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.     

A fenugreek seed extract selectively reduces spontaneous fat consumption in healthy volunteers

Purpose  

Fenugreek seeds (Trigonella foenum-graecum L.) are an old herbal remedy used to treat metabolic and nutritive dysfunctions. They have been shown to modulate feeding behaviour in animals, but strong clinical data are lacking. The aim of this study was to investigate the effects of a repeated administration of a fenugreek seed extract on energy intake and eating behaviour in healthy human volunteers.     

Effects of olanzapine and ziprasidone on glucose tolerance in healthy volunteers.

Atypical antipsychotics have been linked to a higher risk for glucose intolerance, and consequentially the development of type 2 diabetes mellitus (DM2). We have therefore set out to investigate the acute effects of oral administration of olanzapine and ziprasidone on whole body insulin sensitivity in healthy subjects. Using the standardized hyperinsulinemic euglycemic clamp technique we compared whole body insulin sensitivity of 29 healthy male volunteers after oral intake of either olanzapine 10 mg/day (n = 14) or ziprasidone 80 mg/day (n = 15) for 10 days. A significant decrease (p<0.001) in whole body insulin sensitivity from 5.7 ml/h/kg ( = mean, SM = 0.4 ml/h/kg) at baseline to 4.7 ml/h/kg ( = mean, SM = 0.3 ml/h/kg) after oral intake of olanzapine (10 mg/day) for 10 days was observed. The ziprasidone (80 mg/day) group did not show any significant difference (5.2+/-0.3 ml/h/kg baseline vs 5.1+/-0.3 ml/h/kg) after 10 days of oral intake. Our main finding demonstrates that oral administration of olanzapine but not ziprasidone leads to a decrease in whole body insulin sensitivity in response to a hyperinsulinemic euglycemic challenge. Our finding is suggestive that not all atypical antipsychotics cause acute direct effects on glucose disposal and that accurate determination of side effect profile should be performed when choosing an atypical antipsychotic.     

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

RATIONALE: Both psychotropic drugs and mental disorders have typical signatures in quantitative electroencephalography (EEG). Previous studies found that some psychotropic drugs had EEG effects opposite to the EEG effects of the mental disorders treated with these drugs (key-lock principle). OBJECTIVES: We performed a placebo-controlled pharmaco-EEG study on two conventional antipsychotics (chlorpromazine and haloperidol) and four atypical antipsychotics (olanzapine, perospirone, quetiapine, and risperidone) in healthy volunteers. We investigated differences between conventional and atypical drug effects and whether the drug effects were compatible with the key-lock principle. METHODS: Fourteen subjects underwent seven EEG recording sessions, one for each drug (dosage equivalent of 1 mg haloperidol). In a time-domain analysis, we quantified the EEG by identifying clusters of transiently stable EEG topographies (microstates). Frequency-domain analysis used absolute power across electrodes and the location of the center of gravity (centroid) of the spatial distribution of power in different frequency bands. RESULTS: Perospirone increased duration of a microstate class typically shortened in schizophrenics. Haloperidol increased mean microstate duration of all classes, increased alpha 1 and beta 1 power, and tended to shift the beta 1 centroid posterior. Quetiapine decreased alpha 1 power and shifted the centroid anterior in both alpha bands. Olanzapine shifted the centroid anterior in alpha 2 and beta 1. CONCLUSIONS: The increased microstate duration under perospirone and haloperidol was opposite to effects previously reported in schizophrenic patients, suggesting a key-lock mechanism. The opposite centroid changes induced by olanzapine and quetiapine compared to haloperidol might characterize the difference between conventional and atypical antipsychotics.     

Pharmacokinetic study of omeprazole in elderly healthy volunteers.

