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.     

Evaluation of efficacy and plasma concentrations of ropivacaine in continuous axillary brachial plexus block: high dose for surgical anesthesia and low dose for postoperative analgesia

BACKGROUND AND OBJECTIVES: Ropivacaine is a potent local anesthetic that, experimentally at low concentrations, produces an effective block of pain conducting nerve fibers. Therefore, it was hypothesized that 0.1% and 0.2% ropivacaine would provide clinically adequate postoperative analgesia in continuous axillary plexus block. METHODS: Sixty patients (ASA I-II) scheduled for elective hand or forearm surgery received 5 mg/kg of 0.75% ropivacaine for axillary block using nerve stimulator technique. One hour later, in random order, a continuous infusion of either 0.1% ropivacaine (0.125 mg/kg/h), 0.2% ropivacaine (0.25 mg/kg/h) or saline 6 to 11 mL/h was started. RESULTS: The mean total ropivacaine dose for the surgical block was 5.1 to 5.2 mg/kg with the supplementation. All patients were pain free for the first 12 to 15 hours after the block. The need for postoperative analgesics during the infusion was similar in all groups. After the initial block, the maximum plasma concentrations (mean 2.5 microg/mL) were measured at 45 or 60 minutes after injection. The highest individual plasma concentration was 4.2 microg/mL. Despite the high venous peak concentration, no toxic reactions were observed. The mean peak plasma concentration (Cmax) was 2.2+/-0.5 microg/mL for saline, 2.6+/-0.8 microg/mL for 0.1% ropivacaine, and 2.6+/-0.7 microg/mL for 0.2% ropivacaine. During the continuous infusion of 24 hours, the ropivacaine concentration declined steadily. CONCLUSIONS: Ropivacaine is safe and effective for axillary brachial plexus block. The continuous infusion of 0.1% or 0.2% ropivacaine was no more beneficial than an infusion of saline in relieving postoperative pain in patients having elective hand surgery. None of the infusions were sufficient to adequately treat the patients' pain without the addition of adjunct agents.     

Pharmacokinetics of intermittent intraperitoneal ceftazidime

Ceftazidime is currently recommended as an alternative first-line agent in the treatment of peritonitis and for Pseudomonas peritonitis. The pharmacokinetics of intermittent intraperitoneal (i.p.) ceftazidime have been poorly characterized. This study was designed to characterize the pharmacokinetic disposition of a single dose of ceftazidime in anuric and non-anuric CAPD patients, over 48 hours. This was a prospective, open label, pharmacokinetic study. The study was conducted in an independent, outpatient dialysis center. Ten volunteer continuous ambulatory peritoneal dialysis (CAPD) patients with and without residual renal function, no peritonitis or antibiotics in the previous 4 weeks, and on CAPD for at least 2 months were recruited. Patients received a single dose of i.p. ceftazidime (15 mg/kg) in the first daytime exchange over a 6-hour dwell, after an overnight dwell. Serum, urine, and dialysate were collected over a 48-hour period. A high-pressure liquid chromatography (HPLC) assay was used to analyze ceftazidime in these samples. Pharmacokinetic parameters were calculated. Six of the 10 patients were non-anuric with a mean residual renal creatinine clearance of 2.9 +/- 1.6 mL/min. The mean +/- SD bioavailability was 72% +/- 14%, and the volume of distribution was 0.34 +/- 0.08 L/kg. The mean serum elimination half-life of 22 +/- 5 hours. The peritoneal clearance was 5.74 +/- 1.6 mL/min. No difference was detected between anuric and nonanuric patients. Mean plasma and dialysate concentrations at 24 hours were 24 +/- 6 microg/mL and 18 +/- 7 microg/mL, respectively, and were 12.0 +/- 3.6 microg/mL and 7.4 +/- 3.1 microg/mL at 48 hours, respectively. Once-daily i.p. dosing of ceftazidime achieves serum and dialysate levels greater than the MIC of sensitive organisms over 48 hours.     

