Comparative single-dose pharmacokinetics of clonazepam following intravenous, intramuscular and oral administration to healthy volunteers.

The objective was to assess the single-dose pharmacokinetics of clonazepam following i.m., p.o. and i.v. administration. In an open-label, three-way crossover study, 12 healthy volunteers were randomized to receive a single dose of 2 mg clonazepam either by the i.m., p.o. or i.v. route. Serial blood samples were collected up to 120 h after drug administration. Plasma concentrations of clonazepam were determined by electron-capture gas-liquid chromatography. The absorption rates of clonazepam after i.m. and p.o. administration of clonazepam were significantly different from each other, as reflected by the respective mean values of maximum plasma concentration (C(max) 11.0 vs. 14.9 ng.ml(-1)) and time to reach maximum concentration (t(max) 3.1 vs. 1.7 h). Secondary plasma peaks of clonazepam were observed in 9 volunteers after i.m. injection (C(max) 9.9 ng.ml(-1); t(max) 10.4 h). A comparison of the area under the plasma concentration-time curves (AUC) shows that the i.m. route is equivalent to the oral route (AUC(0- infinity ) 620 vs. 561 ng.h.ml(-1)). Clonazepam was almost completely absorbed after i.m. and p.o. administration, as shown by the mean absolute bioavailability of 93 and 90%, respectively. No significant differences existed between the elimination half-lives (i.v. 38.0 h; i.m. 43.6 h; p.o. 39.0 h). The average clearance and volume of distribution (V(Z)) were 55 ml.min(-1) and 180 liters, respectively. In conclusion, the observed differences in C(max) and t(max) after i.m. and p.o. administration were consistent with a slower absorption rate of clonazepam after i.m. injection. The systemic exposure to clonazepam was not affected by the route of extravascular administration. Statistical evaluation of these kinetic data showed differences in the absorption rate, so that clonazepam given by the i.m. route is not bioequivalent to the oral route. On the basis of the results of this study, we would recommend the same i.m. and p.o. dose in epileptic patients, but therapeutic response would be expected to be less predictable and to occur later in the case of i.m. administration.

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy volunteers.

The objective was to assess the single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following administration of a new dual-release and conventional slow-release formulation of levodopa/benserazide in the dose ratio of 4:1. In an open-label, two-way cross-over study, 20 healthy volunteers were randomized to receive first either Madopar DR or Madopar HBS for 8 days. Then they crossed over to the other formulation. A first dose of 200 mg levodopa and 50 mg benserazide ('250' mg) was given on day 1, '125' mg t.i.d. on the subsequent 6 days (days 2-7), followed by '250' mg on day 8. The two treatment periods of 8 days were separated by a wash-out period of at least 7 days. Blood samples were taken at specific times over a 12-hour period (day 1) or a 36-hour period (day 8). Plasma concentrations of levodopa and 3-O-methyldopa were measured by high-performance liquid chromatography for pharmacokinetic evaluation. The pharmacokinetics of levodopa after a single-dose administration (day 1) of Madopar DR and Madopar HBS were significantly different as reflected by the respective mean values of maximum plasma concentration (C(max) 1.99 vs. 0.82 mg x l-1), time to reach maximum concentration (t(max) 0.7 vs. 2.6 h) and area under the plasma concentration-time curve (AUC(0- infinity ) 4.52 vs. 3.18 mg x h x l-1). The respective values after multiple doses (day 8) were: C(max) 1.98 vs. 0.93 mg x l-1, t(max) 0.7 vs. 2.3 h and AUC(0-infinity ) 4.84 vs. 3.96 mg x h x l-1. The relative bioavailability (Madopar DR vs. Madopar HBS) was 1.73 on day 1 and 1.32 on day 8. Bioequivalence could not be demonstrated for log-transformed data of AUC and C(max) within a predefined range of 80-125 and 70-143%, respectively. In conclusion, the observed differences in C(max), t(max) and AUC are consistent with a faster rate and higher extent of levodopa absorption after administration of Madopar DR. Statistical evaluation of these kinetic data showed that Madopar DR is not bioequivalent to Madopar HBS.

