Single-dose pharmacokinetics of 3-O-demethylfortimicin A in humans after intravenous and intramuscular administration.

The pharmacokinetics of 3-O-demethylfortimicin A were evaluated in 16 healthy adult male volunteers after bolus intramuscular (i.m.) and 30-min intravenous (i.v.) infusion administration of doses ranging from 0.25 to 16 mg/kg. Mean calculated peak levels of the drug in plasma after the 0.25-, 0.5-, 1-, 2-, 4-, 8-, and 16-mg/kg i.m. doses were 1.1, 1.9, 3.5, 4.9, 11.0, 21.8, and 41.3 micrograms/ml, respectively, occurring about 60 min after dosing. The biphasic decline in levels of the drug in plasma after i.v. administration was not apparent after i.m. dosing, presumably because absorption of the drug from the injection site obscured the alpha elimination phase. Mean calculated peak levels for the 1-, 2-, 4-, 8-, and 16-mg/kg 30-min i.v. infusions were 5.9, 12.2, 20.1, 36.7, and 66.4 micrograms/ml, respectively. A statistically significant trend of increasing apparent volume of distribution with increasing dose size was noted for the i.m. dose group only. Plasma drug clearance was dose level and route independent, with an excellent linear relationship between the area under the plasma drug level curve and the dose. The mean 0- to 48-h urinary recoveries of 3-O-demethylfortimicin A after the i.m. injections and i.v. infusions were 90 and 102%, respectively. After the i.m. dosings, the half-life of the drug in plasma averaged 2.0 h, and after the i.v. dosings it averaged 2.7 h. The results of the study indicated that most of the drug was cleared by renal mechanisms.     

Time-dependent effects of dexamethasone administration on the suppression of plasma hydrocortisone, assessed with a pharmacokinetic model.

The influence of the time of dexamethasone (DEX) administration (0.5 mg i.v.) on the suppression of plasma hydrocortisone (HC) was investigated in six healthy subjects, by comparing dosage times of 8 and 20 hr. To estimate HC production after DEX administration a pharmacokinetic model was developed and applied to the time course of plasma HC. This model was based on the assumption that HC production could be described as a continuous i.v. infusion, that stops and starts instantaneously. After DEX at 8 hr, HC production was reduced instantaneously to a minimum level and HC disappeared rapidly from plasma with an elimination half-life of 1.32 +/- 0.28 hr (mean +/- S.D.). Almost complete suppression of HC production lasted for 20 hr. The nocturnal increase in HC production at 20 hr after DEX administration was still attenuated compared to the preceding night. After DEX administration at 20 hr, plasma HC was lower than control for about 20 hr, but it was not reduced to the very low level observed after DEX dosage in the morning. Approximately 20 hr after dosage of DEX at 20 hr, HC production seemed to follow the normal diurnal variation of the control values again. To explain the difference in HC suppression by DEX at different dosage times, we constructed a curve describing the relationship between DEX concentration and suppression of the sudden increase in HC production during the night. This curve indicates that HC suppression by DEX could be completely dependent on DEX concentration, without a DEX independent circadian variation.     

Pharmacokinetics and metabolism of 14C-isepamicin in humans following intravenous administration.

Twelve healthy adult male volunteers received 1 g (base equivalent) of 14C-isepamicin (131 microCi) as an intravenous bolus over 5 min. The areas under the plasma concentration-time curves at infinity for isepamicin (196 micrograms*h/ml) and total radioactivity (164 micrograms*h/ml) were similar, indicating no biotransformation of isepamicin. The disappearance of isepamicin from plasma followed a triexponential decline, with half-lives of 0.17, 2.12, and 34 h for the alpha, beta, and gamma phases, respectively. However, the contribution of the gamma phase to the total area under the concentration-time curve was only 2.6%. There were no detectable metabolites in plasma and urine, confirming that isepamicin was not biotransformed. The cumulative levels of isepamicin and total radioactivity excretion in urine from 0 to 120 h were 97.3 and 92.1% of the dose, respectively, indicating that the drug was excreted mainly as unchanged isepamicin in urine.     

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous administration in rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (T(max) = 12 h) and incomplete bioavailability (F = 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21-24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (S(max) = 1.87 and SC(50) = 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.     

Pharmacokinetics of cefadroxil after oral administration in humans.

