吡格列酮对Zucker fa/fa大鼠模型药效学初步研究

目的探讨吡格列酮对自发性Zucker fa/fa大鼠药效的检测指标及评价标准。方法将45只雄性Zucker fa/fa大鼠按体重均一原则分为正常对照组、模型对照组和吡格列酮组(每组各15只)。吡格列酮组以吡格列酮作为处理因素,8mg.kg-1灌胃给药;正常对照组和模型对照组则给予相应剂量的生理盐水。每天1次,连续3周。给药前及给药期间每周监测1次空腹胰岛素水平;给药前及给药3周后测定总胆固醇、甘油三酯及游离脂肪酸并行正常血糖-高胰岛素钳夹实验。结果吡格列酮能明显降低血清胰岛素、甘油三酯及游离脂肪酸水平(P<0.05);正常血糖-高胰岛素钳夹实验结果表明,能明显提高吡格列酮组大鼠的葡萄糖输注率与胰岛素敏感指数(P<0.05)。结论可将甘油三酯、游离脂肪酸及血清胰岛素水平与高胰岛素-正常血糖钳夹实验结果为评价指标,用于自发性ZF大鼠模型评价吡格列酮的药效作用。     

胰岛素抵抗大鼠模型的建立与评价

目的探讨应用高胰岛素-正葡萄糖钳夹技术（钳夹法）对模型动物进行胰岛素敏感性评价的可行性。方法雄性Wistar大鼠喂以富含不饱和脂肪酸的特殊高脂肪膳食5周。应用钳夹法评价大鼠的胰岛素敏感性。结果与常规喂养大鼠相比,高脂膳食组的葡萄糖输注率显著降低,空腹血浆胰岛素显著升高。同时,高脂膳食大鼠出现高脂血症。结论应用钳夹法评价大鼠的胰岛素敏感性较为灵敏、准确、可靠。     

米力农诱导的胰岛素抵抗对大鼠糖脂代谢的影响

目的　探讨选择性磷酸二酯酶Ⅲ (PhosphdiesteraseⅢ ,PDE3)抑制剂米力农 (milrinone)对大鼠胰岛素分泌、血糖、血浆游离脂肪酸 (freefattyacid ,FFA)的影响和剂量依赖关系 ,及其在胰岛素钳夹状态下对大鼠糖代谢和胰岛素敏感性的影响。方法　由植入导管给予大鼠不同剂量的米力农 ( 1,5 ,2 5 μmoL·kg- 1 )在不同时相测定血糖、血浆FFA和胰岛素水平并与对照组比较。在意识清醒状态下建立大鼠高胰岛素 正常血糖钳夹技术 ,并在钳夹 12 0min时分别经导管给予米力农 ( 2 5 μmoL·kg- 1 )和 2 5 %二甲基亚砜 (DMSO ,对照组 )。采用气相色谱 -质谱仪 (GC MS)测定糖代谢率。结果　 3个不同剂量米力农组血浆FFA浓度明显高于对照组和给药前 ,在注射后 2min ,各组FFA升高的百分数为 :5 0 %、5 2 %、5 5 % ( 1,5 ,2 5 μmoL·kg- 1 )。在 ( 5 ,2 5 )μmoL·kg- 1 组血浆胰岛素水平也明显高于对照组和给药前 ,仅 2 5 μmoL·kg- 1 组血糖浓度高于对照组和给药前。在胰岛素钳夹研究中 ,米力农处理组大鼠血浆FFA明显高于给药前 ( 173± 15vs 6 34± 87μmoL·kg- 1 ) ,肝糖输出 (HGP)也明显高于给药前( - 5 1± 3 1vs 7 5± 2 0mg·kg- 1 ·min)。葡萄糖输注率 (Glucoseinfusionrate,GIR)明显低于对照组和给药前 (     

高胰岛素-正葡萄糖钳夹技术的研究进展*

高胰岛素-正葡萄糖钳夹技术（简称正糖钳技术）已被公认为测定胰岛素敏感性的金标准,并在糖尿病及其治疗药物的研究中得到日益广泛且深入的应用。该技术通过同时输注外源性胰岛素与葡萄糖,升高血浆胰岛素水平,同时维持血糖在基础稳态水平。该技术减少了内源性因素对实验的影响,具有准确可靠、重复性好、避免低血糖发生等优点。现介绍该技术的原理、方法、应用等,以促进该技术在我国的进一步完善、发展及应用。     

重组人胰高糖素样多肽-1(7-36)对胰岛β细胞分泌功能影响的实验研究

目的观察重组人胰高糖素样多肽-1（7-36）（促胰岛素生成药）对大鼠血糖和胰岛β细胞功能的影响.方法12周龄OLETF大鼠随机分为给药组和模型组（n=10）,并以同种系非糖尿病LETO大鼠作为对照组;干预2,8周后,处死;于12,14及20周龄时,行口服葡萄糖耐量试验,测定血糖及血清胰岛素.结果经该药治疗,能降低2型糖尿病OLETF大鼠的进食量和体质量,增加血清胰岛素水平,部分改善葡萄糖耐量.结论重组人胰高糖素样多肽-1（7-36）能够改善OLETF大鼠分泌胰岛素的功能,降低血糖.     

