Clinical pharmacokinetic and pharmacodynamic profile of midazolam nasal spray.

The benzodiazepine midazolam (MDZ) is commonly used as first-line treatment in patients with acute seizures. This review summarizes the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of MDZ nasal spray (MDZ-NS), which can be administered by non-health care providers in the outpatient, ambulatory setting. Intranasal administration leads to rapid (tmax 9.0-21.5 min), consistent, and extensive absorption of MDZ, with fast distribution to the central nervous system (CNS), as demonstrated by the onset of sedation within 10 min after administration and the occurrence of peak psychomotor impairment at approximately 17-120 min after administration. Rapid plasma clearance of MDZ and its active metabolite 1-OH-MDZ (t½ 3.6-8.1 h) results in a return to baseline alertness and psychomotor functionality by approximately 240 min post dose. The lack of first-pass metabolism reduces the potential for drug-drug interactions compared with oral dosing. Age (≥ 12 years), sex, race, body weight, body mass index, normal to moderately impaired renal function, and concomitant administration of cytochrome P450 (CYP)3A-inducing drugs are not considered important factors for MDZ-NS dosing. However, coadministration of MDZ-NS with moderate or strong CYP3A4 inhibitors should be avoided, and MDZ-NS should be used with caution when coadministered with mild CYP3A4 inhibitors, as these may result in prolonged MDZ effects owing to a decrease in plasma clearance. Taken together, the PK and PD properties of MDZ-NS, with a short tmax that translates into rapid CNS PD effects of sedation and psychomotor impairment, demonstrate rapid CNS penetration and onset of action, supporting its use for acute treatment of seizure clusters.

Fetal Intraventricular Hemorrhage Due to Antiphospholipid Syndrome: A Case Report.

Obstetric Antiphospholipid Syndrome (OAPS) is an autoimmune disease characterized by certain pregnancy complications in association with persistent antiphospholipid antibodies. These antibodies are generally known for their prothrombotic characteristics and may affect mother and fetus during the entire pregnancy. The clinical criteria for OAPS, including recurrent fetal loss, intra-uterine growth restriction and premature birth due to severe preeclampsia, all suggest uteroplacental vascular insufficiency. Although rare, thrombotic complications have been described in neonates born to mothers with OAPS, mainly ischemic stroke. We report on the first case of extensive fetal intraventricular hemorrhage related to OAPS. We share our diagnostic search and analysis for this unusual antenatal event, including cranial ultrasound findings and postmortem MRI images. We will also present a short review of the etiology and prognosis of antenatal intraventricular hemorrhage. We suggest that women with severe or early preeclampsia and/or a history of pregnancy loss should be evaluated for OAPS and carefully monitored throughout pregnancy. Further, we advise to test mothers for OAPS in the case of idiopathic fetal hemorrhage.

Phase I study assessing the safety, tolerability, and pharmacokinetics of avibactam and ceftazidime-avibactam in healthy Japanese volunteers.

Avibactam is a novel non-ß-lactam ß-lactamase inhibitor that has been shown to restore the in vitro activity of ceftazidime against pathogens producing Ambler class A, C, and some class D ß-lactamases. This study aimed to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of avibactam alone or with ceftazidime in healthy Japanese subjects. In this Phase I, double-blind study (NCT01291602), 16 healthy Japanese males, mean age 28.8 years, were randomized in a 2:2:1 ratio to receive avibactam 500 mg (n = 6), ceftazidime 2000 mg plus avibactam 500 mg (n = 7), or placebo (n = 3), each administered as a 100 ml intravenous infusion over 2 h, once on Day 1, every 8 h on Days 3-6, and once on Day 7. There were no deaths or serious adverse events. Nine treatment-emergent adverse events were reported in three subjects in the avibactam group - including one elevation in transaminase levels, and three vital signs events (tachycardia, palpitations, and orthostatic hypotension) - and one in the ceftazidime-avibactam group. All events were considered mild. After single or multiple dosing, plasma concentrations of avibactam and ceftazidime declined in a multi-exponential manner. No plasma concentration accumulation was observed, and the majority of avibactam was excreted unchanged in urine within 24 h. No clinically relevant changes in intestinal bacterial flora were observed. In conclusion, avibactam alone and ceftazidime-avibactam were generally well tolerated in healthy male Japanese subjects, and avibactam pharmacokinetics were comparable whether administered alone or in combination with ceftazidime.

