Plasma paracetamol concentrations after different doses of rectal paracetamol in older children A comparison of 1 g vs. 40 mg x kg(-1)

We compared the plasma paracetamol levels attained after the administration of different doses of rectal paracetamol in healthy children to see if they attained therapeutic levels (> 10 microg x ml(-1)). We recruited 24 children (ASA I-III) over 25 kg undergoing elective surgery. They were randomly assigned to receive rectal paracetamol at a dose of 1 g or 40 mg x kg(-1). Blood samples were taken for analysis at 2, 3, 4 and 5 h post dose. Most children in the 1 g group failed to attain therapeutic plasma levels, whereas those in the 40 mg kg(-1) group did achieve therapeutic levels (mean maximum concentration = 7.8 vs. 15.9 microg x ml(-1), p = 0.009).     

A pharmacokinetic study of piroxicam in children

Feldene Melt (piroxicam) is commonly used for analgesia following day case surgery. The manufacturer's recommended paediatric dose is 0.4 mg.kg(-1) once daily. In children, plasma piroxicam levels of 3-5 microg.ml(-1) are associated with effective analgesia. However, in adults a single dose of 20 mg piroxicam (0.4 mg.kg(-1) for a 50-kg adult) produces plasma levels of only 1.5-2.2 microg.ml(-1). We therefore studied plasma levels achieved by 0.4 mg.kg(-1) or 1.0 mg.kg(-1) piroxicam in 22 children aged between 3 and 16 years, undergoing elective orthopaedic surgery, in order to investigate the adequacy of single dosing. The first 12 patients received 0.4 mg.kg(-1) Feldene Melt pre-operatively. Following assay of plasma piroxicam levels, a further 10 patients received 1.0 mg.kg(-1) Feldene Melt. In both groups, five blood samples were taken at 2-hourly intervals. The mean (95% CI) piroxicam level following 0.4 mg.kg(-1) was 2.90 (2.33-3.54) microg.ml(-1), compared to 5.87 (4.58-7.16) microg.ml(-1) following 1.0 mg.kg(-1) (p = 0.0003).     

Trimethoprim-sulfamethoxazole pharmacokinetics during continuous ambulatory peritoneal dialysis

Eight adult patients without peritonitis maintained on chronic ambulatory peritoneal dialysis (CAPD) were administered a single oral dose of 320 mg trimethoprim (TMP) and 1600 mg sulfamethoxazole (SMX) to characterize the pharmacokinetics of TMP and SMX. Ten blood samples were drawn following the dose. TMP and SMX-active (SMXA) concentrations were quantified in serum and dialysate. The half-life of TMP and SMXA determined by model independent methods were 33.7 +/- 10.5 h (mean +/- SD) and 13.8 +/- 2.2 h respectively. Total body clearance of TMP was 32.8 +/- 10.1 ml/min and SMXA was 21.9 +/- 6.4 ml/min. CAPD clearance of TMP was 2.27 +/- 0.81 ml/min and SMXA was 1.72 +/- 0.93 ml/min. The average peritoneal dialysate concentrations over the 72-hour collection period of TMP and SMXA were 0.9 +/- 0.1 mg/l and 5.3 +/- 0.8 mg/l respectively. A dose of 320 mg TMP and 1600 mg SMX every 48 hours is recommended for CAPD patients with mild to moderate systemic infections.     

Diffusion of ketoprofen into the cerebrospinal fluid of young children

BACKGROUND: The objective was to examine whether or not ketoprofen enters the cerebrospinal fluid after a single oral dose of 1 mg.kg-1 syrup, and to find out what is the lowest plasma concentration that will achieve a measurable level in the cerebrospinal fluid. METHODS: We measured ketoprofen concentrations both in plasma and cerebrospinal fluid of 10 young and healthy children (aged 9-86 months) after surgery with spinal anaesthesia. Samples of cerebrospinal fluid were collected 30 min after drug administration, at the same time as venous blood samples. A validated high-performance liquid chromatography method with a lower limit of 0.02 microg x ml(-1) was used to detect ketoprofen concentrations in cerebrospinal fluid and plasma. RESULTS: Ketoprofen was detectable in the cerebrospinal fluid only in the child who had the highest plasma concentration, 7.4 microg x ml(-1), while at plasma concentrations 6.5 microg x ml(-1) or less, cerebrospinal fluid (CSF) concentrations remained unmeasurable. The detected CSF/plasma ratio was 0.008. CONCLUSIONS: These results indicate that ketoprofen at a dose of 1 mg x kg(-1) is too low to produce measurable CSF levels within 30 min of oral administration.     