The pharmacokinetics of omeprazole and its metabolites were studied in 8 healthy elderly volunteers using [14C]omeprazole. In another 6 healthy elderly volunteers, the pharmacokinetics of omeprazole were studied using unlabelled drug. Each volunteer received single doses of omeprazole intravenously (20mg) and orally (40mg) as solutions in a randomized crossover design. The plasma concentrations and urinary excretion of omeprazole and metabolites were followed for 24 and 96h, respectively. The results indicate that the average metabolic capacity of omeprazole is decreased in the elderly compared with that found in earlier studies of healthy young individuals. This was reflected in an increase in bioavailability from 56 to 76%, a reduction in mean systemic clearance by approximately 50% (0.25 L/min) and a prolongation of the mean elimination half-life from 0.7 to 1.0h compared with the young. Despite these findings, the considerable overlap in these parameters between young and old volunteers, together with data from previous pharmacodynamic studies and the wide therapeutic range of omeprazole, indicate that dosage reductions are not needed in the elderly.     

Motor-learning impairment by amantadine in healthy volunteers.

NMDA receptor antagonists impair learning and memory in animal models, presumably by inhibiting long-term potentiation in the motor cortex. Human studies are limited and restricted by the paucity of safe NMDA antagonists. Here, we investigated the contribution of glutamatergic neurotransmission to the capacity of acquiring motor-adaptation learning in humans. In a double-blind design, 200 mg of amantadine (a low-affinity NMDA receptor channel blocker) or a matching placebo were given orally to groups of 14 and 13 human healthy young volunteers, respectively. Blood samples were collected 3 h after treatment to assay plasma concentrations, and the subjects were then tested using a motor-adaptation paradigm consisting of an eight-target-pointing task. To rule out drug-related generalized impairments such sedation, tests measuring motor dexterity and attention were also administered pre- and post-treatment. Comparison of the mean performance levels on the motor-adaptation task revealed that subjects in the amantadine group performed at a lower level than those in the placebo group, but this difference did not reach significance. Interestingly, however, despite plasma amantadine concentrations being relatively low, ranging from 2.09 to 4.74 microM (mean=3.3 microM), they nevertheless correlated negatively with motor learning. Furthermore, when the amantadine group was divided into low-performance and high-performance subgroups, subjects in the former subgroup displayed mean amantadine concentrations 36% higher than the latter subgroup, and performed significantly worser than the placebo group. No change in performance was found on the motor-dexterity and attention tests. Altogether, our results lend support to the hypothesis that normal NMDA receptor function is necessary for the acquisition of motor adaptation.     

Metamizole-furosemide interaction study in healthy volunteers

Summary The pharmacokinetic and pharmacodynamic interactions between metamizole (dipyrone) and furosemide were investigated in 9 of 12 healthy female subjects able to complete the study. They received oral metamizole 3×1 g for 3 days or placebo (cross-over) and on the last day of both study periods furosemide 20 mg IV. On the last two days a balanced sodium diet (120 mEq) and on Day 3 an oral water load (600 ml) were given. Metamizole significantly inhibited basal urine flow, whereas the fractional excretion of sodium and chloride and the 12 h-GFR remained unchanged. Metamizole significantly reduced furosemide clearance (175 vs 141 ml · min^–1), furosemide-stimulated plasma renin activity (1.42 vs 0.79 ng AI · ml^–1 · h^–1) and the urinary excretion of prostacyclin metabolites and of prostaglandin F₂ (by 70–81%). The renal clearance and terminal half-life of furosemide, peak renal chloride and volume excretion were unchanged. Thus, metamizole did not interact with the renal excretion and the diuretic effect of furosemide, although prostaglandin synthesis was significantly reduced.Parts of the results have been presented at the Ninty-first Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics, March 21–23, 1990, San Francisco     

Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.

1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17-32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg-1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg-1 BW in normal saline. A constant infusion of 5 mg glucose kg-1 ideal BW min-1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [-1 s.d- +1 s.d.]; 47.0 [27.8-79.4] mu l-1) were significantly greater than those after quinidine (19.8 [6.1-65.2] mu l-1) and saline (7.5 [0-21.5] mu l-1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/- 4.4 mg l-1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/- 0.8 mg l-1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of etersalate on human platelet responsiveness. A study in healthy volunteers

Ex vivo antiplatelet properties of 2-(p-acetamido-phenoxy)ethyl-o-acetoxybenzoate (etersalate, Daital) and its effects on serum thromboxane A2 (TXA2) levels and prostaglandin I2 (PGI2) generation were studied in human volunteers at two levels of oral dosing. Etersalate inhibited at the lower dosage platelet function and decreased TXA2 levels, but PGI2 generation from rat aortic rings was stimulated when incubated with plasma from etersalate-treated donors. Blood coagulation parameters remained within normal values. It is suggested that etersalate administration could act on platelet arachidonate metabolism at a different level than that of the cyclooxygenase pathway.     