Optimal prophylactic dosage and disposition of micafungin in living donor liver recipients

Micafungin, a new candin antifungal drug, has a good safety profile and a significant therapeutic effect against Candida and Aspergillus. Little is known, however, about the optimal prophylactic dosage and the disposition of micafungin in liver transplant recipients, or about the effect of continuous venovenous hemodialysis (CVVH) on the pharmacokinetics of micafungin. Six living donor liver transplant patients were enrolled in this study. The mean C(max) and C(min) (trough) values of micafungin in plasma were 6.31 +/- 1.08 and 1.65 +/- 0.54 microg/mL, respectively. The mean elimination half-life (t(1/2)) and mean area under the curve up to 12 h post-dosing (AUC 0-12 h) were 13.63 +/- 2.77 h and 50.04 +/- 6.48 microg.h/mL, respectively. The concentrations of micafungin at the inlet and outlet of the dialyzer were very similar. The mean (+/-SD) ratio of micafungin concentrations at the inlet and outlet of the dialyzer (coutlet/cinlet) and the clearance of micafungin were 0.96 +/- 0.04 and 0.054 +/- 0.04 mL/min/kg, respectively. The amount in the ultrafiltrate was 1.0 mg. Micafungin effectively prevents systemic fungal infection in patients who have undergone liver transplantation. No significant differences were observed in the disposition of micafungin in recipients, and the therapeutic drug level can be achieved by administration of micafungin at a dosage of 40-50 mg/d. The CVVH had little effect on micafungin kinetics, and no dose adjustment or modification of dosing interval was needed during CVVH.     

Differential pharmacokinetic interaction of tacrolimus and cyclosporine on everolimus

OBJECTIVE: We characterized the pharmacokinetics of tacrolimus and everolimus in a combined immunosuppressive regimen. METHODS: This was an open-label exploratory trial in eight maintenance renal transplant patients with calcineurin inhibitor intolerance initially receiving mycophenolate mofetil (MMF) and tacrolimus. At enrollment, MMF was discontinued and replaced with everolimus 1.5 mg twice a day in study period 1 (days 1 to 10). In period 2 (day 11 to month 3), tacrolimus dose was reduced by half. RESULTS: At study entry tacrolimus trough level (C0) was 7.9 +/- 3.9 ng/mL and area under the curve over a dosing interval (AUC) was 132 +/- 56 ng x h/mL. The addition of everolimus in period 1 did not change tacrolimus exposure: C0 8.4 +/- 4.0 ng/mL, AUC 134 +/- 70 ng x h/mL. Everolimus pharmacokinetics in the presence of tacrolimus in period 1 were: C0 3.3 +/- 1.2 ng/mL, Cmax 10.4 +/- 5.1 ng/mL, AUC 58 +/- 20 ng x h/mL. When compared to pharmacokinetic data from a previous study in 47 renal transplant patients receiving everolimus at the same fixed dose (1.5 mg twice a day) with cyclosporine, everolimus exposure was 2.5-fold higher with cyclosporine relative to the data in this study with tacrolimus. After tacrolimus dose reduction in period 2, there was no clinically relevant change in everolimus exposure: C0 3.0 +/- 1.1 ng/mL, Cmax 8.2 +/- 1.3 ng/mL, AUC 49 +/- 10 ng x h/mL. CONCLUSIONS: Tacrolimus appears to have a minimal effect on everolimus blood levels compared with the influence of cyclosporine. The dose of everolimus when combined with tacrolimus needs to be higher than when combined with cyclosporine in order to reach a given everolimus blood level.     

