Identification of Patients Who Require Two-Point Blood Sampling for the Peak and Trough Values Rather Than One-Point Blood Sampling for the Trough Value for the Evaluation of AUC of Vancomycin Using Bayesian Estimation.

OBJECTIVES: It is recommended to adjust the dose of vancomycin (VCM) with a target area under the concentration-time curve (AUC) of 400-600 µg·h/mL. Factors that affect the deviation between AUCs are estimated from the trough value alone and the trough and peak values using practical AUC-guided therapeutic drug monitoring (PAT) for vancomycin. In this study, factors that affect AUC were evaluated. METHODS: AUCs were estimated from a single trough value and trough and peak values, and the patients were classified into those who showed a 10% or greater deviation (deviation group) and those in whom the deviation was less than 10% (no-deviation group). Risk factors related to ≥ 10% deviation of AUC were identified by univariate and multivariate analysis. RESULTS: As a result of univariate and multivariate analysis of 30 patients in the deviation group and 344 patients in the no-deviation group, a creatinine clearance (CLcr) of ≥ 110 mL/min (odds ratio (OR) = 3.697, 95% confidence interval (CI) = 1.616-8.457, p = 0.002), heart failure with a brain natriuretic peptide (BNP) of ≥ 300 pg/mL (OR = 4.854, 95%CI = 1.199-19.656, p = 0.027), and the concomitant use of angiotensin converting enzyme inhibitor or angiotensin II receptor blocker (ACE-I/ARB) (OR = 2.544, 95%CI = 1.074-6.024, p = 0.034) were identified as risk factors of ≥ 10% deviation of AUC. CONCLUSIONS: Estimation of AUC by two-point blood sampling for the trough and peak values rather than one-point blood sampling for the trough value is suggested to improve the prediction accuracy in patients with enhanced renal function, severe heart failure, and patients using ACE-I/ARB.

Relationship between nephrotoxicity and area under the concentration-time curve of vancomycin in critically ill patients: a multicenter retrospective study.

We aimed to assess the frequency of acute kidney injury (AKI) in different areas under the concentration-time curve (AUC) values of vancomycin (VAN) using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. This multicenter retrospective observational study was conducted in eight hospitals. We retrospectively analyzed the data of patients who had received VAN in an intensive care unit (ICU) between January 2020 and December 2022. The primary outcome was the incidence of AKI. Patients were classified into three groups according to the AUC24-48h at the initial therapeutic drug monitoring (TDM) as follows: <500, 500-600, and ≥600 µg·h/mL. The AUC24-48h values were calculated using the Bayesian estimation software Practical AUC-guided TDM. Among 146 patients [median age (interquartile range), 67 (56-78) years; 39% women], the AUC24-48h <500 µg·h/mL had an AKI rate of 6.5% (7/107), the AUC24-48h 500-600 µg·h/mL had an AKI rate of 28.0% (7/25), and the AUC24-48h ≥600 µg·h/mL had an AKI rate of 42.9% (6/14). In multivariate Cox proportional hazard analysis, the AUC24-48h 500-600 µg·h/mL [hazard ratio 5.4, 95% confidence interval (CI) 1.64-17.63] and the AUC24-48h ≥600 µg·h/mL (hazard ratio 7.0, 95% CI 2.31-21.18) significantly correlated with a higher incidence of AKI compared with the AUC24-48h <500 µg·h/mL. In conclusion, we identified an association between AUC on day 2 and the risk of AKI in ICU patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. IMPORTANCE: Vancomycin (VAN) is a glycopeptide antibiotic and one of the most commonly used antibiotics for severe infections caused by methicillin-resistant Staphylococcus aureus. However, higher VAN concentrations have been associated with an increased risk of acute kidney injury (AKI). Herein, we aimed to assess the frequency of AKI in different areas under the concentration-time curve (AUC) values of VAN using a two-point blood collection method, allowing for accurate AUC assessment in critically ill patients. We identified an association between AUC on day 2 and the risk of AKI in intensive care unit patients, suggesting that not only AUCs above 600 µg·h/mL but also those between 500 and 600 µg·h/mL pose a risk for AKI. Therefore, individualized dosing is feasible, with pharmacists being able to optimize VAN doses to attain appropriate targets.

