Assessment of the biological activity of synthetic salmon calcitonin by intranasal administration in healthy volunteers.

The authors conducted an open crossover trial of the biological activity of single-dose salmon calcitonin (sCT) 100 I.U. by nasal spray versus single-dose sCT 50 I.U. by intramuscular route in six healthy volunteers. The biological activity of the hormone was assessed on the changes in the blood levels of calcium, cAMP and osteocalcin recorded in the 4 h following administration. The increase in plasma cAMP shows that the hormone acts effectively by the nasal route. Further, the lack of statistically significant differences between the two modes of administration in any of the parameters considered demonstrates the bioequivalence of 50 I.U. of sCT i.m. and 100 I.U. of sCT intranasally.     

Liquid chromatographic assay and disposition of carvedilol in healthy volunteers

Quantitative determination of serum concentrations of carvedilol [(+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl) amino]-2-propanol], a combined alpha- and beta-adrenergic receptor antagonist, was obtained using HPLC with spectrofluorometric detection. Carvedilol was extracted from alkalinized serum with ether and was subsequently back extracted with diluted phosphoric acid. This method proved to be sensitive and reproducible (mean coefficient of variation of 6.1% for 0.25 to 150 nanograms per milliliter of serum). A single dose of carvedilol (5, 10, or 15 mg) was given as an intravenous infusion to three healthy volunteers. Carvedilol serum concentration-time profiles were fitted best to a three-compartment model and the pharmacokinetic data revealed the following mean values: Vdss of 1.97 L/kg, mean residence time (MRT) of 4.66 h, and CL of 0.437 L X h-1 X kg-1.     

格列吡嗪片在健康志愿者体内的生物等效性评价

目的比较两种格列吡嗪片剂在健康志愿者体内的药动学及生物等效性.方法12例男性健康志愿受试者,采用标准两周期交叉设计自身对照试验法,单剂量口服进口和国产格列吡嗪片10mg,以高效液相色谱法测定血浆中格列吡嗪的经时浓度,以双单侧t检验统计法比较两种格列吡嗪片之间的差异.结果两种格列吡嗪片在健康志愿者体内的药-时曲线均符合一级吸收的单室模型,国产格列吡嗪片主要的药动学参数Tmax、Cmax和AUC(0-17)分别为(2.6±0.5)h,(609.7±112.9)ng·ml-1和(4499.8±969.0)ng·h-1·ml-1;进口格列吡嗪片主要的药动学参数Tmax、Cmax和AUC(0-17)分别为(2.6±0.5)h,(568.8±101.9)ng·ml-1和(4108.3±724.9)ng·h·     

应用改良的E—screen实验评估天然物质的类雌激素活性

目的:改良E-screen实验,提高其筛选具有雌激素样作用物质的准确性.方法:构建雌激素受体反义RNA表达质粒pCASER,以脂质体转染MCF-7细胞,G418筛选阳性克隆.PCR检测雌激素受体的DNA是否整和地MCF-7细胞的基因组DNA中,Westernblot检测雌激素受体的表达;MTT法检测细胞的增殖.结果:筛选出一株雌激素受体反义RNA表达克隆(MTASER).17β-雌二醇,金雀异黄素,Dro-loxifen,Miyabenol和Kobophenol在一定浓度均可促进MCF-7细胞增殖,且对MCF-7的促增殖作用大于对MTASER的促增殖作用;表皮生长因子对两株细胞的促增殖作用的差别无显著意义.结论:改良的E-screen实验筛选具有雌激素样作用物质的准确性高于通常的E-screen实验.     

麦考酚酸酯分散片在健康志愿者体内的生物等效性评价

目的:评价麦考酚酸酯(MMF)分散片与其胶囊(商品名:骁悉)的生物等效性。方法:20名健康志愿者按随机双周期交叉试验方案设计,单剂量口服MMF分散片或其胶囊各500mg,采用RP-HPLC荧光检测法测定MMF的活性代谢产物麦考酚酸(MPA)的血药浓度。用非房室模型计算MPA药动学参数,用方差分析和双单侧t检验评价两者之间的生物等效性。结果:MMF分散片与其胶囊的主要药动学参数AUC0-48分别为(32.7±6.6)与(30.6±9.9)mg.L-1.h,AUC0-∞分别为(35.8±7.4)与(33.3±10.2)mg.L-1.h,Cmax分别为(17.0±4.5)与(15.8±4.8)mg.L-1,tmax分别为(0.45±0.29)与(0.6±0.3)h,t1/2β分别为(13.4±4.7)与(12.7±4.4)h。MMF分散片相对于其胶囊的生物利用度F为(111.6±24.0)%,经统计学检验,两者差异无显著性(P>0.05)。结论:MMF分散片与其胶囊具有生物等效性。     