Pharmacokinetics of oral valganciclovir solution and intravenous ganciclovir in pediatric renal and liver transplant recipients.

In an open-label, prospective, pharmacokinetic assessment, we evaluated total drug exposure (area under the curve [AUC]) of intravenous (IV) ganciclovir (GCV) and oral (p.o.) valganciclovir when normalized for body surface area (BSA) in pediatric liver (n=20) and renal (n=26) transplant patients Reference doses for IV GCV (200 mg/m(2)) and p.o. valganciclovir (520 mg/m(2)) were based on adult doses, and adjusted for BSA initially, and BSA and renal function (estimated via creatinine clearance [CrCL]) thereafter. Renal transplant patients received GCV on days 1-2, valganciclovir 260 mg/m(2) on day 3, and valganciclovir 520 mg/m(2) on day 4. Liver transplant patients received twice daily GCV from enrollment to day 12, and then valganciclovir twice daily on days 13-14. GCV pharmacokinetics were described using a population pharmacokinetic approach. Type of solid organ transplant (kidney or liver) had no effect on GCV pharmacokinetics. Median GCV exposure following valganciclovir 520 mg/m(2) was similar to that with IV GCV, and to that reported in adults. Patients <5 years of age had AUC values approximately 50% of those compared with older age ranges; dosing based on both BSA and CrCL increased drug exposure in younger patients. A dosing algorithm based on BSA and CrCL should be tested in future studies.

Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients.

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients < or =2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 x body surface area x creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 +/- 11.9 microg * h/mL; liver 61.7 +/- 29.5 microg * h/mL; heart 58.0 +/- 21.8 microg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults.

Safety and pharmacokinetics of daclizumab in pediatric renal transplant recipients.

This study examined the safety and pharmacokinetics/pharmacodynamics of daclizumab in combination with mycophenolate mofetil (or azathioprine), corticosteroids, and cyclosporine or tacrolimus, in 61 pediatric renal allograft recipients in three age groups: less than or equal to five yr (n = 18), 6-12 yr (n = 18), and 13-17 yr (n = 25). The dosing regimen was daclizumab 1.0 mg/kg before transplantation, followed by four biweekly doses. The pharmacokinetics of daclizumab were described using NONMEM software. Median (range) estimated trough daclizumab levels achieved on day 56 (before dose 5) were 3.88 microg/mL (2.48-8.78), 4.54 microg/mL (1.79-18.7), and 4.94 microg/mL (0.05-10.6) in the less than or equal to five yr (n = 15), 6-12 yr (n = 17), and 13-17 yr (n = 22) age groups, respectively. Steady-state median (range) daclizumab exposures were 2040 mg x h/mL (1585-3778), 2757 mg x h/mL (1873-3494) and 3297 mg x h/mL (1705-6453), respectively. Saturation of the IL-2R occurred rapidly and was maintained for greater than or equal to three months after transplantation. Daclizumab was generally well-tolerated with no acute allergic or anaphylactic reactions, deaths or malignancies during the study. The proportion of patients who developed acute rejection at six and 12 months was 8.5% and 16.7%, respectively. This study shows that adding daclizumab at 1 mg/kg to standard immunosuppressive therapy provides safe and effective IL-2R blockade.

Viral Infections In Children Receiving Anticancer Chemotherapy

OBJECTIVE: To determine the presence of bacterial and viral infectious agents in children with fever during anticancer chemotherapy. DESIGN: Analysis of data obtained during a prospective cohort study. SETTING: The pediatric oncology unit of Tygerberg Children's Hospital; Cape Town. SUBJECTS: All patients up to the age of 15 years who deve- loped fever secondary to anticancer chemotherapy from February 9th 2000 to April 9th 2001. OUTCOME MEASURES: Viruses were isolated or antigens detected on venous blood samples; nasopharyngeal aspirates; throat swabs; urine and feces where possible. Blood for aerobic and anaerobic culture was obtained from an indwelling intravenous catheter and/or a peripheral vein. RESULTS: Thirty-four children were analyzed for a total of 102 febrile episodes. The absolute neutrophil count on admission was below 0.5*109/L in 57 (56) episodes and thus considered neutropenic. Thirty-five viral isolates were identified in 31 (30) febrile episodes: HSV-1 (n=14); HSV-2 (n=2); CMV (n=10); rotavirus (n=5); adenovirus (n=2); Para influenza type 3 (n=1) and hepatitis B (n=1). The blood culture was positive in 24 (24) febrile episodes. Within these; a combined viral and bacterial infection was demonstrated in 6 (6) episodes. Infections were more frequent in neutropenic compared to non-neutropenic episodes; however; this was not significant. CONCLUSIONS: Viral infections clearly are an important cause of fever in children receiving anticancer therapy and may occur together with a bacterial infection. Diagnostic tests for viral infections should be used more frequently and could be of considerable value in evaluating fever and establishing appropriate treatment in these patients