Effect of diltiazem on plasma glucose,insulin and glucagon during an oral glucose tolerance test in healthy volunteers

Summary The effect of the calcium antagonist, diltiazem, on glycoregulation was investigated in 12 healthy volunteers using a standard glucose tolerance test. No significant change was observed in plasma glucose, insulin or glucagon levels after oral treatment for B days with diltiazem 180 mg/day.     

Bioequivalence study of tramadol by intramuscular administration in healthy volunteers

Tramadol hydrochloride (CAS 36282-47-0) is a centrally acting analgesic agent binding to mu opiate receptors. The bioavailability of a new tramadol hydrochloride injection (Limadol) was compared with a commercially available reference product by intramuscular administration in twelve healthy Chinese male volunteers by a standard two-way cross-over trial. Each volunteer received a single 100 mg injection of tramadol HCl in each phase. The bioavailability was compared using the area under the plasma concentration-time curve from time 0 to 30 h (AUC0-30), the area under the plasma concentration-time curve from time 0 to infinity (AUC0-infinity), peak plasma concentration (Cmax), and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the Tmax, Cmax, AUC0-30 and AUC0-infinity of the two preparations. It is concluded that test and reference formulations of tramadol hydrochloride are bioequivalent for both the extent and rate of absorption after a single intramuscular injection.     

国产氟罗沙星健康志愿者药物动力学研究

研究了７名健康志愿者口服单剂国产氟罗沙星４００ｍｇ后的药物动力学特征。用高效液相色谱法（ＨＰＬＣ）测定血清和尿中药物浓度。该药在体内转运过程以二室模型拟合为优，其显著特点是消除半衰期长（１１．２７ｈ）、血药峰浓度高（４．５９μｇ／ｍｌ）、表观分布容积大（０．８７Ｌ／ｋｇ）、血药时曲线下面积和系统清除率分别为６７．７８μｇｈ／ｍｌ和１０２．１ｍｌ／ｍｉｎ。尿药浓度在服药后２～４ｈ达到高峰为２９８±１１５μｇ／ｍｌ，４８～６０ｈ仍可达１４．３±８．４μｇ／ｍｌ。服药后２４、６０ｈ，尿药排泄率分别为５２．６％和６７．６％。结果表明：口服单剂国产氟罗沙星４００ｍｇ后血和尿中可迅速达到有效抗菌浓度且维持时间长     

国产司帕沙星在人体内的药物动力学研究

研究了８名健康志愿者口服单剂国产司帕沙星４００ｍｇ后的药物动力学特征。用高效液相色谱法（ＨＰＬＣ）测定血清和尿中药物浓度。该药在体内转运过程以二室模型拟合为佳。峰浓度（Ｃｍａｘ为１４９±０．２８ｍｇ／Ｌ,达峰时间（Ｔｍａｘ）为７．１２±１．１７ｈ,消除半衰期（Ｔ１／２β）为２２±６．８３ｈ,系统清除率（Ｃｌｍ）为８．８５±２．１６Ｌ／ｈ,表观分布容积（Ｖｄ）为２．７３Ｌ／ｋｇ,血药－时曲线下面积（ＡＵＣ）为４７．３５±１０．２４（ｍｇｈ）／Ｌ,滞后时间（Ｔｌａｇ）为０．８９±０．８８ｈ。服药后２４、９６ｈ尿药排泄率仅为９．１６％和１５．６８％。     

诺氟沙星在健康人体内的药动学

本文用尿药浓度法,研究了6名志愿者单剂量口服诺氟沙星胶囊400mg后的药物动力学,其药动学参数分别是:β=0.1789h~(-1);T_(1/2β)=3.87h;AU~(0→24)=108.925mg;累积尿药排泄率为27.23%。     

