Short acting insulin analogues in intensive care unit patients

Blood glucose control in intensive care unit(ICU) patients, addressed to actively maintain blood glucose concentration within defined thresholds, is based on two major therapeutic interventions: to supply an adequate calories load and, when necessary, to continuously infuse insulin titrated to patients needs: intensive insulin therapy(IIT). Short acting insulin analogues(SAIA) have been synthesized to improve the chronic treatment of patients with diabetes but, because of the pharmacokinetic characteristics that include shorter onset and off-set, they can be effectively used also in ICU patients and have the potential to be associated with a more limited risk of inducing episodes of iatrogenic hypoglycemia. Medical therapies carry an intrinsic risk for collateral effects; this can be more harmful in patients with unstable clinical conditions like ICU patients. To minimize these risks, the use of short acting drugs in ICU patients have gained a progressively larger room in ICU and now pharmaceutical companies and researchers design drugs dedicated to this subset of medical practice. In this article we report the rationale of using short acting drugs in ICU patients(i.e., sedation and treatment of arterial hypertension) and we also describe SAIA and their therapeutic use in ICU with the potential to minimize iatrogenic hypoglycemia relatedto IIT. The pharmacodynamic and pharmachokinetic characteristics of SAIA will be also discussed.

Conformational flexibility of the pharmacologically important insulin analogues

Understanding the conformational flexibility of the insulin drugs is of great importance for the treatment of diabetes mellitus. Once in the body, the drug must have a certain degree of mobility within a specified period of time for the manifestation of its pharmacological properties. This mobility ensures conformational states necessary for binding with the insulin receptor and activating specific biological processes. In this work we investigated conformational flexibility of the pharmacologically important insulin analogues—insulin lispro, insulin aspart, insulin glulisine, and insulin glargine, using the molecular dynamics simulation method. This study provides new insight into the nature of behaviour of A-and B-chains. It has been found out that B-chain substitutions result in rapid acting, while long-lasting action can be achieved by substitutions in both chains. The results of this study can be used for development of new insulin-based antidiabetic drugs.

Glycated haemoglobin reduction and fixed ratio combinations of analogue basal insulin and glucagon-like peptide-1 receptor agonists:A systematic review

BACKGROUND Fixed ratio combinations(FRCs)of analogue basal insulin and glucagon-like peptide-1 receptor agonists are a newer addition to the therapeutic armamentarium for the management of type 2 diabetes mellitus.They reduce treatment complexity by combining two injectables in a single daily injectable,thus potentially improving adherence and persistence.Clinicians wanting to use FRCs would need to choose between members of the class.AIM To describe and contrast the glycated haemoglobin reduction of two FRCs of analogue basal insulin and glucagon like peptide-1 receptor agonist in adults with type 2 diabetes mellitus.METHODS The following Population,Intervention,Comparison,Outcome question was used for the primary analysis:Among adult patients with type 2 diabetes mellitus[P],what is the effect of iGlarLixi[I]compared to IDegLira[C]for bringing about glycaemic control(as measured by reduction in glycosylated haemoglobin)[O]?The Prisma Statement was used as a guideline for framing this systematic review.We searched PubMed,EMBASE and Cochrane library databases and Clinicaltrials.gov using various keywords and medical search headings related to type 2 diabetes mellitus,iGlarlixi,IDegLira and glycated haemoglobin A1c.RESULTS All 14 studies identified by the systematic search met the primary efficacy endpoint of reduction in glycated haemoglobin.There were no head-to-head studies between the FRCs of iGlarlixi and IDegLira,and we therefore did an indirect comparison based on a common comparator of insulin glargine U100.Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin when compared to insulin glargine U100.However,using indirect comparisons,IDegLira had a greater haemoglobin A1c reducing ability(0.6%vs 0.3%).The indirect comparison is limited by the differences between the studies;the fasting blood glucose targets were slightly higher for iGlarLixi studies when compared to the IDegLira studies(4.0-5.0 mmol/L and 4.4-5.6 mmol/L),and the IDegLira study used a greater average dose of insulin glargine when compared to the iGlarLixi studies(66 U/d vs 40 U/d).CONCLUSION Both iGlarLixi and IDegLira effectively reduce glycated haemoglobin.Indirect comparisons,using insulin glargine as the common comparator,suggest that IDegLira reduces glycated haemoglobin to a greater extent than iGlarLixi.However,given the limitations of indirect comparisons,robust head to head studies and real-world data would better inform clinician choice and clinical practice guidelines.

