Pharmacokinetic and pharmacodynamic modeling of levetiracetam: investigation of factors affecting the clinical outcome.

This study aimed to evaluate the pharmacokinetics and pharmacodynamics of oral levetiracetam therapy in drug refractory adult epileptic outpatients, as well as factors affecting them. Concentration-time data were collected at steady state, while seizure recurrence was monitored for 13 months. Non-linear mixed effects modeling was applied, and covariates assessed included weight, height, age, daily dose and creatinine clearance.Plasma concentrations of levetiracetam were best described by a one-compartment pharmacokinetic model (V/F = 34.7 L) with first-order absorption (ka = 0.616 h-1) and clearance (CL/F = 3.26 L/h). Patient's CrCL was found to significantly affect levetiracetam clearance (beta = 0.795). Time to seizure occurrence followed an exponential distribution and the mean time to seizure occurrence was estimated Te = 22.08 days. Seizure rate per month followed a Poisson distribution, while mean seizure rate per month was estimated λ = 1.33. Daily dose significantly affected the mean estimated time to seizure (beta = -2.2) and the mean monthly seizure rate (beta = 2.27) in a reverse way. Using discrete time Markov chains, it was shown that the transition probability from focal seizures to focal to bilateral tonic-clonic is significantly altered in relation to patient's CrCL.Simulations showed that dose should be adjusted in relation to CrCL, while low doses of levetiracetam are more effective for seizure control. Modeling and simulation in every-day clinical practice may provide significant information for the optimization of seizure control using well-known agents.

Ropivacaine, Interleukin-6 and Tumor Necrosis Factor Alpha Plasma Levels during Intermittent Epidural and Continuous Wound Infusion of Ropivacaine for Analgesia after Hysterectomy or Myomectomy: An Observational Study.

BACKGROUND/AIMS: The concentration-time profile of the long-acting local anesthetic ropivacaine after epidural (EP) administration at fixed time intervals or continuous subcutaneous (SC) infusion has not been fully evaluated. The objective of this work was to determine total plasma concentrations of ropivacaine and changes in cytokine interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels during EP and SC. METHODS: In this prospective randomized controlled trial, 18 patients undergoing abdominal hysterectomy or myomectomy were randomly selected to receive ropivacaine either every 6 h via an EP catheter or by continuous wound infusion along the skin incision, after a bolus dose, for 48 h. Total plasma ropivacaine concentrations were measured before the bolus and 2, 4, 8, 24, 48, and 50 h after the bolus using high-performance liquid chromatography-UV and IL-6 and TNF-α levels were measured at 0, 8 and 24 h with ELISA and analyzed statistically. RESULTS: During EP, mean ± SD ropivacaine concentrations were relatively stable up to 50 h postoperatively, that is, 239 ± 89 ng/ml, while during SC, initial concentrations between 2 and 8 h were comparatively lower (101.5 ± 42.9 ng/ml) than 24-50 h concentrations (437.1 ± 206 ng/ml). An increase in IL-6 levels was noted between 0 and 24 h during EP and SC, but TNF-α levels increased slightly, between 0 and 24 h, only during EP. CONCLUSION: Ropivacaine plasma concentrations with both EP and SC were found to be safe throughout the administration time interval. IL-6 levels increased during the same time interval, while TNF levels varied only slightly.

Combined intravenous and intraventricular administration of colistin methanesulfonate in critically ill patients with central nervous system infection.

Colistin pharmacokinetics were prospectively studied after intravenous administration of colistin methanesulphonate in critically ill patients without central nervous system infection (controls, n = 5) and in patients with external ventricular drain-associated ventriculitis after intravenous administration (EVDViv, n = 3) or combined intravenous/intraventricular administration (EVDVcomb, n = 4). Cerebrospinal fluid (CSF)/serum colistin concentration ratios were higher in EVDViv than in control patients (11% versus 7%, P ≤ 0.05) and in EVDVcomb compared to all other patients (P < 0.0001). CSF colistin concentrations above the MIC of 0.5 µg/ml were achieved only in EVDVcomb patients.

Hepatokine Profile in Adolescents with Polycystic Ovary Syndrome: A Case-Control Study.