Initial and subsequent dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic study of new dose recommendations

BACKGROUND: Recent studies have determined that an initial rectal acetaminophen dose of approximately 40 mg/kg is needed in children to achieve target antipyretic serum concentrations. The timing and amount of subsequent doses after a 40-mg/kg dose has not been clarified for this route of administration. Based on the authors' previous pharmacokinetic data, they examined whether a 40-mg/kg loading dose followed by 20-mg/kg doses at 6-h intervals maintain serum concentrations within the target range of 10-20 microg/ml, without evidence of accumulation. METHODS: Children (n = 16) received rectal acetaminophen (40 mg/kg) and up to three additional doses of 20 mg/kg at 6-h intervals. Venous blood samples were taken every 30 min for 4 h, then every 60 min for 4 h, and every 4 h for 16 h. The authors assessed whether their published pharmacokinetic parameters predicted the acetaminophen concentrations in the present study. They also assessed their dosing regimen by determining the fraction of time each individual maintained the target concentration. RESULTS: All patients received the initial loading dose; 10 of 16 patients received three subsequent doses. Serum concentrations with the initial dose were in the target range 38 +/- 25% of the time. With subsequent dosing, the target range was maintained 60 +/- 29% of the time. The highest serum concentration with initial or subsequent dosing was 38.6 microg/ml. Pharmacokinetic parameters from the earlier study predicted the serum concentrations observed for both initial and subsequent doses. CONCLUSIONS: A rectal acetaminophen loading dose of 40 mg/kg followed by 20-mg/kg doses every 6 h results in serum concentrations centered at the target range of 10-20 microg/ml. There was large interindividual variability in pharmacokinetic characteristics. There was no evidence of accumulation during the 24-h sampling period.     

Mycophenolic acid pharmacokinetics in stable pediatric renal transplantation

Mycophenolate mofetil (MMF) is given to children in fixed doses based either on body weight or body surface area. There are data indicating mycophenolic acid (MPA) blood levels should be monitored in the early period of transplantation. However, there is little information regarding MPA pharmacokinetics (PK) in stable pediatric recipients. We evaluated MPA-PK in 20 stable renal transplant children (11.7+/-1.9 years) under long-term (46+/-31 months) MMF (26.1+/-7 mg/kg per day or 785+/-183 mg/m(2) per day) therapy plus prednisone and cyclosporin A (n=16), tacrolimus (n=3), or MMF/prednisone (n=1). Total MPA levels were measured using the EMIT-MPA assay at 0, 1, 2, 3, 4, 6, and 8 h after an oral dose of MMF. The level at 12 h was considered equal to the trough level for AUC(0-12) calculation. Mean C(0), C(max), AUC (0-12), and T(max )were 3.46+/-1.32, 13.5+/-0.58 microg/ml, 63.2+/-24.4 microg x h/ml, and 1.3+/-0.6 h, respectively. Six (30%) children were considered to have an adequate exposure (36-54 microg x h/ml) to MPA, 11 (55%) showed an AUC(0-12 )>54 microg.h/ml, and 3 (15%) showed an AUC(0-12 )<36 microg x h/ml. A C(max )>/=10 microg/ml was seen in 13 (65%) children. MMF dose did not correlate with AUC(0-12) or C(max). The combination of variables C(0), C(1), and C(4 )provided an equation to predict exposure (r(2)=0.75) where AUC(0-12)=12.62+(7.78 x C(0))+(0.90 x C(1))+(1.30 x C(2)) (P<0.001). The use of MMF without monitoring MPA blood levels may cause unnecessary overexposure to the drug in stable pediatric recipients.     

