甲状旁腺素治疗骨质疏松研究进展

甲状旁腺素及其类似物对于男性骨质疏松患者可增加骨密度并降低骨折风险,其促进骨生成的作用可针对性地治疗绝经后骨质疏松。相关药物特立帕肽已在美国上市,目前推荐治疗方案为皮下注射特立帕肽20μg/d,但患者终身仅可接受为期24个月的治疗。同时由于皮下注射长期治疗依从性较差,新型透皮贴剂提供了更加方便的给药方式。对特立帕肽与抑制骨吸收药物的联合使用方案及其与阿仑膦酸钠的序贯疗法也在不断探索中。特立帕肽最危险的不良反应是骨肉瘤,在使用前必须询问患者有无相关病史,并评价临床使用特立帕肽的安全性。     

甲状旁腺激素相关肽与骨质疏松

甲状旁腺激素相关肽（PTHrP,1-36)是体内一种真实的分泌形式,它与甲状旁腺激素（PTH,1－34）具有很高的同源性,不仅一级序列同源,三级结构相似,而且能与共同的受体PTH／PTHrP受体相结合,在实验动物和人体上均有效地促进骨骼合成。本文从理论上解释了PTHrP(1-36)作为骨质疏松潜在药物的可能性。     

甲状旁腺素研究进展

甲状旁腺素是治疗骨质疏松症的重要药物,具有刺激骨骼生长,加强骨组织微结构,降低骨脆性的作用。但是,甲状旁腺素属于肽类药物需注射给药且价格昂贵,发展新型非肽类骨质疏松症治疗药物成为当前研究热点。文章综述了甲状旁腺素的生物学活性、结构特征及其构效关系,并对甲状旁腺素与受体的结合机制进行了总结,为开发新型非肽类抗骨质疏松症药物提供了理论依据。     

甲状旁腺素相关肽核定位序列与C末端缺失致肾发育异常的研究北大核心CSCD

目的探索甲状旁腺素相关肽(PTHrP)核定位序列(NLS)与C末端在肾发育中的作用。方法按照小鼠基因型进行分组,同窝野生型(WT)小鼠为对照组;PTHrP Knock In^(-/-)小鼠为实验组。观察2组小鼠体型、肾的形态与结构;采用Masson染色、免疫组织化学、免疫荧光染色、TUNEL染色、蛋白质印迹法比较分析2组小鼠肾纤维化、增殖、凋亡与衰老相关指标,及炎症反应相关分子的表达变化。结果对照组和实验组小鼠的体质量分别为(5.61±0.15)和(2.07±0.11)g;肾质量分别为(35.50±1.59)和(16.18±1.06)mg;Masson染色纤维化面积百分比分别为(1.30±0.15)%和(5.28±0.81)%;PCNA阳性细胞数百分比分别为(12.75±1.95)%和(5.82±0.85)%;TUNEL染色阳性细胞数百分比分别为(2.05±0.50)%和(7.20±1.06)%;p16蛋白相对表达水平分别为0.45±0.11和1.01±0.07;IL-1β阳性面积百分比分别为(6.67±2.01)%和(35.74±3.83)%;实验组的上述指标与对照组相比,差异均有统计学意义(均P<0.05)。结论PTHrP NLS和C末端缺失可通过抑制肾细胞增殖、促进肾细胞凋亡,上调炎症因子的表达而导致肾发育异常。     

重组人甲状旁腺素治疗骨质疏松症的研究进展

本文就重组人甲状旁腺素治疗骨质疏松症的研究概况作一综述,重点介绍重组人甲状旁腺素(1- 34)和重组人甲状旁腺素(1-84)的药理毒理和临床研究工作,为研究和开发甲状旁腺素提供参考。     

甲状旁腺素在肾结石患者病因中的意义

目的探讨甲状旁腺素在肾结石患者病因中的意义。方法选择我院2005年1月至2011年12月收治的134例肾结石患者,其中22例患者为反复肾结石发作。根据疾病复发情况将其分为肾结石组与反复肾结石组。选择同期50例健康体检者为对照组。分别检测三组患者的血清甲状旁腺素(PTH)、降钙素(CT)、骨钙素(BGP)、睾酮(T)、雌二醇(E2)、孕酮(P)、甲状旁腺激素相关蛋白(PTHrP)、钙离子(Ca2+)、血清磷(P3-)、镁离子(Mg2+),比较三组间的差异。结果肾结石组、反复肾结石组患者血清BGP、T、E2、P、PTHrP水平显著高于对照组,差异具有统计学意义(P<0.05);反复肾结石组患者血清PTH显著高于肾结石组与对照组,差异具有统计学意义(P<0.05);反复肾结石组患者血清Ca2+、P3-浓度高于对照组和肾结石组患者,差异具有统计学意义(P<0.05)。结论甲状旁腺激素升高是引起肾结石患者反复发作的原因之一,是不可忽略的泌尿系统结石病因。     