Population pharmacokinetics and pharmacodynamic target attainment analysis of cefazolin using total and unbound serum concentration in patients with prostatectomy or nephrectomy.

The aim of this study was to analyze the population pharmacokinetics of total and unbound concentrations of prophylactic cefazolin (CFZ) in patients with prostatectomy or nephrectomy. We also aimed to calculate a pharmacodynamics target unbound concentration that exceeded the minimum inhibitory concentration (MIC), to design an effective dosing regimen. Briefly, 614 total concentration and 610 unbound concentration samples from 152 individuals were evaluated, using a nonlinear mixed-effects model. The obtained pharmacodynamics index target value reflected the probability of maintaining CFZ unbound trough concentrations exceeding MIC90, 0.5 mg/L, and MIC50, and 1.0 mg/L, to account for methicillin-susceptible Staphylococcus aureus (MSSA) or Escherichia coli. Population pharmacokinetics were estimated using a two-compartment model with nonlinear protein binding. Unbound systemic clearance (CL) was significantly associated with creatinine clearance, while the maximum protein-binding constant was significantly associated with albumin levels. The probability of achieving an unbound concentration exceeding the MIC50 for E. coli or MIC90 for MSSA in a patient with normal renal function following a 1 g CFZ infusion over 15 min was above 90% at 3 h after the initial dose. Our findings indicated that population pharmacokinetic parameters are useful for determining unbound CFZ pharmacokinetics and evaluating intraoperative CFZ redosing intervals.

Flowchart for predicting achieving the target area under the concentration-time curve of vancomycin in critically ill Japanese patients: A multicenter retrospective study.

INTRODUCTION: In therapeutic drug monitoring (TDM) of vancomycin (VCM), the area under the concentration-time curve (AUC) is related to the clinical efficacy and toxicity. Therefore, herein, we examined the factors associated with achieving the target AUC at follow-up and developed a decision flowchart for achieving the target AUC in critically ill patients. METHODS: This multicenter retrospective observational study was conducted at eight hospitals. We retrospectively analyzed data from patients who had received VCM in the intensive care unit from January 2020 to December 2022. Decision-tree (DT) analysis was performed using factors with p < 0.1 in univariate analysis as the independent variables. Case data were split up to two times, and four subgroups were included. The primary endpoint was achieving the target AUC at the follow-up TDM (AUCfollow-up) and target AUCfollow-up achievement was defined as an AUC of 400-600 µg‧h/mL. The initial AUC values were calculated with the 2-point concentrations (peak and trough) using the Bayesian estimation software Practical AUC-guided TDM (PAT). RESULTS: Among 70 patients (median age [interquartile range], 66 [56, 79] years; 50 % women), the AUCfollow-up was achieved in 70 % (49/70). Three factors were selected for the decision flow chart: predicted AUCfollow-up of 400-600 µg‧h/mL, dosing at 12-h intervals, and CCr of 130 mL/min/1.73 m2 or higher; the accuracy was adequate (92 %, R2 0.52). CONCLUSION: We successfully identified the factors associated with achieving the target AUC of VCM at follow-up TDM and developed a simple-to-use DT model. However, the validity of the findings needs to be evaluated.

Association between ratio of area under the concentration-time curve to minimum inhibitory concentration of vancomycin and clinical outcomes in Enterococcus faecium bacteremia.