Effects of reduction of the caudal morphine dose in paediatric circumcision on quality of postoperative analgesia and morphine-related side-effects

This study compared the efficacy and adverse effects of three low doses of morphine (10, 15 and 30 microg x kg(-1)) for caudal epidural analgesia in children undergoing circumcision. A total of 135 boys undergoing out-patient circumcision were randomly assigned to receive 10, 15 or 30 microg x kg(-1) of caudal morphine. Anaesthesia was induced and maintained with propofol. After induction, the morphine was added to 0.5 ml.kg(-1) 1% lignocaine solution with adrenaline 5 microg.ml(-1) and injected caudally. Anaesthesia quality, postoperative pain and adverse events in a 24-hour period were evaluated. Paracetamol (20 mg.kg(-1) orally) was used as rescue analgesia as required. No patient required paracetamol in the first eight hours after the caudal injections. In the first 24 hours postoperatively no further analgesia was required in 66.7%, 77.8% and 91.1% of the patients in the 10, 15 and 30 microg.kg(-1) groups, respectively (P=0.01 for 10 vs. 30 groups). All patients had excellent analgesia. No respiratory complications were observed. Nausea-vomiting occurred in 13.3%, 20% and 46.7% of the patients in the 10, 15 and 30 gg.kg(-1) groups (P=0.002 for 10 vs. 30 and 0.044 for 15 vs. 30). Pruritus occurred in 8.9%, 11% and 15.6% in the 10, 15 and 30 microg.kg(-1) groups but was localised and did not require treatment. This study was not powered to assess concerns that low dose epidural morphine may rarely be associated with delayed apnoea and is therefore considered unsuitable for outpatient use in many centres. Increases in caudal morphine dose above 10 microg.kg1 produce some 'paracetamol sparing' but no improvement in analgesia, some pruritus and a significant increase in nausea and vomiting.     

Plasma concentrations of fluconazole after a single oral dose and administration in drinking water in cockatiels (Nymphicus hollandicus)

Candidiasis frequently affects the oropharynx, esophagus, and crop of juvenile birds with immature immune systems and adult birds that have received long-term antibiotic treatment. Fluconazole is used extensively in human medicine to treat mucosal and invasive candidiasis and has been used in birds; however, there have been few pharmacokinetic studies in avian species to guide safe and effective treatment. The purpose of the present study was to investigate the disposition of fluconazole in cockatiels (Nymphicus hollandicus) after single oral dose administration and to determine if therapeutic plasma concentrations could be safely achieved by providing medicated water. Twenty-eight cockatiels were placed into 7 groups and were orally administered a 10 mg/kg fluconazole suspension. Blood samples were collected from each group for plasma fluconazole assay at serial time points. Fluconazole-medicated drinking water was prepared daily and offered to 15 cockatiels at a concentration of 100 mg/L for 8 days. Blood was collected for plasma fluconazole assay at 2 time points on days 3 and 7. When using naive averaged data in the single-dose study, pharmacokinetic parameters were similar for both compartmental and noncompartmental analyses. The elimination half-life of fluconazole was 19.01 hours, maximum plasma concentration was 4.94 microg/mL, time until maximal concentration was 3.42 hours, and the area under the plasma concentration versus time curve (AUC) was 149.28 h x microg/mL. Computer-simulated trough and peak plasma concentrations at steady-state after multiple doses of fluconazole at 10 mg/kg every 24 hours, 10 mg/kg every 48 hours, and 5 mg/kg every 24 hours were approximately 4.1-8.5 microg/mL, 1.2-6.0 microg/mL, and 2.0-4.3 microg/mL, respectively. Mean +/- SD plasma fluconazole concentrations for the 100 mg/L medicated water study at 0800 and 1600 hours on day 3 were 3.69 +/- 1.22 microg/mL (range, 1.73-5.26 microg/mL) and 4.17 +/- 1.96 microg/mL (range, 3.58-7.49 microg/mL), respectively, and at 0800 and 1600 hours on day 7 were 4.78 +/- 0.91 microg/mL (range, 2.62-6.11 microg/mL) and 6.61 +/- 1.67 microg/mL (range, 3.76-8.78 microg/ mL), respectively. Treatment with fluconazole administered orally at a dosage of 5 mg/kg once daily or 10 mg/kg every 48 hours or fluconazole administered in the drinking water at a concentration of 100 mg/L is predicted to maintain plasma concentrations in most cockatiels that exceed the minimum inhibitory concentration of 90% or therapeutic AUC:MIC of most strains of Candida albicans (by using susceptibility data from humans). The compounded oral suspension was stable for 14 days when stored at 5 degrees C (41 degree sF) and protected from light.     