Pharmacodynamics and pharmacokinetics of polyethylene glycol-hirudin in patients with chronic renal failure

BACKGROUND: Hirudin selectively inhibits thrombin without cofactors and is eliminated via the kidneys. Recombinant hirudin (r-hi) has a terminal elimination half-life (t1/2) of about 50 to 100 minutes. Coupling of polyethylene glycol (PEG) to r-hi, giving PEG-hirudin (PEG-Hi), prolongs its t1/2 while enhancing efficacy. We looked at the pharmacodynamic and pharmacokinetic behavior of PEG-Hi in patients with impaired renal function. METHODS: Anticoagulant activity and the pharmacokinetic parameters of a single intravenous bolus injection of 0.05 mg/kg body weight PEG-Hi were studied in 38 subjects. They were assigned to five groups: group IA, creatinine clearance (CCr) >/= 80 mL/min, 8 healthy volunteers; group IB, CCr >/= 80 mL/min, 8 patients with normal renal function); group II, CCr 79 to 50 mL/min, 7 patients with mild chronic renal failure (CRF); group III, CCr 49 to 20 mL/min, 10 patients with moderate CRF; and group IV, CCr 相似文献   

Elimination of alfentanil delivered by infusion is not altered by the chronic administration of atorvastatin

BACKGROUND AND OBJECTIVE: Statins are prescribed for patients with hypercholesterolemia. Atorvastatin is metabolized by cytochrome P4503A4 and inhibits P4503A4 activity in vitro. Alfentanil is a potent opioid used in clinical anaesthetic practice and is also metabolized by P4503A4. This study tested the hypothesis that chronic atorvastatin administration inhibits the metabolism of alfentanil. METHODS: Sixteen patients undergoing elective surgery were studied as matched pairs. One member of each pair was maintained on standard doses of atorvastatin for at least 4 months. Each patient received an alfentanil bolus (80 microg kg(-1)) intravenously (i.v.), followed by an alfentanil infusion (0.67 microg kg(-1) min(-1)) for 90 min. Serial plasma alfentanil concentrations were measured using gas chromatography-nitrogen phosphorous detection. Pharmacokinetic parameters were calculated using two-compartment linear modelling. RESULTS: One patient and the corresponding match were excluded from the analysis. The elimination half-life of alfentanil was similar in the control and atorvastatin groups (98.8 +/- 12.4 versus 98.3 +/- 11.3 min, respectively). The clearance (Cl), volume of distribution at steady-state (Vdss) and area under the curve (AUC) were similar in the two groups (Cl = 0.20 (+/- 0.06) and 0.22 (+/- 0.04) L min(-1), Vdss = 0.38 (+/- 0.07) and 0.39 (+/- 0.07) L kg(-1), AUC = 0.05 (+/- 0.02) and 0.04 (+/- 0.01) mg min mL(-1)). CONCLUSIONS: Concurrent atorvastatin administration does not alter the pharmacokinetics of alfentanil in patients undergoing elective surgery.     

Prophylactically-administered rectal acetaminophen does not reduce postoperative opioid requirements in infants and small children undergoing elective cleft palate repair

Rectal acetaminophen (Ac) is often administered prophylactically at anesthesia induction for postoperative pain management in small children and is thought to have an opioid-sparing effect. We assessed in this double-blinded, prospective, randomized study early opioid requirements after three doses of Ac (10, 20, and 40 mg/kg versus placebo) in 80 children (ASA physical status I, age 11.4 +/- 9.9 mo) undergoing cleft palate repair. Single Ac plasma concentrations were measured. Pain scores assessed in the postanesthesia care unit of > or = 4 of 10 resulted in the IV administration of 25 microg/kg piritramide, a popular European mu receptor agonist (lockout time, 10 min; maximum 0.125 mg/kg). There were no significant differences between groups with regard to the early postoperative pain scores and the overall cumulative IV opioid requirements. Maximal plasma concentrations achieved were only subtherapeutic (Ac 10 mg/kg: 8 microg/mL; Ac 20 mg/kg: 13 microg/mL; Ac 40 mg/kg: 21 microg/mL after 122, 122, and 121 min, respectively). We conclude that rectal Ac up to 40 mg/kg has no opioid-sparing effect, does not result in analgesic Ac plasma concentrations, and lacks proof of its efficacy in infants and small children undergoing cleft palate repair, whereas titrated IV opioid boluses produced rapid and reliable pain relief. IMPLICATIONS: Acetaminophen is widely used prophylactically for postoperative analgesia in children and is thought to have an opioid-sparing effect. We showed that rectal acetaminophen up to 40 mg/kg administered at anesthesia induction lacked proof of efficacy, whereas IV opioid boluses resulted in reliable pain relief in children undergoing cleft palate repair.     