99mTc-MIBI显像甲状旁腺素在原发性甲状旁腺功能亢进中的应用

目的 了解99mTc-MIBI显像在原发性甲状旁腺功能亢进症患者的诊断价值及与甲状旁腺紊(PTH)放射免疫分析的关系.方法 31例怀疑原发性甲状旁腺功能亢进症患者根据其后手术病理结果分为腺瘤组7例、增生组3例、正常组(经检查排除甲旁亢)21例,静脉注射370 MBq(10mCi),99mTc-MIB行双时相采集,观察甲状旁腺病灶,显像前均进行了血清PTH放射免疫分析检测.结果 腺瘤组7例中6例99mTc-MIBI显像阳性,增生组3例中2例辨99mTc-MIBI显像阳性,正常组无1例发现甲状旁腺病灶,根据病理结果显像发现腺瘤敏感性为85.7%,显像发现增生敏感性为66.7%,特异性为100?mTc-MIBI显像阳性患者的PTH:(251.91±113.56)ng/dl,99mTc-MIBI显像阴性患者的PTH:(35.37±29.78)ng/dl,两组P＜0.05,有显著性差别;血清PTH水平≥100mg/dl(≥正常上限5倍)患者,MIBI敏感性88.9%,血清PTH水平≥200 ng/dl,MIBI显像敏感性100%.结论 99mTc-MIBI显像对原发性甲状旁腺功能亢进症的诊断敏感性高,尤其是腺瘤,其检测敏感性与高血清PTH水平相一致,类似于剂量依赖方式.     

脑钠肽和肽素在心血管疾病中的临床研究进展

<正>近年来,脑钠肽和肽素在评估心血管疾病的风险及预后中的作用日益受到重视。虽然脑钠肽与和肽素的生理功能不尽相同,但二者在评价心血管事件中却有显著的相关性,本文主要就二者在心力衰竭诊断的价值以及在冠状动脉硬化性心脏病的临床应用作一综述。     

影响维持性血液透析患者甲状旁腺素水平的相关因素分析

继发性甲状旁腺功能亢进(SHPT)是慢性肾功能衰竭的常见并发症之一.随着血液透析和腹膜透析2种肾脏替代治疗模式的发展,尿毒症患者的生存期延长,SHPT的发病率也有所增加.甲状旁腺素(PTH)作为一种尿毒症毒素也日益引起人们关注,它不但是SHPT的标志,而且可以引起多种器官损伤.     

Investigational parathyroid hormone receptor analogs for the treatment of osteoporosis

Introduction: Intermittent parathyroid hormone (PTH) administration, acting through multiple signaling pathways, exerts an osteoanabolic effect on the skeleton that surpasses the effect of other antiosteoporotic agents. However, its efficacy is limited by the coupling effect and relatively common adverse events. Thus, the development of more sophisticated PTH receptor analogs seems imperative.

Areas covered: In this review, the authors summarize the role of PTH signaling pathway in bone remodeling. The authors also summarize investigational analogs targeting this pathway, which may be potential treatments for osteoporosis.

Expert opinion: β-arrestins are multifunctional cytoplasmic molecules that are decisive for regulating intracellular PTH signaling. Recently, in preclinical studies, arrestin analogs have achieved the anabolic bone effect of PTH without an accompanying increase in bone resorption. However, it is not yet known whether these analogs have adverse effects and there are no clinical data for their efficacy to date. On the other hand, several molecules derived either from PTH and PTH-related protein (PTHrP) molecules have been developed. Alternative routes of PTH 1 – 34 delivery (oral, transdermal), the PTH analog ostabolin and the N-terminal PTHrP analogs PTHrP 1 – 36 and abaloparatide, have recently been or are currently being tested in clinical trials and are more likely to become available for use in the near future.     

Conformational studies of a potent Leu11, D-Trp12-containing lactam-bridged parathyroid hormone-related protein-derived antagonist

