A prospective evaluation of the continuous infusion of cis-atracurium for neuromuscular blockade in the pediatric intensive care unit patient: efficacy and dosage requirements.

PURPOSE: To prospectively evaluate the efficacy and dosage requirements of cis-atracurium administered by continuous infusion for neuromuscular blockade in a pediatric intensive care unit population. METHODS: Neuromuscular function was monitored by a train-of-four (TOF) over the ulnar or peroneal nerve. cis-Atracurium was administered as a bolus dose (0.2 mg/kg) followed by a continuous infusion starting at 3 microg/kg/min. The infusion was increased or decreased by 1 mIcrog/kg/min to maintain one twitch of the TOF. All patients also received a benzodiazepine infusion. Results: The study population included 15 children ranging in age from 10 months to 11 years and in weight from 4-28 kg. The duration of the infusion varied from 18-224 hours for a total of 1088 hours in the 15 patients. The cis-atracurium infusion requirements varied from 2.1 to 3.8 microg/kg/min (3.1 +/- 0.6) on day 1, to 1.4 to 6.4 microg/kg/min (3.4 +/- 1.4) on day 2, to 2.9 to 8.1 microg/kg/min (4. 5 +/- 1.6) on day 3. Overall, the infusion requirements varied from 1.4-22.7 microg/kg/min. The highest infusion requirements (22.7 and 10.2 microg/kg/min) were noted in patients who received cis-atracurium for prolonged periods of time (150 and 224 hours, respectively). The lowest infusion requirement occurred with the use of hypothermia to treat increased intracranial pressure. Conclusions: cis-Atracurium can be used by continuous infusion to provide neuromuscular blockade in the pediatric intensive care unit patient. Because of the variability in infusion requirements, monitoring of neuromuscular function is suggested.     

Pharmacokinetics in Non-Insulin-Dependent Diabetics of the Aldose Reductase Inhibitor, Zopolrestat

The pharmacokinetics of zopolrestat have been examined in non-insulin-dependent diabetic patients after oral administration of a single dose of 1000 mg zopolrestat. T(max) ranged from 2 to 4 h with a mean C(max) of 100 &mgr;g ml(minus sign1). Mean plasma half-life of zopolrestat was 26.9 h. The same patients were also administered oral doses of 1000 mg day(minus sign1) for 10 consecutive days. Mean T(max) was 4.3 h and mean C(max) was 208 &mgr;g ml(minus sign1). Plasma accumulation, the ratio of AUC((0--24)) for the last dose to AUC((0--24)) for the first dose, was 2.67. Apparent oral clearance was 5.71 ml min(minus sign1) and apparent volume of distribution was 12.9 L. The mean urinary excretion of unchanged drug over the 24-h period following the last dose was 36% of the dose while another 7% of the dose appeared in the urine as an acylglucuronide of zopolrestat. Renal clearance of zopolrestat was 1.82 ml min(minus sign1). Binding of zopolrestat to plasma proteins exceeded 99% and was concentration dependent.     

氨甲环酸与体外循环下心脏手术患者出血的相关性

目的研究和分析氨甲环酸与体外循环下心脏手术病人出血的相关性。方法选取185例体外循环心脏手术患者作为研究对象,根据患者术中是否应用氨甲环酸将患者分为观察组81例(术中应用氨甲环酸)和对照组104例(术中未应用氨甲环酸)。对2组患者术前和术后24h的红细胞压积(HCT)、血小板计数(PLT)、凝血酶原时间(PT)、活化部分凝血酶原时间(APTT)、纤维蛋白原(FIB)等血常规及凝血功能指标水平进行检测和比较。对2组患者的体外循环时间、主动脉阻断时间、术中肝素应用量、术中鱼精蛋白应用量进行记录和比较。对2组患者术中和术后24 h出血量、输注浓缩红细胞量、输注血浆量、输注血小板量、因出血行二次开胸手术发生率进行观察和比较。对2组患者术后急性肾功能衰竭、肾功能不全、神经系统并发症、低心排综合征、二次插管、肺部感染的发生率及住院死亡率进行观察和比较。结果 2组患者术后24 h的HCT水平、PLT水平、FIB水平均较治疗前显著下降(P0.05),对照组患者术后24 h的PLT水平显著低于观察组(P0.05)。对照组患者的术中和术后出血量、各项输血量及因出血行二次开胸手术发生率均显著高于观察组(P0.05)。2组患者的各项手术相关指标的差异均无统计学意义(P0.05)。2组患者术后各项并发症发生率及住院死亡率的差异均无统计学意义(P0.05)。结论在体外循环心脏手术中应用氨甲环酸可有效减少患者的术中、术后出血量和输血量,保护患者的凝血功能。     