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.     

Pharmacokinetics of mycophenolate mofetil in stable pediatric liver transplant recipients receiving mycophenolate mofetil and cyclosporine.

There are few pharmacokinetic data for mycophenolate mofetil (MMF) when used in combination with cyclosporine (CsA) in pediatric liver transplant recipients. The aim of this study was to assess the pharmacokinetics of MMF in stable pediatric liver transplant patients and estimate the dose of MMF required to provide a mycophenolic acid (MPA) exposure similar to that observed in adult liver transplant recipients receiving the recommended dose of MMF (target area under the plasma concentration-time curve from 0 to 12 hours [AUC(0-12)] for MPA of 29 mug.hour/mL in the immediate posttransplantation period and 58 microg x hour/mL after 6 months). A 12-hour pharmacokinetic profile was collected for 8 pediatric patients (mean age 20.9 months) on stable doses of MMF and CsA who had received a liver transplant > or = 6 months prior to entry and who had started on MMF within 2 weeks of transplantation. Mean MMF dosage was 285 mg/m(2) (range, 200-424 mg/m(2)). Of 8 patients, 7 had a MPA AUC(0-12) (range, 11.0-37.2 microg x hour/mL) well below the target. One patient had an AUC(0-12) > or = 58 microg x hour/mL but was considered an outlier and was excluded from analyses. Mean MPA AUC(0-12) and maximum plasma concentration values were 22.7 +/- 10.5 microg x hour/mL and 7.23 +/- 3.27 microg/mL, respectively; values normalized to 600 mg/m(2) (the approved pediatric dose in renal transplantation) were 47.0 +/- 21.8 microg x hour/mL and 14.5 +/- 4.21 microg/mL. In conclusion, assuming that MPA exhibits linear pharmacokinetics, when used in combination with CsA, a MMF dose of 740 mg/m(2) twice daily would be recommended in pediatric liver transplant recipients to achieve MPA exposures similar to those observed in adult liver transplant recipients. This finding should be confirmed by a prospective trial.     

Pharmacokinetics of mycophenolic acid in liver transplant patients after intravenous and oral administration of mycophenolate mofetil.

The bioavailability of mycophenolic acid (MPA) after oral administration of mycophenolate mofetil (MMF) has been reported to be more than 90% in healthy volunteers, and in kidney and thoracic organ transplant patients. Such information is limited in liver transplant (LTx) patients. The present study compares the pharmacokinetics of MPA after intravenous (IV) and oral administrations of MMF in LTx recipients. Pharmacokinetic parameters were calculated using WinNonlin software. A total of 12 deceased donor LTx patients initially received IV MMF and were switched to oral MMF after 2-7 days (mean, 3.3 +/- 1.7) when oral feeds were started. Multiple blood samples were drawn immediately prior to and after IV or oral MMF and the plasma concentration of MPA was measured. The mean peak plasma concentrations and the area under the plasma concentration vs. time curve (AUC) were significantly higher after IV MMF compared to oral MMF (peak plasma concentrations of 10.7 +/- 2.1 microg/mL for IV vs. 4.5 +/- 2.8 microg/mL for oral; P = 0.0001; and AUC of 28.9 +/- 7.1 microg . hr/mL for IV vs. 12.8 +/- 4.2 microg . hr/mL for oral; P = 0.0001). The oral bioavailability of MPA was 48.5 +/- 18.7%. The systemic clearance, half-life, and steady state volume of distribution of MPA were 26.9 +/- 6 L/hour, 5.5 hours, and 85 liters, respectively. The terminal disposition half-life was not significantly different between the 2 routes of administration. In conclusion, during the early postoperative period, LTx recipients have MPA exposure with oral MMF of less than half that of IV MMF. Use of IV MMF immediately post-LTx may provide an immunological advantage.     