The purpose of this study was to evaluate the relationship between the treatment resolution of Enterococcus faecium bacteremia and the pharmacodynamic targets of vancomycin. This is a retrospective single-center cohort study involving patients with E. faecium bacteremia on vancomycin therapy hospitalized between January 2010 and December 2021. The average vancomycin area under the concentration-time curve (AUC)0 -24 was computed using the Bayesian approach. The minimum inhibitory concentration (MIC) was determined using the broth microdilution method, and The AUC24/MIC value over the initial 24-48 h of therapy was calculated. We assessed 30-day mortality, as the primary outcome. Classification and regression tree analysis (CART) was used to identify the vancomycin AUC24/MIC target associated with 30-day mortality. Eighty-seven patients with E. faecium bacteremia were included in this study, with 14 (16.1%) being non-survivors. In the CART analysis, vancomycin AUC/MIC ≥414.3 was associated with a higher treatment success. In multivariate analysis, an AUC/MIC ≥414.3 was a significant factor for treatment success (adjusted odds ratio = 17.5, 95% confidence interval, 3.7-83.9). Our findings suggest that a target vancomycin AUC/MIC ≥414.3 is a good prognostic indicator and could be useful for treatment monitoring of E. faecium bacteremia.

Pre-Vaccination Anti-Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Seroprevalence in Workers at Three Japanese Hospitals.

BACKGROUND: Antibody testing is essential for accurately estimating the number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This study aimed to investigate the influence of background factors on seroprevalence by testing for anti-SARS-CoV-2 antibodies in blood samples obtained from the staff of three hospitals. METHODS: This cross-sectional observational study was conducted from June 8 to July 4, 2020, as part of a mandatory health examination. Leftover blood samples collected during the health examinations at each hospital were used to test for the presence of anti-SARS-CoV-2 antibodies. The Elecsys Anti-SARS-CoV-2 RUO assay was used for antibody detection. The relationship between staff age, gender, body mass index, blood pressure, work environments with different exposure risks, place of residence, and campus location and seroprevalence was investigated. The data were anonymized prior to analysis. RESULTS: A total of 3,677 individuals were included in the study, comprising 2,554 females (69.5%) and 1,123 males (30.5%). Anti-SARS-CoV-2 antibody (immunoglobulin G) was detected in 13 participants (0.35%). Seroprevalence was slightly higher in males than females (0.62% vs. 0.23%, P=0.08). By occupation, anti-SARS-CoV-2 antibodies were found in 6 (0.75%) physicians, 6 (0.31%) nurses, and one individual (0.11%) in the medical personnel group, with slightly higher levels in physicians. No significant difference was noted in the seroprevalence in terms of all background factors. CONCLUSIONS: Our study shows that the background factors do not impact seropositivity rates. Thorough daily infection control and adherence to recommended health guidelines were found to reduce infection risk.

Timing of re-dosing based on population pharmacokinetic-pharmacodynamics target attainment analysis of cefmetazole in subjects undergoing lower gastrointestinal surgery.

INTRODUCTION: This study was conducted to evaluate the population pharmacokinetics of prophylactic cefmetazole sodium (CMZ) based on the serum concentrations and establish a pharmacodynamics target concentration exceeding the minimum inhibitory concentration (MIC) to design the re-dosing interval. METHODS: Serum (n = 362) samples from 107 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index obtained was regarded as the probability of maintaining CMZ serum trough exceeding the minimal inhibitory concentration (MIC) of 2 mg/L. This MIC was chosen to account for methicillin-susceptible Staphylococcus aureus (MSSA), E. coli, and Klebsiella pneumoniae RESULTS: The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance and body weight were identified as significant covariates influencing the central clearance and volume of distribution in the central compartment. The probability of achieving serum concentrations exceeding the MIC90 for MSSA, E. coli, and Klebsiella pneumoniae for a 1 g dose with a 10 min intravenous infusion was above 90% except for good renal function (CLcr â‰§ 95 mL/min) at 2 h after the initial dose. For patients with good renal function (CLcr â‰§ 95 mL/min), a CMZ of 2 g re-dosing interval seemed necessary to meet the achievement probability. In patients with impaired renal function (CLcr ≤20 mL/min), the probability of achievement exceeded 90% even when the dosing interval was extended to 8 h. CONCLUSIONS: We evaluated re-dosing intervals based on the population pharmacokinetics. Re-dosing intervals should be determined based on renal function.

