Effect of lidocaine on the absorption,disposition and tolerance of intramuscularly administered cefoxitin

Summary The use of lidocaine HCl solution at concentrations of 0.5 and 1.0% to reconstitute sodium cefoxitin relieves the pain associated with intramuscular injections of the antibiotic. Cefoxitin absorption by the intramuscular route is initially rapid and is virtually complete. Peak serum concentrations, corresponding to about one-half those of a comparable intravenous infusion, are achieved in 30 min. Continuing absorption tends to maintain higher serum concentrations for longer times. Renal clearance and serum half-life of cefoxitin do not appear to be affected by lidocaine at its effective anaesthetic concentrations.     

Absence of interaction between tenoxicam and warfarin

Summary The influence of tenoxicam on plasma warfarin concentrations and on its anticoagulant effect has been studied in healthy volunteers. Tenoxicam did not alter the plasma warfarin concentration versus time profile. Treatment with it for 14 days had no effect on the average dose of warfarin required to maintain the prothrombin time within a specified range. The coumarin dose index, an indicator of warfarin sensitivity, remained unchanged during tenoxicam administration. The results demonstrate the lack of a clinically relevant effect of tenoxicam on warfarin-induced anticoagulation.     

Bioavailability of diltiazem as a function of the administered dose

Diltiazem undergoes extensive first-pass metabolism; extrapolation from single to repeated administration thus underestimates plasma concentration values. In order to validate the hypothesis of a partially saturable first-pass effect, four single doses of diltiazem (10, 20, 40, and 120 mg) were administered at weekly intervals to eight healthy volunteers. Results showed that: (a) the inter-subject variability was highest at the lowest dose at the highest dose; (b) bioavailability was almost nil in 3 of 8 of the subjects after the administration of the 10 mg dose; (c) the mean bioavailability increased with the dose from 11.8 +/- 2.5 per cent after 10 mg to 28.2 per cent after 120 mg; (d) the elimination half-life was dose-related; (e) the renal excretion of diltiazem increased with the administered dose from 1.0 +/- 0.3 per cent after 10 mg to 3.0 +/- 0.5 per cent after 120 mg; (f) the greatest amounts of circulating metabolites were present after the lowest doses. These results are consistent with a partially saturable first-pass effect for diltiazem.     

The countering of diazoxide-induced vasodilatation by tenoxicam in normal volunteers

The effect of the nonsteroidal anti-inflammatory drug, tenoxicam, on diazoxide-induced lowering of standing diastolic blood pressure was explored in 10 normal volunteers.With diazoxide there was a significant fall in the 5-min standing diastolic pressure, i.e. a median drop of 15.5, 11.0, 9.5 and 7.0 mm Hg at 10, 35, 75 and 105 min, respectively, but with the tenoxicam-diazoxide regimen this pressure did not differ significantly from baseline at any time point. Tenoxicam did not modify the diazoxide-induced changes in blood glucose and plasma insulin.It may be that prostaglandins normally contribute to the lowering of peripheral vascular resistance, or that acutely-administered diazoxide enhances the release of vasodilatory prostaglandins.     

Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution

The bioavailability of quinidine sulfate after oral administration of a commercial sustained-release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrammes of each product was administered to each subject in standard cross-over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level-time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0–46h) value for the tablet, 8744.4 ng × h ml^?1, comparable to that of the solution, 9145.9 ng × h ml^?1.     

The effect of haemodialysis on the pharmacokinetics of tenoxicam in patients with end-stage renal disease

Summary We have studied the pharmacokinetics of tenoxicam after single and multiple oral doses of 20 mg in five patients (2 men and 3 women) with end-stage renal disease undergoing haemodialysis.After a single dose, tenoxicam had a half-life (t_1/2) of 33 h, an apparent clearance (CL·f^–1) of 4.3 ml·min^–1, and an apparent volume of distribution (V_z·f^–1) of 11.8 l. The maximum tenoxicam concentration (C_max) was 4.3 mg·l^–1 at a median t_max of 1.7 h. There were no significant differences between the values calculated from the pre- or post-dialyser port plasma samples.Tenoxicam plasma concentrations measured during once daily dosing before and after haemodialysis showed that tenoxicam does not accumulate.Our findings suggest that dosage adjustment may not be required in patients with end-stage renal disease on haemodialysis taking tenoxicam.     