Fructose-1,6-diphosphate alone and in combination with cyclosporine potentiates rat cardiac allograft survival and inhibits lymphocyte proliferation and interleukin-2 expression

BACKGROUND: Fructose-1,6-diphosphate (FDP) reduces postischemic reperfusion injury and is used alone and in combination with cyclosporine A (CsA) as an immunosuppressant. METHODS: Wistar-Furth rat hearts were grafted to Lewis rats. Activated T-cell proliferation, viability, and interleukin-2 expression were determined. RESULTS: Mean survival in days were: saline 7.12+/-0.64, FDP 350 mg/kg perioperatively 13.5+/-1.4, FDP 350 mg/kg twice daily 11.4+/-0.75, CsA 2.5 mg/kg daily 12+/-0.81, CsA 5.0 mg/kg daily 12.4+/-0.81, CsA 2.5 mg/kg + FDP 350 mg/kg twice daily 17.6+/-0.4, and CsA 5 mg/kg + FDP 350 mg/kg twice daily 28.2+/-0.97. FDP maximally inhibits T-cell proliferation and concomitantly increases cell viability at 5,000 to 500 microg/mL, whereas CsA inhibits at 500 ng/mL. FDP completely inhibited interleukin-2 expression at 5,000 to 500 microg/mL, whereas CsA partially inhibited at 50 to 500 ng/mL. CONCLUSION: FDP + CsA prolongs cardiac survival and FDP inhibits T-cell proliferation.     

Continuous interpleural infusion of bupivacaine for postoperative analgesia after surgery with flank incisions: a double-blind comparison of 0.25% and 0.5% solutions.

Postoperative analgesia, as assessed by visual analogue scale scores (0-10) and patient-controlled analgesia morphine requirements, pulmonary function (forced vital capacity and forced expiratory volume in 1 s), and plasma bupivacaine concentrations were studied in patients receiving interpleural blockade with bupivacaine after surgery with a flank incision. Two groups of 10 patients received either 0.5% or 0.25% bupivacaine, both with epinephrine (5 micrograms/mL). Pain relief was initiated when patients had visual analogue scale scores greater than or equal to 4. Patients received 21 mL of bupivacaine 0.25% or 0.5% in a double-blind fashion. One hour later, a continuous infusion of 5 mL/h of the study solution was started. At the same time, patient-controlled analgesia became accessible to the patients. The onset time of pain relief and the area under the visual analogue scale score-time curves over the first 8 h were similar in both groups. Patient-controlled analgesia morphine use was also similar in the 0.25% (21.3 +/- 14.6 mg) and 0.5% (21.0 +/- 16.0 mg) groups (mean +/- SD). In both groups, forced vital capacity and forced expiratory volume in 1 s improved significantly within 60 min (P less than 0.05). Peak plasma concentrations (Cmax) and the area under the plasma concentration-time curve (AUC) over 24 h were higher (P less than 0.001) in the 0.5% group (Cmax, 1.47 +/- 0.37 micrograms/mL; AUC, 1511 +/- 323 micrograms.mL-1.min) than those in the 0.25% group (Cmax, 0.55 +/- 0.22 micrograms/mL; AUC, 680 +/- 118 micrograms.mL-1.min) (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)     

Continuous infusion versus bolus administration of sufentanil and midazolam for mitral valve surgery