Relationship between insulin A chain regions and insulin biological activities

AIM To study the relationship between insulinA chain regions and insulin biological activities,we designed a series of insulin analogues withchanges at A21,A12-18 of C-terminal helicalregion and A8-10 Iocated in the region of A6-A11intra-chain disulphide bond.METHODS Insulin A-chain analogues wereprepared by stepwise Fmoc solid-phase manualsynthesis and then combined with natural B-chain of porcine insulin to yield correspondinginsulin analogues.Their biological activitieswere tested by receptor binding,mouseconvulsion and immunological assay.RESULTS[A21Ala]Ins retains 70.3% receptorbinding capacity and 60% in vivo biologicalactivity.[DesA13-14,A21Ala]Ins and[DesA12-13-14-15,A21Ala]Ins still have definite biologicalactivity,7.9% and 4.0% receptor binding,and6.2% and 3.3% in vivo biological activityrespectively.[A15Asn,A17Pro,A21Ala]Insmaintains 10.4% receptor binding and 10% invivo biological activity.[A8His,A9Arg,A10Pro,A21Ala]Ins,[A8His,A9Lys,A10Pro,A21Ala]Insand [A8His,A9Lys,A10Arg,A21Ala]Ins have51.9%,44.3% and 32.1% receptor bindingrespectively,50%,40% and 30% in vivobiological activity respectively,and 28.8%,29.6% and 15.4% immunological activityrespectively. CONCLUSION A21Asn can be replaced bysimple amino acid residues.The A chains withgradually damaged structural integrity in A12-18helical region and the demolition of the A12-18helical region by the substitution of Pro and Asnfor A17Glu and A15Gln respectively can combinewith the B chain and the combination productsshow definite biological activity,the helicalstructure of A12-18 is essential for biologicalactivities of insulin.A8-10 is not muchconcerned with biological activities,but is muchmore important antigenically in binding to itsantibodies,these results may help us design anew type of insulin analogue molecule.

人胰岛素及其类似物中残留溶剂测定方法研究

目的建立人胰岛素及其类似物中有机溶剂残留测定方法,用同一方法测定目前在人胰岛素及类似物生产工艺中普遍存在的甲醇、乙醇、异丙醇、乙腈和正丙醇5种残留溶剂。方法采用顶空气相色谱法,使用DB-624毛细管柱(30 m×0.53 mm,3μm),载气为氮气,流速为2.5 ml/min,检测器为氢火焰离子化检测器,检测器温度为250℃,进样口温度为200℃,分流比为5:1,顶空平衡温度为85℃,平衡时间为20 min,柱温程序为:起始温度40℃,保持10 min,随后以5℃/min升至80℃,随后以20℃/min升至200℃。结果甲醇、乙醇、异丙醇、乙腈及正丙醇峰之间分离良好;专属性、耐用性、精密度良好;甲醇、乙醇、异丙醇、乙腈和正丙醇分别在1.5~60.8、1.1~98.9、0.8~100.4、0.7~10.4、0.8~100.1μg/ml浓度范围内呈良好的线性关系(r2均大于0.99);甲醇、乙醇、异丙醇、乙腈和正丙醇检出限分别为0.6、0.3、0.2、0.2、0.2μg/ml,定量限分别为1.5、1.1、0.8、0.7、0.8μg/ml;各溶剂在人胰岛素及其类似物中平均加标回收率(n=9)均在90%~110%范围内,准确度良好。结论该方法可操作性强、准确、灵敏度高,适用于人胰岛素及其类似物中甲醇、乙醇、异丙醇、乙腈和正丙醇5种残留溶剂测定。

长效胰岛素类似物的安全性回顾:从成人2型糖尿病到妊娠期高血糖

长效胰岛素类似物进入中国市场已有20年,临床应用中得到普遍认可且积累了长足的经验。以德谷胰岛素和甘精胰岛素U300为代表的新型超长效胰岛素也先后进入中国市场,在起效时间、峰值时间、作用持续时间上,更接近生理性基础胰岛素分泌模式,变异性更低,低血糖风险更小,安全性更高。EXPECT研究证实了德谷胰岛素妊娠期应用的疗效和安全性,最新版说明书已做出修订,指出“如果临床需要,可以考虑在妊娠期间使用德谷胰岛素进行治疗”。因此,本文将从临床研究、指南角度,对比分析四种长效胰岛素类似物的特点,解析德谷胰岛素与多个长效胰岛素类似物在临床应用的安全性,尤其是妊娠期高血糖使用德谷胰岛素的安全性。

Prolonged control of insulin-dependent diabetes via intramuscular expression of plasmid-encoded single-strand insulin analogue