Establishing pharmacokinetic bioequivalence of valganciclovir oral solution versus the tablet formulation.

Dosing with valganciclovir tablets may not be appropriate in some patients, such as those on hemodialysis or children. A "tutti-frutti" flavored oral valganciclovir solution has been developed to provide flexibility in dosage needed to accommodate these patients. An adult, multicenter, open-label randomized trial was conducted to establish bioequivalence between valganciclovir oral solution and valganciclovir tablets. Pharmacokinetic profiles and safety of the oral solution versus the tablet formulation were determined in 23 renal transplant recipients with estimated creatinine clearance>or=60 mL/min who had been receiving cytomegalovirus prophylaxis with valganciclovir for >or=4 days prior to the administration of the study drug. Patients received two doses of 900 mg valganciclovir either by tablet or oral solution in random order once daily over 6 days. Plasma concentrations of ganciclovir were assessed on days 2, 4, and 6 predose and at 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12 hours after the dose. Maximum mean plasma concentrations (Cmax) were 6.73 microg/mL and 6.39 microg/mL for the valganciclovir tablet and oral solution, respectively, with identical mean AUC0-24 of 51.2 microg.h/mL. For both the AUC0-24 and Cmax ratio, the 90% Cl of the mean ratios of the oral solution relative to the tablet formulation lies within the acceptance region (80% to 125%) required by the US Food and Drug Administration and European Agency for the Evaluation of Medicinal Products. With the demonstration of bioequivalence and no differences in the incidence of adverse effects, it will be possible to interchangeably use the oral formulation.

Pharmacokinetics, safety, and efficacy of mycophenolate mofetil in combination with sirolimus or ciclosporin in renal transplant patients.

AIMS: To compare the pharmacokinetics of mycophenolic acid (MPA) and its metabolite (MPAG) when mycophenolate mofetil (MMF) is administered in combination with sirolimus or ciclosporin (CsA) in renal allograft recipients. Safety and efficacy (biopsy-proven acute rejection (BPAR)) were also assessed. METHODS: Patients (n = 45) were randomized 2 : 1 to receive treatment with sirolimus (n = 30; dosed to maintain trough concentrations of 10-25 ng ml(-1) until week 8, and then 8-15 ng ml(-1) thereafter) or CsA (n = 15; administered as per centre practice) both in combination with daclizumab, oral MMF and corticosteroids. Pharmacokinetic assessments were performed at day 7, week 4, and months 3 and 6 post-transplant. The primary endpoint was the AUC(0,12 h) for MPA and MPAG. The pharmacokinetics of sirolimus were also assessed. RESULTS: MPA exposure was 39-50% lower (month 6 mean AUC(0,12 h) (95%CI): 40.4 (33.8, 47.0) vs. 68.5 (54.9, 82.0) microg ml(-1) h) and MPAG exposure was 25-52% higher (722 (607, 838) vs. 485 (402, 569) microg ml(-1) h at month 6) in the presence of CsA compared with sirolimus across visits. BPAR was 40.0% with sirolimus and 13.3% with CsA. The incidence of hypertension, tremors and hirsutism was higher with CsA than with sirolimus, while the incidence of diarrhoea, hyperlipidaemia and impaired wound closure was higher with sirolimus. No deaths, malignancies or graft losses were reported. CONCLUSIONS: Co-administration of sirolimus with MMF led to greater MPA exposure, but lower MPAG exposure, than co-administration with CsA. As rejection rates were higher in the absence of CsA, further study of calcineurin inhibitor-free regimens is required before general recommendations can be made.