The current guidelines suggest routine screening for non-alcoholic fatty liver disease (NAFLD) in patients with polycystic ovary syndrome (PCOS). Hepatokines seem to be promising surrogate endpoints for the diagnosis and severity of NAFLD. PCOS has its onset in adolescence and its metabolic sequalae begin during the same period. There are scarce data on the hepatokine profile of adolescent PCOS patients. This case-control study examined the serum profile of the hepatokines sex hormone-binding globulin (SHBG), selenoprotein P, fibroblast growth factor 21 (FGF21), and fetuin A in a sample of adolescent PCOS patients, and their association to metabolic and hormonal parameters. The selenoprotein P and SHBG serum concentrations were significantly decreased in PCOS patients vs. the controls (median (IQR), 2.47 (0.40) vs. 2.66 (0.36) µg/mL, p = 0.025; mean ± SD, 41.71 ± 19.41 vs. 54.94 ± 22.12 nmol/L, p = 0.011, respectively), whereas selenoprotein P was significantly and positively associated with testosterone (r = 0.325, p = 0.007) and the free androgen index (r = 0.361, p = 0.002). The SHBG demonstrated multiple significant negative correlations with adverse metabolic parameters. Among the PCOS patients, the FGF21 concentrations were significantly higher in those with NAFLD, whereas a 1 pg/mL increase in the FGF21 concentration increased the odds of NAFLD diagnosis by liver ultrasound by 1%, suggesting FGF21 as a potential biomarker for hepatic disease in females with PCOS in adolescence. Fetuin A was the least differentiated hepatokine between the PCOS patients and controls with the least associations with metabolic and hormonal parameters.

Colistin pharmacokinetics in intensive care unit patients on continuous venovenous haemodiafiltration: an observational study.

OBJECTIVES: Available data on colistin pharmacokinetics in patients undergoing continuous renal replacement therapy (CRRT) are limited. Our aim was to study colistin pharmacokinetics in critically ill patients treated with colistin methane sulphonate for Gram-negative sepsis and undergoing continuous venovenous haemodiafiltration for acute renal failure. PATIENTS AND METHODS: Three patients were studied. The colistin methane sulphonate dose administered was at the discretion of the attending physician and was in all cases lower than that recommended for individuals with intact renal function. Colistin methane sulphonate was administered intravenously over 30 min, and blood samples were collected from each patient pre- and post-filter for the HPLC determination of colistin levels in serum before infusion, at 10, 60, 120, 240, 360, 480 and 600 min from the end of infusion, and immediately before the next dose. Concurrently, spot samples of effluent from the haemofilter were also collected and analysed. Both colistin total extracorporeal clearance and clearance in the effluent were calculated. RESULTS: Extracorporeal clearance resulted in substantial removal of colistin (43%-59% of total colistin clearance). Total colistin clearance was found to be reduced (varying between 3.3 and 4.5 L/h), compared with patients with normal renal function. Colistin methane sulphonate dosage resulted in clearly suboptimal colistin steady-state concentrations. CONCLUSIONS: In spite of substantial extracorporeal clearance, total colistin clearance was reduced, compared with patients with normal renal function. Colistin adsorption by the haemofilter contributed to its extracorporeal clearance to a large extent. Studies on other patients receiving colistin methane sulphonate and undergoing CRRT are required before more appropriate dosage regimens can be recommended.

Systematic Review and Meta-Analysis of the Efficacy and Safety of Metformin and GLP-1 Analogues in Children and Adolescents with Diabetes Mellitus Type 2.

Diabetes mellitus type 2 (DMT2) is one of the most frequent glucose metabolism disorders, in which serum glucose concentrations are increased. In most cases, changes in lifestyle and diet are considered as the first step in addressing its therapy. If changes in lifestyle and diet fail, drugs, such as metformin, must be added. Lately, apart from metformin or insulin, the FDA has approved the use of glucagon-like peptide-1 (GLP-1) analogues for children and adolescents. Little is known about their efficacy and safety at this young age. The main aim of this systematic review/meta-analysis was to assess the safety and efficacy of metformin and GLP-1 analogues, exenatide and liraglutide, compared with placebos or other antidiabetic drugs used for DMT2 in children and adolescents. Metformin did not seem to demonstrate pharmacologic superiority, while GLP-1 analogues were found superior to placebos. GLP-1 analogues may be considered a useful alternative for the treatment of DMT2 in children and adolescents.

Pharmacokinetic Characteristics of Nebulized Colistimethate Sodium Using Two Different Types of Nebulizers in Critically Ill Patients with Ventilator-Associated Respiratory Infections.

