中国科技论文统计源期刊 中文核心期刊  
美国《化学文摘》《国际药学文摘》
《乌利希期刊指南》
WHO《西太平洋地区医学索引》来源期刊  
日本科学技术振兴机构数据库(JST)
第七届湖北十大名刊提名奖  
医药导报, 2017, 36(2): 213-215
doi: 10.3870/j.issn.1004-0781.2017.02.024
唑来膦酸注射液对原发性骨质疏松患者体温的影响
Influence of Zoledronic Acid Injection on Body Temperature of Patients with Primary Osteoporosis
张春燕, 任晓蕾, 张海英, 张斌, 冯婉玉

摘要: 目的探讨唑来膦酸注射液治疗原发性骨质疏松患者体温变化和预防用药的影响及方式选择。方法回顾性调查北京大学人民医院2013—2014年使用唑来膦酸注射液治疗的原发性骨质疏松患者共142例,查阅并记录患者用药前一天及用药后不同时间的体温,采用SPSS17.0版统计软件进行数据处理。结果静脉滴注唑来膦酸注射液后不同时间患者体温差异有统计学意义(P=0.000),预防使用非甾体类抗炎药(NSAIDs),可显著降低唑来膦酸注射液使用后第2天患者体温。结论预防使用NSAIDs从静脉滴注唑来膦酸当天开始,连续3 d口服给药为宜。
关键词: 唑来膦酸注射液 ; 体温 ; 预防用药

Abstract:
ObjectiveTo investigate the influence of zoledronic acid injection on body temperature of patients with primary osteoporosis. MethodsA total of 142 patients with primary osteoporosis who received intravenous zoledronic acid treatment in Peking university people’s hospital during 2013-2014 were enrolled in this study. The body temperature before and after intravenous zoledronic acid treatment were recorded and analyzed with SPSS 17.0 software. ResultsThe patients' body temperature at different time points after intravenous zoledronic acid treatment was significantly different (P=0.000). Prophylactic use of NSAIDs could significantly reduce patients' body temperature at the second day after intravenous zoledronic acid. ConclusionNSAIDs can be given orally on the same day of intravenous injection of zoledronic acid, and continued for three days.
Key words: Zoledronic acid injection ; Body temperature ; Prophylactic use

唑来膦酸注射液治疗骨质疏松症,具有用药剂量小、次数少、作用时间长、疗效可靠稳定的特点,只需每年静脉给药1次(5 mg) ,连续使用3年即可取得良好的疗效。在我国2011年原发性骨质疏松诊治指南中明确推荐唑来膦酸注射液用于治疗原发性骨质疏松[1]。但在使用过程中,国内外文献均报道唑来膦酸的不良反应发生率较高,尤其急性期不良反应(APR)较为常见[1-2]。APR指静脉使用唑来膦酸后3 d内发生的不良反应[2-3],主要包括发热、肌肉骨骼痛、厌食、恶心、低钙血症、急性肾损伤等,其中发热最常见,发生率15%~85%[4-8]。笔者拟分析使用唑来膦酸注射液对疗骨质疏松患者的体温的影响,分析预防用药,从而为临床合理用药提供参考。

1 材料与方法
1.1 一般资料

回顾性调查我院2013—2014年使用唑来膦酸注射液治疗的原发性骨质疏松住院患者,排除患有可能影响体温的疾病及使用可能影响体温药物的患者,有完整记录用药前后体温的患者142例,分为预防用药组及非预防用药组。预防用药组57例,男12例,女45例,年龄(68.28±10.63)岁,身高(1.58±0.22) m,体质量(59.96±17.62) kg,用药前一天体温(36.8±0.5) ℃。非预防用药组85例,男15例,女70例,年龄(66.20±11.34)岁,身高(1.59±0.07) m,体质量(59.71±15.20) kg,用药前一天体温(36.7±0.4) ℃。两组患者年龄、身高、体质量、用药前一天体温比较,差异无统计学意义(P>0.05),具有可比性。