The human oral pharmacokinetics of cefadroxil were studied in parallel at doses of 250, 500, and 1,000 mg in three groups of 10 healthy young male volunteers. Renal excretion of intact cefadroxil, accounted for 82, 79, and 77% of the above doses. Mean peak serum levels were dose linear: 9, 18, and 35 microgram/ml at 250, 500, and 1,000 mg, respectively. However, overall pharmacokinetics were linear only in the 250- to 500-mg dose range; apparent serum clearances were 10 liters/h, and true renal clearances were 9 and 8 liters/h at 250 and 500 mg. At 1,000 mg, apparent serum clearance dropped to about 7 liters/h, true renal clearance, dropped to 6 liters/h, and the area under the curve increased disproportionately. At 250 and 500 mg, mean half-life was about 1.2 h; at 1,000 mg, however, it was 1.6h. The nonlinear decrease in clearance could be related to saturation of active renal tubular secretion of cefadroxil between the 500- and 1,000-mg doses. Previous results indicating that cefadroxil has greater persistence than other oral cephalosporins such as cephalexin, cephradine, cefaclor were confirmed.     

Mechanisms of anti-inflammatory action of dexamethasone: blockade by hydrocortisone mesylate and actinomycin D of the inhibitory effect of dexamethasone on leukocyte infiltration in inflammatory sites

The present study was designed to clarify molecular mechanisms underlying inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site. For the assay of leukocyte infiltration, two or four blebs were made s.c. on the back of rats by injecting with 2% carboxymethyl cellulose solution containing a chemoattractant, casein. Leukocyte accumulation in the bleb was inhibited considerably by local application of dexamethasone at a concentration of 0.6 X 10(-6) M. Hydrocortisone mesylate, which was reported in the study with hepatoma tissue culture cells to be a long-acting antagonist against glucocorticoid in binding to the corticoid receptor, blocked the above leukocyte inhibitory effect of dexamethasone when applied simultaneously with dexamethasone. The leukocyte infiltration was unaffected by the application of hydrocortisone mesylate alone. Treatment with androstenedione, which was reported to be inactive in the hepatoma tissue culture cells, did not interfere with the inhibitory effect of dexamethasone at all. Actinomycin D, when applied simultaneously with dexamethasone, significantly suppressed the leukocyte-inhibitory effect of dexamethasone. In contrast with those observations, the inhibitory effect of dexamethasone was not affected at all in cases that actinomycin D and hydrocortisone mesylate, respectively, were applied after the administration of dexamethasone. These results indicate essential roles of glucocorticoid receptor and gene expression for the manifestation of the inhibitory effect of dexamethasone on leukocyte infiltration in the inflammatory site.     

Profiles of opioid analgesia in humans after intravenous bolus administration: alfentanil, fentanyl and morphine compared on experimental pain

This report examines the relationship of plasma drug concentration to analgesic effect following bolus doses of alfentanil, fentanyl and morphine and assesses individual differences in analgesic response among volunteers. We predicted that the 3 opioids would yield disparate analgesic profiles because their physicochemical and pharmacokinetic characteristics differ. Ten healthy volunteers received intravenous bolus doses of either alfentanil, fentanyl, morphine or normal saline on different days. We stimulated their teeth electrically and measured brain evoked potential (EP) and pain report (PR) repeatedly over 2 h to assess analgesic effect. Concurrently, we drew 18 blood samples to assess opioid plasma concentrations during the test period. The relationship between opioid plasma concentration and analgesic effect was well defined for alfentanil but ambiguous for morphine. Fentanyl exhibited a marked hysteresis. We observed noteworthy individual differences in analgesic response with all 3 drugs but these differences were greatest for morphine and least for alfentanil. Inter- and intrasubject variability in analgesic response across drugs is related to the physicochemical properties of the drugs tested.     

Absolute bioavailability of clarithromycin after oral administration in humans.

The absolute bioavailability of clarithromycin, a new macrolide antimicrobial agent, was assessed in a three-way, randomized, single-dose, crossover study conducted with 22 healthy volunteers, 19 of whom provided analyzable study data. The bioavailability parameters of two 250-mg oral tablet formulations were calculated with reference to an identical dose administered by intravenous infusion of the lactobionate salt. After adjustment for formulation potency, the mean absolute bioavailabilities of the two oral formulations were 52 and 55%, on the basis of the appearance of parent compound in the systemic circulation. Metabolite peak concentration and area under the plasma concentration-time curve data after oral dosing were generally greater than those after intravenous infusion, suggesting that marked first-pass metabolism of clarithromycin occurs after oral administration. Pharmacokinetic analysis of the parent drug and the active 14-hydroxy metabolite data suggests complete (or nearly complete) absorption of the drug after oral administration.     