COMT inhibition by tolcapone further improves levodopa pharmacokinetics when combined with a dual-release formulation of levodopa/benserazide. A novel principle in the treatment of Parkinson's disease.

The objective of the study reported here was the investigation of the effect of catechol-O-methyl transferase (COMT) inhibition by tolcapone on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new dual-release formulation (dual-RF) of levodopa/benserazide (200/50). The study had a double-blind, placebo-controlled, randomized, crossover design and was conducted in 18 healthy young subjects. On the 2 treatment days, separated by a washout period of 7 days, the dual-RF was administered in combination (blinded) with tolcapone (200 mg) or placebo. Both treatment combinations were well tolerated. Tolcapone increased the bioavailability (AUC 0-infinity) and apparent elimination half-life (t(1/2)) of levodopa by 80 and 40%, respectively, compared to placebo. The maximal plasma concentration (Cmax) was slightly elevated by tolcapone. In the presence of tolcapone, formation of 3-OMD was substantially reduced. In conclusion, the effect of tolcapone on levodopa pharmacokinetics after administration of the dual-RF is similar to the one observed after immediate- and slow-RFs and leads to a marked improvement in levodopa pharmacokinetics and subsequently to an optimization of levodopa therapy.

Lack of bioequivalence of a generic mefloquine tablet with the standard product.

OBJECTIVE: To assess the bioequivalence between a generic tablet of mefloquine (Mephaquin = M1) with the reference tablet (Lariam = M2) in healthy volunteers. METHODS: This open label, randomized two-way crossover study was performed in a single centre. Following an overnight fast, eighteen healthy volunteers received a single oral dose of 750 mg mefloquine either in the form of three M1 lactabs or three M2 tablets. Serial blood samples were collected up to 8 weeks after drug administration. Plasma samples were analysed for mefloquine and its carboxylic acid metabolite using liquid chromatography and subsequent tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters of mefloquine and its metabolite were estimated by non-compartmental methods. RESULTS: The pharmacokinetics of mefloquine after administration of M1 and M2 tablets were significantly different as reflected by the respective mean values of maximum plasma concentration (Cmax 656 vs 1018 ng x ml(-1)), time to reach maximum concentration (tmax 46 vs 13 h) and area under the plasma concentration-time curve (AUC0-->infinity 338 vs 432 microg x h x ml(-1)). No significant differences existed between the elimination half-lives of the two formulations (394 vs 396 h). The relative bioavailability (M1 vs M2) was 0.78 and ranged from 0.38 to 1.37. Bioequivalence could not be demonstrated for log-transformed data of AUC0-->infinity or AUC0-->last within a predefined range of 80-125% and for Cmax within a range of 70-143%. CONCLUSIONS: The observed differences in Cmax, tmax and AUC are consistent with a slower rate and lower extent of mefloquine absorption after administration of M1. Statistical evaluation of these kinetic data showed that the M1 tablet is not bioequivalent to the M2 tablet. Clinical consequences of this finding cannot be excluded.

Comparative single- and multiple-dose pharmacokinetics of levodopa and 3-O-methyldopa following a new dual-release and a conventional slow-release formulation of levodopa and benserazide in healthy subjects.

A multiple-dose study was performed to assess the pharmacokinetic profile of a new levodopa/benserazide dual-release formulation (DRF) in comparison with a conventional slow-release formulation (SRF). The study was of an open label, randomized, two-way cross-over design and was conducted in 18 subjects. Assessment of the two formulations was at day 1 (single-dose) and at day 7 after a 5-day t. i.d. pre-treatment (100 mg levodopa and 25 mg benserazide) in fasting state. The pharmacokinetic parameters reflecting bioavailability, accumulation and metabolism of levodopa were determined. The levodopa pharmacokinetics of the new DRF showed rapid absorption (tmax=1.1 h), followed by sustained levodopa plasma concentrations, similar to the SRF. Following multi-dose administration, the peak plasma concentration of the new DRF was 90% higher compared to the SFR (Cmax=2.1 and 1.1 microg/ml, respectively). The bioavailability was significantly increased by 40% (AUC0-infinity=6.1 and 4.3 microg x h/ml, respectively). The new DFR was well tolerated as shown by the low incidence of mild side effects. In conclusion, the results of this study confirmed the levodopa dual-release properties of this new levodopa/benserazide formulation.