胰岛素治疗糖尿病的不良反应

胰岛素按作用长短分为短效、中效、长效3类.短效胰岛素是唯一可静脉注射的胰岛素制剂,可使血糖迅速下降,通常给药后20～30min血糖降至最低点,中效胰岛素及长效胰岛素成分相近,均为混悬液,2者区别在于长效胰岛素精蛋白含量较高.     

重组人胰岛素样生长因子1对db／db小鼠血糖的影响

目的:研究重组人胰岛素样生长因子1(rhIGF-1)对近似于人类2型糖尿病的db/db小鼠的降血糖作用.方法:正常饲养db/db及同品系的正常小鼠,定期监测血糖和血胰岛素水平.待db/db小鼠表现出明显的高血糖及高胰岛素血症后随机分为4组,每日皮下注射溶媒、胰岛素或不同剂量的rhlGF-1,共2周.首次给药后每30min测定血糖1次,观测不同干预方式的即时降糖效果.再于每次给药前测定血糖,观察2周内的变化趋势.结果:db/db小鼠饲养至8周龄时表现出明显的血糖升高及高胰岛素血症.所用剂量的胰岛素对db/db小鼠未表现出明显的降血糖作用;rhIGF-1特别是高剂量rhIGF-1即时及短期降糖效果均较明显,可有效保护db/db小鼠.结论:rhIGF-1对db/db小鼠有较好的降血糖作用,对伴有明显胰岛素抵抗的糖尿病患者具有临床应用前景.     

GB-03无针注射器对重组人胰岛素注射液生物活性的影响

目的 考察GB-03无针注射器对重组人胰岛素注射液生物活性的影响,比较无针注射与传统皮下注射重组人胰岛素注射液的生物等效性。方法 采用小鼠双交叉实验生物检定法,用重组人胰岛素注射液(作为对照品)标定经无针注射器处理的重组人胰岛素注射液的生物效价;家兔常规皮下注射和无针注射器注射相同剂量的重组人胰岛素注射液,比较给药后6 h内血糖的变化。结果 经无针注射器处理的重组人胰岛素效价为109.7%;在注射后6 h内观察,采用2种给药途径的家兔各时间点血糖值差异无统计学意义。结论 GB-03无针注射器对重组人胰岛素注射液生物活性无明显影响,家兔无针注射器注射重组人胰岛素注射液与皮下注射具有生物等效性。     

甘精胰岛素联合短效胰岛素治疗高血糖状态30例临床观察

目的探讨甘精胰岛素联合短效胰岛素治疗对明显高血糖的2型糖尿病的疗效及安全性。方法对空腹血糖（FPG）〉11.1mmol/L的2型糖尿病患者30例进行短期甘精胰岛素联合短效胰岛素治疗,观察血糖达标情况及低血糖事件的发生情况。结果采用甘精胰岛素联合短效胰岛素治疗后,30例伴有明显高血糖的2型糖尿病患者血糖能迅速平稳达标,夜间无明显低血糖事件。结论甘精胰岛素联合短效胰岛素治疗能有效模拟人生理胰岛素分泌,有效控制高血糖状态。     

葛根素对高脂饮食大鼠胰岛素敏感性的影响

目的观察葛根素(puerarin,pue)对高脂饮食诱导的胰岛素抵抗(insulin resistance,IR)大鼠胰岛素敏感性的影响。方法以尾静脉注射小剂量链脲菌素(streptozotocin,STZ)和高脂饲料喂养诱导IR大鼠模型,给药治疗8wk后,采用改良的高血浆胰岛素-正常血糖钳夹技术,评价葛根素对大鼠胰岛素敏感性的影响。结果高脂饲料喂养诱导IR大鼠基础血糖值(BBG)、基础血浆胰岛素(BINS)、稳态血浆胰岛素(SINS)均较正常组明显增高,而葛根素治疗组BBG、BINS、SINS较IR模型组均明显降低;高血浆胰岛素-正常血糖钳夹试验中60~120min的平均葡萄糖输注率(GIR60-120),IR模型组明显低于正常组,而葛根素高、中剂量组较IR模型组升高。结论葛根素可降低实验性IR大鼠的血糖和血浆INS水平,改善机体对胰岛素的敏感性。     