Glycine and ammonia plasma concentrations during sedation with remifentanil in critically ill patients

Objectives To investigate glycine and ammonia plasma concentrations during a 72-h remifentanil infusion and the relationship between glycine concentration and remifentanil infusion rate. Design and setting A prospective open-label observational clinical trial in a trauma and a neurosurgical intensive care unit in a university teaching hospital. Patients Nine consecutive patients requiring sedation and ventilatory support for at least 72 h. One was excluded due to acute cardiac failure. Interventions Patients were sedated with remifentanil and propofol. Glycine and ammonia plasma concentrations were measured every 12 h during an intravenous remifentanil infusion performed over 72 h, and 24 h after the end of the infusion. Cumulative remifentanil dose and rate of infusion were recorded for each patient. Clinical and biological signs of glycine toxicity were evaluated. Measurements and results Glycine and ammonia plasma concentrations did not exceed the toxic threshold at any time. Plasma glycine concentration measured at the end of remifentanil infusion was significantly correlated with the mean weighted rate of remifentanil infusion and with the cumulative remifentanil dose. A correlation between plasma glycine concentration and creatinine clearance at the end of remifentanil infusion was also documented. Conclusions Plasma glycine concentration was correlated with the remifentanil cumulative dose and the infusion rate and did not reach the toxic threshold. As glycine concentration was also correlated with creatinine clearance and because remifentanil was the only source of exogenous glycine, additional data are necessary to ascertain the safety of remifentanil infusion in ICU patients. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users     

A method for calculating the additional quantity of protamine sulfate during cardiosurgical operations

The paper describes a method for calculating the additional dose of protamine sulfate solution during incomplete heparin neutralization after cardiac surgery under extracorporeal circulation, by estimating the anti-Xa-activity of venous blood plasma. The method may be an alternative to the use of devices to measure the blood concentration of free heparin, such as a "Hepcon" apparatus.     

Medication errors involving continuously infused medications in a surgical intensive care unit

OBJECTIVE: To document the incidence of medication errors related to medications administered by continuous infusion. DESIGN: Observational study. SETTING: Sixteen-bed surgical intensive care unit. MEASUREMENTS AND MAIN RESULTS: All continuous infusions in the surgical intensive care unit were evaluated at least once daily for correct flow-sheet charting, concentration, infusion rate, and dose administered, as well as patients' heights and weights (actual, ideal, and "dry"). Collected information was examined to determine the error rate, types of errors occurring, and weight used for dose calculation. Variations inpatient weight measures were compared. Seventy-one patients with 202 total infusions were observed. Errors involving continuously infused medications in our surgical intensive care unit occurred at a rate of 105.9 per 1,000 patient days. For nonweight-based infusions, 94% of doses were delivered correctly. Slightly >10% of the doses administered for weight-based infusions (dose based on dry body weight) were incorrect. Significant differences were found between the weight measurements recorded, but this did not translate into statistically significant differences in the apparent calculated doses delivered. CONCLUSIONS: Medications delivered by continuous infusion, particularly those that are weight based, can contribute to medication errors in the intensive care unit. A large proportion (87.6%) of doses for weight-based infusions was calculated based on estimated or unreliable admission weights. There were no severe consequences resulting from the errors observed in this 1 month investigation; however, depending on the pharmacokinetic characteristics of the drug being administered, there is a potential to deliver artificially low or high doses resulting in subtherapeutic or adverse effects.     