Plasma mexiletine concentrations following combined oral and intramuscular administration

Summary Mexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil_® — for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75–2 µg/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.     

A comparison of faecal blood loss caused by tenoxicam and piroxicam in normal healthy male volunteers

Summary

Faecal blood loss arising from tenoxicam at a dose of 20?mg/day was compared to that arising from piroxicam at a dose of 20?mg/day in a double-blind, parallel comparative study in 12 healthy male volunteers. Faecal blood loss was measured for a 1-week run-in on placebo, during 4 weeks of treatment and for a 2-week post-treatment period in both groups. Plasma levels for tenoxicam and piroxicam confirmed good compliance in all subjects. Mean blood loss during the placebo run-in period was 0.35?mil day. Mean blood loss during treatment with tenoxicam was 0.84 milday and with piroxicam 0.81 milday. There was no significant difference between these measurements. On cessation of treatment, faecal blood loss continued both in the tenoxicam group (mean 1.30 ml/day) and piroxicam group (mean 1.41 milday). The difference between these was not statistically significant. No significant haematological or biochemical abnormality resulted from either of the two trial drugs during the period of the study. Urinalysis and NAG/creatinine ratio also remained unaltered in both treatment groups.     

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

The objective of this study was to enhance the oral bioavailability (BA) of zanamivir (ZMR) by increasing its intestinal permeability using permeation enhancers (PE). Four different classes of PEs (Labrasol^®, sodium cholate, sodium caprate, hydroxypropyl β-cyclodextrin) were investigated for their ability to enhance the permeation of ZMR across Caco-2 cell monolayers. The flux and P_app of ZMR in the presence of sodium caprate (SC) was significantly higher than other PEs in comparison to control, and was selected for further investigation. All concentrations of SC (10-200 mM) demonstrated enhanced flux of ZMR in comparison to control. The highest flux (13 folds higher than control) was achieved for the formulation with highest SC concentration (200 mM). The relative BA of ZMR formulation containing SC (PO-SC) in plasma at a dose of 10 mg/kg following oral administration in rats was 317.65% in comparison to control formulation (PO-C). Besides, the AUC_{0-24 h} of ZMR in the lungs following oral administration of PO-SC was 125.22 ± 27.25 ng hr ml^-1 with a C_max of 156.00 ± 24.00 ng/ml reached at 0.50±0.00 h. But, there was no ZMR detected in the lungs following administration of control formulation (PO-C). The findings of this study indicated that the oral formulation PO-SC containing ZMR and SC was able to enhance the BA of ZMR in plasma to an appropriate amount that would make ZMR available in lungs at a concentration higher (>10 ng/ml) than the IC₅₀ concentration of influenza virus (0.64-7.9 ng/ml) to exert its therapeutic effect.     

柴葛口服液中葛根素在犬体内的药动学及绝对生物利用度

目的:研究柴葛口服液中主要成分葛根素在犬体内的药物动力学及绝对生物利用度。方法:家犬6只,随机分为2组,采用单剂量交叉给药方案,分别给予单剂量口服柴葛口服液和静脉注射葛根素注射液,用HPLC法测定血药浓度,并用3p97程序拟合药动学参数。结果:柴葛口服液在家犬体内的药-时数据符合二室模型,主要药动学参数为t1/2(β)=14.84 min,CL=16.48ml·h-1·kg-1,Cmax=25.74μg·ml-1,Tmax=36.24min,AUC(0→∞)=328 129.05μg·ml-1·min,F=40.43%。绪论:柴葛口服液的生物利用度较好。     

Bioavailability and stability of intravenous iron sucrose originator versus generic iron sucrose AZAD

Abstract

Context: Severe iron deficiency requires intravenous iron supplementation to replenish iron stores. Intravenous iron sucrose has been used for decades for the treatment of anemia. New generic iron sucrose products are now marketed for the use in several countries and there is an ongoing discussion about the safety and efficacy of iron sucrose similars.

Objective: In this study, we compared the iron sucrose originator Venofer® and the generic iron sucrose AZAD (ISA) regarding bioavailability, toxicity and stability in human THP-1 cells and HepG2 cells.