Continuous epidural analgesia with bupivacaine-fentanyl versus patient-controlled analgesia with i.v. morphine for postoperative pain relief after knee ligament surgery

BACKGROUND: Both epidural analgesia and intravenous patient-controlled analgesia (PCA) have been found efficacious after various types of surgery. We compared the efficacy, safety, side effects and patient satisfaction of these methods in a randomized double-blind fashion after elective anterior cruciate ligament reconstruction of the knee. METHODS: Fifty-six patients had an epidural catheter placed at the L2-L3 interspace. Spinal anaesthesia with 15 mg of plain bupivacaine 5 mg/ml was performed at the L3-L4 interspace. After surgery the patients were randomly divided into three groups: 19 received a continuous epidural infusion with bupivacaine 1 mg/ml and fentanyl 10 mg/ml (F10), 19 patients received bupivacaine 1 mg/ml and fentanyl 5 microg/ml (F5) and 18 patients received saline (S). The rate of the epidural infusions was 0.1 ml kg(-1) h(-1). Each patient could also use an intravenous (i.v.) PCA device with 40 microg/kg bolus doses of morphine with a lockout period of 10 min and a maximum dose 240 microg kg(-1) h(-1). At the end of surgery ketoprofen 100 mg i.v. was given and continued orally three times a day. Patients were assessed for pain with a visual analogue scale (VAS) at rest and during activity, side effects and satisfaction at 3, 9 and 20 h. RESULTS: Both epidural infusions (F10, F5) provided better analgesia than epidural saline plus i.v. PCA (S) (P<0.05). There was slightly less nausea in the S group (NS). In spite of the difference in the quality of pain relief, there was no difference between the groups in patient satisfaction regarding analgesic therapy. CONCLUSION: Epidural infusion of fentanyl (1 microg kg(-1) h(-1) or 0.5 microg kg(-1) h(-1)) and bupivacaine (0.1 mg kg(-1) h(-1)) provided better pain relief but more side effects than intravenous morphine patient-controlled analgesia after knee ligament surgery. Almost all patients in all groups were satisfied with their pain relief.     

Antibiotic prophylaxis with cefazolin and gentamicin in cardiac surgery for children less than ten kilograms

OBJECTIVE: Antibiotic prophylaxis is recommended in pediatric cardiac surgery, but no data concerning the current antibiotic regimen were available. DESIGN: Prospective study from April to June 2000. SETTING: University hospital operating room and postoperative intensive care unit. PARTICIPANTS: Nineteen consecutive infants less than 10 kg with normal renal function undergoing cardiac surgery with cardiopulmonary bypass longer than 30 minutes. INTERVENTIONS: Intravenous administration of cefazolin, 40 mg/kg, and gentamicin, 5 mg/kg, at induction of anesthesia; followed by cefazolin, 35 mg/kg every 8 hours, and gentamicin, 2 mg/kg every 12 hours, over 48 hours. MEASUREMENTS AND MAIN RESULTS: Levels of serum antibiotics were measured: cefazolin (microbiologic) and gentamicin (fluorescence immunoassay) with 8 intraoperative and 5 postoperative samplings. Intraoperatively, cefazolin levels decreased from 166 +/- 44 (mean +/- standard deviation) down to 54 +/- 16 microg/mL and gentamicin from 20.8 +/- 9.5 down to 5.9 +/- 1.5 microg/mL. The postoperative trough levels were 12 +/- 7, 15 +/- 10, and 19 +/- 22 microg/mL for cefazolin and 1.1 +/- 0.5, 0.8 +/- 0.4, and 0.8 +/- 0.9 microg/mL for gentamicin. CONCLUSIONS: Antibiotic serum levels are consistent with satisfactory efficacy, but intraoperative gentamicin peak levels appeared too high.     