A lecithin-based microemulsion of rh-insulin with aprotinin for oral administration: Investigation of hypoglycemic effects in non-diabetic and STZ-induced diabetic rats

The aim of this study was to develop a microemulsion formulation providing an improved efficacy of orally administered insulin. The microemulsions were prepared using Labrafil M 1944 CS, Phospholipon 90 G (lecithin), absolute alcohol and bi-distilled water. The microemulsions of recombinant human (rh)-insulin and aqueous solution (200 IU/kg) were administered intragastrically by a canulla to diabetic and non-diabetic rats. Aprotinin (2500 KIU/g) was added as the enzyme inhibitor to the formulation. Upon the administration of intragastric rh-insulin solution (IS) to non-diabetic rats, the plasma glucose and insulin levels were not changed significantly. Therefore, the hypoglycemic effect caused by subcutaneous rh-insulin solution (SC), microemulsion containing rh-insulin (IME) and microemulsion containing rh-insulin and aprotinin (IMEA) were analyzed in diabetic rats. The area above the plasma glucose levels time curves (AAC), minimum glucose concentration (Cmin) and time to Cmin (tmin) were derived from the plasma glucose profiles. IME and IMEA caused approximately 30% decrease in plasma glucose levels. The decrease in the plasma glucose levels continued after the 90th min. The highest AAC value was obtained when IMEA was administered to rats. The maximum plasma insulin concentration (Cmax), time to reach Cmax (tmax), terminal half-life (t(1/2)), area under the plasma concentration-time curve (AUC), mean residence time (MRT) and elimination rate constant (k(el)) values were also calculated. It was observed that t(1/2) values varied between 0.53 and 1.31h. No significant difference could be found between the pharmacokinetic parameters of the IME and IMEA administered groups. Addition of aprotinin to the microemulsion containing rh-insulin increased bioavailability when compared to those not containing it, although the difference is not significant.     

Needle-free subcutaneous sumatriptan: in the acute treatment of migraine attacks or cluster headache episodes

A needle-free device for delivering a 6?mg fixed dose of sumatriptan into subcutaneous tissues has been developed and approved for the acute treatment of migraine and cluster headache in the US and some EU countries. In a pivotal registration study in healthy adult volunteers, a single dose of needle-free subcutaneous sumatriptan 6?mg demonstrated bioequivalence to a single dose of traditional, needle-based subcutaneous sumatriptan 6?mg when delivered into the abdomen or the thigh, but not the arm. In a noncomparative, multicentre, phase IV study, the administration of (one or two doses of) needle-free subcutaneous sumatriptan 6?mg consistently provided rapid and sustained relief from migraine pain and associated symptoms during the treatment of up to four migraine attacks over a period of up to 60 days among current triptan users. Moreover, the use of needle-free subcutaneous sumatriptan was associated with a significant improvement in treatment satisfaction in these patients who were less than 'very satisfied' with their usual symptomatic therapy. Needle-free subcutaneous sumatriptan was generally well tolerated in the phase IV study. Although the overall adverse event profile of the needle-free delivery system was similar to that previously reported for the needle-based delivery system, it was associated with a numerically higher incidence of administration/injection-site reactions in clinical trials that enrolled healthy adult volunteers.     

Evaluation of the pharmacokinetics of two recombinant human erythropoietin preparations: epoetin zeta and epoetin alfa. 2nd Communication: A monocentric, double-blind, randomized, single dose, three-period crossover trial in healthy volunteers

The subcutaneous bioavailability of a new recombinant erythropoietin preparation (epoetin zeta, CAS 604802-70-2) and the pharmacokinetic properties of this drug compared to a reference product (epoetin alfa, CAS 113427-24-0) were analyzed after a single intravenous bolus injection or subcutaneous injection of 10,000 IU in a three-period crossover design in 48 healthy volunteers. Peripheral venous blood samples were obtained pre-dose, and 0:05, 0:20, 0:40, 1:00, 1:20, 1:40, 2:00, 3:00, 4:00, 6:00, 8:00, 12:00, 24:00, 36:00, 48:00, and 72:00 h post dosing. Samples from 48 volunteers were analyzed by means of a specific immunoassay (ELISA). The systemic bioavailability of epoetin zeta after subcutaneous administration is approximately 24%. Comparison of both preparations showed nearly identical pharmacokinetic properties after subcutaneous administration. The usual bioequivalence limits were fulfilled for all relevant pharmacokinetic parameters.     

