特立帕肽致不良反应文献分析

目的:探讨特立帕肽致不良反应(ADRs)的规律和特点,为临床安全用药提供参考.方法:检索2002年1月-2020年12月PubMed、Web of Science、Springer Link、中国知网(CNKI)、万方数据知识服务平台及维普数据库中特立帕肽致不良反应的病例报道,对纳入文献的有效信息进行提取并分析.结果:...     

特立帕肽与骨肉瘤风险的研究进展

特立帕肽作为促骨形成药物,被批准用于治疗骨质疏松症,2011 年在中国上市。因大鼠毒理学研究发现特立帕肽增加骨肉瘤风险,美国食品药品监督管理局（U.S. Food and Drug Administration, FDA）和国家药品监督管理局药品审评中心（Center for Drug Evaluation, CDE）在批准的说明书给予黑框警示。本文将从分子机制、动物研究、临床研究及上市后安全性研究等多维度论证特立帕肽治疗与骨肉瘤风险间的相关性,以期为骨质疏松患者临床用药提供参考,使黑框警告不再成为其治疗的阻碍。     

甲状旁腺激素激动剂特立帕肽

骨质疏松症是一种以低骨量和骨组织退化为特征的最常见的代谢性骨病。这种疾病将导致大量骨质丢失，骨骼脆性增加，容易发生骨折。常见骨折部位是髋骨、脊椎骨和腕骨。市场上多数治疗骨质疏松症的药物，如雌激素、双磷酸盐类和降血钙素均属骨吸收抑制剂。而其他一些药物如氟化物、甲状旁腺激素(PTH)是骨形成促进剂。     

特立帕肽不良反应分析

目的 分析特立帕肽不良反应的发生规律及特点,为临床安全用药提供参考.方法 检索2002年1月1日至2020年3月31日中国知网、维普网、万方数据、中国生物医学文献数据库、PubMed数据库、Embase,收集特立帕肽致不良反应的个案报道并进行统计分析.结果 收集17篇文献20例不良反应个案报道,主要涉及肌肉骨骼损害、代...     

首批重组特立帕肽国家标准品的研制与标定

目的:为满足国内重组特立帕肽(重组人甲状旁腺激素1-34,rhPTH1-34)及相关制剂质量控制的需要,研制并标定首批重组特立帕肽国家标准品.方法:采用免疫斑点、质谱、Ⅳ端氨基酸测序、反相HPLC鉴别、氨基酸组成以及肽图等方法对用于待标品制备的原液进行定性及结构确认;以WHO第2批rhPTH1-34国际标准品15/30...     

高效液相色谱法测定特立帕肽含量的方法研究

目的:建立HPLC测定特立帕肽含量的方法。方法:采用Kromasil C18(4.6 mm×250 mm,5μm)色谱柱,流动相为0.05mol.L-1氯化钾溶液(磷酸调节至pH 4.5)-乙腈(75∶25),流速1.0 mL.min-1;检测波长210 nm;柱温为室温;进样量20μL。结果:特立帕肽浓度在0.05~0.84 mg.mL-1范围内具有良好的线性关系,r=0.9999。结论:本方法简便、准确,灵敏度高,重现性好,可用于测定特立帕肽的含量。     

国产注射用特立帕肽的过敏性及免疫原性研究

目的 考察国产注射用特立帕肽在动物中的过敏性及免疫原性.方法 对豚鼠和家兔分别于0d和14 d注射一定浓度的特立帕肽,观察豚鼠全身变态反应及对家兔的免疫原性,并采用ELISA分析家兔血清抗体的变化规律.结果 给药后豚鼠未见明显全身变态反应.家兔免疫原性实验结果表明,低剂量组（1 μg/kg）血清中的IgE含量经免疫后无明显上升;中剂量组（5μg/kg）和高剂量组（10 μg/kg）血清中IgE含量在首次免疫后略有快速上升,但随后中剂量组恢复正常,而高剂量组在加强免疫后IgE含量仍有一定上升.结论 国产注射用特立帕肽在拟定的人用剂量范围内具有很好的安全性,可供皮下注射给药.     

重组特立帕肽注射液对去卵巢所致大鼠骨质疏松模型的药效学观察

目的观察重组特立帕肽注射液对去卵巢大鼠骨质疏松治疗作用,并对市售原研产品复泰奥进行比较。方法选择60只雌性SD大鼠,依据动物的体质量、骨密度分为Sham组和双侧去卵巢(OVX)组,OVX组动物切除双侧卵巢;手术8周后,对OVX组再随机分为6组,分别接受赋形剂或不同剂量受试药及复泰奥治疗,连续治疗8周;取各组动物第L1~L4截段进行BMD检测,取L4腰椎和左股骨进行生物力学评价。结果治疗结束时赋形剂亚组BMD显著低于假手术组及受试药和复泰奥各组,相同剂量的受试药物和复泰奥均无显著性差异。结论重组特立帕肽注射液可显著改善去卵巢动物的BMD及腰椎最大荷载,受试药和复泰奥的药效表现相似。     