Optimal dosing of intravenous tacrolimus following pediatric heart transplantation.

BACKGROUND: Early experience with intravenous tacrolimus at high doses (0.1-0.15 mg/kg/day) was associated with frequent clinical toxicity. The optimal dosing regimen after pediatric heart transplantation is unknown. METHODS: We retrospectively reviewed data on the last 45 pediatric heart transplant recipients to document the time required to achieve therapeutic blood levels and the safety of 2 differing intravenous dosing regimens (tacrolimus 0.03 & 0.05 mg/kg/day as continuous i.v. infusion). Target plasma levels were (1.2-1.7 ng/ml) with levels >2.0 ng/ ml considered toxic, and target whole blood levels were 15-20 ng/ml with levels >25 ng/ml considered toxic. RESULTS: Mean age at transplantation was 7.5 +/- 5.6 years (0.1-18), and 14 were infants. Intravenous tacrolimus was commenced at a mean of 7 +/- 3 hours (range 2-16) after arrival in the ICU. Eight patients were excluded from analysis because of protocol modifications. Of the remaining 37 pts, 9 received initial infusion at 0.03 mg/kg/day; 3 (33%) achieved 'therapeutic' levels within 48 hours and 1 patient had a toxic level (27 ng/ml) at 36 hours. Twenty-eight patients received 0.05 mg/kg/day; 18 (64%) achieved therapeutic levels within 48 hours and 9 (32%) developed toxic levels. Patients with toxic whole blood levels had higher tacrolimus levels on first blood assay compared to those who did not develop toxicity (16.4 +/- 3.4 vs 9.3 +/- 3.9, p < .0001; level >10 ng/ml on first assay in 7/7 toxic patients vs 7/19 without toxicity, p = .004). Patients receiving the higher dose regimen had fewer episodes of moderate or severe rejection (> or =Grade 3A) at first biopsy than those receiving the lower dose infusion (32% vs 75%; p = .046). No patient required renal dialysis. CONCLUSIONS: Dosing below 0.05 mg/kg/day may result in clinically important delay in achieving therapeutic levels. Toxicity may be reduced by frequent monitoring of levels for the first 48 hours after transplantation especially when the initial level is >10 ng/ml.     

Ondansetron with propofol reduces the incidence of emesis in children following tonsillectomy

PURPOSE: This study tested the hypothesis that the antiemetic effects of a combination of ondansetron and propofol were superior to propofol alone in children undergoing tonsillectomy surgery. METHODS: A prospective, randomized, double-blind, placebo-controlled study design was employed. Young children underwent mask induction with halothane, nitrous oxide and oxygen and then had i.v. access established: older children had i.v. induction with propofol. All patients received 0.3 mg x kg(-1) mivacurium and 2-4 microg x kg(-1) fentanyl i.v. and 30 mg x kg(-1) acetaminophen pr to a maximum dose of 650 mg. Following induction, patients received either 100 microg x kg(-1) ondansetron or placebo. Anaesthesia was maintained with 120-140 microg x kg(-1) x min(-1) propofol, nitrous oxide and oxygen to maintain vital signs within 20% of baseline. After surgery, in all patients the tracheas were extubated in the operating room without use of neuromuscular reversing agents. Episodes of emesis were recorded by PACU nurses for four to six hours. A telephone interview on the following day was also used for data recovery. Groups were compared in relation to age using the Mann-Whitney test, and with respect to sex and number of episodes of vomiting using the Fisher Exact Test. RESULTS: Three of the 45 patients who received ondansetron vomited (6.7%), whereas 10 of the 45 patients who received placebo vomited (22.2%). (P = 0.035) CONCLUSION: Ondansetron in a dose of 100 microg x kg(-1), when combined with propofol for children undergoing tonsillectomy reduced the incidence of postoperative vomiting to very low levels.     