Methods: The bioavailability of Venofer® and ISA was investigated in both cell types by a ferrozin-based assay. The release of incorporated iron was assayed by atomic absorption spectroscopy. Ferritin content was measured by enzyme-linked immunosorbent assay (ELISA). HepG2 cells were used to investigate the intracellular labile iron pool (LIP), which was measured by the fluorescent calcein assay. The amount of redox-active iron within the iron formulations was assayed using fluorescent dichlorofluorescein.

Results: We found no significant differences in all parameters between Venofer® and ISA in regard of bioavailability, toxicity and stability in vitro.

Discussion: ISA shows identical physico-chemical features and identical bioavailability in vitro. This study is a profound basis for future clinical tests with generic iron sucrose compounds.     

In Vitro Percutaneous absorption of tenoxicam from pressure-sensitive adhesive matrices across the hairless mouse skin

To investigate the feasibility of developing a new tenoxicam plaster, the effects of vehicles and penetration enhancers on the in vitro permeation of tenoxicam from a pressure-sensitive adhesive (PSA) matrices across the dorsal hairless mouse skin were studied. Vehicles employed in this study were propylene glycol (PG)-oleyl alcohol (OAI), PG-oleic acid (OA), and diethylene glycol monoethyl ether (DGME)-propylene glycol monolaurate (PGML) cosolvents with/without fatty acids. In this study, amines such as triethanolamine (TEA) and tromethamine (TM) were additionally used as a solubilizer. Among PSAs used, Duro-Tak 87-2510 showed much higher release rate than either Duro-Tak 87-2100 or Duro-Tak 87-2196. The relatively high flux rate was obtained with the formulation of DGME-PGML (40:60, v/v) with 3% OA and 5% TM, and the flux increased as a function of the dose; the initial flux up to 12 h was 4.98 +/- 1.38 microg/cm2/h at the tenoxicam dose of 50 mg/70 cm2. This flux was much higher than that of a commercial piroxicam patch (Trast) (1.24 +/- 0.73 microg/ cm2/hr) with almost only one-third that of the commercial patch. Therefore, these observations indicated that these composition of tenoxicam plaster may be practically applicable.     

Pharmacokinetics of physostigmine intramuscularly administered to guinea pigs

Physostigmine pharmacokinetics was determined in guinea pigs following im administration of 5-146 micrograms/kg. Eighteen male guinea pigs were divided into three equal groups and given dosages of 5, 27, and 146 micrograms/kg, respectively. Physostigmine was given in the right hind limb and blood samples were collected at various times up to 300 min postinjection via an indwelling carotid catheter. Unbound physostigmine plasma concentrations were analyzed by HPLC. The concentration-time profile for each animal was fitted to standard pharmacokinetic models. A one-compartment open model with first-order absorption and elimination provided the best fit. For all dosage groups, physostigmine concentrations peaked in approximately 30 min. Apparent volumes of distribution (assuming 100% bioavailability) ranged from 1.9 to 2.2 L/kg. Systemic clearances and elimination half-lives were 30-36 mL/min/kg and 40-50 min, respectively. The area under the concentration-time curve and the Cmax were linearly related to the dose, indicating pharmacokinetic linearity. In conclusion, physostigmine, intramuscularly administered to the guinea pig, is absorbed, distributed, and eliminated rapidly, and the pharmacokinetics behave linearly within the 5-146-micrograms/kg dosage range.     