肝素地塞米松封管预防留置针致静脉炎的效果分析

静脉留置针已经在临床上广泛应用，它具有操作简单、易于固定、保留时间长、方便危重病人的抢救等优点，同时可减少病人因反复穿刺引起的痛苦，减轻护士工作强度。但留置过程中常出现静脉炎是影响留置时间的主要原因。如何减少静脉炎的发生，延长留置时间，已成为留置针应用研究的一个重要方向。本文对采用不同封管液封管静脉炎发生率做一对比研究。现报道如下。     

肝素地塞米松封管预防留置针致静脉炎的效果分析

静脉留置针已经在临床上广泛应用,它具有操作简单、易于固定、保留时间长、方便危重病人的抢救等优点,同时可减少病人因反复穿刺引起的痛苦,减轻护士工作强度。但留置过程中常出现静脉炎是影响留置时间的主要原因。如何减少静脉炎的发生,延长留置时间,已成为留置针应用研究的一个重要方向。本文对采用不同封管液封管静脉炎发生率做一对比研究。现报道如下。1资料及方法1.1临床资料选择2005年3月—5月在四川大学华西医院临床免疫科住院治疗,使用静脉留置针的141例病人,排除由于其他原因,如治疗方案改变、出院、病人意愿等拔除留置针的病人26…     

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An Smax of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.     

The effect of intravenous sodium cromoglycate on the bronchoconstriction induced by sulphur dioxide inhalation in man

Ten healthy subjects received, on separate occasions, intravenous infusions of 0.9% NaCl solution (saline) and of sodium cromoglycate given in a double-blind cross-over fashion. After 20 min of infusion the specific airway conductance (sGaw) of each subject was measured in a body plethysmograph. The subject then breathed first a low (1-20 p.p.m.) and then a higher (4-40 p.p.m.) concentration of sulphur dioxide (SO2) for 2 min while the infusion continued. Measurements of sGaw were repeated after each inhalation of SO2. Sodium cromoglycate infusion did not affect the sGaw measured before challenge with SO2. During the infusion of sodium cromoglycate, the falls in sGaw in response to both concentrations of SO2 were significantly less than those which occurred during saline infusion. Plasma concentrations of sodium cromoglycate were found to be 209 +/- 22 nmol/l at the end of the drug infusion. This is about one-hundredth of lowest dose required to stabilize mast cells in vitro. We conclude that sodium cromoglycate acted by a mechanism which did not involve mast cells. Other possible modes of action are discussed.     

Acute cardiodepressant effects induced by bolus intravenous administration of amiodarone in rabbits

Amiodarone is a potent anti-arrhythmic with a large pharmacological spectrum that shares the mechanisms of action of all classes of anti-arrhythmic drugs. Originally used in the treatment of supraventricular arrhythmias, it has also been used to treat ventricular tachyarrhythmias. The recent inclusion of amiodarone in the Advanced Cardiac Life Support protocols warrants the characterization of the hemodynamic profile resulting from the rapid venous administration of the drug. Thus, the main purpose of the present study was to investigate the acute hemodynamic profile resulting from the bolus i.v. injection of amiodarone, compared with bolus i.v. administration of lidocaine. We investigated the acute hemodynamic effects of amiodarone and lidocaine, in an experimental model of open-chest pentobarbital-anesthetized rabbits (n = 24). Amiodarone (5 mg/kg) induced immediate reductions in mean arterial pressure (MAP) of 32 +/- 5% (P < 0.001), accompanied by reductions in cardiac contractility and relaxation, as assessed by left ventricular (LV) +dP/dt(max) and -dP/dt(max) (40 +/- 4 and 36 +/- 4% respectively) (P < 0.001), heart rate (HR) 10 +/- 1% (P < 0.05), cardiac output (CO) 24 +/- 5% (P < 0.001) and systemic vascular resistance (SVR) 19 +/- 3.5% (P < 0.05). Lidocaine (3 mg/kg) induced reductions in: MAP of 18 +/- 7% (P < 0.001), LV +dP/dt(max) and -dP/dt(max) (40 +/- 5 and 22 +/- 7% respectively) (P < 0.001), HR 7 +/- 1% (P < 0.01) and CO of 23 +/- 6% (P < 0.001). SVR increased by 9 +/- 1.5% (P > 0.05). It is concluded that rapid i.v. administration of both amiodarone and lidocaine induces significant cardiovascular depression mainly characterized by immediate reductions in cardiac contractility.     

Cisapride and dexamethasone in the prevention of delayed emesis after cisplatin administration

 Management of delayed emesis (DE) remains unsatisfactory, and only 50% of the patients achieve complete protection. Cisapride is a strong prokinetic gastrointestinal drug that could have a role in the prevention of DE. We enrolled 31 adult naive outpatients who were scheduled to receive cisplatin chemotherapy at doses of ≥75 mg/m². All patients received the same prophylactic treatment for acute emesis (20 mg dexamethasone and 8 mg ondansetron i.v.) and, as preventive therapy for DE, oral cisapride, 10 mg every 8 h on days 2–4, combined with dexamethasone i.m., 8 mg twice daily on days 2 and 3, and 4 mg twice daily on day 4. All patients were evaluable for activity. Complete protection from acute vomiting was 80.7%, from nausea 71% and from nausea/vomiting 64.5%. The overall protection from DE (days 2–4) was 74.1% for vomiting, 64.5% for nausea and 58% for nausea/vomiting. In our study the combination of cisapride and dexamethasone was effective, giving 58% of complete protection from DE, and it is therefore worthy of further studies. Published online: 7 June 2000     

Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses.