Pharmacokinetic studies with a dual-release formulation of levodopa, a novel principle in the treatment of Parkinson's disease.

The objectives of the two studies reported here were the investigation of the influence of tablet breaking and food on the pharmacokinetics of levodopa and 3-O-methyldopa (3-OMD) after administration of a new levodopa/benserazide formulation with a biphasic drug delivery profile (Madopar DR). Both studies had an open-label, randomised, two-way crossover design and were conducted in 12 healthy young subjects. The pharmacokinetics of levodopa and 3-OMD after one intact or two halved tablets were very similar with average Cmax and tmax 1.9 mg x l(-1) and 1.2 h, respectively. Administration of the formulation after a standard breakfast did not influence the extent of levodopa absorption but increased the absorption rate. Cmax and tmax were on average 2.1 mg x l(-1) and 1.3 h, respectively, in the fed condition and 1.5 mg x l(-1) and 2.5 h in the fasted condition. The presence of food did not markedly affect the plateau in levodopa levels between about 1 and 3 h after intake. In conclusion, the release characteristics in healthy subjects of the new levodopa/benserazide formulation are influenced only to a minor extent by concomitant intake of food or by tablet breaking.

Stereoselective passage of mefloquine through the blood-brain barrier in the rat.

The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine and (-)-mefloquine. When 50 mg kg-1 racemic mixture was administered orally for 22 days, plasma concentrations of the (+) enantiomer were 2-3 times higher than those of the (-) enantiomer whereas the opposite was true in every part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum). Different concentrations of mefloquine were found in the different regions of the brain; the lowest concentrations of (+/-)-mefloquine (27.0 nmol g-1) were in the cerebellum and the highest (110.0 nmol g-1) in the hippocampus. The main metabolite, carboxymefloquine, was detected in plasma but not in the brain. The results indicate the mefloquine crosses the blood-brain barrier stereoselectively.

Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics.

AIMS: The objectives of the study were to investigate the pharmacodynamics of the peripheral decarboxylase inhibitor benserazide during multiple-dose regimens. METHODS: Two groups of eight healthy male subjects were consecutively treated for periods of 14 days with benserazide 5, 25, 100 mg three times daily and 12.5, 50, 200 mg three times daily, respectively. Plasma levels of levodopa, 3-O-methyldopa (3-OMD) and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined before benserazide treatment and during all benserazide dosing regimens, as existing endogenously and after administration of 250 mg levodopa. RESULTS: Endogenous concentrations of levodopa and 3-OMD increased dose-dependently (from 8 up to 52 microg l(-1) and from 0.02 up to 0.50 mg l(-1) , respectively, at doses of 200 mg) with ascending doses of benserazide whereas DOPAC levels remained unchanged. There were no indications of a plateau in the effects of benserazide on the plasma levels of the analytes. The area under the concentration-time curve (AUC) of exogenously administered levodopa increased from 1.2 in the control group to 5.9 mg l(-1) h at benserazide doses of 100-200 mg three times daily. Benserazide caused a dose-dependent increase in the AUC of 3-OMD from 7.4 to 106 mg l(-1) h at doses of 200 mg. Formation of DOPAC was dose-dependently suppressed, with benserazide 5 mg three times daily already halving its AUC. CONCLUSIONS: The benserazide-dose response data obtained suggest that even at very high doses extracerebral decarboxylase is not yet completely inhibited.

Tolerance of mefloquine by SwissAir trainee pilots.