Influence of biophase distribution and P-glycoprotein interaction on pharmacokinetic-pharmacodynamic modelling of the effects of morphine on the EEG.

BACKGROUND AND PURPOSE: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. EXPERIMENTAL APPROACH: Male rats received a 10-min infusion of morphine as 4 mg kg(-1), combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg(-1). EEG signals were recorded continuously and blood samples were collected. KEY RESULTS: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k(1e)) was 0.038 min(-1), being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (k(eo)) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal E(max) model. The values of the pharmacodynamic parameters E(0), E(max), EC(50) and Hill factor were 45.0 microV, 44.5 microV, 451 ng ml(-1) and 2.3, respectively. CONCLUSIONS AND IMPLICATIONS: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations.

Population pharmacokinetic modelling of non-linear brain distribution of morphine: influence of active saturable influx and P-glycoprotein mediated efflux.

BACKGROUND AND PURPOSE: Biophase equilibration must be considered to gain insight into the mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) correlations of opioids. The objective was to characterise in a quantitative manner the non-linear distribution kinetics of morphine in brain. EXPERIMENTAL APPROACH: Male rats received a 10-min infusion of 4 mg kg(-1) of morphine, combined with a continuous infusion of the P-glycoprotein (Pgp) inhibitor GF120918 or vehicle, or 40 mg kg(-1) morphine alone. Unbound extracellular fluid (ECF) concentrations obtained by intracerebral microdialysis and total blood concentrations were analysed using a population modelling approach. KEY RESULTS: Blood pharmacokinetics of morphine was best described with a three-compartment model and was not influenced by GF120918. Non-linear distribution kinetics in brain ECF was observed with increasing dose. A one compartment distribution model was developed, with separate expressions for passive diffusion, active saturable influx and active efflux by Pgp. The passive diffusion rate constant was 0.0014 min(-1). The active efflux rate constant decreased from 0.0195 min(-1) to 0.0113 min(-1) in the presence of GF120918. The active influx was insensitive to GF120918 and had a maximum transport (N(max)/V(ecf)) of 0.66 ng min(-1) ml(-1) and was saturated at low concentrations of morphine (C(50)=9.9 ng ml(-1)). CONCLUSIONS AND IMPLICATIONS: Brain distribution of morphine is determined by three factors: limited passive diffusion; active efflux, reduced by 42% by Pgp inhibition; low capacity active uptake. This implies blood concentration-dependency and sensitivity to drug-drug interactions. These factors should be taken into account in further investigations on PK-PD correlations of morphine.

Assessment of type I error rates for the statistical sub-model in NONMEM.

The aim of this study was to assess the type I error rate when applying the likelihood ratio (LR) test, for components of the statistical sub-model in NONMEM. Data were simulated from a pharmacokinetic one compartment intravenous bolus model. Two models were fitted to the data, the simulation model and a model containing one additional parameter, and the difference in objective function values between models was calculated. The additional parameter was either (i) a covariate effect on the interindividual variability in CL or V, (ii) a covariate effect on the residual error variability, (iii) a covariance term between CL and V, or (iv) interindividual variability in V. Factors in the simulation conditions (number of individuals and samples per individual, interindividual and residual error magnitude, residual error model) were varied systematically to assess their potential influence on the type I error rate. Different estimation methods within NONMEM were tried. When the first-order conditional estimation method with interaction (FOCE INTER) was used the estimated type I error rates for inclusion of a covariate effect (i) on the interindividual variability, or (ii) on the residual error variability, were in agreement with the type I error rate expected under the assumption that the model approximations made by the estimation method are negligible. When the residual error variability was increased, the type I error rates for (iii) inclusion of covariance between etaCL-etaV were inflated if the underlying residual distribution was lognormal, or if a normal distribution was combined with too little information in the data (too few samples per subject or sampling at uninformative time-points). For inclusion of (iv) etaV, the type I error rates were affected by the underlying residual error distribution; with a normal distribution the estimated type I error rates were close to the expected, while if a non-normal distribution was used the type I errors rates increased with increasing residual variability. When the first-order (FO) estimation method was used the estimated type I error rates were higher than the expected in most situations. For the FOCE INTER method, but not the FO method, the LR test is appropriate when the underlying assumptions of normality of residuals, and of enough information in the data, hold true. Deviations from these assumptions may lead to inflated type I error rates.