OBJECTIVE: In the present study, the authors compared continuous infusion to bolus administration of sufentanil and midazolam in patients undergoing mitral valve surgery. The purpose of the study was to evaluate the hemodynamic variability, total dose, effective plasma drug concentrations, and simplicity of the two anesthetic techniques. DESIGN: Prospective, randomized study. SETTING: University hospital. PARTICIPANTS: Thirty patients scheduled for elective mitral valve surgery. INTERVENTIONS: Induction of anesthesia was similar in both groups and consisted of sufentanil, up to 2 microg/kg, and midazolam, 0.05 to 0.15 mg/kg, followed by atracurium, 0.5 mg/kg. Anesthesia was maintained in the bolus group with predetermined boluses of sufentanil, 2 microg/kg, and midazolam, 0.03 mg/kg. Boluses were not administered if blood pressure was within 20% of baseline. The continuous-infusion group received sufentanil, 3.6 microg/kg/h, and midazolam, 0.08 mg/kg/h, started immediately after induction. The infusion rate was reduced to sufentanil, 1.8 microg/kg/h, and midazolam, 0.04 mg/kg/h, after sternotomy and was discontinued at skin closure. Atracurium was infused at a rate of 0.5 mg/kg/h up to sternal closure in both groups. No inhalation agents were used. MEASUREMENTS AND MAIN RESULTS: Hemodynamic variability between the groups was not significant. Total sufentanil dose was 773 +/- 186 microg in the continuous-infusion group and 610 +/- 184 microg in the bolus group (p = 0.01). Total midazolam dose was 14.4 +/- 3 mg and 11.2 +/- 3 mg in the continuous-infusion and bolus groups, respectively. There were 3.46 (range, 0 to 7) additional bolus injections in the bolus group and 0.31 (range, 0 to 1) in the continuous-infusion group (p < 0.001). Plasma sufentanil concentrations at extubation were similar in both groups (0.5 ng/mL). Plasma midazolam concentrations at extubation in the bolus group (17 +/- 6.7 ng/mL) were similar to those in the continuous-infusion group (23 +/- 5 ng/mL). CONCLUSION: The simplicity of the continuous infusion is a major advantage. This technique provides hemodynamically safe and stable conditions similar to those of bolus administration.     

The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women

Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women. 16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20 μg sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 μg sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 5-CNAC. Doses were given ≥6 days apart. All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 μg (Forsteo?). Mean+/-SD hPTH134 Cmax values were, respectively, 74+/-59, 138+/-101, 717+/-496, and 1624+/-1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean+/-SD AUC (0-last) values were, respectively, 30+/-40, 62+/-69, 320+/-269, and 627+/-633 h*pg/mL. The corresponding estimates for teriparatide 20 μg sc were 149+/-35 for Cmax and 236+/-58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 μg sc, with a comparable incidence of AEs in healthy postmenopausal women.     

The Effect of Orally Administered Marbofloxacin on the Pharmacokinetics of Theophylline

As certain quinolones can interfere with the metabolism of theophylline by competitive inhibition of the hepatic microsomal cytochrome P450 system, concomitant use of these drugs with theophylline could result in theophylline toxicity. This study investigated the effect of orally administered marbofloxacin (2 and 5 mg/kg each once daily) on steady‐state plasma pharmacokinetics of theophylline after concomitant oral administration of a sustained release theophylline preparation in dogs. Marbofloxacin caused some alteration in theophylline metabolism. A 2 mg/kg dose of marbofloxacin did not clearly result in an increased area under the concentration – time curve (AUC) or decreased clearance of theophylline, but at a dose of 5 mg/kg, a statistically significant increase in AUC and a decrease in the total clearance of theophylline was found. The 26% reduction in theophylline clearance is probably not clinically significant in healthy dogs, but for dogs with renal impairment, there might be a chance of theophylline accumulation when dosed concomitantly with marbofloxacin.     

Comparison of pharmacokinetics of Neoral and Sandimmune in stable pediatric liver transplant recipients.