Background: Rising antimicrobial resistance has led to a revived interest in inhaled colistin treatment in the critically ill patient with ventilator-associated respiratory infection (VARI). Nebulization via vibrating mesh nebulizers (VMNs) is considered the current standard-of-care, yet the use of generic jet nebulizers (JNs) is more widespread. Few data exist on the intrapulmonary pharmacokinetics of colistin when administered through VMNs, while there is a complete paucity regarding the use of JNs. Methods: In this study, 18 VARI patients who received 2 million international units of inhaled colistimethate sodium (CMS) through a VMN were pharmacokinetically compared with six VARI patients who received the same drug dose through a JN, in the absence of systemic CMS administration. Results: Surprisingly, VMN and JN led to comparable formed colistin exposures in the epithelial lining fluid (ELF) (median (IQR) AUC0-24: 86.2 (46.0-185.9) mg/L∙h with VMN and 91.5 (78.1-110.3) mg/L∙h with JN). The maximum ELF concentration was 10.4 (4.7-22.6) mg/L and 7.4 (6.2-10.3) mg/L, respectively. Conclusions: Based on our results, JN might be considered a viable alternative to the theoretically superior VMN. Therapeutic drug monitoring in the ELF can be advised due to the observed low exposure, high variability, and appreciable systemic absorption.

Do we need to adopt antifungal stewardship programmes?

Background: Although antimicrobial stewardship programmes are one of the highest priorities in healthcare systems and many articles have been published, few refer to the implementation of antifungal stewardship and highlight specific points on which efforts should be focused. Objective: To assess the percentage of patients with confirmed candidaemia in whom de-escalation was conducted, and the economic impact of step-down or step-up antifungal therapy. Additionally, we attempted to estimate the potential increase in drug minimum inhibitory concentrations or to detect resistant strains of Candida species. Methods: We selected, retrospectively, patients who had received systemic antifungal therapy between 2011 and 2016 for documented candidaemia. Statistical analysis and diagrams were used to assess the results. Results: Of 157 patients with confirmed candidaemia, 58 received azoles, 74 echinocandinsand 18 liposomal amphotericin B for empirical therapy. 51 patients were eligible to step-down to fluconazole but only 23 patients did so. Furthermore, in nine patients unjustified step-up from fluconazole to echinocandins or liposomal amphotericin B was carried out. The additional cost incurred bythe healthcare system due to high prices of echinocandins and liposomal amphotericin B in comparison with fluconazole was€211 837. Interestingly, it was found that one strain of C. albicans and two strains of C. glabrata were resistant to echinocandins. Conclusion: The presence of a multidisciplinary team, including an infection control specialist and a clinical pharmacist, would limit the prescription of advanced antifungal agents as empirical therapy. Moreover, this team would control the de-escalation process-where applicable-leading to a reduction in costs and, probably, a decrease in the emergence of resistant Candida species. These facts contribute to the broader discussion on the adoption of antifungal stewardship programmes.

Caffeine versus theophylline for apnea of prematurity: a randomised controlled trial.

AIM: To compare standard doses of theophylline and caffeine for apnea of prematurity in terms of apnea frequency and assess the need for therapeutic drug monitoring. METHODS: Seventy neonates less than 33 weeks gestation, breathing spontaneously, were randomly assigned (open-label) to receive either theophylline or caffeine for treatment or prevention of apnea. The primary outcome measure was the difference in apnea frequency between theophylline and caffeine patient groups. Methylxanthine serum levels were measured on the 1st, 3rd and 7th days of therapy and every 7 days thereafter. RESULTS: Thirty-seven neonates received theophylline (T) and 33 caffeine (C) for treatment (8 T/10 C) or prevention of apnea (29 T/23 C). Treatment with either methylxanthine significantly decreased apnea events (T, P= 0.012; C, P= 0.005) while only C prophylaxis appeared to control apnea in infants at risk. Analysis of combined (treatment plus prophylaxis) data showed a significant decrease in apnea frequency only in those infants receiving caffeine (P= 0.001). However, there was no sustained benefit of C over T beyond the first week of therapy. T and C concentrations (2.2-13.9 mg/L; 5.5-23.7 mg/L, respectively) in the majority of cases fell within the recommended therapeutic ranges and were not significantly associated with apnea events. CONCLUSIONS: This study shows an advantage of C over T for premature infants <33 weeks gestation during the first week of therapy. Standard regimens of both methylxanthines do not seem to require routine concentration monitoring in the first 3 weeks of treatment unless indicated by clinical effect.