Tolerability,pharmacokinetics and pharmacodynamics of CMAB001, an anti-CD11a antibody,in Chinese healthy volunteers and psoriatic patients

Aim:

To evaluate the pharmacokinetics (PK), pharmacodynamics (PD) and primary tolerability of an anti-CD11a monoclonal antibody (CMAB001) in Chinese healthy volunteers and psoriatic patients.

Methods:

Two open-label studies were conducted. One was a parallel-group, single-center, dose-escalation test, including 24 healthy adult volunteers from 18 to 45 years in age. All subjects randomly received a single subcutaneous injection dose of 0.5, 1.0 or 2.0 mg/kg. The other was a multiple-dose study: 10 adult psoriatic patients were administered weekly subcutaneous injections of 1.0 mg/kg for 7 weeks.

Results:

CMAB001 was well tolerated in the single- and multiple-dose studies. Slow absorption was observed in both studies. In the single-dose study, the concentration of CMAB001 reached its highest level 2 d later after the injection, and the C_max increased in an approximate dose-proportionate manner, while the area under curve (AUC) showed much greater than dose-proportionate increase. In the multiple-dose study, the steady-state serum concentration level was attained following the 4th injection.

Conclusion:

CMAB001 exhibited a nonlinear pharmacokinetic profile over the dose range from 0.5 to 2.0 mg/kg, and was well tolerated in healthy volunteers and psoriatic patients.     

Enhanced Bioavailability of Subcutaneously Injected Insulin Coadministered with Collagen in Rats and Humans

The present study was undertaken to develop an agent that stabilizes insulin injected subcutaneously. ¹²⁵I-Porcine insulin with 0.2 U/kg unlabeled porcine insulin was subcutaneously injected with or without collagen in the rat under the depilated skin of the back. At various times, the radioactivity in subcutaneous tissue was assayed for insulin and its metabolites by gel filtration. The degradation and absorption rate constants of insulin at the subcutaneous injection site were estimated according to a one-compartment model. The degradation rate constant of insulin in the presence of collagen at the injection site was less than half of the control rate. The inhibition was confirmed by increases in the immunoreactive insulin plasma levels and the hypoglycemic effect in rats and healthy volunteers. We postulate that collagen prevents insulin from being degraded by inhibiting proteolytic enzymes, mainly collagenase-like peptidase, in subcutaneous tissue.     

Enhanced Bioavailability of Subcutaneously Injected Insulin by Pretreatment with Ointment Containing Protease Inhibitors

The present study was undertaken to develop an ointment preparation containing a protease inhibitor for stabilizing subcutaneously injected insulin. The ointment containing the protease inhibitor, gabexate mesilate or nafamostat mesilate, was applied to the skin around the insulin injection site. Three results were obtained. First, gabexate and nafamostat inhibited insulin degradation in subcutaneous tissue homogenates in vitro. Second, after application of gabexate or nafamostat ointment, an appreciable amount of gabexate or nafamostat appeared in the subcutaneous tissue of rats or hairless mice and their concentrations were comparable to those seen in the in vitro experiment. Third, insulin degradation at the subcutaneous injection site in the rat was depressed after pretreatment with gabexate or nafamostat ointment. Pretreatment with gabexate or nafamostat ointment increased the plasma immunoreactive insulin (IRI) levels and the hypoglycemic effect of insulin in healthy volunteers. These results indicate that gabexate or nafamostat ointments stabilize subcutaneously injected insulin.     

Pharmacokinetic/pharmacodynamic modeling of glucose clamp effects of inhaled and subcutaneous insulin in healthy volunteers and diabetic patients

The pharmacokinetics and pharmacodynamics (PK/PD) of inhaled insulin in humans have not been modeled previously. We rationalized a model for the effects of inhaled insulin on glucose infusion rate during a euglycemic clamp study based on the mechanism of insulin action and compared parameter estimates between subcutaneous and inhaled insulin in healthy and diabetic subjects. Published data from two studies in 11 healthy volunteers and 18 type 1 diabetes patients were digitized. The subjects received four different doses of inhaled insulin and one or three different doses subcutaneously at the start of a 10 h glucose clamp. All data were modeled simultaneously using NONMEM VI. Insulin pharmacokinetics were described by a one-compartment model with one (inhaled) or two (subcutaneous insulin) first-order absorption processes and first-order elimination. Insulin effects on glucose were described by an indirect response model. A biophase direct effect equation for the glucose infusion rate was implemented. Pharmacodynamic parameter estimates were 15.1 mg/min/kg for maximal glucose infusion rate (GIR(max)) and 88.0 mIU/L for SC(50) for diabetic patients and 62.9 mIU/L for healthy subjects. A PK/PD model based on fundamental principles of insulin action and glucose turnover suggests comparable potencies of inhaled and subcutaneous insulin.     