Cyclosporine (Sandimmune; Novartis Pharmaceuticals UK Ltd) is an effective immunosuppressive drug, but its lipid formulation and variable absorption may expose children to the risk of rejection during episodes of gastroenteritis after liver transplantation. Neoral (Novartis) is a microemulsified form of cyclosporine that may be better absorbed. In this study, the pharmacokinetic profiles of Neoral and Sandimmune were compared in stable children after liver transplantation to evaluate whether Neoral is more predictably absorbed. Eight children, 6 boys and 2 girls, with a mean age of 4.5 years (range, 1.2-12) were studied between 4 and 12 months after liver transplantation. Pharmacokinetic profiles were performed on each child by using the same dose (mg/kg) of Neoral or Sandimmune. Tmax, Cmax, Ctrough, and the area under the curve (AUC) were calculated and side effects were documented in children taking either drug for more than 3 months. Mean peak cyclosporine levels were higher and were achieved significantly sooner with Neoral (Cmax 790.5 +/- 216.5 ng/mL, P =.06; Tmax 1.8 +/- 1.0 hr, P =.01) than with Sandimmune (Cmax 589.4 +/- 313 ng/mL, Tmax 2.5 +/- 1.7 hr), implying more rapid and better absorption. There was no significant difference in overall drug exposure (AUC) and 12-hour trough levels between the two formulations (P >.05). Children with Roux-en-Y loop biliary anastomosis taking Neoral, however, showed greater increases in AUC (mean increase = 37%) than those with duct-to-duct anastomosis (mean increase = 16%). There was no correlation between 12-hour trough level and AUC for either Neoral (r2 = 0.48) or Sandimmune (r2 = -0.08); however, for both drugs, AUC correlated very well with the 2-hour post-dose level (r2 = 0.68 and 0.7, respectively). Hirsutism was reported in 4 of 6 children on Neoral and may be associated with higher peak levels. Neoral is more consistently absorbed than Sandimmune in children after liver transplantation and may be more effective prophylaxis against rejection. Because of the increased peak levels and drug exposure, which may influence side effects, particularly in children with Sandimmune malabsorption, we recommend a 1:0.75 dose conversion ratio in patients being converted from Sandimmune to Neoral.     

Effect of the calcimimetic NPS R-467 on furosemide-induced nephrocalcinosis in the young rat

BACKGROUND: Furosemide induces nephrocalcinosis in both humans and animals. We showed previously that parathyroidectomy protected against the development of furosemide-induced nephrocalcinosis in young rats, indicating a possible role for parathyroid hormone (PTH) in its pathogenesis. Calcimimetic agents such as NPS R-467 are potent and selective agonists at the calcium-sensing receptor in parathyroid glands and inhibit PTH secretion. METHODS: To determine whether NPS R-467 could, like parathyroidectomy, prevent furosemide-induced nephrocalcinosis, we studied 35 6-week-old male Sprague-Dawley rats, divided into five groups. Group A served as control, group B received intraperitoneally furosemide (40 mg/kg), groups C, D, and E received furosemide and NPS R-467 intraperitoneally at doses of 10, 20, and 40 micromol/kg, respectively, daily for 8 days. During the last 3 days, animals were placed in metabolic cages for measurement of urine output, food, and water intake. Blood and kidneys were collected on day 8, 60 to 90 minutes after the last doses. Kidney calcium content was measured and nephrocalcinosis scoring (0 to 5) was assessed histologically. RESULTS: Furosemide increased urine output and fluid intake, and decreased body weight gain similarly in all groups. Serum PTH levels (mean +/- SD) were significantly higher in furosemide-treated control animals (276 +/- 226 pg/mL vs. 64 +/- 21 pg/mL); NPS R-467 induced a dose-dependent decrease in PTH levels (52 +/- 51 pg/mL, 18 +/- 7 pg/mL, and 13 +/- 3 pg/mL in groups C, D, and E, respectively). Plasma Ca(2+) was slightly, but significantly lower in all three NPS R-467 treated groups (5.1 +/- 0.4 mg/dL, 4.8 +/- 0.3 mg/dL, and 4.5 +/- 0.3 mg/dL in groups C, D, and E, respectively) compared to 5.7 +/- 0.1 mg/dL and 5.5 +/- 0.2 mg/dL in groups A and B, respectively. Furosemide treatment induced a substantial increase in kidney calcium content (1819 +/- 664 microg/g dry weight vs. 126 +/- 26 microg/g dry weight) and nephrocalcinosis scoring (5.0 +/- 0.0 vs. 0.0 +/- 0.0). Treatment with NPS R-467 ameliorated the furosemide-induced increase in kidney calcium content (673 +/- 312 microg/g, 361 +/- 188 microg/g, and 563 +/- 291 microg/g) and nephrocalcinosis scoring (2.2 +/- 1.2, 0.7 +/- 0.8, and 1.0 +/- 1.2) in groups C, D, and E, respectively. CONCLUSION: The calcimimetic agent NPS R-467 prevents the development of hyperparathyroidism and attenuates nephrocalcinosis in the furosemide-treated young rat.     