Netilmicin in the neonate: pharmacokinetic analysis and influence of parenteral nutrition.

OBJECTIVE: The aim of this study was to investigate the impact of parenteral nutrition on netilmicin pharmacokinetics in critically ill neonates during the first week of life. METHOD: A total of 200 neonates (gestational ages 26.4-41 weeks) treated with netilmicin (4-5 mg/kg in extended dosing intervals) for postnatal sepsis in the first week of life received either fluid therapy or parenteral nutrition. Netilmicin peak and trough serum concentrations were monitored and netilmicin pharmacokinetic parameters were compared with and without parenteral nutrition. RESULTS: There were no statistically significant differences between the pharmacokinetic parameters of netilmicin (volume of distribution, elimination half-life, clearance) in critically ill neonates >32 weeks during the first week of life that received either fluid therapy or parenteral nutrition. For neonates <32 weeks this comparison was not feasible as the majority were parenterally fed. CONCLUSION: Provision of parenteral nutrition (versus fluid therapy) in critically ill neonates >32 weeks did not significantly affect netilmicin pharmacokinetics and therefore does not require modification of recommended netilmicin dosage regimens.

Systematic review and network meta-analysis of approved medicines for the treatment of idiopathic pulmonary fibrosis.

Background: Clinical practice guidelines for the treatment of idiopathic pulmonary fibrosis (IPF) currently recommend pirfenidone and nintedanib. However, there is a lack of evidence from head-to-head comparisons. Objectives: To perform a systematic review and network meta-analysis (NMA) to access the efficacy and tolerability of two new treatments for IPF, pirfenidone and nintedanib. Methods: Randomized controlled trials (RCTs) selection (CENTRAL, MEDLINE, Embase), data extraction, risk of bias analysis, and GRADE assessment were carried out by two authors separately. Direct estimates were calculated using standard pairwise meta-analysis. A Bayesian mixed treatment comparison approach for NMA estimates, with 95% confidence intervals (CI), was used to compare the treatments, calculating odds ratios (OR) and number needed to treat (NNTB) or harm (NNTH). Results: The NMA on 10 randomized controlled trials showed that each drug had a positive effect on percentage of forced vital capacity (FVC) decline ≥ 10% (pirfenidone OR = 0.54 [95% CI = 0.37-0.80], NNTB = 9 [95% CI = 7-22]; nintedanib OR = 0.59 [95% CI = 0.41-0.84], NNTB = 9 [95% CI = 6-23]), but no significant differences were noted when comparing pirfenidone and nintedanib with respect to acute exacerbations, mortality, and serious adverse events (FVC decline OR = 0.91 [95% CI = 0.45-2.03]) or dropouts (OR = 0.75 [95% CI = 0.33-1.27]). Nintedanib showed an effect on dropouts, OR = 1.61 (1.13-2.28) and NNTH = 14 (8-61). Conclusions: Based on RCTs of 12 month duration in patients with IPF, a positive effect on FVC decline was noted for both treatments and on dropouts for nintedanib, but no significant differences were noted between treatments.

Serum kisspeptin concentrations are negatively correlated with body mass index in adolescents with anorexia nervosa and amenorrhea.

OBJECTIVE: To measure, for the first time, serum kisspeptin concentrations in adolescent females with anorexia nervosa (AN) and associated amenorrhea, and investigate potential correlations of kisspeptin with anthropometric, bone and hormonal data. DESIGN: Setting: University Adolescent Medicine Center. PARTICIPANTS: Females aged 12-20 years with typical or atypical AN (based on DSM-5 diagnostic criteria) and controls. INTERVENTIONS: Measurement of body mass index (BMI), whole body/lumbar spine bone mineral density and serum concentrations of kisspeptin, follicle stimulating hormone, luteinizing hormone (LH), prolactin (PRL), thyroid stimulating hormone (TSH), free thyroxine, triiodothyronine, estradiol (E2), 17-hydroxyprogesterone. MAIN OUTCOME MEASURES: Kisspeptin serum concentrations and correlations between kisspeptin and AN-related anthropometric, bone and hormonal changes. RESULTS: Participants included 37 females, 22 with AN (typical AN group=17, atypical AN group=5) and 15 in the control group. All typical AN patients had secondary amenorrhea. Wide inter-subject variation (101.9-709.1 ng/L) in kisspeptin levels was observed with no significant differences among study groups; there was a trend toward higher concentrations in the atypical AN group. Adolescents with typical AN had significantly lower BMI (P<0.001), lumbar spine z-score (P=0.016), serum E2 (P<0.001), LH (P=0.016), PRL (P=0.034) and TSH (P=0.045) than controls. They also had lower BMI (P=0.009) and TSH (P=0.027) than girls with atypical AN. An inverse correlation between BMI and serum kisspeptin was noted in the typical AN group (r=-0.60, P=0.012). CONCLUSIONS: Serum kisspeptin concentrations overlapped between patients and controls; in typical anorexic adolescents kisspeptin concentrations were negatively correlated with BMI. Future studies are needed to explore kisspeptin physiology in AN.