Evaluation of aprotinin and tranexamic acid in different in vitro and in vivo models of fibrinolysis, coagulation and thrombus formation

BACKGROUND: The serine protease inhibitor aprotinin and plasminogen inhibitor tranexamic acid are used in coronary artery bypass graft (CABG) surgery to reduce bleeding. Clinicians may consider these agents as readily substitutable regarding their pharmacological profiles. OBJECTIVE: These agents were evaluated in assays of hemostasis to elucidate their underlying mechanism(s) of action. METHODS: In human plasma, effects on both clot fibrinolysis and coagulation were spectrophotometrically quantified in vitro. Rat-tail bleeding and arteriovenous shunt thrombus formation models were conducted in vivo. RESULTS: Fibrinolysis was inhibited by aprotinin (IC(50), 0.16 +/- 0.02 micromol L(-1)) and tranexamic acid (IC(50), 24.1 +/-1.1 micromol L(-1)). In vivo, aprotinin dose-dependently reduced rat-tail bleeding time (minimal effective dose, 3 mg kg(-1) bolus plus 6 mg kg(-1 )h(-1) infusion); tranexamic acid reduced bleeding time (minimal effective dose, 100 mg kg(-1) h(-1)). In vitro, coagulation time was doubled by aprotinin at 3.2 +/- 0.2 micromol L(-1), while tranexamic acid showed no effect at concentrations up to 3 mmol L(-1). Aprotinin inhibited thrombus formation in vivo in a dose-dependent manner (minimal effective dose, 3 mg kg(-1) bolus plus 6 mg kg(-1) h(-1) infusion). Conversely, tranexamic acid dose-dependently increased thrombus formation and thrombus weight (minimal effective dose, 100 mg kg(-1 )h(-1) infusion). CONCLUSIONS: These data show that aprotinin and tranexamic acid have differential effects on hemostasis and are not necessarily substitutable with respect to mechanism of action. Although both agents have been shown to reduce bleeding in patients undergoing CABG, their divergent effects on thrombus formation observed in vitro and in vivo should be critically evaluated clinically.     

Preservation of collagen-induced whole blood platelet aggregation by tranexamic acid therapy in primary cardiac valve surgery

Haemostatic disorder is one of the most common complications following cardiac surgery with cardiopulmonary bypass (CPB). Tranexamic acid reduces blood loss and allogeneic blood transfusion requirement in cardiac surgery. It had been thought that tranexamic acid inhibited fibrinolysis alone following CPB. In the present study, the haemostatic effects of tranexamic acid (20 mg/kg body weight bolus after induction of anaesthesia followed by continuous infusion at 2 mg/kg/h), including fibrinolysis and platelet function, were investigated in 22 patients (tranexamic acid group n = 12; control group n = 10) undergoing primary cardiac valve surgery. Fibrinolysis following CPB was reduced significantly in the tranexamic acid group. Following protamine administration, the reduction of collagen-induced whole blood platelet aggregation was mitigated significantly in the tranexamic acid group compared with the control group (36% reduction in the tranexamic acid group vs 58% in the control group; p = 0.011), although platelet counts did not differ between the two groups. In conclusion, tranexamic acid not only inhibits fibrinolysis directly, but also may preserve platelet function following CPB.     

Magnesium sulfate administered via continuous intravenous infusion in pediatric patients with refractory wheezing

PURPOSE: To evaluate the dosing and safety of intravenous magnesium sulfate administered via continuous infusion for refractory wheezing. MATERIALS AND METHODS: All patients admitted to the pediatric intensive care unit (PICU) between January 1998 and March 2001 who were prescribed magnesium sulfate via continuous infusion were identified via retrospective chart review. The patient's medical history, demographic data, vital signs, magnesium dosing history, and concurrent medications were recorded. RESULTS: Forty PICU patients represent our study population. The mean age was 82.6 +/- 64.6 mo; 18 patients were boys.The mean magnesium loading dose (mg/kg) was 29.6 +/- 13.2 with a mean infusion dose (mg/kg/h) of 18.4 +/- 6.5 with a significant difference in dosing noted between patients weighing less than 30 kg and those with a higher weight. The mean magnesium loading dose (mg/kg) in the less than 30 kg group was 35.3 +/- 12.7 compared with 21.9 +/- 9.9 in the higher weight group (P <.05). Mean infusion doses (mg/kg/h) were 21.6 +/- 6 and 14.6 +/- 4.2, respectively (P <.05). There was no significant difference between the mean concentrations (mg/dL) reported between the 2 groups (less than 30 kg group = 3.9 +/- 0.6; higher weight group = 3.6 +/- 0.5). All patients received nebulized albuterol, ipratropium, and intravenous methylprednisolone before magnesium therapy. Aminophylline and ketamine were prescribed to 28 and 4 patients, respectively. No cardiovascular adverse effects were noted during magnesium therapy. CONCLUSIONS: For the treatment of refractory wheezing, intravenous magnesium sulfate administered via continuous infusion represents a safe mode of drug delivery.     