Due to presumed adverse performance impact, a World Health Organization clause currently restricts the use of mefloquine malaria chemoprophylaxis in individuals requiring fine coordination and spatial discrimination. We conducted a double-blind, placebo-controlled, cross-over study to quantitatively assess the effects of mefloquine at steady state on performance in 23 trainee airline pilots. Flying performance was assessed using a flight simulator, psychomotor function was evaluated, sleep and wake cycles were monitored, and symptoms and moods were assessed using standardized questionnaires. A simplified postural sway meter recorded sway in three test positions. In the mefloquine loading dose phase, there was one withdrawal due to dizziness, diarrhea, and flu-like symptoms, and three volunteers reported nonserious, sleep-related adverse events. There was no significant difference in flying performance, psychomotor functions, or mean sway for any test position. Nonsignificant reductions in mean total nocturnal sleep (mefloquine = 450 min versus placebo = 484 min) and poorer sleep quality were detected in the mefloquine phases. The mood findings indicated a predominance of positive states, with vigor the predominant mood in all phases. No significant performance deficit was documented under laboratory conditions during use of mefloquine at steady state.

Food increases the bioavailability of mefloquine.

OBJECTIVES: To assess the effect of food on the pharmacokinetics of the antimalarial mefloquine and its major plasma metabolite in healthy volunteers. METHODS: In an open, two-way cross-over study, 20 healthy male volunteers who had fasted overnight were randomised to receive a single oral dose of 750 mg mefloquine in the absence or presence of a standardised, high-fat breakfast, administered 30 min before drug administration. Blood samples were taken at specific times over an 8-week period. Plasma concentrations of mefloquine and its carboxylic acid metabolite were determined by high-performance liquid chromatography for pharmacokinetic evaluation. RESULTS: The parameters Cmax and AUC of both mefloquine and its metabolite were significantly (P < 0.05) higher under post-prandial conditions than under fasting conditions (mefloquine: mean Cmax 1500 vs 868 micrograms.l-1, mean AUC 645 vs 461 mg l-1.h; metabolite: Cmax 1662 vs 1231 micrograms.l-1, AUC 1740 vs 1310 mg l-1.h). The intersubject variability in Cmax and AUC of mefloquine was less than 30% (coefficient of variation). The time to peak plasma concentration of mefloquine was significantly shorter after food intake (17 vs 36 h). Compared with absorption in volunteers who had fasted, food did not alter t1/2 (mefloquine and its metabolite) and tmax (metabolite). CONCLUSION: Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible.

Effects of mefloquine alone and with alcohol on psychomotor and driving performance.

OBJECTIVE: To determine whether mefloquine, a quinoline antimalarial drug, affects psychomotor and actual driving performance when given in prophylactic regimen, alone or in combination with alcohol. METHODS: Forty male and female volunteers were randomly assigned in equal numbers to two groups, and were treated double-blind for one month with mefloquine and placebo. The medication was taken in a 250 mg dose on the evenings of Days 1, 2, 3, 8, 15, 22 and 29. Testing was done on Days 4, 23 and 30, the latter after repeated doses of alcohol sufficient to sustain a blood concentration of about 0.35 mg.ml-1. Two real driving tests were used to measure prolonged (1 h) road tracking and car following performance. Critical Flicker/Fusion Frequency (CFF), critical instability tracking and body sway were also measured in the laboratory. RESULTS: Mefloquine caused no significant impairment in any test at any time relative to placebo. It significantly improved road tracking performance on Day 4. A significant interaction between prior treatment and alcohol was found in the body sway test, as the alcohol-induced change was less after mefloquine than placebo. The sensitivity of the driving test and the CFF test were shown by the significant overall effect of alcohol which did not discriminate between the two prior treatments. CONCLUSION: Mefloquine did not impair driving performance but rather improved it in the longer test, suggesting that the drug may possess psychostimulating properties.

The chemotherapy of rodent malaria. LII. Response of Plasmodium yoelii ssp. NS to mefloquine and its enantiomers.

A comparison was made between the blood schizontocidal action in mice of racemic mefloquine hydrochloride and the free bases of its (+)- and (-)-enantiomers (Ro 13-7224 and Ro 13-7225) against chloroquine-resistant Plasmodium yoelii ssp. NS. The racemic hydrochloride was two to three times as active against this parasite in mice as either of the enantiomer free bases, which were of similar activity to each other. Under drug selection pressure, the parasites acquired resistance in approximately the same time for each of the three compounds.