Acute administration of vitamin E triggers preconditioning via K(ATP) channels and cyclic-GMP without inhibiting lipid peroxidation.

Vitamin E (VitE) is considered an antioxidant agent. One or more brief periods of ischemia (isc), followed by short reperfusion (rep), increase the tolerance of the heart to a subsequent prolonged ischemia, a phenomenon known as ischemic preconditioning (PC). Mitochondrial KATP channels (mitoKATP), cyclic-GMP (cGMP), and free radicals are involved in the mechanism of PC, whereas some antioxidants abolish this benefit. The purpose of this study was to evaluate the effect of VitE on infarct size, PC, and the oxidative status in vivo. Male rabbits were divided into seven groups and were subjected to myocardial ischemia (isc) and reperfusion (rep) with the following interventions: (1) control (no intervention); (2) E150 (iv VitE at a dose of 150 mg/kg for 75 min, starting 40 min before index isc and lasting through 5 min of rep); (3) E300 (iv VitE 300 mg/kg as previously described); (4) PC (two cycles of 5 min isc and 10 min rep), (5) combined E150-PC; and (6) combined E300-PC. In the last two groups VitE was given 40 min before index ischemia. Blood samples were taken for malondialdehyde (MDA) and conjugated dienes (CDs) measurement. In a second series of experiments heart tissue samples were taken at the time of long ischemia for MDA and CD determination and for cGMP assay. In order to test whether combined treatment with VitE (as the E150 group) and the mitoKATP blocker 5-hydroxydecanoic acid (5-HD) changes the infarct size, an additional group was assessed in the first series of experiments. Tissue VitE concentration was evaluated in myocardium. VitE at both doses reduced the infarct size (19.7 +/- 2.8% for E150 and 18.8 +/- 4.9% for E300 vs 47.4 +/- 2.6% in control, P < 0.05) without attenuating the effect of PC (10.2 +/- 3.1% for E150-PC, 12.4 +/- 2.2% for E300-PC, vs 13.5 +/- 3.3% for PC). Combined VitE and 5-HD treatment abrogates this benefit (37.4 +/- 6.5%, P < 0.05 vs E150 and NS vs control). VitE increases intracellular cGMP and CDs levels (P < 0.05 vs control) to the same extent as PC (P < 0.05 vs control), with no effect on MDA (P = NS between all the groups). Peripheral markers of oxidative stress are increased during reperfusion in all groups (P < 0.05 vs baseline). Overall, VitE limits infarct size via mitoKATP and cGMP, while preserving the benefit of ischemic PC.

Breast-feeding in Athens, Greece: factors associated with its initiation and duration.

OBJECTIVES: To determine the prevalence, examine the influence of hospital practices and investigate potential determinants of breast-feeding in Athens. PATIENTS AND METHODS: Three hundred twelve mothers provided information regarding feeding practices at certain maternity hospitals in Athens, at 40 days and 6 months postpartum. Multiple logistic regression analysis was performed to evaluate the association between the initiation and maintenance of breast-feeding and potential risk factors. RESULTS: Although almost 90% of newborn infants were given a breast milk substitute one or more times during the first 2 days at the maternity hospital, the exclusive breast-feeding percentage on the last day of hospital stay reached 85%. Breast-feeding and exclusive breast-feeding percentages dropped to 55% and 35%, respectively, at 40 days postpartum and to 16% and 12%, respectively, at 6 months postpartum. While in the hospital, 3% of mothers initiated breast-feeding within 1 hour of labor, only 34% were informed about the advantages of breast-feeding by health professionals and 42% were trained to breast-feed by the midwives. "Rooming-in" was not practiced in the private hospitals. The educational level was positively associated with the initiation of breast-feeding [odds ratio (OR): 1.36, confidence interval (CI): 1.02-1.81], the mother's body mass index was negatively associated with the maintenance of breast-feeding for 40 days (OR: 0.56, CI: 0.32-0.98) and 6 months (OR: 0.28, CI: 0.06-1.26) and a caesarean section was negatively associated with the initiation (OR: 0.24, CI: 0.11-0.49) and maintenance of breast-feeding (OR: 0.42, CI: 0.20-0.89). CONCLUSIONS: Breast-feeding is not appropriately supported in certain maternity hospitals in Athens, and this is probably the cause of observed low breast-feeding prevalence.