Elimination of methohexitone after long-term, high-dose infusion in patients with critically elevated intracranial pressure.

OBJECTIVE: To determine the plasma elimination of methohexitone in patients with critically elevated intracranial pressure (ICP) who received the drug in high doses for several days. DESIGN: Drug-monitoring study. SETTING: Intensive care unit at a university hospital. PATIENTS: Twelve intensive care unit patients with brain injuries who received methohexitone as a final therapeutic approach after routine therapy had proved to be insufficient in controlling critically elevated ICP. MEASUREMENTS AND MAIN RESULTS: Plasma samples were taken during methohexitone infusion, before cessation, and in distinct, short increments after discontinuation of the infusion. Methohexitone was determined in plasma by reverse-phase high-pressure liquid chromatography and photometric detection. The median duration of infusion of methohexitone was 137 hrs (minimum, 27 hrs; maximum, 445 hrs), with a median infusion rate of 62.5 microg/kg/min (minimum, 22.5 microg/kg/min; maximum, 116.2 microg/kg/min). Plasma concentrations of methohexitone at burst suppression under concomitant analgesic sedation ranged from 1.6 to 17.3 microg/mL (median, 4.7 microg/mL). After cessation of methohexitone infusion, the decline of plasma concentrations followed a biexponential function. Clearance rates, volume of distribution at steady state, context-sensitive half-time, and initial and terminal elimination half-times were calculated. Pharmacokinetic data showed remarkable interindividual variability that could not be correlated to the infusion rate, to the duration of the infusion, or to obvious differences in physiology or the disease states of these patients. Even in patients with high plasma concentrations who received the drug for a considerable length of time, the initial decline in plasma concentration was exponential, indicating redistribution. CONCLUSIONS: We conclude that the elimination kinetics of methohexitone after long-term, high-dose infusion in critically ill patients with brain injuries may favor the use of methohexitone over thiopentone for controlling critically elevated ICP by allowing for a more timely neurologic examination after cessation.     

Kinetics and dynamics of lorazepam during and after continuous intravenous infusion

OBJECTIVE: To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point. METHODS: Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 microg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs. RESULTS: The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins. CONCLUSION: Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.     

The new phosphodiesterase inhibitor enoximone in patients following cardiac surgery — pharmacokinetics and influence on parameters of coagulation

Enoximone is a selective inhibitor of the phosphodiesterase-III enzyme (PDE-III) and possesses positive inotropic and vasodilatory properties. The PDE-inhibitor amrinone has been associated with adverse effects on coagulation by decreasing platelets. To investigate the influence of enoximone on hemostasis, 18 patients undergoing elective aorto-coronary bypass grafting and receiving enoximone were compared to a control group (n=18). In addition, the plasma levels of enoximone and its major metabolite (enoximonesulfoxide) were studied following a single injection (0.5 mg/kg) and during a continuous infusion (5 and 10 g/kg·min) before, during and after extracorporeal circulation (ECC). No difference between study and control groups was found for the parameters of coagulation during the investigation period; in particular there were no differences in platelet count and platelet function (thrombelastography). Following the single bolus, peak plasma levels decreased during ECC to ineffective levels. Continuous infusion, however, maintained effective plasma levels of enoximone; sulfoxide levels were twice as high as enoximone concentrations up until the end of the investigation period. It is concluded that enoximone can be judged to be safe in respect to its effects on coagulation even following ECC and at relatively high doses. The use of continuous infusion results in plasma levels which remain at an effective concentration through to the time that the patient is transferred to the intensive care unit.     

Evaluation of a dosing regimen for continuous vancomycin infusion in critically ill patients: An observational study in intensive care unit patients

Purpose

We aimed to evaluate a dosing algorithm for continuous vancomycin administration in intensive care unit patients.

Materials and Methods

This observational study was conducted in a medical intensive care unit (German university hospital; June 2012-February 2013). Following a loading dose of 20 mg per kg actual body weight, vancomycin was administered continuously (20 or 30 mg of vancomycin per kg actual body weight over 24 hours depending on renal function). The vancomycin infusion rate was adjusted to achieve a target serum vancomycin concentration of 20-30 mg/L.