特立帕肽联合维生素D和口服钙，有助于牙槽骨组织再生

特立帕肽是一种含有34种氨基酸的甲状旁腺激素类药物，周期性服用特立帕肽有助于骨组织的合成。特立帕肽在治疗骨质疏松和骨折等方面功效显著，但目前有关其对牙槽骨组织再生方面的数据比较匮乏。本试验旨在研究特立帕肽在促进牙槽骨组织再生方面的疗效。     

A review of teriparatide and its clinical efficacy in the treatment of osteoporosis

Until recently, antiresorptive medications such as bisphosphonates and raloxifene represented the main pharmacological treatment options for patients with osteoporosis. With the introduction of teriparatide (rhPTH_(1–34)), a recombinant formulation of parathyroid hormone (PTH) consisting of the first 34 amino acids of the N-terminal region, bone-forming therapy has now become possible. Preclinical, as well as human studies, have shown increases in trabecular as well as cortical bone mass with subsequent improvements in bone microstructure and cortical thickness. The subcutaneous daily dose of teriparatide 20 μg has been shown to decrease the occurrence of new vertebral fractures in caucasian women (70 years of age) by 65%, in a large randomised, double-blind placebo-controlled trial. Moderate-to-severe fractures or multiple vertebral fractures could be reduced by 90 and 77%, respectively. There was also a significant beneficial effect on new nonvertebral fractures (-35%) by the end of the 21-month treatment period. The reduction in nonvertebral fractures became evident after ～ 8 – 12 months of treatment. Smaller studies in men with low bone mass showed similar effects on bone mineral density and changes in bone turnover markers when compared to the results obtained in postmenopausal women. Recent data suggest that teriparatide is best given as monotherapy and not in combination with a bisphosphonate. Previous bisphosphonate treatment is also likely to diminish the bone anabolic potential of teriparatide. In order to preserve bone mass gained during the recommended 18- to 24-month treatment period, antiresorptive medication should be prescribed following teriparatide treatment. Studies so far have not shown serious PTH-related side effects. Hypercalcaemia is usually mild and transient and the osteosarcoma risk reported in rat toxicology studies is very unlikely to be predictive of a similar risk in humans. As teriparatide is expensive, its use at the moment should be limited to patients with more severe forms of osteoporosis, usually with the presence or history of one or more fractures because of those patients’ high risk for subsequent fractures.     

Study description and baseline characteristics of the population enrolled in a multinational,observational study of teriparatide in postmenopausal women with osteoporosis: the Asia and Latin America Fracture Observational Study (ALAFOS)

Objective: To describe the study design and baseline patient characteristics of the Asia and Latin America Fracture Observational Study (ALAFOS) to better understand the profile of patients receiving teriparatide during the course of routine clinical practice in Asia, Latin America, the Middle East and Russia.

Methods: Prospective, observational, non-interventional study in postmenopausal women with osteoporosis who are prescribed teriparatide for up to 24?months, according to local medical standards, with a 12?month post-treatment follow-up.

Measures: Demographics, risk factors for osteoporosis and fractures, history of fracture, prior osteoporosis medications, comorbidities, physical function, back pain and quality of life (QoL).

Results: In total 3031 postmenopausal women (mean age 72.5?years) recruited at 152 sites in 20 countries were analyzed; 62.9% had a history of fragility fracture after age 40 (33.0% of patients with spinal, 14.2% with hip fractures). The mean (SD) bone mineral density T-scores at baseline were ?3.06 (1.40) and ?2.60 (1.05) at the lumbar spine and femoral neck, respectively. At entry, 43.7% of patients were naïve to prior osteoporosis treatments; 40.5% of patients reported ≥1 fall in the past year. The median (Q1; Q3) EuroQoL Visual Analog Scale (EQ-VAS) for perceived overall health status was 60 (50; 80). The mean (SD) worst back pain Numeric Rating Scale in the last 24?hours was 4.6 (3.3).

Conclusions: Our data indicates that patients who were prescribed teriparatide in the ALAFOS participant countries had severe osteoporosis, high prevalence of fractures, disabling back pain and poor QoL. The frequency of patients receiving prior osteoporosis medications was lower than in previous observational studies conducted in other locations.     