In this double-blind, single-dose phase I study, the safety and tolerance of cefepime were assessed in 24 healthy male subjects, with ceftazidime as the control drug. Four subjects in each of the six dose groups (62.5, 125, 250, 500, 1,000, or 2,000 mg as a 30-min intravenous infusion) received each antibiotic, according to a crossover design, with a 2-day washout period between treatments. Blood and urine samples were obtained to characterize the pharmacokinetics of cefepime. Plasma and urine samples were assayed for intact cefepime. Samples containing ceftazidime were discarded. The adverse effects observed in the study were mild and infrequent, with prompt recovery from adverse experiences and abnormal laboratory values. The cefepime pharmacokinetic parameters for the therapeutically significant doses of 250 to 2,000 mg appeared to be proportional to dose and similar to literature values for ceftazidime. The elimination half-life of about 2 h was independent of the dose. Urinary recovery of intact cefepime was invariant with respect to dose; an overall mean value of 82% of dose was obtained for the four highest levels. Mean renal clearance was 105 ml/min and suggestive of glomerular filtration as the primary excretion mechanism. In normal humans, the safety and pharmacokinetic profiles of cefepime are very similar to those of ceftazidime.     

右美托咪啶对静吸复合全身麻醉苏醒期恢复质量的影响

目的探讨在静吸复合全身麻醉中应用右美托咪啶抑制苏醒期应激反应、减少并发症、提高患者的恢复质量的有效性及可行性。方法采用双盲研究,将60例患者随机分为实验组和对照组,所有患者均采用静吸复合全身麻醉,其中实验组在麻醉过程中泵注右美托咪啶,而对照组泵注生理盐水。记录苏醒期恢复过程(呼唤睁眼时间,拔管时间,完全清醒不再嗜睡时间)、苏醒期MAAS评分及VAS评分、血流动力学变化情况[麻醉前、拔管即时、拔管后30 min的心率(HR)、平均动脉压(MAP)]以及术后有无发生恶心呕吐、呼吸抑制等不良反应。结果两组患者呼唤睁眼时间、拔管时间、完全清醒不再嗜睡时间两组无显著性差异(P>0.05)。拔管后30 min VAS评分实验组较对照组明显降低(P<0.05)。拔管后5 min MAAS评分值实验组明显低于对照组(P<0.05)。两组患者麻醉前MAP、HR组间比较,差异无统计学意义(P>0.05);拔管即时、拔管后30 min与麻醉前比较,对照组MAP水平明显升高、HR明显增快(P<0.05),而实验组MAP、HR变化不明显(P>0.05);组间比较,拔管即时、拔管后30 min对照组MAP、HR均明显高于实验组(P<0.05)。对照组有7例患者出现寒颤而实验组所有患者均无出现寒颤,两组差异有统计学意义(P<0.05)。结论右美托咪啶能有效抑制静吸复合全身麻醉清醒期应激反应,减少并发症,提高患者的恢复质量,值得推广应用。     

Microvascular rheology of Definity microbubbles after intra-arterial and intravenous administration.

The microvascular rheology and extent of pulmonary retention of second-generation microbubble ultrasound contrast agents has not previously been well characterized. We assessed the microvascular behavior of Definity, a lipid-shelled microbubble agent containing perfluoropropane gas, using intravital microscopy of either rat spinotrapezius muscle or mouse cremaster muscle. Immediately after intra-arterial injection, which was performed to model pulmonary retention, larger microbubbles (> 5 microm) were entrapped within small arterioles and capillaries. The retention fraction of microbubbles was low (1.2% +/- 0.1%) and entrapment was transient (85% dislodged by 10 minutes), resulting in no adverse hemodynamic effects. Leukocyte or platelet adhesion at the site of entrapment was not seen. After intravenous injection, no microbubble entrapment was observed and the velocities of microbubbles in arterioles, venules, and capillaries correlated well with those of red blood cells. We conclude that after intravenous injection and pulmonary passage, the microvascular rheology of Definity microbubbles is similar to that of red blood cells. Microbubble entrapment within the pulmonary microcirculation after venous injection should be negligible and transient. These findings are important for establishing the safety of this agent.