Lidocaine with fentanyl, compared to morphine, marginally improves postoperative epidural analgesia in children

PURPOSE: To compare the epidural administration of fentanyl (1 microg/mL) combined with lidocaine 0.4% to preservative-free morphine for postoperative analgesia and side effects in children undergoing major orthopedic surgery. METHODS: In a prospective, double-blind study, 30 children, ASA I-II, 2-16-yr-old, were randomly allocated to receive immediately after surgery either epidural F-L (epidural infusion at a rate of 0.1-0.35 mL/kg/hr of 1 microg/mL of fentanyl and lidocaine 0.4%) or epidural M (bolus of 20 microg/kg of morphine in 0.5 mL/kg saline every eight hours). Both groups received 40 mg/kg of iv metamizol (dipyrone) every six hours. In the F-L Group, blood samples were taken on the second and third postoperative day to determine total lidocaine concentrations. Adequacy of analgesia using adapted pediatric pain scales (0-10 score) and side-effects were assessed every eight hours postoperatively. RESULTS: Resting pain scores were under 4, 95% of the time in the F-L Group and 87% of the time in the M Group (Chi square=4.674, P <0.05). The frequency of complications was very similar in both groups. The F-L Group total plasma lidocaine concentrations were directly related to the dose received, and below the toxic range in all patients. CONCLUSIONS: Postoperative epidural fentanyl with lidocaine infusion provides slightly better analgesia than conventional bolus administration of epidural morphine. Side-effects or risk of systemic toxicity were not augmented by the addition of lidocaine to epidural opioids.     

Plasma lidocaine levels and risks after liposuction with tumescent anaesthesia

BACKGROUND: It is common today to use tumescent anaesthesia with large doses of lidocaine for liposuction. The purpose of the present study was to evaluate lidocaine plasma levels and objective and subjective symptoms during 20 h after tumescent anaesthesia with approximately 35 mg per kg bodyweight of lidocaine for abdominal liposuction. METHODS: Three litres of buffered solution of 0.08% lidocaine with epinephrine was infiltrated subcutaneously over the abdomen in eight female patients during monitored intravenous (i.v.) light sedation. Plasma levels of lidocaine and signs of subjective and objective symptoms were recorded every 3 h for 20 h after liposuction. RESULTS: Lidocaine 33.2 +/- 1.8 mg/kg was given at a rate of 116 +/- 11 ml/min. Peak plasma levels (2.3 +/- 0.63 microg/ml) of lidocaine occurred after 5-17 h. No correlation was found between peak levels and dose per kg bodyweight or total amount of lidocaine infiltrated. One patient experienced tinnitus after 14 h when a plasma level of 3.3 microg/ml was recorded. CONCLUSION: Doses of lidocaine up to 35 mg/kg were sufficient for abdominal liposuction using the tumescent technique and gave no fluid overload or toxic symptoms in eight patients, but with this dose there is still a risk of subjective symptoms in association with the peak level of lidocaine that may appear after discharge.     

Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas

OBJECTIVE: The purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODS: BSH (non-10B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTS: Blood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 microg/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean +/- standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1+/-5.8 and 17.3+/-10.1 microg/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 microg/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6+/-5.1 and 5.5+/-3.9 microg/g and the tumor/normal brain tissue ratios were3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 microg/ml at 2 hours to 63 microg/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 microg/g, respectively, during the 3- to 7-hour sampling period. CONCLUSION: When tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.     