定量PCR法和DNA杂交法检测聚乙二醇修饰尿酸酶原液中DNA残留量的比较

目的 建立快速准确的聚乙二醇修饰重组尿酸酶(PEGylated uricase,PEG-UHC)原液DNA残留量测定法,为其他多位点PEG修饰蛋白药物的DNA残留量检测提供参考。方法 参照中国药典2020年版三部“外源性DNA残留量检测法”第一法DNA探针杂交法和第三法定量PCR法,检测PEG-UHC原液DNA残留量;对定量PCR法进行检测限度、线性范围、准确度和精密度等方法学验证;进行3批次PEG-UHC原液DNA残留量测定。结果 探针杂交法DNA残留量测定线性范围为1×10^-4~0.1 ng·µL^-1,3批次PEG-UHC原液未见明显显色,DNA残留量均低于每剂10 ng。PCR法检测限度为1×10^-5 ng·µL^-1,DNA浓度在1×10^-4~100 ng·µL^-1内线性关系良好(R²=0.999)。不同浓度的标准DNA在PEG-UHC原液中的回收率范围为92.57%~114.17%,表明PEG偶联物对定量PCR影响较小。3批次PEG-UHC原液中DNA残留量分别为每剂0.143,0.187,0.154 ng,符合国家药品监督管理局限量要求。结论 DNA探针杂交法为传统定性检测,耗时较长,准确度较低。定量PCR法操作简便快速、灵敏度高,且可定量分析,适于PEG-UHC等多位点PEG修饰蛋白药物DNA残留量测定。     

Real-world effectiveness of daily teriparatide in Japanese patients with osteoporosis at high risk for fracture: final results from the 24-month Japan Fracture Observational Study (JFOS)

Objective: The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients.

Methods: In routine clinical practice, Japanese patients initiated on teriparatide 20?μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected.

Results: Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6–12 months, 51.6% during 12–18 months, and 58.8% during 18–24 months (all p?Conclusions: JFOS demonstrated effectiveness of teriparatide 20?μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.     

荧光染色法测定重组酵母乙型肝炎疫苗原液中残留DNA的影响因素分析

目的: 对荧光染色法测定重组酵母乙肝疫苗原液中残留DNA的影响因素进行探索分析,以了解该方法对本疫苗残留DNA检定的适用性。方法: 参照探针杂交法对乙肝疫苗原液残留DNA的测定结果,对乙肝疫苗原液中可能存在Tween-20、PEG、蛋白等物质对荧光染色法测定残留DNA含量的影响进行分析,对该方法的线性范围、用于乙肝疫苗原液残留DNA检定的准确性和重复性进行了研究,并对不同来源DNA标准存在的差异进行比较。结果: 荧光法测定酵母乙肝疫苗残留DNA线性范围为2.5 ng.mL-1~80 ng.mL-1;发现Tween-20、PEG等对残留DNA检测影响较小,加标回收率均在80%-120%之间;而蛋白质对检测影响较大,经酚-三氯甲烷抽提后可有效去除蛋白质干扰,回收率达到90%左右,CV小于10%;同时发现不同来源的DNA标准品存在荧光标记效率的差异。 结论: 乙肝疫苗原液经处理去除蛋白干扰后可采用荧光染色法进行残留DNA含量的测定,但应注意使用与疫苗表达系统相同宿主来源的DNA标准品。     

Drug safety evaluation of parathyroid hormone for hypocalcemia in patients with hypoparathyroidism

Introduction: Hypoparathyroidism is a rare disorder characterized by low serum calcium levels and high serum phosphate levels, and low or inappropriately normal levels of parathyroid hormone (PTH). This disease is commonly treated with calcium supplements and active vitamin D metabolites or analogues, but large doses of these supplements are often utilized to relieve the symptoms caused by hypocalcemia, without guarantee of a physiological normalization of calcium-phosphate homeostasis.

Areas covered: Several studies have investigated replacement therapy with recombinant human PTH [rhPTH (1-84) and rhPTH (1-34)] for subjects with hypoparathyroidism. In 2015, The Food and Drug Administration (FDA) approved, in the United States, rhPTH (1–84), named Natpara®, a bioenginerred rhPTH, for the management of chronic hypoparathyroidism not well controlled with conventional therapy. This article evaluates the safety and tolerability of rhPTH (1–84) in patients with chronic hypoparathyroidism, and also describes the studies conducted so far on rhPTH (1-34) used for chronic hypoparathyroidism.

Expert opinion: The research done in this field has shown that replacement treatment with rhPTH is an attractive option for subjects with hypoparathyroidism who are unable to maintain stable and safe serum and urinary calcium levels. However, since therapy with rhPTH is a long-term management option in hypoparathyroidism, more long-term safety data are needed.     

关于生物制品残余DNA质量控制问题

随着生物医药技术的飞速发展,越来越多的哺乳动物细胞,尤其是连续传代细胞系用于生产疫苗和治疗性生物制品。重组蛋白制品的用量随着临床治疗效果的需求越来越大,由微克级上升到了毫克甚至克级,需要长期反复用药的生物制品也越来越多。同时疫苗的使用者为健康人群,而且很多疫苗使用人群也扩大到婴幼儿,这使得药品监管部门不得不更加重视疫苗等生物制品的安全性,其中细胞残余DNA的质量控制一直是人们关注的热点。本文就不同时期国内外对于DNA残留问题的看法、DNA残留量质控标准的制定、DNA残留量检测方法等研究进展作一综述,并提出残余DNA问题未来需要进一步开展的工作。