密度等方面都优于其它两组,因此,本组资料认为伊班膦酸钠联合放射治是一种值得推广的骨肿瘤姑息治疗手段。     

伊班膦酸钠的临床研究进展

伊班膦酸钠属第 3代二膦酸盐类药物 ,是迄今为止本类药物中抑制骨重吸收能力最强、毒性最低的药物。本文综述了伊班膦酸钠用于治疗癌症骨转移或肿瘤引发的高钙血症的临床资料以及伊班膦酸钠的临床药动学资料 ,并对该药的临床安全性进行了评价。此外 ,国外正在进行伊班膦酸钠治疗绝经后骨质疏松症和变形性骨炎的临床试验 ,获得良好效果     

伊班膦酸钠输注液和阿仑膦酸钠片治疗老年性骨质疏松症的疗效-成本分析

目的：探究分析伊班膦酸钠注射液和阿仑膦酸钠片治疗老年骨质疏松的疗效,并对其疗效-成本进行分析。方法：将我院自2013年12月～2014年12月期间收治的200例老年性骨质疏松症患者随机分为两组：伊班膦酸钠组和阿仑膦酸钠组,各100例。结果：治疗1个疗程后,伊班膦酸钠组患者腰椎骨密度较治疗前增加7.57%,阿仑膦酸钠组患者较治疗前增加5.39%,伊班膦酸钠注射液产生单位骨密度增高效果的成本为630.85元,阿仑膦酸钠片的成本为734.17元。结论：据药物经济学分析,阿仑膦酸钠片更适于治疗老年性骨质疏松症。     

伊班膦酸钠注射液的流动注射化学发光法测定

建立了流动注射化学发光法测定伊班膦酸钠.伊班膦酸钠被破坏转化为无机磷,与钼酸铵在酸性条件下形成磷钼杂多酸,与鲁米诺在碱性条件下反应产生化学发光.伊班膦酸钠溶液在5～25 μg/ml浓度范围内线性关系良好.回收率大于97.6％,RSD小于2.0％.     

伊班膦酸钠注射液的过敏性、溶血性和刺激性比较试验

目的 评价伊班膦酸钠注射液的过敏性、溶血性和刺激性并与参比制剂比较一致性。方法 通过对豚鼠全身主动过敏试验和被动皮肤过敏试验来检测伊班膦酸钠注射液的过敏性。通过体外溶血试验检测伊班膦酸钠注射液的溶血性。通过对兔耳血管刺激性试验来检测伊班膦酸钠注射液的刺激性。结果 伊班磷酸钠注射液无过敏性、溶血性和刺激性。结论 伊班磷酸钠注射液（南京恒生制药有限公司）与参比制剂（Roche Pharma(Schweiz)Ltd）毒性反应一致。     

阿仑膦酸钠合成工艺研究

目的研究阿仑膦酸钠的合成工艺。方法将4-氨基丁酸和亚磷酸投入到氯苯溶液中，在90℃和95℃之间反应至溶液澄清后，将溶液温度降低，在搅拌下缓慢滴加三氯化磷，然后升温继续反应，反应结束后再加三氯化磷，继续升温反应，结束后经水解、成盐，于低温冷却结晶，滤过干燥得到阿仑膦酸钠粗品。粗品溶液经活性碳脱色，结晶得到阿仑膦酸钠精制品。结果阿仑膦酸钠总收率为70％。结论该合成路线反应步骤短、操作简单、经济合理。     

伊班膦酸钠的药理作用及临床应用进展

目的阐述伊班膦酸钠的药理作用及临床应用。方法综述近年来伊班膦酸钠的药理研究结果及临床治疗恶性肿瘤骨转移和肿瘤相关疾病的治疗效果并加以分析。结果伊班膦酸钠可治疗恶性肿瘤骨转移性高钙血症,抑制溶骨损害,并能预防恶性肿瘤骨转移的发生;联合放疗治疗恶性肿瘤骨转移,起效快,且疼痛缓解率高;治疗骨质疏松症亦有良好效果。结论伊班膦酸钠的临床适应证多限于恶性肿瘤或恶性肿瘤骨转移诱发的高钙血症,能缓解骨痛,对延长患者生存期、改善患者生活质量有一定作用。     

Therapy of osteoporosis in patients with Crohn's disease: a randomized study comparing sodium fluoride and ibandronate