Human parathyroid hormone-related protein (PTHrP) is expressed in various tissues where it acts as an endocrine/paracrine factor involved in cellular growth, differentiation and development of fetal skeleton. As for parathyroid hormone (PTH), which is the hormone responsible for regulation of extracellular calcium homeostasis, the N-terminal 1-34 fragment can reproduce the full spectrum of calciotropic activities inherent in full-length PTH. Truncation of six amino acid residues from the N-terminus of both hormone sequences generates 7-34 fragments which act as weak antagonists. Although PTH(7-34) is a pure antagonist, PTHrP(7-34) acts as partial agonist against the receptor shared by both hormones, the PTH/PTHrP receptor. In the current study, we analyzed the conformation of [Leu¹¹,d -Trp¹²,Lys²⁶,Asp³⁰]PTHrP(7-34)NH₂ (hybrid-lactam) in a 1:1 mixture of H₂O/TFE-d₃ at pH 4 by circular dichroism, nuclear magnetic resonance and distance geometry calculations. This weak antagonist (K_b= 650 nm ) combines two modifications: Leu¹¹,d -Trp¹² (K_b= 5.1 nm ), reported to eliminate partial agonism and enhance potency, and Lys²⁶-Asp³⁰ lactamization (K_b= 31 nm ), aimed to stabilize the helical structure of the principal binding domain attributed to residues 25-34. The helical content in 30% trifluoroethanol is 88%, i.e., higher than the corresponding linear analog, and comprises the d -Trp¹²-Thr³³ segment. This hybrid lactam contains a rigid helical segment spanning the 14-18 sequence followed by a hinge motif around Arg^19-20, but the sequence 14-18 forms a stable helix. In all potent lactam-containing, PTHrP-derived agonists and antagonists studied so far, the dominant structural motif consists of two helical domains at the two ends of the sequence and of two hinge regions centered around Gly¹²-Lys¹³ and Arg¹⁹. The weakly active agonists and antagonists do not exhibit the “hinge” around position 19. These findings suggest that the presence and location of discrete hinge regions that connect the N- and C-terminal helices are essential for generating the bioactive conformation of ligands for the PTH/ PTHrP receptor.     

吸烟对终末期肾病患者全段甲状旁腺激素与左心室重塑的影响

目的研究并分析吸烟对终末期肾病患者全段甲状旁腺激素（ierH）水平的影响以及与左心室重塑的关系。方法根据吸烟情况将139例慢性肾小球肾炎终末期肾病非透析患者分组,测定各组的iPTH及其他临床化验指标,并计算各组左心室质量指数（LVMI）。分析吸烟对ipTH的影响以及与LVMI的相关性。结果吸烟组iPTH高于不吸烟组,重度吸烟组iPTH高于轻度吸烟组,吸烟与iPTH独立正相关,且iPTH随着吸烟量增加而升高,呈剂量依赖关系;有左心室肥厚组iPTH高于无左心室肥厚组,iPTH与LVMI独立正相关。结论血iPTH指标的提升是终末期肾病吸烟患者高发左心室肥厚症状的关键因素,值得临床重视。     

甲状旁腺激素构效关系的研究进展

甲状旁腺激素(PTH)是生物体内调节钙、磷代谢最为重要的肽类激素之一,其氨基端1-34片段具有全分子PTH与受体结合的能力及生物活性,被广泛用于研究PTH的结构与功能。PTH二级结构中富含α-螺旋,该螺旋结构在PTH与受体相互作用中起重要作用,其中羧基端负责与受体结合,氨基端负责生理活性。现从甲状旁腺激素的结构、与受体的相互作用和构效关系等角度出发,综述了甲状旁腺激素近年来的研究状况,为开发新型骨质疏松症治疗药物提供理论依据。     

甲状旁腺素1-34肽的固相合成

目的以Wang树脂为载体 ,应用芴甲氧羧基 /tBu方法合成人甲状旁腺素。方法芴甲氧羧基保护氨基酸用 1 氧 3 双二甲胺羧基苯骈三氮唑四氟化硼盐 / 1 羧基苯并三氮唑活化后 ,进行缩合反应。合成的多肽用三氟乙酸处理 ,从Wang树脂上切除。所得粗肽用SP Sepharose FF色谱柱和半制备型高效液相色谱分离纯化。结果用反相高效液相色谱法和毛细管电泳法鉴定纯度在 92 %以上。通过电喷雾质谱法测定其分子量为 4 1 1 6D ,与计算值相符。总收率为 8%。结论此工艺简单 ,易于扩大 ,适合于规模化生产     

Parathyroid hormone and related peptides for the treatment of postmenopausal osteoporosis

Osteopenia, a skeletal condition characterised by bone loss, affects over 10% of the North American population, with a worldwide incidence of 200 m. In the absence of treatment, osteopenia usually progresses to osteoporosis, characterised by more severe bone loss and, ultimately, by fractures. In the US alone osteoporosis affects more than 25 m people, and causes more than 1.3 m fractures a year. This skeletal deterioration is accelerated subsequent to menopause and thus can affect women at a relatively young age. Treatment of postmenopausal osteoporosis primarily involves the use of hormones (calcitonin, oestrogen) or organic molecules (bisphosphonates) which are able to prevent skeletal loss through inhibition of osteoclastic bone resorption. While this may be adequate prior to significant skeletal deterioration and fractures, the patient who has already lost large amounts of bone, in the presence or absence of fractures, requires more aggressive therapy to rapidly rebuild the skeleton. There is now substantial evidence that parathyroid hormone (PTH) is an agent capable of reversing such skeletal loss characteristic of osteoporosis. Numerous animal studies, in conjunction with investigator-initiated clinical trials, have demonstrated the anabolic effects of PTH and related peptides in osteoporotic conditions associated with lack of oestrogen. Large, well-controlled clinical trials are underway to evaluate the safety and efficacy of PTH and PTH-like peptides in postmenopausal osteoporosis. The addition of these agents to the clinician’s armamentarium should provide more effective treatment of this condition, thereby preventing the fractures and debilitation that frequently accompany osteoporosis.     