Influence of hemodialysis on plasma concentration-time profiles of mefloquine in two patients with end-stage renal disease: a prophylactic drug monitoring study.

Prophylactic drug monitoring of mefloquine and its carboxylic acid metabolite were studied in two patients with end-stage renal disease undergoing long-term hemodialysis treatment. The patients, short-term travellers to areas where malaria is endemic, took 250 mg of mefloquine (Lariam) once weekly for 2 weeks before and during their 3-week stay abroad and for one week after their return. Pre- and postdialysis blood samples were drawn before their departure and after their return. The concentration-time profiles of mefloquine and its metabolite in plasma samples taken before and after the 3- to 4-h dialysis sessions were similar. Mefloquine and its metabolite could not be detected in the dialysate. These findings show that mefloquine and its metabolite are not, or are very poorly, removed by hemodialysis. Concentrations in plasma and accumulation kinetics were similar to those reported for healthy volunteers and were associated with high prophylactic efficacy against malaria. No special dosage adjustments have to be made in patients undergoing hemodialysis treatment to achieve concentrations in plasma similar to those in healthy volunteers. The prophylactic dose of mefloquine could be given before, during, or after the hemodialysis session.

Pharmacokinetics of ceftriaxone in patients with typhoid fever.

Ceftriaxone in short courses has emerged as an effective alternative to chloramphenicol for the treatment of typhoid fever. To study the pharmacokinetics of ceftriaxone in acute typhoid fever, 10 febrile Nepalese adolescents and young adults with blood culture-positive illness were treated with 3 g of ceftriaxone (intravenous infusion for 30 min) daily for 3 days. On the 1st and 3rd day of treatment, blood and urine samples were collected at defined intervals for measurements of drug concentrations. Kinetic parameters including concentrations at the end of infusion (Cmax) and 24 h after the end of infusion (Cmin), elimination half-life (t1/2), area under the plasma concentration-time curve (AUC), total plasma clearance, renal clearance, percentage excreted in urine, and volume of distribution were estimated. On day 1, mean values were as follows: Cmax, 291 micrograms/ml; Cmin, 21.7 micrograms/ml; plasma t1/2, 5.2 h; AUC, 1,428 micrograms.h/ml; total plasma clearance, 37 ml/min; renal clearance, 19 ml/min; percentage excreted in urine, 49.7%; and volume of distribution, 16.1 liters. Mean values on day 3 were not significantly different from those on day 1. Compared with published values for healthy volunteers who received the same dose, our mean t1/2s and AUCs were lower and our mean total plasma clearances, renal clearances, and volumes of distribution were higher. The good clinical responses of these patients to therapy and the adequate Cmins support the use of ceftriaxone once daily for the treatment of typhoid fever.

Stereoselective pharmacokinetics of mefloquine in healthy Caucasians after multiple doses.

Mefloquine (MQ) is a chiral antimalarial agent effective against chloroquine-resistant Plasmodium falciparum. It is commercially available as a racemic mixture of the (+) and (-) enantiomers for oral administration. The pharmacokinetics of the (+) and (-) enantiomers of MQ were studied in eight healthy volunteers after administration of a first oral dose of 250 mg of racemic MQ and at steady state after 13 repeated doses of 250 mg given at 1-week intervals. Plasma samples were collected, and concentrations of each enantiomer were determined using a previously described achiral-chiral double column-switching liquid chromatographic method. At each time point, higher plasma concentrations values were found for the (-) enantiomer (p < 0.001). At steady state, Cmax values of (-)-MQ were higher than those of (+)-MQ (1.42 +/- 0.19 versus 0.26 +/- 0.05 mg/L; p < 0.001). Similarly, the plasma concentrations 7 days after the final dose were higher for (-)-MQ (1.01 +/- 0.26 versus 0.11 +/- 0.04 mg/L; p < 0.001). AUC values at steady state were also higher for (-)-MQ (197.3 +/- 36.7 versus 30.1 +/- 8.9 mg/L x h; p < 0.001). The terminal half-life values (T1/2beta) were longer for (-)-MQ (430.4 +/- 225.2 versus 172.8 +/- 56.5 h; p < 0.001). This study shows that the pharmacokinetics of MQ is highly stereoselective.