Suppression of thyroid function by interferon-alpha2 in man

Summary Profound biological changes occur in patients treated with interferon. Observations of endocrine changes prompted us to examine the effects of subcutaneous alpha-interferon administration in single doses on circulating levels of thyroid stimulating hormone, total thyroxine, and total triiodothyronine in 10 volunteers (5 healthy subjects and 5 patients with hepatitis C). Blood samples were taken on an out-patient basis immediately before and 2, 12, 24, 48, and 72 h after administration of 1, 3, or 5 × 10⁶ units of recombinant alpha-interferon. Application of the different dose levels was randomly assigned. Plasma samples were stored at –80°C; after collection of samples had been completed hormone levels were measured using commercially available test kits. At all time points before and after injection of alpha-interferon, standard deviations of measured hormone levels of healthy control subjects and patients overlapped to a considerable extent. At a dose level of 5 × 10⁶ units, alpha-interferon significantly increased cortisol levels as described, and decreased the level of thyroid stimulating hormone in the group receiving alpha-interferon as compared to placebo-treated healthy volunteers. The effects occurred 12 h after injection. Maximum suppression of thyroid stimulating hormone levels was observed 24 h after injection, when serum levels of thyroxine and triiodothyronine also were significantly reduced. We conclude that subcutaneous alpha-interferon treatment with doses as low as 5 x 106 units affects the control of thyroid function. Send offprint requests to: C. J. Wiedermann at the above address     

Preclinical and Clinical <Emphasis Type="BoldItalic">In Vitro In Vivo</Emphasis> Correlation of an hGH Dextran Microsphere Formulation

Purpose To investigate the in vitro in vivo correlation of a sustained release formulation for human growth hormone (hGH) based on hydroxyethyl methacrylated dextran (dex-HEMA) microspheres in Pit-1 deficient Snell dwarf mice and in healthy human volunteers. Materials and Methods A hGH-loaded microsphere formulation was developed and tested in Snell dwarf mice (pharmacodynamic study) and in healthy human volunteers (pharmacokinetic study). Results Single subcutaneous administration of the microspheres in mice resulted in a good correlation between hGH released in vitro and in vivo effects for the hGH-loaded microsphere formulation similar to daily injected hGH indicating a retained bioactivity. Testing the microspheres in healthy volunteers showed an increase (over 7–8 days) in hGH serum concentrations (peak concentrations: 1–2.5 ng/ml). A good in vitro in vivo correlation was obtained between the measured and calculated (from in vitro release data) hGH serum concentrations. Moreover, an increased serum concentration of biomarkers (insulin-like growth factor-I (IGF-I), IGF binding protein-3 (IGFBP-3) was found again indicating that bioactive hGH was released from the microspheres. Conclusions Good in vitro in vivo correlations were obtained for hGH-loaded dex-HEMA microspheres, which is an important advantage in predicting the effect of the controlled drug delivery product in a clinical situations.     

Absolute bioavailability and pharmacokinetics of treprostinil sodium administered by acute subcutaneous infusion

The objective of this study was to evaluate the absolute bioavailability and acute pharmacokinetics of treprostinil sodium administered by continuous, short-term subcutaneous infusion in normal subjects. Fifteen healthy volunteers received treprostinil via an intravenous infusion at 15 ng/kg/min over 150 minutes, followed by a 5- to 7-day washout and a subcutaneous infusion at the same rate administered over 150 minutes. Serial plasma samples were collected predosing, during dosing, and postdosing, and plasma treprostinil concentration levels were measured by a validated liquid chromatography atmospheric pressure ionization tandem mass spectrometry (LC/MS/MS) method with a lower limit of quantitation (LLOQ) of 25 pg/mL. Acute administration of treprostinil administered by subcutaneous infusion at a rate of 15 ng/kg/min for 150 minutes achieved a mean Cmax of 1.47 ng/mL. Mean AUC infinity values for intravenous and subcutaneous dosing were 3.52 and 3.97 ng.h/mL, respectively, resulting in a mean apparent absolute bioavailability of 113% for subcutaneous administration. It was possible that the area under of the curve for the intravenous administration was underestimated because most of the terminal elimination phase could not be documented due to the LLOQ of the assay. The mean apparent elimination half-life of treprostinil following subcutaneous administration was 1.38 hours, compared to 0.87 hours following intravenous administration. It was concluded that treprostinil administered by subcutaneous administration is completely absorbed, with a slightly longer half-life compared to intravenously administered treprostinil.