Results

Vancomycin was administered for a median (interquartile range) of 7 (5-9) days. The median vancomycin dose given as an initial bolus was 1750 (1400-2000) mg. The median daily vancomycin dose ranged from 480 (180–960) mg (day 6) to 3.120 (2596-3980) mg (day 1). Altogether, the achieved median serum vancomycin concentration was 29.0 (25.2-33.2) mg/L. On treatment days 1 to 7, we observed target serum vancomycin levels (20-30 mg/L) in 48%, 39%, 33%, 26%, 43%, 57%, and 69% of patients. Supra-therapeutic serum vancomycin concentrations (> 30 mg/L) were observed in 36%, 52%, 61%, 63%, 39%, 19%, and 15% of patients on treatment days 1 to 7.

Conclusions

The evaluated vancomycin dosing regimen for continuous infusion allowed rapid achievement of sufficient vancomycin serum levels. However, we frequently observed supra-therapeutic serum vancomycin concentrations in the first days of vancomycin treatment.     

右美托咪啶在外科重症监护病房中的镇静镇痛作用

目的:研究右美托咪啶对外科重症患者的镇静、镇痛作用.方法:将本院外科重症监护病房需要镇静、镇痛120例患者按照随机原则分为右美托咪啶组(58例)和咪达唑仑组(62例).右美托咪啶组经静脉泵人负荷剂量1 μg·kg-1、10 min,继以0.2～0.7μg·kg-1·h-1维持;咪达唑仑组给予负荷剂量0.06 mg·kg-1,再以0.04～0.20 mg·kg-1·h-1维持.结果:右美托咪啶组视觉模拟法(VAS)评分低于咪达唑仑组[(2.38±0.48)分&(6.07±0.79)分,P<0.01];唤醒所需时间显著短于咪达唑仑组[(0.17±0.03)h&(1.63±0.56)h,P<0.01].右美托咪啶组出现血压下降3例,自主呼吸频率无明显变化;咪达唑仑组出现血压下降10例,出现自主呼吸频率下降3例(P<0.05).右美托咪啶组中有6例产生顺行性遗忘,咪达唑仑组所有患者均产生顺行性遗忘(P<0.05).结论:右美托咪啶是外科重症监护病房较为理想的镇静、镇痛药物.     

Dobutamine pharmacokinetics and pharmacodynamics in pediatric intensive care patients.

OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of dobutamine in critically ill children. DESIGN: A prospective study of pediatric patients receiving continuous infusions of dobutamine in a stepwise format from 2.5 to 10.0 micrograms/kg/min. SETTING: A pediatric critical care unit. PATIENTS: Twelve children ranging in age from 1 month to 17 yrs with primary medical conditions. MEASUREMENTS: Plasma dobutamine concentrations and hemodynamic responses were measured at each infusion rate at steady state. Dose response data were analyzed to determine the threshold or minimum plasma dobutamine concentration necessary for discernible hemodynamic effects. MAIN RESULTS: Dobutamine plasma clearance rates ranged from 40 to 130 mL/kg/min. Each patient presented a linear increase in the plasma dobutamine concentration at each infusion rate (r2 = .97, p less than .001). Plasma clearance rate vs. actual dobutamine concentration did not vary. Cardiac output, BP, and heart rate increased 30%, 17%, and 7%, respectively, at maximal dose. The dobutamine concentration thresholds for changes in cardiac output, BP, and heart rate were 13 +/- 6, 23 +/- 14, and 65 +/- 30 ng/mL, respectively. CONCLUSIONS: There was no effect of plasma dobutamine concentration or infusion rate on plasma clearance rate. For this group of patients, over the range of the intravenous doses studied, dobutamine pharmacokinetics followed a first-order kinetic model. Threshold values for dobutamine usually show increases in cardiac output before changes in heart rate. These data demonstrate that dobutamine is an effective inotropic agent in critically ill pediatric patients and has minimal chronotropic action.     

Pharmacokinetic studies in women of 2 novel oral formulations of tranexamic acid therapy for heavy menstrual bleeding

Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (≥5 μg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 μg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3-g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding.     