Serum concentration of oral midazolam as pediatric preanesthetic medication and factors related to the sedation level.

BACKGROUND: Preanesthetic medication is important to eliminate surgical anxiety in pediatric patients and facilitate their smooth transfer to the operating room. Midazolam is the most commonly used preanesthetic medication. However, it has been reported that the sedative effect varies from patient to patient. In this study, the pharmacokinetics of midazolam were examined, and the aim was to assess the factors affecting the quality of sedation. METHODS: The participants were children ranging in age from 6 months to 8 years scheduled for surgery. Midazolam 0.5 mg/kg was administered orally 30 min before entering the operating room, and the sedation level was evaluated at the time of mask application. Blood was collected after slow induction, and the serum concentration of midazolam was measured using high-performance liquid chromatography. RESULTS: A total of 98 patients were registered. There was no difference in serum concentrations between the effective sedation group and the ineffective sedation group (48.0 vs. 49.1 ng/mL), regardless of the effect of midazolam. Percentages of ineffective sedation by age (0 to 7 years) were 66.6%, 60%, 33.3%, 11.1%, 0%, 0%, 12.5%, and 0%, respectively. On multivariate logistic regression analysis, siblings (OR = 3.9, CI: 1.1-14.0, p = .03) and age (OR = 3.2, CI:1.2-8.5, p = .02) were related to an insufficient sedative effect. CONCLUSION: The serum concentration of oral midazolam reached effective levels even in patients in whom the sedative effect was inadequate. It is important to manage the perioperative period with appropriate concurrent premedication taking into account patient age and social background characteristics. CLINICAL TRIAL REGISTRATION: Clinical trial registry: UMIN R000052504.

Evaluation of a carbapenem antimicrobial stewardship program and clinical outcomes in a Japanese hospital.

INTRODUCTION: Microorganisms can evolve and become resistant to antimicrobials, and this is known as antimicrobial resistance (AMR). Inappropriate use of antibiotics contributes to AMR, and antimicrobial stewardship programs have been developed to mitigate AMR. The Appropriate Use of Carbapenems Program was implemented in March 2019 in a university hospital and its effect was evaluated. METHODS: We conducted a prospective audit and feedback on carbapenems at the time of prescription daily. Additionally, we compared a monthly survey of the total days of therapy (DOTs) per 1000 patient-days for carbapenems, piperacillin/tazobactam, and fluoroquinolones. The susceptibility of Pseudomonas aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin was tested before (January 2018 to February 2019) and after (March 2019 to December 2020) the intervention. RESULTS: The monthly median DOTs of carbapenem usage decreased after the intervention; carbapenem use immediately declined during the intervention period. The monthly median DOTs of piperacillin/tazobactam and fluoroquinolones also decreased and continued to decline significantly after the intervention. Susceptibility of P. aeruginosa to meropenem, piperacillin/tazobactam, and levofloxacin did not change significantly during the study. CONCLUSION: The implementation of the Appropriate Use of Carbapenems Program was effective in reducing the use of broad-spectrum antibiotics and maintaining the antibiotic susceptibility of P. aeruginosa.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

Initial trough concentration may be beneficial in preventing linezolid-induced thrombocytopenia.

We assessed whether prospective therapeutic drug monitoring to optimise the therapeutic range could prevent linezolid-induced thrombocytopenia. This prospective interventional study was conducted from September 2017 to October 2020 among 37 adult patients receiving linezolid. Patients were administered one of the following two initial dosages: 600 mg twice or once daily for patients with a creatinine clearance rate of ≥50 or <50 mL/min, respectively. Linezolid dosage adjustment was performed on days 3-5 based on the trough concentration. The serum linezolid levels in 22 and 15 patients were within and above the therapeutic range (2-7 µg/mL), respectively. The incidence of thrombocytopenia was significantly lower among patients whose linezolid levels were within the therapeutic range (4.5%;1/22) than in those whose levels were above the therapeutic range (80%; 12/15). It is important to maintain the linezolid level within the therapeutic range at the first therapeutic drug monitoring to prevent thrombocytopenia.