Monitoring of subcutaneous dalteparin in patients with renal insufficiency under intensive care: an observational study.

OBJECTIVE: The objective of this study was to investigate the pharmacodynamic parameters of dalteparin in patients with renal insufficiency under intensive care. MATERIALS AND METHODS: In this open, nonrandomized, nonblinded, prospective, single-dose observational study, 10 critically ill patients with renal insufficiency (mean creatinine clearance = 29.5 +/- 6.42 mL/min) were administered a single 5000-IU subcutaneous dose of dalteparin. RESULTS: Dalteparin blood levels were estimated indirectly over a 12-hour period by measuring anti-Xa activity and by performing a clotting assay known as the ATHU (AHEPA Thrombosis and Hemostasis Unit) test. Maximum anti-Xa activity (ie, 0.42 +/- 0.13 IU/mL) was achieved 4 hours after administration (in 8 of 10 patients). Adequate anticoagulant activity was maintained throughout the 12-hour dosage interval in all study patients. However, at time 0 hour of the study, 36 hours after the administration of a previous dose of dalteparin, considerable anti-Xa activity (ie, 0.39 +/- 0.11 IU/mL) was measured in 6 patients. A good correlation was found between anti-Xa activity and the results of the ATHU test. CONCLUSIONS: The presence of medium/severe edema and the concurrent administration of 1 to 3 inotropic drugs appear to contribute to a decrease in the rate of elimination of dalteparin, resulting in a greater-than-expected (as a result of decreased renal function) prolongation of its pharmacologic activity. We recommend that care be taken with repeated dosing of dalteparin in intensive care unit patients taking inotropic drugs until observed results can be confirmed.

Amikacin dosing and monitoring in spinal cord injury patients: variation in clinical practice between spinal injury units and differences in experts' recommendations.

The objective of this article was to determine the current practice on amikacin dosing and monitoring in spinal cord injury patients from spinal cord physicians and experts. Physicians from spinal units and clinical pharmacologists were asked to provide protocol for dosing and monitoring of amikacin therapy in spinal cord injury patients. In a spinal unit in Poland, amikacin is administered usually 0.5 g twice daily. A once-daily regimen of amikacin is never used and amikacin concentrations are not determined. In Belgium, Southport (U.K.), Spain, and the VA McGuire Medical Center (Richmond, Virginia), amikacin is given once daily. Whereas peak and trough concentrations are determined in Belgium, only trough concentration is measured in Southport. In both these spinal units, modification of the dose is not routinely done with a nomogram. In Spain and the VA McGuire Medical Center, monitoring of serum amikacin concentration is not done unless a patient has renal impairment. In contrast, the dose/interval of amikacin is adjusted according to pharmacokinetic parameters at the Edward Hines VA Hospital (Hines, Illinois), where amikacin is administered q24h or q48h, depending on creatinine clearance. Spinal cord physicians from Denmark, Germany, and the Kessler Institute for Rehabilitation (West Orange, New Jersey) state that they do not use amikacin in spinal injury patients. An expert from Canada does not recommend determining serum concentrations of amikacin, but emphasizes the value of monitoring ototoxicity and nephrotoxicity. Experts from New Zealand recommend amikacin in conventional twice- or thrice-daily dosing because of the theoretical increased risk of neuromuscular blockade and apnea with larger daily doses in spinal cord injury patients. On the contrary, experts from Greece, Israel, and the U.S. recommend once-daily dosing and determining amikacin pharmacokinetic parameters for each patient. As there is considerable variation in clinical practice across spinal units and experts differ on ideal dosing and monitoring of amikacin therapy in spinal cord injury patients, there is an urgent need to develop best-practice guidelines.

Penetration of gentamicin into the alveolar lining fluid of critically ill patients with ventilator-associated pneumonia.