Efficacy and safety of remifentanil in coronary artery bypass graft surgery: a randomized,double-blind dose comparison study

OBJECTIVES: To compare the efficacy and safety of 3 doses of remifentanil as part of a total intravenous anesthesia technique with low-dose propofol in patients undergoing coronary artery bypass graft (CABG) surgery. DESIGN: Multicenter, multinational, double-blind, randomized, dose comparison study. SETTING: Nine hospitals in 5 countries. PARTICIPANTS: One hundred forty-one patients undergoing first-time elective CABG surgery. INTERVENTIONS: Patients were premedicated with a short-acting oral benzodiazepine up to 2 h before surgery and randomized to receive continuous infusions of remifentanil 1.0 microg/kg/min (n = 45), 1.5 microg/kg/min (n = 44), or 2.0 microg/kg/min (n = 43), in combination with propofol 3 mg/kg/h. Nine patients received remifentanil 1.0 microg/kg/min on an open-label basis. Three different induction sequences (IS) were used. In IS 1 (n = 31), induction was started with remifentanil infusion followed 5 minutes later by propofol 0.5 mg/kg bolus and infusion at 3 mg/kg/h. Further bolus doses of propofol (10 mg) were given if loss of consciousness (LOC) was not attained after 5 minutes; pancuronium, 0.04 to 0.1 mg/kg, was administered at LOC. In IS 2 (n = 68), a priming dose of pancuronium, 0.015 mg/kg, was administered just before starting remifentanil. In IS 3 (n = 42), bolus doses of propofol, 10 mg every 10 seconds, were given until LOC, followed by pancuronium, 0.04 to 0.1 mg/kg, and the remifentanil and propofol infusions were started. MEASUREMENTS AND MAIN RESULTS: There were no significant differences among the remifentanil dose groups with regard to the primary outcome measure, responses to sternotomy/sternal spread/maximal sternal spread. Responses to these stimuli were recorded in 11%, 11%, and 14% of patients in the remifentanil 1.0, 1.5, and 2.0 microg/kg/min dose groups, respectively. Similarly, there were no significant differences in the responses to other surgical stimuli. There was a high incidence of muscle rigidity when remifentanil was used to induce anesthesia. CONCLUSIONS: All 3 remifentanil dose regimens provided profound suppression of responses to surgical stimuli in the majority of patients. There was no apparent advantage in starting the remifentanil infusion rate above 1.0 microg/kg/min. Remifentanil is not suitable for use as a sole induction agent.     

The pharmacokinetics of the intravenous formulation of fentanyl citrate administered orally in children undergoing general anesthesia

The bioavailability of oral transmucosal fentanyl citrate (OTFC) in children is similar to that of fentanyl solution administered orally to adults. We hypothesized that administering an oral fentanyl solution to children would result in similar fentanyl plasma concentrations and pharmacokinetic variables as administering comparable doses of OTFC. In this pilot study, 10 healthy children requiring postoperative analgesia were enrolled. Each received the undiluted IV fentanyl formulation orally (approximately 10-15 microg/kg; maximum, 400 microg). Venous blood samples were collected from 15 to 600 min after administration. Pharmacokinetic variables were determined using noncompartmental analysis and were compared with a previously studied population of children who received a similar dose of OTFC. Pharmacokinetic variables for the orally administered IV fentanyl formulation were as follows: time to reach peak concentration = 1.7 +/- 1.6 h, peak concentration = 1.83 +/- 1.19 ng/mL, half-life = 4.7 +/- 2.8 h, area under the plasma concentration time curve = 6.46 +/- 3.96 h . ng(-1) . mL(-1), apparent oral volume of distribution (V/F) = 17.5 +/- 7.2 L/kg, apparent oral clearance (CL/F) = 3.33 +/- 2.25 L . kg(-1) . h(-1). Although both OTFC and orally administered IV fentanyl resulted in similar pharmacokinetic variables and plasma concentrations for a given dose, there was marked interpatient variability, particularly in the early hours after oral administration of the IV formulation of fentanyl. This suggests that this method of administration be used with caution until further data are available.     