Daily insulin injection is necessary for the treatment of the insulin-dependent diabetes. However, the process is painful and inconvenient. Accordingly, we have made exploratory efforts to establish an alternative method for continuous insulin supply via intramuscular injection of a designed plasmid encoding the single-strand insulin analogue (SIA), which provides safe, effective and prolonged control of insulin-dependent diabetes. To generate a SIA, a short flexible peptide was alternatively introduced into the natural proinsulin to replace its original long and rigid C-peptide. Then, the synthetic promoter SP301 was used to drive potent and specific expression of SIA in skeletal muscle cells. By combining the Pluronic L64 and low-voltage electropulse (L/E), the specialized gene delivery technique was applied to efficiently transfer the constructed plasmid into skeletal muscle cells via intramuscular injection. Through these efforts, a plasmid-based intramuscular gene expression system was established and improved, making it applicable for gene therapy. The plasmid-expressed SIA showed biological functions that were similar to that of natural insulin. A single L/E-pSP301-SIA administration provided sustained SIA expression in vivo for about 1.5 months. In addition, the diabetic mice treated with L/E-pSP301-SIA were much healthier than those with other treatments. This plasmid-based system was safe for the treatment of diabetes and did not cause immune responses or pathological damage. The results confirmed that, in a mouse model, long-term positive effects were achieved by a single intramuscular L/E-pSP301-SIA injection, which consequently provided reliable experimental basis for its clinical application for the treatment of diabetes mellitus with promising prospects.

高血糖危象患者静脉输注胰岛素向皮下注射速效胰岛素类似物的转换时机研究

目的 分析高血糖危象患者静脉输注胰岛素向皮下注射速效胰岛素类似物的转换时机。方法 回顾性分析68例高血糖危象患者的临床资料,均予以胰岛素持续静脉泵入,依据速效胰岛素类似物皮下注射不同转换时机分为对照组(30例)和观察组(38例)。对照组在停止静脉输注胰岛素前的1 h予以胰岛素类似物皮下注射,观察组在停止静脉输注胰岛素同时开展速效胰岛素类似物皮下注射。比较两组患者停泵前1 h、停泵前0.5 h、停泵时、停泵后0.5 h、停泵后1 h、停泵后2 h的血糖水平以及血糖波动值,同时记录两组患者低血糖发生情况。结果 观察组患者停泵前1 h、停泵前0.5 h、停泵时、停泵后0.5 h、停泵后1 h、停泵后2 h血糖水平分别为(15.20±2.54)、(15.64±2.62)、(15.70±2.52)、(16.78±2.62)、(16.92±2.50)、(15.54±2.58)mmol/L,与对照组的(15.38±2.46)、(15.59±2.50)、(15.95±2.56)、(16.12±2.48)、(16.56±2.54)、(15.52±2.60)mmol/L比较,差异均无统计学意义(P>0.05)。观察组患者停泵前0.5 h、停泵时、停泵后0.5 h、停泵后1 h、停泵后2 h血糖波动值分别为(0.32±0.10)、(0.38±0.11)、(0.52±0.09)、(0.82±0.12)、(0.11±0.02)mmol/L,与对照组的(0.31±0.10)、(0.40±0.12)、(0.48±0.14)、(0.78±0.15)、(0.10±0.03)mmol/L比较,差异均无统计学意义(P>0.05)。两组于停泵24 h内均未观察到低血糖发生。结论 高血糖危象患者胰岛素静脉输注停止的同时开展速效胰岛素类似物皮下注射能达到胰岛素静脉输注向皮下注射的连续转换,同时将胰岛素水平维持在相对恒定状态,值得采用。

Preliminary crystallographic studies on two insulin analogues which retain high biological activities after alterations in A chain

Using Fmoc solid phase synthesis and site-directed gene mutagenesis, two insulin analogues, [A13-14GABA,A21Ala] porcine insulin and [A3Thr] human insulin, have been prepared respectively, which retain high biological activities. The results show that non-coded y-amino butyric acid (GABA) could replace the dipeptide, Leu-Tyr, in A13-A14 of insulin and

Supramolecular assembly of Cp1-11 peptide and insulin for rapid-acting formulation

In order to improve the life quality of diabetic patients,it is very important to develop rapid-acting insulin formulations that can mimic the physiological meal-time secretion profile of insulin in healthy people.Although several insulin analogues have been designed to provide postprandial glycemic control,still there are some serious disadvantages.A supramolecular strategy is presented here to inhibit insulin aggregation and improve its bioactivity by using Cp1-11 peptide.As a fragment of C-peptide in proinsulin,Cp1-11 peptide was found to influence insulin oligomerization by supramolecular interactions.This work demonstrates that the Cp1-11 peptide can interact with oligomeric insulin and facilitate its disaggregation into the physiologically active monomeric form.Computer simulation indicates that Cp1-11 can insert into the space between the C-terminal tail and the N-terminal helix of the B-chain of insulin,causing dissociation of the insulin dimer.The supramolecular assembly of Cp1-11 and insulin can improve the bioavailability and therapeutic effect of insulin on the control of in vivo blood glucose levels.These results suggest that Cp1-11 peptide can modulate the intermolecular interaction of aggregated insulin and prevent the transition from monomeric to multimeric states,and shows great potential for the development of an effective rapid-acting strategy to treat diabetes.