STUDY OBJECTIVES: To estimate the penetration of gentamicin into lung tissue by measuring its concentrations in alveolar lining fluid (ALF) and blood in critically ill patients with ventilator-associated pneumonia (VAP). PATIENTS AND INTERVENTIONS: The study population consisted of 24 patients who were admitted to an ICU for respiratory failure and developed VAP. Patients were scheduled to undergo bronchoscopy with BAL after IV administration of a once-daily, 240-mg schedule of gentamicin for the treatment of VAP. Patients were assigned at random to one of four groups of six patients each according to the scheduled time for bronchoscopy (1, 2, 4, or 6 h, respectively). A serum sample was obtained at 0.5 h (n = 24), and both serum and ALF samples (n = 6) were collected at each of the above specified times for measurement of antibiotic concentrations. MEASUREMENTS AND RESULTS: Mean +/- SEM gentamicin concentrations in the ALF were 2.95 +/- 0.37, 4.24 +/- 0.42, 3.10 +/- 0.39, and 2.65 +/- 0.35 microg/mL at 1, 2, 4, and 6 h, respectively, after the start of antibiotic infusion. Maximum gentamicin concentrations in serum (13.39 +/- 0.91 mug/mL, n = 24) and ALF (4.24 +/- 0.42 microg/mL, n = 6) were achieved at 0.5 h and 2 h, respectively, giving a penetration ratio of 0.32. The mean ratios of ALF/serum concentrations between 1 h and 6 h ranged from 0.30 to 1.14. After completion of the distribution phase, a significant positive correlation (p = 0.02) was found between gentamicin concentrations in the serum and ALF. CONCLUSIONS: Once-daily IV administration of 240-mg gentamicin achieved average peak antibiotic concentrations of 4.24 microg/mL in the ALF 2 h after administration, and an ALF/serum penetration ratio of 32%. Higher gentamicin doses to produce higher peak blood levels than those found with the study dose are necessary to obtain active alveolar concentrations against less sensitive microorganisms in the treatment of VAP in ICU patients.

Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen.

STUDY OBJECTIVES: To study the concentration-effect relationships of the nonsteroidal antiinflammatory drugs (NSAIDs) indomethacin, diclofenac, and ibuprofen; to investigate whether standard doses of these drugs inhibit prostaglandin concentrations to a similar extent, determined by measuring the concentration of a surrogate marker of prostaglandin E 2 (PGE 2 ); and to determine the extent to which dose increases produce analogous increases in prostaglandin inhibition. DESIGN: Single-dose, randomized, crossover trial with a 1-week washout period. SETTING: University biopharmaceutics and pharmacokinetics laboratory. SUBJECTS: Eight healthy adult volunteers younger than 35 years old. INTERVENTION: Subjects were administered two different standard doses of regular formulations (not enteric coated) of each NSAID on separate occasions. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected for determination of drug and 13,14-dihydro-15-keto-PGE 2 (PGEM; the surrogate marker of PGE 2 ) concentrations at regular intervals after administration of each NSAID dose. Statistically significant linear correlations were found between the percent reduction in PGEM concentration and the concentrations of diclofenac, indomethacin, and ibuprofen in plasma (R 2 = 0.992-0.999). The PGEM plasma concentrations correlated inversely with NSAID plasma concentrations, indicating maximum inhibition when the highest NSAID plasma concentrations were achieved. Statistically significant differences in the percent inhibition of PGEM concentrations were observed between the two doses for each NSAID (p<0.05), but not between subjects for each NSAID. Doubling the dose (100% increase) of diclofenac and indomethacin produced a 60-65% increase in maximum inhibition of PGEM concentrations, whereas a 50% increase in dose produced a 44% increase in the maximum effect of ibuprofen. CONCLUSION: Prostaglandin inhibition, as measured by changes in PGEM concentrations, correlated significantly with NSAID concentrations in plasma and differed significantly between high and low NSAID doses. Measurement of PGEM plasma concentrations appears to be a promising marker for estimation of relative potency of NSAIDs.

Recovery and cognitive function after fentanyl or remifentanil administration for carotid endarterectomy.