Association of serum and fat tissue antibiotic concentrations with surgical site infections in lower gastrointestinal surgery.

BACKGROUND: During surgery, the effectiveness of perioperative prophylactic antibiotic administration against surgical site infections is inferred from serum concentrations and not from tissues where local infections occur. This study aimed to measure the serum and tissue concentrations of cefmetazole in colorectal surgery cases to clarify whether there is an association between the incidence of surgical site infections and antibiotic concentrations. METHODS: This prospective cohort study was performed at a single tertiary care center. The data of 105 patients who underwent colorectal surgery between October 2017 and September 2019 were evaluated. The primary outcome was the incidence of surgical site infections. Univariate analysis was performed to investigate the association between surgical site infections, perioperative factors, and the serum and tissue concentrations of cefmetazole. RESULTS: The incidence of surgical site infections was 13/105 (12.4%). Cefmetazole concentrations were measured at initial incision (serum; 101 vs 93.1 mg/L, P = .75, subcutaneous fat tissue; 2.8 vs 3.7 mg/g, P = .15), intestinal resection (serum; 35.1 vs 36.7 mg/L, P = .63, mesenteric adipose tissue; 1.3 vs 1.7 mg/g, P = .55), and at skin closure (serum; 34.5 vs 44.8 mg/L, P = .18, subcutaneous fat tissue; 1.0 vs 2.2 mg/g, P = .09). In univariate analysis with P ≤ .10, cefmetazole concentration in subcutaneous fat tissue at skin closure was found to be a significant risk factor for surgical site infections. Age, additional intraoperative administration of cefmetazole, and creatinine clearance were also significant risk factors for the occurrence of surgical site infections. CONCLUSION: Low subcutaneous fat cefmetazole concentrations at skin closure during gastrointestinal operations may also be involved in the occurrence of surgical site infections.

Population Pharmacokinetic and Pharmacodynamic Target Attainment Analysis of Cefazolin in the Serum and Hip Joint Capsule of Patients Undergoing Total Hip Arthroplasty.

The objectives of this study were to evaluate the population pharmacokinetics of prophylactic cefazolin (CFZ) from its serum and hip joint capsule concentrations in patients undergoing total hip arthroplasty and to establish the pharmacodynamic target concentration exceeding the MIC for designing an effective dosing regimen for serum and the hip joint capsule. We analyzed 249 serum samples and 125 hip joint capsule samples from 125 individuals using a nonlinear mixed-effects model. The pharmacodynamic index target value obtained from our results indicates the probability of maintaining CFZ trough and hip joint capsule concentrations exceeding the MIC of 1 mg/liter to account for methicillin-susceptible S. aureus (MSSA). We estimated the population pharmacokinetics using a two-compartment model. The estimated population pharmacokinetic parameters were as follows: clearance (CL) (liters/h) = 1.46 × (creatinine clearance [CLcr] [ml/min]/77)0.891, volume of distribution of the central compartment (Vc) (liters) = 7.5, central-hip joint capsule compartment clearance (Q) (liters/h) = 3.38, and volume of distribution in the hip joint capsule compartment (VJC) (liters) = 36.1. The probability of achieving concentrations exceeding the MIC90 for MSSA was approximately 100% for serum and 100% for the hip joint capsule at 3 h after the initial dose. Our findings suggest that population-based parameters are useful for evaluating CFZ pharmacokinetics and that individual dosages should be determined based on the dosage regimen that achieves and maintains adequate tissue CFZ concentration.

Optimal dosage of cefmetazole for intraoperative antimicrobial prophylaxis in patients undergoing surgery for colorectal cancer.