1.2 方法

1.2.1 给药方法 唑来膦酸注射液(商品名:密固达,诺华制药有限公司,进口商品注册证号: H20070127,规格:每支5 mg∶100 mL)静脉滴注,按药物说明给药,一次静脉滴注唑来膦酸(无水物) 5 mg,100 mL水溶液以输液管恒定速度滴注,滴注时间≥15 min,给药前静脉注射0.9%氯化钠注射液250~1 000 mL进行水化。预防用药组于当天静脉滴注唑来膦酸注射液前给予对乙酰氨基酚片650 mg,qd; 650 mg,bid,口服1 d;650 mg,tid,连续口服3 d。

1.2.2 观察指标 按体温≥37.5 ℃为发热,记录并分析预防用药组及非预防用药组患者出现发热的例数、出现发热时间分布及最高体温出现的时间分布情况。查阅并记录患者用药前1天、用药当天、用药后第1天、用药后第2天及用药后第3天的体温。

1.2.3 统计学方法 采用SPSS17.0版统计软件进行数据处理,分别对预防用药组及非预防用药组用药当天、用药后第1天、用药后第2天及用药后第3天的体温进行单因素方差分析,检验水准α=0.05。以P<0.05为差异有统计学意义。

2 结果
2.1 不同时间体温

静脉滴注唑来膦酸注射液患者不同时间体温见图1。

图1 静脉滴注唑来膦酸注射液患者不同时间体温

Fig.1 Curves of body temperature of the patients after intravenous zoledronic acid

2.2 预防用药组患者体温变化

预防用药组静脉滴注唑来膦酸注射液后体温随时间变化见表1。用药后不同时间患者的体温差异有统计学意义(F=9.355,P<0.01)。多重比较结果显示用药当天与用药后第1天体温差异有统计学意义(P<0.01),用药后第1天与用药后第2天及第3天体温比较差异有统计学意义(P<0.01)。用药当天、用药后第2天及第3天的体温均差异无统计学意义(P>0.05)。

表1 预防用药组静脉滴注唑来膦酸注射液后体温随时间变化情况
Tab.1 Variation of body temperature over time after intravenous zoledronic acid in prevention group ℃
时间 最小
最大
平均
平均值95%置信区间 标准
下限 上限
用药当天 35.4 39.1 36.9 36.7 37.0 0.64
用药后第1天 35.8 39.5 37.3 37.1 37.6 0.94
用药后第2天 36.0 38.7 36.9 36.8 37.1 0.65
用药后第3天 35.8 38.5 36.7 36.6 36.8 0.46

表1 预防用药组静脉滴注唑来膦酸注射液后体温随时间变化情况

Tab.1 Variation of body temperature over time after intravenous zoledronic acid in prevention group ℃

2.3 非预防用药组患者体温变化

非预防用药组静脉滴注唑来膦酸注射液后体温随时间变化见表2。用药后不同时间患者的体温差异有统计学意义(F=21.89,P<0.01)。多重比较结果显示用药当天与用药后第1天及第2天体温比较差异有统计学意义(均P<0.01),用药后第1天与用药后第2天及第3天体温比较差异有统计学意义(均P<0.01),用药后第2天与第3天体温差异有统计学意义(P<0.01),用药当天与用药后第3天体温差异无统计学意义(P=0.533)。

表2 非预防用药组静脉滴注唑来膦酸注射液后体温随时间变化情况
Tab.2 Variation of body temperature over time after intravenous zoledronic acid in non-prevention group ℃
时间 最小
最大
平均
平均值95%置信区间 标准
下限 上限
用药当天 35.5 38.7 36.7 36.6 36.8 0.46
用药后第1天 36.0 40.3 37.4 37.2 37.6 0.95
用药后第2天 36.0 39.1 37.1 37.0 37.2 0.67
用药后第3天 35.1 38.1 36.7 36.5 36.7 0.47