A multicentre trial comparing different concentrations of ropivacaine plus sufentanil with bupivacaine plus sufentanil for patient-controlled epidural analgesia in labour

BACKGROUND AND OBJECTIVE: To determine the optimal concentration of ropivacaine for bolus-only patient-controlled epidural labour analgesia, three different doses of ropivacaine were evaluated in comparison with bupivacaine in a double-blinded multicentre study. METHODS: Four hundred-and-fifty labouring parturients at term in three different academic institutions were randomized to four groups receiving bupivacaine 0.125% with sufentanil 0.75 microg mL(-1), ropivacaine 0.125% or 0.175% with sufentanil 0.75 microg mL(-1), or ropivacaine 0.2%. After an initial bolus of 10 mL of the study solution, and once visual analogue scores (VAS) were below 30 mm, patient-controlled epidural analgesia was initiated with a bolus of 4 mL, a lockout interval of 15 min and without a background infusion. Variables studied were the quality of analgesia, incidence of side-effects, the degree of motor blockade, and the mode of delivery. RESULTS: Bupivacaine 0.125% and ropivacaine 0.125% with sufentanil proved equally effective in providing labour analgesia without a difference in local anaesthetic consumption (48.6 +/- 23 mg bupivacaine vs. 52.1 +/- 38 mg ropivacaine), motor blockade or mode of delivery. Ropivacaine 0.175% plus sufentanil enhanced the quality of analgesia of the initial loading dose, whereas ropivacaine 0.2% without sufentanil increased the consumption of local anaesthetics (80.2 +/- 34 mg; P < 0.05) and the degree of motor blockade. CONCLUSION: Despite recent studies indicating that bupivacaine and ropivacaine may not be equipotent, both local anaesthetics provided equi-effective analgesia at equal doses without a difference in side-effects.     

Comparative systemic toxicity of convulsant and supraconvulsant doses of intravenous ropivacaine, bupivacaine, and lidocaine in the conscious dog

This study evaluated the systemic toxicity, arrhythmogenicity, and mode of death of convulsant and supraconvulsant doses of lidocaine, bupivacaine, and ropivacaine. Experiments in awake dogs were designed to mimic the clinical situation of an accidental intravenous (IV) injection of local anesthetics. On the first experimental day, lidocaine (8 mg.kg-1.min-1), bupivacaine (2 mg.kg-1.min-1), and ropivacaine (2 mg.kg-1.min-1) were infused intravenously until seizures occurred (n = 6 for each group). The average dose and arterial plasma concentration at seizure onset was 20.8 +/- 4.0 mg/kg and 47.2 +/- 5.4 micrograms/mL for lidocaine, 4.31 +/- 0.36 mg/kg and 18.0 +/- 2.7 micrograms/mL for bupivacaine, and 4.88 +/- 0.47 mg/kg and 11.4 +/- 0.9 micrograms/mL for ropivacaine. The margin of safety between the convulsive and lethal doses was determined by administering two times the convulsive dose 24 h later. Two dogs given lidocaine died because of progressive hypotension, respiratory arrest, and finally cardiovascular collapse with an average peak plasma concentration (Cmax) of 469 micrograms/mL. No ventricular arrhythmias were observed in this group. Ventricular arrhythmias occurred in five of six dogs receiving bupivacaine. Four animals died because of hypotension, respiratory arrest, and cardiovascular collapse. One additional animal died because of ventricular fibrillation. The Cmax for bupivacaine was 70.1 +/- 14.6 micrograms/mL in nonsurvivors. In the ropivacaine group one animal died because of hypotension, respiratory arrest, and cardiovascular collapse (Cmax = 72.4 micrograms/mL). A surviving dog had transient premature ventricular contractions. Twenty-four hours later three times the convulsive dose was administered to the survivors.(ABSTRACT TRUNCATED AT 250 WORDS)