长效基础胰岛素类似物甘精胰岛素

甘精胰岛素是一种安全、有效的长效基础胰岛素类似物,其降低血糖作用平稳而持久;每日剂量的甘精胰岛素不会引起蓄积作用,与中性鱼精蛋白锌胰岛素(NPH)相比,甘精胰岛素的低血糖发生率,特别是夜间低血糖的发生率较低,可用于1型和2型糖尿患者的基础血糖控制治疗。综述了甘精胰岛素的作用机制、药动学及临床评价。

胰岛素类似物与新型降糖激素类药物

近年来一些适合人体生理需要和使用的胰岛素类似物和非注射式胰岛素逐步上市,胰淀素类似物和胰高血糖素样肽类新型降糖激素类药物也已研发上市。这些新药的出现,为糖尿病患者平稳地控制血糖提供了更多的选择。现着重对其作用特点、临床应用及安全性加以介绍和比较。

治疗糖尿病药物的研究进展

随着对糖尿病基础研究的深入以及临床药理学的迅速发展 ,目前治疗糖尿病用药已打破了传统的磺酰脲类、双胍类等化学结构 ,新的药物相继开发。本文介绍了已在临床使用或正在临床研究的格列美脲、瑞格列奈、那格列奈、AC2 993、曲格列酮、罗格列酮、吡格列酮、米格列醇、pramlintide等 10多个药物的作用机制。

新型基础胰岛素类似物地特胰岛素

通过文献检索综述了地特胰岛素的作用机制、药动学及临床评价。地特胰岛素是一种安全、有效的长效基础胰岛素类似物,与其他长效胰岛素相比,由于其药物分子之间的牢固结合及药物分子与血浆白蛋白的结合,从而延长了其进入循环和产生作用的时间,此作用特点使其降低血糖作用平稳而持久;与中性鱼精蛋白胰岛素相比,地特胰岛素的低血糖发生率特别是夜间低血糖发生率和增加体重的几率较低,可用于1型及2型糖尿病患者的基础血糖控制治疗。

用诺和锐和诺和灵R持续皮下输注治疗2型糖尿病的疗效对比

目的 比较速效胰岛素类似物 (诺和锐 )和短效人胰岛素 (诺和灵R)用外置的胰岛素泵持续皮下输注 (CSⅡ )治疗 2型糖尿病 (T2DM )的疗效。 方法 该研究为持续 2 4周随机、开放、交叉实验 ,2 9例T2DM患者 ,随机分为诺和锐组和诺和灵R组 ,诺和锐为餐前即刻输注 ,诺和灵R为餐前 30min输注 ,12周治疗后两组交换用药。观察两种不同治疗方式患者糖化血红蛋白 (HbA1c)、8个时点 (3餐前后、睡前、凌晨 2点 )血糖、低血糖及胰岛素泵的安全性的差异。 结果 接受诺和锐治疗组的患者HbA1c指标好于诺和灵R组 (P <0 0 1)。 8个时点血糖检测显示诺和锐组三餐后及睡前血糖水平均低于诺和灵R组 (P <0 0 1～ 0 0 5 )。两组患者胰岛素用量、低血糖发生率及胰岛素泵的安全性均无差异。 结论 诺和锐与诺和灵R均可安全有效的降低血糖及HbA1c ,诺和锐用于CSⅡ控制餐后血糖更具优点。