表2 非预防用药组静脉滴注唑来膦酸注射液后体温随时间变化情况

Tab.2 Variation of body temperature over time after intravenous zoledronic acid in non-prevention group ℃

2.4 3 d内发患者热例数比较

本研究中142例用药期间出现体温>37.5 ℃患者有68例,占全部患者的47.89%。预防用药组共出现发热26例,非预防用药组共出现发热42例,具体见表3。

表3 两组患者3 d内发热例数比较
Tab.3 Comparison of fever within 3 days between two groups of patients
组别 例数 用药当天 用药后第1天 用药后第2天 用药后第3天
% % % %
预防用药组 57 8 14.04 25 43.86 9 15.79 2 3.51
非预防用药组 85 4 4.71 37 43.53 22 25.88 3 3.53

表3 两组患者3 d内发热例数比较

Tab.3 Comparison of fever within 3 days between two groups of patients

2.5 体温峰值分布情况

预防用药组体温峰值出现在用药后第1天的例数最多,达19例,非预防用药组体温峰值也是出现在用药后第一天的例数最多,达29例,具体见表4。

表4 两组患者体温峰值分布情况
Tab.4 Distribution of temperature peak in two groups of patients
组别 发热例数 用药当天 用药后第1天 用药后第2天 用药后第3天
% % % %
预防用药组 26 4 15.38 19 73.08 3 11.54 0 0.00
非预防用药组 42 1 2.38 29 69.05 10 23.81 2 4.76

表4 两组患者体温峰值分布情况

Tab.4 Distribution of temperature peak in two groups of patients

3 讨论

唑来膦酸是第3代双膦酸盐制剂,其抑制骨转移和抗骨吸收的活性是前几代药物100~850倍[6],是目前药理活性最强的双膦酸盐。在唑来膦酸不良反应中,发热最常见,发生率较高,其可能的机制是唑来膦酸是FPP合成酶最强有力的抑制剂,其通过抑制FPP合成酶而导致异戊烯基二磷酸和二甲基丙烯二磷酸在细胞内的累积,从而间接激活γδT 细胞增殖、活化,释放白细胞介素(IL)-6 及肿瘤坏死因子α(TNF-α),致使机体体温升高[7]

两组全部患者体温整体变化趋势一致,用药当天体温低于37 ℃,用药后第1天体温明显升高,用药后第2天及第3天体温较第1天明显下降。预防用药组用药后第1天体温最高,与用药当天、用药后第2天及第3天体温之间差异均有统计学意义,其他几天体温比较差异无统计学意义;非预防用药组用药后第1天体温最高,与用药当天、用药后第2天及第3天体温之间均差异有统计学意义;而用药后第2天体温较第1天有所下降,但仍与用药当天及用药后第3天体温之间差异有统计学意义。

对使用唑来膦酸注射液期间体温>37.5 ℃的68例患者不同时间体温升高分布进行分析,用药当天体温升高概率预防用药组高于非预防用药组,用药后第1天及第3天两组患者体温升高概率相当,用药后第2天预防用药组体温升高概率较非预防用药组明显降低。对静脉滴注唑来膦酸注射液患者最高体温出现时间分布进行分析,最高体温出现在用药当天及用药后第1天的概率,预防用药组高于非预防用药组,最高体温出现在用药后2天及用药后第3天的概率,预防用药组低于非预防用药组。

从本研究结果来看,预防用药对静脉滴注唑来膦酸患者用药当天及用药后第1天的体温影响不大,但可明显降低用药后第2天的体温。文献报道预防用药的方式多为用药前口服给予非甾体类抗炎药,本研究中不同科室用药习惯不同,有的科室只在用药前给予对乙酰氨基酚650 mg,口服一次;有的科室用药当天给予对乙酰氨基酚650 mg,bid,口服;有的科室从用药当天开始给予对乙酰氨基酚650 mg,tid,连续口服3 d。从患者体温变化趋势分析,预防用药应选择从用药当天开始连续3 d口服非甾体类抗炎药的方式更为适合,与王暖风等[9]报道一致,有关预防用药的具体方式有待大样本研究进一步证实。

The authors have declared that no competing interests exist.