STUDY OBJECTIVE: To compare recovery and restoration of cognitive function after fentanyl-propofol or remifentanil-propofol anesthesia administration in patients undergoing carotid endarterectomy. DESIGN: Randomized, double-blind, prospective study. SETTING: Department of Anesthesiology, University hospital. PATIENTS: Seventy patients with ASA physical statuses II and III (53 men and 17 women) undergoing elective carotid endarterectomy. INTERVENTIONS: Anesthetic technique and drugs were identical in the 2 groups, with the exception of remifentanil and fentanyl administration. Induction of anesthesia was obtained with a bolus dose of propofol (1-2 mg/kg), maintenance was achieved with a propofol infusion according to hemodynamics and nitrous oxide/oxygen (FIO(2), 0.50). Muscle relaxation was achieved with rocuronium. The remifentanil group received 1 microg/kg of remifentanil as a single dose during the induction of anesthesia and 0.5 microg/kg per minute as an infusion throughout the procedure. The fentanyl group received 2 microg/kg of fentanyl as a single dose during the induction of anesthesia. MEASUREMENTS: Intraoperative hemodynamic adverse events were recorded. All patients were also evaluated with regard to their recovery and the restoration of their cognitive function, recording the immediate recovery times and using the Aldrete score 15 and 60 minutes after surgery and the Hasegawa scale 6 hours after surgery. For evaluation of postoperative pain, the Numeric Pain Scale (0-10) was used. MAIN RESULTS: Patients receiving remifentanil had significantly (P < .05) fewer episodes of intraoperative hypertension and needed nitroglycerine administration less frequently (P < .05) than those receiving fentanyl. Immediate recovery was significantly earlier (P < .05) with remifentanil (eye opening, 5.1 +/- 1.3 [remifentanil] and 7.2 +/- 3.7 [fentanyl] minutes; extubation time, 5.4 +/- 1.9 [remifentanil] and 7.8 +/- 4.1 [fentanyl] minutes). The Hasegawa Dementia Scale scores 6 hours after surgery and Aldrete scores 15 and 60 minutes after surgery did not differ significantly between the 2 groups. Pain levels were also similar for patients taking remifentanil and fentanyl. CONCLUSIONS: Although intraoperative hemodynamics were better preserved and immediate recovery was more rapid with remifentanil, overall postoperative recovery and restoration of cognitive functions as well as postoperative pain intensity seem to be similar for patients receiving remifentanil and for those receiving fentanyl combined with propofol for carotid endarterectomy operations.

Effects of blood loss and fluid volume replacement on serum and tissue gentamicin concentrations during colorectal surgery.

BACKGROUND: The prophylactic administration of antimicrobial agents to surgical patients has become standard practice to minimize the risk for postsurgical infection. During surgery, factors such as renal clearance, fluid administration, and blood loss contribute to drug concentrations achieved in the blood and tissues. The aminoglycoside gentamicin was chosen to investigate these factors because it is used for standard antimicrobial prophylaxis in colorectal surgery. OBJECTIVE: The aim of this study was to investigate the effects of surgical blood loss and fluid volume replacement on gentamicin concentrations in serum and in 3 tissue types (subcutaneous fat, epiploic fat, and colonic wall) in patients undergoing colorectal surgery. METHODS: This uncontrolled, open-label study was conducted at the Aretaieion Hospital (Athens, Greece) between November 2002 and March 2003. Patients selected for this study were scheduled to undergo elective colorectal surgery of ? 2-hour duration with general and epidural anesthesia and to receive gentamicin as major antimicrobial prophylaxis. Blood and tissue samples were obtained concurrently at specific times throughout each procedure. The effect of intraoperative blood loss on gentamicin concentrations and its pharmacokinetic properties was determined. RESULTS: Sixteen patients completed the study (11 men, 5 women; white race, 16 patients [100%]; mean [SD] age, 61 [3] years [range, 39-80 years]). Mean (SEM) serum gentamicin concentration was found to be insufficient; the maximum plasma drug concentration/minimum inhibitory concentration (MIC) ratio was <8:1 for pathogens commonly isolated in the surgical unit of the hospital (MIC: 1-4 microg/mL). The mean (SEM) concentration at first surgical incision was 7.83 (0.82) microg/mL and decreased to 2.60 (0.28) microg/mL at skin closure, resulting in borderline effectiveness even for susceptible gram-positive microorganisms (MIC approximately 1.0). Initially, mean (SEM) tissue gentamicin concentrations in subcutaneous fat, epiploic fat, and colonic wall were low (2.02 [0.34] microg/mL, 2.41 [0.42] microg/mL, and 1.93 [0.38] microg/mL, respectively) and decreased approximately 1.0 microg/mL ( approximately 50%) by skin closure. Statistically significant positive correlations were found between gentamicin concentrations in serum and tissues (P