Blood-brain barrier transport and brain distribution of morphine-6-glucuronide in relation to the antinociceptive effect in rats--pharmacokinetic/pharmacodynamic modelling.

1. The objective of this study was to investigate the contribution of the blood-brain barrier (BBB) transport to the delay in antinociceptive effect of morphine-6-glucuronide (M6G), and to study the equilibration of M6G in vivo across the BBB with microdialysis measuring unbound concentrations. 2. On two consecutive days, rats received an exponential infusion of M6G for 4 h aiming at a target concentration of 3000 ng ml(-1) (6.5 microM) in blood. Concentrations of unbound M6G were determined in brain extracellular fluid (ECF) and venous blood using microdialysis and in arterial blood by regular sampling. MD probes were calibrated in vivo using retrodialysis by drug prior to drug administration. 3. The half-life of M6G was 23+/-5 min in arterial blood, 26+/-10 min in venous blood and 58+/-17 min in brain ECF (P<0.05; brain vs blood). The BBB equilibration, expressed as the unbound steady-state concentration ratio, was 0.22+/-0.09, indicating active efflux in the BBB transport of M6G. A two-compartment model best described the brain distribution of M6G. The unbound volume of distribution was 0.20+/-0.02 ml g brain(-1). The concentration-antinociceptive effect relationships exhibited a clear hysteresis, resulting in an effect delay half-life of 103 min in relation to blood concentrations and a remaining effect delay half-life of 53 min in relation to brain ECF concentrations. 4. Half the effect delay of M6G can be explained by transport across the BBB, suggesting that the remaining effect delay of 53 min is a result of drug distribution within the brain tissue or rate-limiting mechanisms at the receptor level.

Pharmacokinetic-pharmacodynamic modelling of morphine transport across the blood-brain barrier as a cause of the antinociceptive effect delay in rats--a microdialysis study.

PURPOSE: To quantify the contribution of distributional processes across the blood-brain barrier (BBB) to the delay in antinociceptive effect of morphine in rats. METHODS: Unbound morphine concentrations were monitored in venous blood and in brain extracellular fluid (ECF) using microdialysis (MD) and in arterial blood by regular sampling. Retrodialysis by drug was used for in vivo calibration of the MD probes. Morphine was infused (10 or 40 mg/kg) over 10 min intravenously. Nociception, measured by the electrical stimulation vocalisation method, and blood gas status were determined. RESULTS: The half-life of unbound morphine in striatum was 44 min compared to 30 min in venous and arterial blood (p<0.05). The BBB equilibration of morphine, expressed as the ratio of areas under the curve between striatum and venous blood, was less than unity (0.28+/-0.09 and 0.22+/-0.17 for 10 and 40 mg/kg), respectively, indicating active efflux of morphine across the BBB. The concentration-effect relationship exhibited a clear hysterisis with an effect delay half-life of 32 and 5 min based on arterial blood and brain ECF concentrations, respectively. CONCLUSIONS: Eighty five percent of the effect delay was caused by morphine transport across the BBB, indicating possible involvement of rate limiting mechanisms at the receptor level or distributional phenomena for the remaining effect delay of 5 min.

Modelling of the blood-brain barrier transport of morphine-3-glucuronide studied using microdialysis in the rat: involvement of probenecid-sensitive transport.

The objective of this study was to investigate the impact of probenecid on the blood-brain barrier (BBB) transport of morphine-3-glucuronide (M3G). Two groups of rats received an exponential infusion of M3G over 4 h to reach a target plasma concentration of 65 microM on two consecutive days. Probenecid was co-administered in the treatment group on day 2. Microdialysis was used to estimate unbound M3G concentrations in brain extracellular fluid (ECF) and blood. In vivo recovery of M3G was calculated with retrodialysis by drug, preceding the drug administration. The BBB transport was modelled using NONMEM. In the probenecid group, the ratio of the steady-state concentration of unbound M3G in brain ECF to that in blood was 0.08+/-0.02 in the absence and 0.16+/-0.05 in the presence of probenecid (P=0.001). In the control group, no significant difference was found in this ratio between the 2 days (0.11+/-0.05 and 0.10+/-0.02, respectively). The process that appears to be mainly influenced by probenecid is influx clearance into the brain (0.11 microl min(-1) g-brain(-1) vs 0.17 microl min(-1) g-brain(-1), in the absence vs presence of probenecid, P:<0.001). The efflux clearance was 1.15 microl min(-1) g-brain(-1). The half-life of M3G was 81+/-25 min in brain ECF vs 22+/-2 min in blood (P<0.0001). Blood pharmacokinetics was not influenced by probenecid. In conclusion, a probenecid-sensitive transport system is involved in the transport of M3G across the BBB.