阿托伐他汀钙与阿昔莫司联用在中国健康人体的药代动力学

目的 评价阿托伐他汀钙与阿昔莫司联用后在中国健康人体内的药代动力学特征.方法 18名健康受试者单次空腹同时口服阿托伐他汀钙10 mg与阿昔莫司250 mg后,分别用LC-MS/MS,HPLC测定不同时间点血浆中阿托伐他汀与阿昔莫司的浓度,DAS 2.1软件计算相应的药代动力学参数.结果 药代动力学参数如下,阿托伐他汀:t1/2为(11.75±2.48)h,tmax为(0.33 ±0.12)h,Cmax为(11.33±4.36)ng·mL-,AUC0-t为(57.57±25.91)ng·mL-1·h;阿昔莫司:t1/2为(1.55±0.18)h,tmax为(1.32±0.62)h,Cmax为(3.65±1.08) μg·mL-,AUC0-t为(12.84±2.73)μg·mL-·h.与单独给药药代动力学参数基本接近.结论 阿托伐他汀与阿昔莫司联用后彼此药代动力学行为未发生明显改变,联用可能不存在药代动力学方面的相互作用.     

A pharmacokinetic study of intramuscular administration of bulleyaconitine A in healthy volunteers

The pharmacokinetics of bulleyaconitine A (BLA) after a single dose of 0.2 mg intramuscular injection was evaluated in healthy volunteers. Physical exam, vital signs, clinical laboratory tests and electrocardiogram measurements were monitored to assess the safety and tolerance of the drug. The plasma levels of BLA in serial samples, collected over 15 h, were measured by a validated high-performance liquid chromatography (HPLC)-electrospray ionization tandem mass spectrometry (MS-MS) method. It was demonstrated that BLA was absorbed rapidly after intramuscular injection. The pharmacokinetic parameters were as follows: the t(max) value was 0.90+/-0.68 h, the C(max) value was 1.13+/-0.76 ng/ml, the AUC(0-t) was 5.16+/-2.05 ng.h/ml, and t(1/2) was found to be 4.88+/-0.97 h. No subject showed any drug-related clinically significant changes on physical examination, vital signs or laboratory tests. Eight of ten subjects reported a distinct feeling of pain at the site of injection starting approximately at the time of their peak plasma concentration and lasting for 2-6 h. The pain was tolerable, and no subject required additional treatment.     

多剂静脉滴注甲磺酸加替沙星氯化钠注射液药代动力学研究

目的　在中国健康成年志愿者中进行多剂静脉滴注甲磺酸加替沙星氯化钠注射液的药代动力学研究。方法　根据GCP原则设计试验方案 ,须获得伦理委员会批准 ,受试者自愿签署知情同意书。选择 10名 18～ 40岁健康成人男性 ,静脉滴注甲磺酸加替沙星氯化钠注射液每次 40 0mg ,每日 1次 ,连续 14d。首次给药和第 8日给药前及静滴开始后 0 67、1 3 3、2、2 3 3、2 5、3、4、6、8、10、14、2 4h取血 ;此外每日给药前和停药后即刻取血监测峰、谷浓度。应用高效液相色谱法 (HPLC)测定血药浓度 ,采用 3P97软件拟合药代动力学参数。结果　受试者静脉滴注甲磺酸加替沙星氯化钠注射液 ,体内过程为二房室模型。连续给药 8d后AUC0 -∞ 、AUC0 -t值比首次给药显著增加 ,但第 8日给药后AUC0 -t与首次给药后AUC0 -∞ 差异无统计学意义 ;其余参数Cmax、T1/ 2 β、Vd等差异亦无统计学意义。平均稳态血药浓度Cav为 ( 0 971± 0 184)mg/L ,稳态血药浓度 时间曲线下面积AUCss 0 -t为 ( 2 3 3 0 4± 4 42 6)mg·h/L ,累积比 1 2 81± 0 3 2 8,波动系数 1 70 2± 0 0 5 6。稳态时谷浓度实测值与计算值差异无统计学意义。连续给药至 14d的峰、谷浓度与第 1日比较差异无统计学意义。受试者给药期间未出现严重不良反应。结论