Plasma levels of lignocaine during tumescent local anaesthesia in children with burns

The aim of the study was to assess the changes in plasma lignocaine concentrations over time when the tumescent solution is injected into subcutaneous tissue of children undergoing surgical treatment of burns. Sixteen consecutive children with burns were studied using a prospective study design. After induction of general anesthesia, tumescent lignocaine solution 0.1% with adrenaline in nine patients (adrenaline group) for the treatment of postburn sequelae, or without adrenaline in seven patients (no-adrenaline group) for the treatment of acute burns, was injected into the subcutaneous tissue of burned and donor areas. The maximum dose of lignocaine was 7 mg/kg. Blood samples were collected before the start of the injection as well as at 5, 10, 20, 30, 45, 60, 90 minutes and 2, 4, 8, 12, 24 hours after the infiltration was completed. The course of lignocaine plasma levels was chaotic in the adrenaline group and biphasic during the first hour in the no-adrenaline group. The maximum plasma concentration of lignocaine was 2.09 microg/ml in the adrenaline group and 1.98 microg/ml in the no-adrenaline group. No adverse reactions were noted. Tumescent injection in burned children resulted in lignocaine plasma concentrations that were always lower than the often quoted value of 5 microg/ml, considered to be the toxic plasma threshold in adults. These data lend support to the use of lignocaine using the tumescent technique in burned paediatric patients.     

Pharmacokinetics of cyclosporine in monkeys after oral and intramuscular administration: relation to efficacy in kidney allografting

In cynomolgus and rhesus monkeys, the dose-normalized exposure of cyclosporine administered orally as microemulsion preconcentrate (Neoral) was lower than that upon intramuscular administration. For oral administration, mean values ( ± SD) of C_max, 24-h area-under-the curve (AUC) and 24-h trough level, all normalized for a 1 mg/kg dose, were 20 ± 9 ng kg/mg ml, 210 ± 70 ng h kg/mg ml and 2.6 ± 0.9 ng kg/mg ml, respectively. For intramuscular administration, levels were about 5.5-fold, 9-fold and 22-fold higher. Based on pharmacokinetic data, the efficacy of oral cyclosporine treatment (without any other immunosuppressant) was evaluated in life-supporting cynomolgus monkey kidney allotransplantation. Rejection-free kidney allograft survival could be achieved using oral cyclosporine monotherapy with average 24-h trough concentrations above 100 ng/ml during maintenance treatment. Typically, daily oral doses of 100 mg/kg–150 mg/kg during the first two weeks post-transplantation, followed by daily 30 mg/kg–100 mg/kg dose levels during subsequent maintenance can result in long-term allograft survival, with 24-h average trough levels in individual animals during maintenance between 110 ng/ml and 700 ng/ml. Received: 1 October 1997 Revised: 20 April 2001 Accepted: 7 June 2001     

Impairment of stimulated insulin release from the isolated perfused rat pancreas by cyclosporine pretreatment

Cyclosporine was fed to male Wistar rats in a dose of 5, 10, or 50 mg/kg b.wt. for 7 days, and the effect on insulin secretion from the isolated perfused pancreas was investigated. Dose-dependently plasma insulin and pancreatic insulin content decreased while whole-blood CsA levels increased. An increase in blood glucose was only observed after feeding 50 mg/kg b.wt. CsA resulting in whole-blood CsA levels of 7735 ng/ml. Glucose (20 mM)-stimulated total insulin secretion (ng/50 min) was not affected during feeding 5 mg/kg b.wt. CsA, but was significantly reduced after feeding 10 or 50 mg/kg b.wt. CsA. The biphasic insulin secretion was reduced after 5 mg/kg b.wt. during the initial peak (0-10 min) but not during the second peak (10-50 min), whereas after 10 or 50 mg/kg b.wt. CsA both peaks were markedly reduced. The arginine (20 mM) and the arginine (20 mM)-plus-glucose (20 mM) stimulated insulin secretion was less affected after feeding 10 mg/kg b.wt. CsA than after stimulation with glucose (20 mM) alone. The addition of CsA to the perfusate did not influence glucose-stimulated insulin release from normal rat pancreas. Our results demonstrate a toxic effect of CsA on the pancreatic beta cell that is dose dependent and possibly influences both insulin secretion and biosynthesis.