Methodological aspects of the use of a calibrator in in vivo microdialysis-further development of the retrodialysis method.

PURPOSE: To investigate the performance of two alternative retrodialysis recovery methods and to describe the influence of different recoveries on the reliability in estimating unbound extracellular concentrations of morphine. METHODS: Unbound concentrations of morphine in striatum and in blood were determined by microdialysis after a 10 min i.v. infusion in freely moving rats. In vivo recovery of morphine was determined by morphine itself, retrodialysis by drug, and by the calibrator nalorphine, retrodialysis by calibrator. RESULTS: The low calibrator recovery in striatum (8.6%) resulted in large variability in the estimation of unbound extracellular concentrations when retrodialysis by calibrator was used. In blood, where the recovery was higher (36%), the variability was smaller. Also, when retrodialysis by drug was used, the variability remained low. This difference is caused by the propagation of errors in the way retrodialysis recovery is determined. Therefore, calibrator recovery values > or =20% are preferable in concentration estimations using retrodialysis by calibrator. CONCLUSIONS: When no time-dependent change in recovery is observed, retrodialysis by drug determined before the systemic administration is the best method. The calibrator is valuable as a quality control during the experiment.

Application of intracerebral microdialysis to study regional distribution kinetics of drugs in rat brain.

1. The purpose of the present study was to determine whether intracerebral microdialysis can be used for the assessment of local differences in drug concentrations within the brain. 2. Two transversal microdialysis probes were implanted in parallel into the frontal cortex of male Wistar rats, and used as a local infusion and detection device respectively. Within one rat, three different concentrations of atenolol or acetaminophen were infused in randomized order. By means of the detection probe, concentration-time profiles of the drug in the brain were measured at interprobe distances between 1 and 2 mm. 3. Drug concentrations were found to be dependent on the drug as well as on the interprobe distance. It was found that the outflow concentration from the detection probe decreased with increasing lateral spacing between the probes and this decay was much steeper for acetaminophen than for atenolol. A model was developed which allows estimation of kbp/Deff (transfer coefficient from brain to blood/effective diffusion coefficient in brain extracellular fluid), which was considerably larger for the more lipohilic drug, acetaminophen. In addition, in vivo recovery values for both drugs were determined. 4. The results show that intracerebral microdialysis is able to detect local differences in drug concentrations following infusion into the brain. Furthermore, the potential use of intracerebral microdialysis to obtain pharmacokinetic parameters of drug distribution in brain by means of monitoring local concentrations of drugs in time is demonstrated.

Higher incidence of peritonitis in native Canadians on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To determine if the rate of peritoneal dialysis (PD)-related infections in our large Native population was higher than in non-Natives. DESIGN: Prospective study of PD-related infections, 1987 to 1993. PATIENTS: Forty-eight Natives and 136 non-Natives were studied. Comparisons of infection rates were made as well as determinations of the effect of diabetes and of dialysis techniques on infection rate. RESULTS: The chance of remaining free of peritonitis was far lower at 6 and 12 months in Natives versus non-Natives, 40% versus 76% at 6 months, and 24% versus 54% at 12 months (p < 0.01). Having diabetes or adding intraperitoneal insulin did not confer additional risk of peritonitis. The Y-line reduced the risk of peritonitis in non-Natives only. Exit-site infection (ESI) was significantly higher in Natives versus non-Natives, 0.42 versus 0.19 episodes per patient year (p < 0.01) mainly due to Staph. aureus. However, less than 30% of episodes of peritonitis were due to that organism. Staph. epidermidis peritonitis episodes were not more common in Native patients, whereas infections due to most other organisms were. CONCLUSION: The susceptibility to both peritonitis and exit-site infection is increased in Native Canadians compared to non-Natives. The nonprotective effect of the Y-line combined with increased peritonitis due to most organisms except Staph. epidermidis in Natives suggests that host factors could be important in these patients.