BACKGROUND: Osteoporosis is a frequent complication in Crohn's disease. Although the efficacy of both sodium fluoride and aminobisphosphonates in postmenopausal osteoporosis has been investigated in long-term therapy studies, no long-term results are available regarding the effect of these agents in the management of osteoporosis in patients with Crohn's disease. METHODS: Eighty-four patients with Crohn's disease and pathological bone mineral density findings were randomized to receive either vitamin D3 (1000 IU) and calcium citrate (800 mg) daily (group A) or sodium fluoride (25 mg b.d., group B) or intravenous ibandronate (1 mg every 3 months, group C) in addition to daily calcium/vitamin D substitution. On admission to the study and after 12 and 27 months, patients underwent dual-energy X-ray absorptiometry and radiological examination of the spine. RESULTS: Sixty-eight patients completed the 1-year observation period and were available for the intention-to-treat analysis. No new vertebral fractures were diagnosed. In group A, lumbar bone density increased by 2.6% (P = 0.066, N.S.), in group B by 5.7% (P = 0.003) and in group C by 5.4% (P = 0.003). Therapy with sodium fluoride was associated with an increase in osteocalcin (N.S.), whereas administration of ibandronate was associated with a decrease in the resorption parameter, carboxy-terminal cross-linked type-I collagen telopeptide (P < 0.05). Both sodium fluoride and ibandronate resulted in significant decreases in the serum concentration of osteoprotegerin after 9 months (P < 0.001). CONCLUSIONS: The findings of the present study show that both sodium fluoride and ibandronate are effective in combination with calcium and vitamin D substitution in the management of osteopenia and osteoporosis in patients with Crohn's disease. Both agents are safe and well tolerated, and induce continuous increases in lumbar bone density.     

伊班膦酸钠治疗肺癌骨转移疼痛28例

目的观察和评价伊班膦酸钠治疗肺癌骨转移疼痛的疗效与安全性。方法共28例确诊为肺癌骨转移疼痛的患者，均给予伊班膦酸钠4 mg加0.9%氯化钠注射液或5%葡萄糖注射液500～750 mL静脉滴注，滴注持续时间＞2 h，每4周1次，连续治疗2次后评价疗效。结果治疗两次后止痛有效率(疼痛缓解＞50%，缓解持续时间达到4周者所占比例)为75.0%，不良反应较轻微，患者可以耐受。结论伊班膦酸钠对肺癌骨转移引起的疼痛具有良好的止痛效果，且不良反应轻，值得临床推广。     

Stability indicating ion chromatography method for the simultaneous determination of ibandronate sodium drug substance and its impurities

A simple and sensitive ion chromatography method has been developed for the simultaneous assay of ibandronate sodium drug substance and the determination of its impurities. The separation was achieved on Allsep™ anion column 150 mm × 4.6 mm, 7 μm particle diameter. The mobile phase consisted of 1% (v/v) aqueous formic acid and acetone 98:2% (v/v); flow rate 1.0 ml min⁻¹ at ambient temperature. The analytes were monitored by conductometric detector. The drug substance was subjected to stress conditions of hydrolysis, oxidation, photolytic, thermal and humidity degradation. Considerable degradation was achieved only under oxidative conditions. Mass balance was demonstrated in all stress conditions. The method was validated for specificity, precision, linearity, solution stability and accuracy. The limits of detection (LOD) and limits of quantification (LOQ) for impurities were in the range of 0.36–0.80 μg ml⁻¹ and 1.00–2.40 μg ml⁻¹, respectively. For ibandronate LOD was 38 μg ml⁻¹ and LOQ was 113 μg ml⁻¹. The average recoveries for impurities and ibandronate were in the range of 99.0–103.1% and the method can be successfully applied for the routine analysis of ibandronate sodium drug substance.     

Ibandronate in profile: drug characteristics and clinical efficacy

BACKGROUND: Postmenopausal osteoporosis is a serious, chronic condition, for which nitrogen-containing bisphosphonates are now one of the treatments of choice. OBJECTIVE: To review the profile of ibandronate, a monthly oral (150 mg) or quarterly intravenous injection (3 mg) of bisphosphonate. METHODS: The literature search was limited to publications of ibandronate data. RESULTS/CONCLUSION: Ibandronate is rapidly absorbed and distributed in the bone; it is not metabolised and is excreted in urine. Clinical trial data have demonstrated the efficacy of ibandronate in reducing fracture risk, increasing bone mineral density and reducing bone turnover. These data are supported by recent meta-analyses and a large database study that have demonstrated antifracture efficacy with the ibandronate regimens used in clinical practice. Overall, ibandronate has generally been well tolerated. Therefore, ibandronate is a useful treatment for postmenopausal osteoporosis.     

唑来磷酸针与伊班磷酸钠针治疗骨肿瘤的临床对照

目的:探讨唑来磷酸针与伊班磷酸钠针治疗骨肿瘤临床效果,为临床更好治疗骨肿瘤提供依据。方法:选取本院2012年7月－2014年2月我院肿瘤科骨肿瘤患者88例进行研究,按照临床试验数字随机的方法将患者分为A、B两组,其中A组治疗药物为唑来磷酸针(天晴依泰),B组的治疗药物为伊班磷酸钠针(艾本),观察2组治疗后患者疼痛改善情况、不良反应发生情况、治疗费用以及治疗后患者生活质量情况,并对相关数据进行统计学分析。结果:A组治疗后疼痛缓解率为79.55%,显著低于B组的90.91%,差异有统计学意义,P<0.01。A组治疗后的不良反应及患者表现肾毒性明显高于B组,χ²=8.67,P<0.01,差异具有统计学意义。2组费用比较可以看出,唑来磷酸针明显要比伊班磷酸钠针费用高,2组患者的治疗总费用相比,B组更具有经济价值,P<0.01,差异具有统计学意义。A组患者的生活质量(52.27%)较B组(63.64%),P<0.01,差异具有统计学意义。结论:临床上药物治疗骨肿瘤能够很好的改善骨肿瘤患者的生活质量,伊班磷酸钠针治疗骨肿瘤能够明显改善患者的临床骨痛症状,患者治疗费用低,不良反应和毒副作用少,在临床治疗骨肿瘤上具有重要意义,值得在临床上广泛使用。     