门冬胰岛素与人普通胰岛素在老年2型糖尿病胰岛素泵治疗中的疗效比较

目的比较胰岛素泵输注速效胰岛素类似物(门冬胰岛素,诺和锐)与人普通胰岛素(诺和灵R)治疗老年2型糖尿病高血糖的疗效及安全性。方法118例血糖控制不佳的老年2型糖尿病患者行胰岛素泵强化治疗,随机选择泵用门冬胰岛素或人普通胰岛素,比较组间血糖、血糖达标时间、血糖达标时胰岛素用量、治疗过程中低血糖发生率更低(0.13例次/d,0.18例次/d,P<0.01)血糖的波动及低血糖的发生。结果门冬胰岛素组较人胰岛素组血糖达标时间更短〔(6.0±2.8)d vs(7.6±3.7)d,P<0.05〕,平均餐后血糖控制更佳〔(8.0±0.9)mmol/L vs(8.5±0.8)mmol/L,P<0.05〕,胰岛素泵餐前量比重更小〔(54.9±10.2)%vs(60.0±8.5)%,P<0.01〕,治疗过程中血糖波动更小,即治疗前4天血糖标准差更小〔(3.0±1.0)vs(3.8±1.3),P<0.05〕,两组血糖达标时胰岛素用量无统计学差异。结论老年2型糖尿病的胰岛素泵治疗中,输注门冬胰岛素较人胰岛素餐后血糖控制更佳,胰岛素泵餐前量比重更低,血糖达标时间更短,治疗过程中血糖波动更小。

抗糖尿病新药格鲁辛胰岛素

综述了格鲁辛胰岛素的作用机制、药动学及临床评价。格鲁辛胰岛素是一种最新通过美国FDA批准的快速胰岛素类似物,用于控制1型和2型糖尿病。与常规胰岛素相比,它起效快,维持作用时间短,与长效胰岛素合用或用于胰岛素泵,可维持正常的血糖控制。

胰岛素及其类似物与肿瘤相关性研究进展

大量研究发现,在多种癌症患者中均伴有血浆胰岛素水平的升高,而体内高水平的胰岛素尤其是有胰岛素抵抗的患者,患各种肿瘤的危险性明显增高。高水平的血浆胰岛素可能通过胰岛素信号经典途径放大胰岛素的促生长作用,同时,也可通过改变胰岛素样生长因子(insulin-like growth factor,IGF)信号途径作用,产生协同促细胞增殖及抗细胞凋亡作用,从而诱导肿瘤的形成。由于胰岛素现已成为糖尿病患者降血糖的主要手段之一,越来越多的研究者开始关注接受胰岛素治疗的糖尿病者其肿瘤的发生风险是否会增高。结果显示,无论接受人胰岛素还是胰岛素类似物治疗,肿瘤形成的风险均增高,而同人胰岛素相比,使用胰岛素类似物是否会更加促肿瘤的发生尚存争议。

糖尿病药物治疗新进展——来自2005年欧洲糖尿病年会的最新信息

结合2005年欧洲糖尿病年会的最新信息,对近年来已上市和正在试验及研发阶段的新型降糖药物,如非噻唑烷二酮类胰岛素增敏剂、肠促胰岛素、DPP-Ⅳ抑制剂、新型胰岛素类似物等进行综述。

成骨生长肽10~14及其结构类似物G48A对大鼠成骨细胞增殖和分化的影响

目的探讨成骨生长肽10～14(G36G)及其结构类似物G48A对大鼠成骨细胞增殖与分化功能的影响。方法采用无血清培养条件,G36G和G48A各9组:浓度依次为1×10^(-7)、1×10^(-8)、1×10^(-9)、1×10^(-10)、1×10^(-11)、1×10^(-12)、1×10^(-13)、1×10^(-14)和1×10^(-15)mol/L。甲状旁腺激素(PTH)组:培养结束前6 h培养液中的PTH浓度为1×10^(-8)mol/L。对照组:培养液中含1%牛血清白蛋白。分别观察不同浓度G36G及其类似物G48A对大鼠成骨细胞增殖及碱性磷酸酶(ALP)活性的影响,免疫组织化学法检测不同处理因素对成骨细胞胰岛素样生长因子(IGF)-1蛋白表达水平的变化。结果透射电子显微镜下,G36G、G48A和PTH组的成骨细胞形状丰满,核膜清晰,粗面内质网丰富,高尔基器发育良好,胞质内分泌颗粒增多,可见细胞核分裂相;对照组的成骨细胞胞体扁平,胞质内部分细胞器丧失,细胞核分裂相比例降低。G36G、G48A组分别在1×10^(-11)’、1×10^(-13)mol/L时促进成骨细胞增殖的效应最强。PTH组的ALP活性显著高于对照组(P<0.05)。G36G组在1×10^(-13)mol/L时促进ALP活性作用最强,显著高于对照组(P<0.01)。G48A组在1×10^(-15)mol/L时促进ALP活性作用最强,显著高于对照组(P<0.01)。4组间IGF-1蛋白表达水平的差异无统计学意义(P值均>0.05)。结论G36G及其类似物G48A在体外能够促进大鼠成骨细胞的增殖及分化。