注射用阿奇霉素的生物利用度研究

目的　研究比较国产注射用阿奇霉素与进口样品的绝对生物利用度。方法　采取静滴、肌注给药 ,以微生物检定法 ,测定给予进口样品和供试样品的各 10名健康志愿者血中阿奇霉素的浓度 ,经 3P87程序拟合 ,计算药物动力学参数。结果　单剂量静滴及肌注阿奇霉素 5 0 0mg后血药浓度 时间曲线 ,两样品均分别符合恒速静滴的二室模型和有滞后时间的一级吸收的二室模型。肌注滞后时间 (tlag)国产样品和进口样品分别为 0 30 8± 0 0 2 7h和 0 318± 0 0 14h。进口样品静滴和肌注达峰时间 (tmax)分别为 1 10 0± 0 0 74h和 1 4 2 5± 0 0 84h、峰浓度 (Cmax)分别为 3 5 74± 0 5 72mg·L-1和 3 14 4± 0 6 12mg·L-1;血药浓度 时间曲线下面积 (AUC0 ∞)分别为 2 5 896± 4 2 2 1mg·h·L-1及 2 4 135± 3 2 14mg·h·L-1。清除率 (CL)分别为 2 7 32 1±3 4 85L·h-1及 2 4 0 83± 4 2 12L·h-1,绝对生物利用度 (F)为 93 2 0 % ;国产样品静滴和肌注达峰时间 (tmax)分别为 1 2 0 0± 0 0 84h和 1 5 0 5± 0 4 5 2h、峰浓度 (Cmax)分别为 3 4 78± 0 4 89mg·L-1和 3 0 87± 3 5 2 1mg·L-1;血药浓度 时间曲线下面积 (AUC0 ∞)分别为 2 8 92± 3 2 13mg·h·L-1及 2 7 0 4 0± 3 884mg·h·L-1。清除     

注射用阿奇霉素的生物利用度研究

目的 研究比较国产注射用阿奇霉素与进口样品的绝对生物利用度。方法 采取静滴、肌注给药,以微生物检定法,测定给予进口样品和供试样品的各10名健康志愿者血中阿奇霉素的浓度,经3P87程序拟合,计算药物动力学参数。结果 单剂量静滴及肌注阿奇霉素500mg后血药浓度时间曲线,两样品均分别符合恒速静滴的二室模型和有滞后时间的一级吸收的二室模型。肌注滞后时间(t_lag)国产样品和进口样品分别为0.308±0.027h和0.318±0.014h。进口样品静滴和肌注达峰时间(相似文献   

Bioavailability of cadmium in rats fed various diets

Six-week-old female albino rats were fed rat diet or human foods: meat, bread or milk — 3 days before and 6 days after a single oral dose of ^115mCd. All animals were killed 6 days after administration and the radioactivity in the whole body and in the gut-free carcass was determined in a double scintillation counter. Gut retentions were calculated as the difference: whole body minus carcass. All animals fed meat, bread or milk had much higher body retentions than animals fed rat diet (whole body 4–5 times, carcass about 3 times and gut 10–14 times). Our results point out the importance of nutritional factors in metal metabolism and toxicity.     

Bioavailability of orally administered mesna

The bioavailability of orally administered sodium 2-mercaptoethane sulfonate (mesna, Uromitexan drink ampoules) was tested in 18 healthy probands and in 5 tumor patients. Following single oral administration of 20 or 40 mg/kg mesna, 52.4% and 52.6%, respectively, of the dose were excreted in the urine as reactive thiol groups, the remainder as mesna disulfide (dimesna), the only metabolite of mesna; after i.v. injection of 20 mg/kg mesna, 48.7% of the dose administered appeared as thiol groups in the urine. Not until after 13.1 h (20 mg/kg p.o.) and 18.5 h (40 mg/kg p.o.), respectively, concentration drops below the minimum concentration of 100 micrograms/ml presumed to be still reliably protective. However, the elimination pattern and the time when the threshold concentration is reached are subject to marked individual variation. After i.v. administration of 20 mg/kg mesna and 9 times oral administration of 20 mg/kg mesna (the first dose concurrently with the i.v. injection, thereafter every 4 h), or 7 times oral administration of 20 mg/kg mesna (the first dose again concurrently with the i.v. injection, thereafter every 5 h), the percentage of the total dose administered appearing as thiol groups in the urine averaged 41.9% and 37.6%, respectively, up to 17 or 18 h after the last dose. Comparison of periods covering the same time of the day showed the total amount excreted to be higher on day 2 than on day 1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Bioavailability of medroxalol in man

Ten healthy male volunteers received single oral doses of 100 mg of medroxalol administered as a solution, a preliminary tablet formulation and a single dose of 100 mg administered intravenously in a randomized three-way crossover study. Mean terminal half-lives of 12·4, 134, and 11·3 h were observed for the intravenous, solution and tablet formulation, respectively. Mean urinary recovery of parent drug at 48 h was 8·9 per cent, 3·9 per cent, and 3·2 per cent. Absolute bioavailability estimated from plasma AUC was 54 per cent for the solution and 38 per cent for the tablet, and the relative bioavailability from the tablet was 71 per cent.