比卡鲁胺片在健康人体内的药物动力学及生物等效性评价

目的研究比卡鲁胺片在健康人体内的药物动力学,评价两种制剂的生物等效性。方法用单周期平行对照试验设计,采用HPLC法,测定40名健康男性受试者口服比卡鲁胺片或康士得后,不同时刻血浆中比卡鲁胺的浓度,绘制血药浓度-时间曲线,计算主要药物动力学参数。结果40名受试者口服含比卡鲁胺50mg的受试制剂或参比制剂后,血浆中比卡鲁胺的Tmax分别为(19.3±12.4)、(24.6±10.7)h,Cmax分别为(1137.2±202.3)、(1094.2±199.0)ng/mL,t1/2分别为(98.2±22.0)、(106.0±19.4)h。用梯形法计算,AUC0-t分别为(178535.6±36640.9)、(186744.4±44359.9)ng/(h.mL),AUC0-∞分别为(185230.9±38327.7)、(193807.6±46347.8)ng/(h.mL)。以受试者服用受试制剂或参比制剂后AUC0-t的平均值计算,比卡鲁胺片的相对生物利用度为95.6%。结论根据双单侧检验表明,两种制剂具有生物等效性。     

Bioequivalence assay between orally disintegrating and conventional tablet formulations in healthy volunteers

The purpose of this study was to evaluate bioequivalence of two commercial 8 mg tablet formulations of ondansetrona available in the Brazilian market. In this study, a simple, rapid, sensitive and selective liquid chromatography-tandem mass spectrometry method is described for the determination of ondansetron in human plasma samples. The method was validated over a concentration range of 2.5-60 ng/ml and used in a bioequivalence trial between orally disintegrating and conventional tablet ondansetron formulations, to assess its usefulness in this kind of study. Vonau flash (Biolab Sanus Farmacêutica, Brazil, as test formulations) and Zofran (GlaxoSmithKline, Brazil, as reference formulation) were evaluated following a single 8 mg dose to 23 healthy volunteers of both genders. The dose was administered after an overnight fast according to a two-way crossover design. Bioequivalence between the products was determinated by calculating 90% confidence interval (90% CI) for the ratio of C(max), AUC(0-t) and AUC(0-infinity) values for the test and reference products, using logarithmically transformed data. The 90% confidence interval for the ratio of C(max) (87.5-103.8%), AUC(0-t) (89.3-107.2%) and AUC(0-infinity) (89.7-106.0%) values for the test and reference products is within the 80-125% interval, proposed by FDA, EMEA and ANVISA. It was concluded that two ondansetron formulations are bioequivalent in their rate and extent of absorption.     

Dose-dependent effect of dobutamine on chemoreflex activity in healthy volunteers

AIMS: beta-adrenergic agonists increase peripheral chemoreceptor sensitivity in humans. We tested the hypothesis that beta(1)-agonist-related increase in peripheral chemoreflex sensitivity is selective and dose-dependent. METHODS: Using a double-blind, placebo-controlled, randomized, crossover study, we examined the effects of dobutamine (n = 17 healthy subjects) at perfusion rates of 2.5 microg kg(-1) min(-1) (D2.5) and 7.5 microg kg(-1) min(-1) (D7.5) on ventilation, haemodynamics and sympathetic nerve activity during normoxia, isocapnic hypoxia, posthypoxic maximal voluntary end-expiratory apnoea, hyperoxic hypercapnia and cold pressor test (CPT). We analysed the effect of pretreatment with atenolol on dobutamine-evoked chemosensitivity. RESULTS: Dobutamine dose-dependently increased ventilation (placebo 6.7 +/- 0.5 vs. D2.5 7.8 +/- 0.4 vs. D7.5 8.7 +/- 0.4 l min(-1), P < 0.005) during normoxia, enhanced the ventilatory (placebo 14.4 +/- 0.6 vs. D2.5 17.3 +/- 0.8 vs. D7.5 22.5 +/- 1.9 l min(-1), P < 0.0001) and sympathetic (placebo + 215 +/- 31 vs. D2.5 + 285 +/- 19 vs. D7.5 + 395 +/- 50% of baseline, P < 0.03) responses at the fifth minute of isocapnic hypoxia and enhanced the sympathetic response to apnoea performed after hypoxia (increase after 5 min of hypoxia: + 290 +/- 43% for placebo vs.+ 360 +/- 21% for D2.5 vs. 537 +/- 69% for D7.5, P < 0.05). No differences were observed between dobutamine and placebo in the responses to hyperoxic hypercapnia and CPT. Atenolol inhibited the dobutamine-related hyperventilation and apnoea shortening during normoxia and hypoxia. CONCLUSION: Dobutamine enhances peripheral chemosensitivity at low infusion rates selectively and in a dose-dependent manner. There is a beta(1) adrenoceptor component in dobutamine-evoked increase in peripheral chemosensititivity; however, a contribution of additional adrenoceptor subtypes cannot be excluded.     

Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers

Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double-blind, placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours post dose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.     

Nasal glucagon delivery using microcrystalline cellulose in healthy volunteers

We developed an intranasal powder form of glucagon to improve metabolic status and fatty liver in patients with pancreatectomy. Microcrystalline cellulose, which is commonly used in commercial preparations for allergic rhinitis was used as an absorption enhancer. We compared the intranasal powder form with some spray solutions of glucagon with regard to glucagon absorption, concentration of blood glucose, stability and nasal irritation. The absorption of glucagon from the spray solution including 1.5% sodium glycocholate or 1% sodium caprate was 1.3- and 2.6-fold higher than that from the powder form mixed with microcrystalline cellulose at a ratio of 1:69, respectively. The C(max) values of plasma glucose were 2.18, 3.39 and 1.56 mmol l(-1) in the spray solutions including sodium glycocholate and sodium caprate and in the powder form, respectively. However, glucagon in spray solutions was unstable, but that in the powder form was stable at 5 and 25 degrees C for at least 84 days. The spray solution caused strong irritation, but the powder form did not. These results suggested usefulness of the powder form of glucagon for treatment of pancreatectomized patients.     

HPLC-MS/MS法测定血浆中的他林洛尔及人体药动学研究

目的建立一种灵敏、快速、简便的测定人血浆中他林洛尔浓度的高效液相色谱-串联质谱法(HPLC-MS/MS),为研究他林洛尔在人体内的药物动力学提供手段。方法以盐酸氟西汀作为内标(I.S.),血浆样品用乙腈沉淀蛋白,离心后取上清液进样,用预柱Phenomenex C18柱(10 mm×4.6 mm,5μm),Phenomenex C18反相色谱柱(250 mm×4.6 mm,5μm),进行分离,以乙腈∶缓冲液(5 mmol.L-1醋酸胺和0.02%甲酸)(45∶55,V/V)为流动相,柱温40℃,流速:0.9 mL.min-1,HPLC-MS/MS选择m/z为364.3(母离子)和308.3(子离子)监测他林洛尔,m/z为310.0(母离子)和148.3(子离子)监测内标氟西汀。结果他林洛尔及内标盐酸氟西汀在9 min内完全分离,他林洛尔在2.0~320.0ng.mL-1时线性关系良好,相关系数为0.9976;平均萃取回收率大于77%;平均方法回收率大于91%,小于103%;最低定量限为2.0ng.mL-1;日内日间RSD均小于9%。主要药动学参数如下:Cmax(91.90±48.09)ng.mL-1;tmax(2.79±0.89)h;t21(14.67±2.15)h。结论本方法简便快速、灵敏准确,适用于他林洛尔药物动力学的研究。他林洛尔片在中国人体内的药动学参数与文献报道相似。     

盐酸加替沙星胶囊的人体药代动力学及生物等效性评价

目的:研究盐酸加替沙星胶囊在健康人体内的药代动力学特征及相对生物等效性。方法:采用标准二阶段交叉设计自身对照试验法,将18例男性健康志愿受试者随机分为两组,单剂量口服盐酸加替沙星胶囊400mg(试验品)或盐酸加替沙星片400mg(参照品),,以高效液相色谱法测定受试者服药24小时内血浆中加替沙星的经时浓度,计算加替沙星药动学参数。以双单侧t检验统计法比较两种盐酸加替沙星制剂T_(max)、C_(max)和AUC(0￣24h)间的差异。结果:盐酸加替沙星在健康志愿者体内的处置为一级吸收单室模型,试验品和参比品的主要药动学参数T_(max)(实测值)、C_(max)(实测值)、AUC(0￣24h)分别为:(1.51±0.35)小时和(1.53±0.38)小时,(3.46±0.79)和(3.43±0.92)mg/L,(34.51±8.43)和(33.04±10.20)mg/(h·L);试验品的相对生物利用度为105.2%。结论:盐酸加替沙星具有口服后吸收快、血药浓度较高、体内平均滞留时间(MRT)较长的特点;两种盐酸加替沙星制剂在人体内具有生物等效性(P>0.05)。     