BACKGROUND: Few studies have reported the dosage of cefmetazole (CMZ) for intraoperative antimicrobial prophylaxis in patients underwent surgery for colorectal cancer. We therefore examined the optimal intraoperative dosage of CMZ according to pharmacokinetic/pharmacodynamic (PK/PD) theory in patients who undergoing surgery for colorectal cancer. METHODS: The study group comprised 23 patients with colorectal cancer who underwent surgery, using CMZ as antimicrobial treatment to prevent postoperative infection. CMZ was administered intravenously within 60 min before surgery. PK/PD analysis was performed by population pharmacokinetic analysis and Monte-Carlo simulation. RESULTS: The final population pharmacokinetic parameters of CMZ were as follows: CLCMZ = 0.0704 × creatinine clearance (Ccr) and VdCMZ = 0.163 × body weight (Bw). In patients with a Ccr of ≥90 to <130 mL/min, the probability of achieving concentrations exceeding MIC was 52.9 to 82.2% at 2 h after the initial dose and less than 20% at 3 h after the initial dose. CONCLUSIONS: Additional doses of CMZ should be given every 2 h in patients with a Ccr of ≥90 to <130 mL/min, every 3 h in those with a Ccr of ≥50 to <90 mL/min, and every 4 to 5 h in those with a Ccr of ≥10 to <50 mL/min.

Population pharmacokinetic analysis and dosing regimen optimization of penicillin G in patients with infective endocarditis.

BACKGROUND: This study was designed to evaluate the population pharmacokinetics (popPK) of penicillin G in patients with infective endocarditis and establish a dosage regimen based on pharmacokinetic data and clinical outcome. METHOD: Forty-six serum penicillin G samples from 25 individuals were analyzed using a nonlinear mixed-effects model. popPK were estimated using a one-compartment model. We created a receiver operating characteristic (ROC) curve for penicillin G efficacy and the ratio of its minimum concentration (Cmin)/minimum inhibitory concentration (MIC). Simulations were used to optimize the penicillin G dosage regimen using this ratio. RESULT: Estimated popPK were: CL (L/h) = 0.21 × creatinine clearance (CLcr) (mL/min), Vd (L) = 28.9. The areas under the ROC curves were 0.87 for clinical efficacy. The cut-off value of penicillin G Cmin/MIC was 60. The continuous administration of 1 million IU penicillin G/h was necessary to achieve a positive outcome for patients with normal renal function (CLcr ≥ 60 mL/min). CONCLUSION: Our findings suggest that population-based parameters are useful for evaluating penicillin G pharmacokinetics and that an individualized dosage should be determined based on a described dosage regimen.

Population pharmacokinetics and optimization of the dosing regimen of digoxin in adult patients.

BACKGROUND: This study aimed to evaluate the population pharmacokinetics of digoxin in Japanese patients and establish a dosage regimen based on the pharmacokinetic data. METHODS: We analyzed 287 serum digoxin samples from 192 individuals by using the nonlinear mixed effects model. We used simulations to optimize the dosage regimen of digoxin to achieve a high likelihood of the target concentration (0.5-0.8 ng/mL). RESULTS: The total body clearance (CL/F ([L/h]) was calculated using the following formula: CL/F = (1.21 + 0.0532 × CLcr [(mL/min]) × (1 + 0.787 × AMD), where CLcr is the creatinine clearance and AMD is 0 in the case of concomitant administration of amiodarone and 1 otherwise. To achieve the target concentration (0.5-0.8 ng/mL), the dosage of digoxin was 0.0625 mg/day (CLcr < 35 mL/min and AMD = 0); 0.125 mg/day (CLcr, 35-65 mL/min and AMD = 0); 0.1875 mg/day (CLcr, 65-100 mL/min and AMD = 0); 0.0625 mg/every other day (CLcr < 30 mL/min and AMD = 1); and 0.0625 mg/day (CLcr, 30-85 mL/min and AMD = 1). CONCLUSIONS: Our findings suggest that population parameters are useful for evaluating digoxin pharmacokinetics.