Lack of Pharmacokinetic Interaction between Aspirin and Warfarin

An open-label, randomized, two-phase crossover study was conducted on 36 healthy male volunteers to identify the effects of coadministration of aspirin (acetylsalicylic acid; ASA) and crystalline warfarin sodium (Coumadin((R))) on the elimination and disposition kinetics of ASA, salicylic acid (SA) and R- and S-warfarin enantiomers. Twenty-four subjects were administered single doses of 325 mg of ASA alone and in combination with 10 mg of crystalline warfarin sodium with a 1-week washout between ASA doses. ASA and SA pharmacokinetic parameters were determined after each dose. Twelve subjects were administered single doses of 10 mg of crystalline warfarin sodium alone and in combination with 325 mg of ASA with a 4-week washout between warfarin doses. R- and S-warfarin enantiomer pharmacokinetic parameters were determined after each dose. Pharmacokinetic parameters were compared using analysis of variance and 90% confidence intervals. ASA and SA AUCs (the area under the plasma concentration versus time curve from time zero to time infinity) respectively were 3.28 plus minus 0.80 and 66.99 plus minus 11.73 &mgr;g h ml(minus sign1) (ASA alone), and 3.22 plus minus 0.61 and 69.48 plus minus 15.79 &mgr;g h ml(minus sign1) (ASA with warfarin). R-warfarin and S-warfarin AUCs respectively were 33.9 plus minus 9.3 and 23.9 plus minus 16.0 &mgr;g h ml(minus sign1) (warfarin alone) and 33.6 plus minus 10.2 and 22.6 plus minus 14.7 &mgr;g h ml(minus sign1) (warfarin with ASA). The only pharmacokinetic parameter which was statistically significantly different when the combination was administered was the S-warfarin elimination rate constant (p < 0.05), but the difference (9.2% increase in the presence of ASA) was small and no significant difference was found in S-warfarin clearance. It is concluded that there is no pharmacokinetic interaction when a single dose of ASA 325 mg is coadministered with a single dose of crystalline warfarin sodium 10 mg.     

Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit

BACKGROUND: Co-morbidity, medical and surgical interventions often cause alterations to drug plasma concentrations and pharmacokinetic parameters in critically ill patients. In the present study, we investigated parameters influencing plasma caspofungin concentrations in patients of a surgical intensive care unit (SICU). METHODS: In a monocentre open study, caspofungin trough concentrations (C(24)) were determined for a group of SICU patients. A linear-mixed model was then used to assess factors influencing caspofungin plasma concentrations. RESULTS: A total of 40 SICU patients were enrolled. Age and body weight ranged from 22 to 76 years and 47 to 108 kg, respectively. All participants received a caspofungin loading dose of 70 mg and a maintenance dose of 50 mg/day. The median duration of therapy was 10 days. Caspofungin C(24) in SICU patients varied more than those determined for healthy subjects reported in previous studies (0.52-4.08 microg/mL versus 1.12-1.78 microg/mL). According to our model, caspofungin C(24) were predicted to be significantly higher in patients with body weight <75 kg (P=0.019) and patients with albumin concentration >23.6 g/L (P=0.030). CONCLUSIONS: Our results show that body weight and albumin concentration influence caspofungin C(24) in SICU patients and should therefore be considered prognostic factors.     

Single- and Multiple-Dose Pharmacokinetics of Reduced Metabolite (MDL 74,156) following Oral Administration of Dolasetron Mesylate to Normal Male Subjects

Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite of dolasetron has been identified in human plasma and is likely responsible for the antiemetic activity. This study evaluated single and multiple dose pharmacokinetics of the reduced metabolite following oral administration of dolasetron mesylate in healthy male subjects. Five groups (six active/two placebo each) of subjects received either oral doses of dolasetron mesylate ranging from 25 to 200 mg or placebo on day 1 and every 12 h on days 2 through 9. Because plasma dolasetron concentrations were low and sporadic, pharmacokinetics of the parent compound could not be determined. The reduced metabolite appeared rapidly in the plasma and reached a maximal plasma concentration in about 1 h. The maximal plasma concentrations and areas under plasma concentration--time curves were proportional to the dose. The mean apparent oral clearance ranged from 9.89 to 23.10 ml min(minus sign1) kg(minus sign1). The half-life ranged from 5.20 to 10.80 h. Mean renal clearance and fraction of dose excreted in urine were 0.97 to 3.97 ml min(minus sign1) kg(minus sign1) and 7.47 to 31.9%, respectively. The pharmacokinetics of reduced metabolite appears to be dose independent after single and multiple dosing.