伊班膦酸钠联合骨化三醇治疗老年骨质疏松症的临床研究

目的 探讨伊班膦酸钠注射液联合骨化三醇胶丸治疗老年骨质疏松症的临床疗效。方法 选取2016年11月-2017年12月在上海市第三康复医院和第二军医大学附属公利医院收治的123例老年骨质疏松症患者作为研究对象,将患者随机分为骨化三醇组、伊班膦酸钠组、联合组,每组各41例。骨化三醇组患者口服骨化三醇胶丸,2粒/次,1次/d;伊班膦酸钠组患者静脉滴注伊班膦酸钠注射液,2 mg溶于0.9%氯化钠溶液250 mL中,滴注时间大于2 h,1次/3个月;联合组给予伊班膦酸钠注射液联合骨化三醇胶丸,用法用量同上。3组患者均连续治疗12个月。观察3组患者的临床疗效,比较3组患者治疗前后的数字疼痛评分（NRS）、骨密度（BMD）、血磷、血钙、抗酒石酸酸性磷酸酶5b（TRAP-5b）、骨源性碱性磷酸酶（BALP）水平和不良反应。结果 治疗后,骨化三醇组、伊班膦酸钠组、联合组的总有效率分别为82.93%、85.37%和95.12%,联合组总有效率显著优于骨化三醇组和伊班膦酸钠组,差异具有统计学意义（P<0.05）。治疗6、12个月后,3组患者的NRS评分值均显著降低,平均腰椎BMD和平均股骨颈BMD均显著升高,同组治疗前后比较差异具有统计学意义（P<0.05）;治疗6、12个月后,联合组患者的NRS评分值显著低于同期骨化三醇组和伊班膦酸钠组,而平均腰椎BMD和平均股骨颈BMD均明显高于同期骨化三醇组和伊班膦酸钠组,差异具有统计学意义（P<0.05）。治疗后,3组患者血钙、血磷相较于治疗前差异无统计学意义,且联合组患者的血钙、血磷较其他两组差异均无统计学意义。治疗6、12个月后,3组患者TRAP-5b、BALP水平均显著降低,同组治疗前后比较差异具有统计学意义（P<0.05）;治疗6、12个月后,联合组患者TRAP-5b、BALP水平显著低于同期骨化三醇组和伊班膦酸钠组,差异具有统计学意义（P<0.05）。3组患者的不良反应发生情况差异无统计学意义。结论 伊班膦酸钠注射液联合骨化三醇胶丸治疗老年性骨质疏松症具有较好的临床疗效,能够改善骨密度,减少疼痛,维持骨生化指标,具有一定的临床推广应用价值。     

Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE

OBJECTIVES: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2 months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here. PATIENTS AND METHODS: BONE was a randomized, double-blind, placebo-controlled, fractureprevention study in 2946 postmenopausal women (age 55 years-80 years; > or = 5 years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4-L4]). Participants received daily calcium (500 mg) and vitamin D (400 IU) plus either placebo, oral daily ibandronate (2.5 mg) or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations. RESULTS: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo. CONCLUSIONS: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients' geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.     

Renal safety and pharmacokinetics of ibandronate in multiple myeloma patients with or without impaired renal function

In this open-label study, the authors assessed the pharmacokinetics and safety of ibandronate in patients with multiple myeloma and varying renal function. Renal deterioration was graded at baseline depending on creatinine clearance in 4 stages (0: >80; 1: 50-79; 2: 30-49, and 3: <30 mL/min). Patients (n = 40) received intravenous ibandronate 6 mg (30-minute infusion). Ibandronate excretion and serum levels were measured over 24 hours. Serum creatinine, creatinine clearance, and markers of tubular damage were monitored before ibandronate infusion and at 24 and 72 hours following ibandronate infusion. Ibandronate clearance, AUC(0-24), AUC(0-infinity), serum t((1/2)), and C(max) were calculated. There was a significant positive correlation between ibandronate clearance and creatinine clearance (r = 0.858; P < .00001). The AUC for grade 3 renal insufficiency increased by approximately 60% versus grade 0 (P < .01) but was not significantly different between other grades of renal function. The t((1/2)) did not increase significantly, and peak serum levels of ibandronate were similar for the 4 grades of renal function. Serum creatinine, creatinine clearance, and markers of tubular damage did not change significantly within 72 hours of ibandronate infusion. Despite renal function already being compromised in this patient group, there was no evidence of acute nephrotoxicity with ibandronate.