慢性肾衰竭大鼠甲状旁腺激素与肌钙蛋白的相关性分析

目的:探讨慢性肾衰竭(CRF)大鼠甲状旁腺激素(PTH)和肌钙蛋白(cTnI)的相关关系,旨在为临床早期诊断和治疗提供理论依据。方法:雌雄各半Wistar大鼠30只,先随机分为3组:正常组(6只);假手术组(6只),手术组(18只)。然后实行假手术和手术。手术组大鼠喂养4周后,检测血清尿素氮(BUN)、血清肌酐(Scr),确定CRF模型成熟后将其进一步分为CRF组和CRF组+罗钙全组(CRFL组)。用ELISA法检测PTH和cTnI,生化分析仪检测肾功能。结果:手术组和假手术组在大鼠体重、BUN、Scr差异均有显著性;随着给药时间的延长,手术组大鼠PTH和cT-nI均呈下降趋势,且CRF组高于同时间点CRFL组;PTH和cTnI呈直线相关关系。结论:CRF早期即可发生继发性甲状旁腺功能亢进,从而引起心血管系统病变;cTnI是反映CRF大鼠心肌损害的早期指标;重视降低血清PTH在CRF心血管并发症治疗中的作用。     

A novel,mild, specific and indirect maleimido-based radioiodolabeling method

In an effort to design a mild, non-oxidative and site-specific means of radiolabeling bioactive molecules we have employed maleimido-sulfhydryl chemistry to produce bioactive hormone radioligands. We have prepared two novel radioiodolabeled reagents, 3′-maleimidopropanoyl-3-¹²⁵I-tyramide and its retro analog, N-maleoyl-N′-3-(4-hydroxy-3-¹²⁵I-phenyl)propanoy1 ethylenediamide, by either oxidative radioiodination of the precursors or radiolabeling of the phenolic component prior to its incorporation into the radiolabeling reagents. These reagents were then used to radiolabel analogs of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) in an efficient way, yielding reaction mixtures which were easily purified. The radioligands obtained are stable upon storage and bind in a reversible manner to a single population of binding sites displaying affinity in the low nanomolar range. The potencies of these analogs are comparable to the non-modified PTH and PTHrP analogs. This study demonstrates the utility of the novel maleimido-based indirect radioiodination approach and highlights some of its advantages over either direct oxidative procedures or acylation using the Bolton-Hunter reagent.     

Oral delivery of biologically active parathyroid hormone

Purpose. Parathyroid hormone (PTH), the only drug known to stimulate bone formation, is a peptide therapeutic indicated in the treatment of osteoporosis. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH in rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy-4-methoxy)bensoyl]amino caprylic acid (4-MOAC). Methods. 4-MOAC was selected from a group of 100 delivery agents based on in vitro chromotography studies and in vivo screening studies in rats. The PTH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. Results. Monkeys were administered an aqueous solution containing 4-MOAC and PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtained. The relative bioavailability of oral PTH was 2.1% relative to subcutaneous administration. The biological activity of the orally-delivered PTH was further evaluated in a rat model of osteoporosis. These studies showed that the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4-MOAC and PTH. The preliminary evaluation of this interaction by NMR is described. Conclusions. 4-MOAC facilitates the absorption of PTH following oral administration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.     

RP-HPLC法测定注射用重组人甲状旁腺素含量

目的:建立RP-HPLC法测定注射用重组人甲状旁腺素的含量。方法:色谱柱为Agilent Zorbax 300SB C18(150 mm×4.6 mm,3.5μm),流动相为0.2 mol.L-1硫酸盐缓冲液(pH2.3)-乙腈(75∶25),流速0.8 mL.min-1,检测波长为214 nm,柱温为40℃。结果:线性范围:在10~30μg.mL-1浓度范围内与峰面积呈良好线性关系(r=0.9997,n=5),最低检出限为20 ng,平均回收率为99.8%(n=9)。结论:本方法准确,重复性好,可为注射用重组人甲状旁腺素质量评价提供较为可靠的分析方法。