Percutaneous absorption of diclofenac in healthy volunteers after single and repeated topical application of diclofenac Emulgel

The percutaneous absorption of diclofenac was studied in ten healthy volunteers treated with Emulgel containing 1.16% diclofenac diethylammonium for 8 d as follows: a single application of 5 g Emulgel on days 1 and 8, and two applications d^?1 on days 2–7. Plasma concentration profiles of unchanged diclofenac and urinary concentrations of total diclofenac and metabolites (sum of free and conjugated) were determined. High inter-individual variations in plasma and urine data were recorded, due probably to the permeability and the hydration of the skin. Steady state was reached after 2 d of twice-daily administration. Plasma concentrations were low but remained in the range 10–50 nmol L^?1 over the full day for most of the subjects, indicating prolonged absorption from the application site.     

Spontaneous motor activity in healthy volunteers after single doses of haloperidol

Video recordings of the spontaneous motor activity of 6 healthy volunteers after treatment with 0.75 mg haloperidol i.v., or placebo, were transcribed into a time-series protocol of motor behaviour. Characteristic changes seen after the injection of haloperidol consisted in a reduction of the motility of the extremities and prolongation of the phases of both movement and immobility of the head. The tested dose of haloperidol induced a distinct rise in serum prolactin and sedation, but had no effects on the pharmaco-EEG or on the critical flicker-fusion frequency. Analysis of the motor phenomena evoked by neuroleptics in healthy persons and in patients may help, on the other hand, to establish correlations with the motor effects observable in preclinical investigations in animals and might also contribute towards the elucidation of the extrapyramidal side-effects of these drugs.     

Absorption and disposition of furosemide in healthy volunteers, measured with a metabolite-specific assay

The objectives of this study were to qualitatively and quantitatively compare the metabolism, pharmacokinetics, and bioavailability of furosemide in healthy volunteers after intravenous and oral administration. We also determined the plasma protein binding of furosemide in vivo after iv administration. Nine males received furosemide (Hoechst, 40 mg iv and 80 mg po) in a random crossover fashion. Serial plasma samples were collected over 24 hr. Fluid and electrolyte urinary losses were replaced throughout the study. Furosemide as well as its potential metabolites were measured by a rapid, sensitive, and specific spectrofluorimetric HPLC assay. Total plasma clearance averaged 164 +/- 26 (SD) ml/min, of which 66.2 +/- 6.8% represented renal clearance of unchanged drug. Volume of distribution (steady-state) was 109 +/- 19 ml/kg. These clearance and volume measurements are in good agreement with data previously published by our group. The mean absolute bioavailability of furosemide was 42.8 and 44.0%, as calculated from plasma and urine data, respectively. Protein binding of furosemide in vivo was determined by a spectrofluorimetric HPLC assay and ranged from 98.5 to 99.1%. Approximately 5.5 mg of furosemide was excreted as a glucuronide conjugate after iv dosing and about 5.1 mg after po administration. We found no evidence of the proposed metabolite of furosemide, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA) in any of our plasma or urine samples. In addition, we conclusively demonstrated CSA to be an analytical artifact.     

Assessment of the analgesic effect of remifentanil using three pain models in healthy Korean volunteers: a randomized, controlled study

Quantitative pain assessment in human beings is useful for developing new analgesics. This study assessed the analgesic effect of remifentanil in 20 healthy Korean men using three pain models to investigate whether these models can be used in Asians. The study was a double-blind, placebo-controlled, two-way cross-over study. The subjects received intravenous remifentanil with doses starting at 0.01 μg/kg/min. and increasing by 0.01 μg/kg/min. up to 0.10 μg/kg/min. in one session; they received placebo in another session. Heat pain thresholds were assessed at dose levels of 0.02, 0.05, 0.08 and 0.10 μg/kg/min. Pressure pain threshold and tolerance and mechanical pain threshold were assessed at 0.08 μg/kg/min. Remifentanil dose-dependently increased the heat pain threshold. The differences (95% confidence interval) between remifentanil and placebo were 1.54°C (0.78, 2.31), 1.82°C (1.11, 2.54) and 2.47°C (1.55, 3.38) at 0.05, 0.08 and 0.10 μg/kg/min. remifentanil, respectively. Remifentanil conferred a significantly higher pressure pain threshold and tolerance than placebo (p = 0.0001). There was a trend of increasing mechanical pain threshold with remifentanil, although it was not statistically significant. The results suggest that heat pain and pressure pain models are valid in East Asians for assessing analgesic effects.