Epinephrine administered with lidocaine solution does not worsen intrathecal lidocaine neurotoxicity in rats.

BACKGROUND: Epinephrine can potentially worsen the neurotoxic effects of local anesthetics when used for spinal or epidural anesthesia. The vasoconstrictive property of epinephrine reduces dural blood flow, which in turn reduces the clearance of local anesthetics from the subarachnoid space. This study examined the histological and neurofunctional effects of intrathecally administered lidocaine combined with epinephrine in rats. METHODS: Sixty-two rats were divided into 9 treatment groups: 5% or 7.5% lidocaine in 10% glucose solution with or without 0.1 or 0.5 mg/mL epinephrine, or epinephrine alone at 0.1 or 0.5 mg/mL in 10% glucose, or 10% glucose alone. Hind-limb motor function was evaluated immediately after drug injection by walking behavior. Sensory function was assessed by the response to radiant heat stimulation at just before and 1 week after the injection. Seven days after the injection, L3 spinal cord with anterior and posterior roots, the dorsal ganglion, and cauda equina were harvested and examined histologically. RESULTS: Histological lesions were limited to the posterior root just at entry into the spinal cord in rats injected with 7.5% lidocaine, with and without epinephrine. No histological abnormalities were noted in other areas or other groups. There was no significant change in sensory threshold in all groups. Significantly, prolongation of gait recovery time was noted in 5% and 7.5% lidocaine with epinephrine groups compared with 5% or 7.5% lidocaine alone. CONCLUSIONS: Intrathecal epinephrine prolonged the action of intrathecal lidocaine but did not worsen lidocaine-induced histological damage and functional impairment.

Population pharmacokinetics of oxycodone in patients with cancer-related pain.

Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 - Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); V(d) (L) = 193; k(a) (h(-1)) = 0.336; T(lag) (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, V(d): 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

[Liposomal-amphotericin B efficacy and safety].

Liposomal amphotericin B (L-AMB), a lipid-based amphotericin B formulation, has been used in Japan since June 2006 to treat fungal infection. In the 3 years since L-AMB was launched, few reports have been made on its status. To ensure its appropriate use, we restrospectively reviewed its efficacy and safety in treating fungal infections. 25 subjects with fungal infection treated with L-AMB from April 2007 until February 2008. Of those, 16 showed clinical improvement. Elevated serum creatinine occurred in 1 and decreased serum potassium in 6. We found a positive relationship between the serum potassium decrease and L-AMB dose. Logistic regression analysis of this relationship showed that serum potassium tended to fall on day 5 to 6 of L-AMB administration. While L-AMB appears highly effective in fungal infection, it requires serum potassium monitoring to ensure patient safety.

[Pharmacokinetics of controlled-release oxycodone in patients with cancer pain].

Oxycodone is a useful analgesic for cancer patients in pain. However, its pharmacokinetics have not been sufficiently examined and there is a lack of information, with very few reports on pharmacokinetics concerning the absorption process in particular. With this in mind, we studied the pharmacokinetics of controlled-release oxycodone (Oxy contin). We measured its serum concentration in patients with cancer pain, and calculated parameters derived using the nonlinear least-squared method program (MULTI). In the result, pharmacokinetic parameters calculated at CL/F were: 45.6+/-22.0 L/hr (Mean+/-SD), Vd/F: 473.0+/-19 6.7 L, t(1/2): 7.2+/- 6.2 hr, kel: 0.103+/-0.034, kal: 1.082+/-0.604, Lag time: 0.9 9+/-0.40 hr. In addition, the serum oxycodone concentration hardly rose until 1 hour after and just before medication, whereupon a rapid increase was evident after 1 hour. The pharmacokinetics of controlled-release oxycodone in patients with cancer pain were clarified in this study. Especially during the absorption process, the lag time was calculated specifically at about 1 hour, making it approximately equal to MS contin.