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目的:探讨唑来膦酸静脉注射治疗绝经后骨质疏松症出现急性期不良反应( APR)情况及可能的影响因素。方法分析2012年8月-2013年6月期间我院内分泌科、骨科应用唑来膦酸治疗绝经后骨质疏松症的患者107例,均应用 唑来膦酸5mg静脉注射。分为发生APR组[APR(+)]及未发生APR组[APR(-)],比较两组之间年龄、BMI、是否曾服用钙片、非甾体类消炎 药(NSAIDs)、双膦酸盐等因素与APR的相关性。结果(1)107例患者中总不良反应发生率为83.2%;其中发热78例(72.9%);肌肉痛 51例(47.7%);发热和胃肠道反应2例(1.9%);(2) APR(+)组BMI水平、曾使用双膦酸盐比例低于APR(-)组(P<0.05),合并骨质疏松性骨折比例高于APR(-)组(P<0.05);(3) Logistic回归分析显示BMI和使用双膦酸盐为APR的发生的保护因素(P<0.05)。结论唑来膦酸(5mg)静脉注射后急性期不良反应较常见, 多为一过性。高BMI及曾使用双膦酸盐可减少急性期不良反应发生的风险。
[本文引用:1]
[8] 张啟维,王英民,薛庆云,. 唑来膦酸治疗绝经后骨质疏松早期药物不良反应分析[J].中国新药杂志,2011,20(8):757-760.
目的:为了解唑来膦酸注射液治疗绝经后骨质疏松后早期不良反应情况及发生率,分析骨密度、合并骨折、应用钙剂、骨吸收抑制剂与早期不良反应的相关性。方法:对2009年-2010年12月期间行5mg唑来膦酸注射液治疗绝经后骨质疏松58例患者进行随访,记录用药后30 d内不良反应及其发生率,并进行分析。结果:唑来膦酸用药后早期不良反应主要表现为发热、肌肉痛、流感样症状、头痛、关节痛等症状,其发生率分别为48.3%,25.9%,31.0%,41.4%,24.2%。总不良反应率为60.3%。多为一过性,用药后30 d内均完全缓解。经比较发现骨密度差异、是否合并骨折与不良反应发生率无明显统计学差异;治疗前是否应用钙剂在头痛、肌肉痛、关节痛的发生率反面有明显统计学差异(P〈0.05)。治疗前是否应用骨吸收抑制剂药物史的患者与治疗后头痛、肌肉痛、关节痛的发生率有明显统计学差异(P〈0.05)。结论:5 mg唑来膦酸注射液治疗早期安全性较高,不良反应症状多为一过性,早期不良反应发生率与骨密度、合并骨折无关,可能与钙剂、骨吸收抑制剂有关。用药前后应及时预防治疗,早期观察无严重后遗症。
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[9] 王暖风,沈建辉,初海坤,.对乙酰氨基酚合并水化护理与单纯水化护理对注射密固达后副反应的抑制作用比较[J].中国地方病防治杂志,2014,29(1):165.
目的本研究旨在评估对乙酰氨基酚对注射密固达引起的用药后反应的抑制作用。方法研究选择100名绝经且患骨质疏松的女性,所有病人均经水化护理。分A、B两组。A组在注射密固达前口服对乙酰氨基酚,连续三天,每6小时口服一次;B组为常规水化护理组。结果对乙酰氨基酚极大降低了因注射密固达引发的用药后反应发病率和严重性。结论连续3天应用对乙酰氨基酚,极大降低了注射密固达引起的用药后反应的发生率和严重性。
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关键词(key words)
唑来膦酸注射液
体温
预防用药

Zoledronic acid injection
Body temperature
Prophylactic use

作者
张春燕
任晓蕾
张海英
张斌
冯婉玉

ZHANG Chunyan
REN Xiaolei
ZHANG Haiying
ZHANG Bin
FENG Wanyu