Bioavailability and feasibility of subcutaneous 5-fluorouracil.

Continuous intravenous (i.v.) infusion of 5-fluorouracil (5-FU) has been shown to be superior to bolus regimens in terms of response rates and toxicity. However, a continuous infusion is more expensive and prone to complications such as thromboembolism and infections. A way to circumvent these problems would be to administer 5-FU subcutaneously (s.c.). To assess feasibility and bioavailability of s.c. 5-FU, eight patients with advanced cancer received 250 mg 5-FU as an infusion over 90 min either intravenously (i.v.) or s.c. into the abdominal wall. The mean +/- s.d. bioavailability of s.c. 5-FU was 0.89 +/- 0.23. The interpatient variability for the area under the plasma concentration-time curve was 48% for the s.c. and 36% for the i.v. infusion. No local side effects were observed. To test the local tolerance of a more prolonged administration three patients received 930-1,000 mg m-2 5-FU by 24-h continuous s.c. infusion. The steady-state plasma levels were comparable to i.v. infusion. One patient developed a painless skin pigmentation at the s.c. infusion site. However, the same reaction was observed at the forearm after i.v. infusion. We conclude that at the dose studied s.c. 5-FU has an almost complete bioavailability and is well tolerated. Further work will show, whether prolonged s.c. infusion can be used as a safe and economical alternative to i.v. infusion.

Steady state pharmacokinetics of mefloquine in long-term travellers.

Mefloquine is an antimalarial drug with a 3-week elimination half-life, which has led to concerns that toxic accumulation may occur during weekly administration for long-term malaria chemoprophylaxis. Despite the endorsement of weekly mefloquine by the World Health Organization and the United States Centers for Disease Control, mefloquine pharmacokinetics have been incompletely studied in subjects taking the drug once weekly for more than 4 weeks. Our objective was to study plasma mefloquine concentrations in travelers taking mefloquine 250 mg once weekly for 3 months. Multiple mefloquine concentrations were measured by high pressure liquid chromatography following the 1st, 2nd and 10th to 13th of 13 weekly doses of 250 mg mefloquine taken by 15 Canadian travellers (median age 23 years; 6 male, 14 white). Steady state was achieved in all subjects by or before the 10th dose. Mefloquine pharmacokinetic values were comparable to those previously reported by other investigators. In 7 subjects, 2 peaks of mefloquine and metabolite concentration followed ingestion, suggesting redistribution of mefloquine. Mefloquine concentration 14 d after the last dose was 74% of the level 7 d after the last dose. In conclusion, pharmacokinetic values determined by this study support mefloquine weekly dosing for long-term malaria chemoprophylaxis; toxic accumulation does not occur and weekly dosing is associated with significantly higher trough levels than 14 d dosing.

Ceftriaxone--bilirubin-albumin interactions in the neonate: an in vivo study.

The in vivo bilirubin-albumin binding interaction of ceftriaxone (CRO) was investigated in 14 non-jaundiced newborns, aged 33-42 weeks of gestation, during the first few days of life after they had reached stable clinical condition. CRO (50 mg/kg) was infused intravenously over 30 min. The competitive binding effect of CRO on the bilirubin-albumin complex was estimated by determining the reserve albumin concentration (RAC) at baseline, at the end of CRO infusion, and at 15 and 60 min thereafter. Immediately after the end of drug administration, RAC decreased from 91.9 (+/- 25.1) mumol/l to 38.6 (+/- 10.1) mumol/l (P = 0.0001). At the same time the plasma bilirubin toxicity index (PBTI) increased from 0.64 (+/- 0.40) before drug infusion to 0.96 (+/- 0.44) thereafter (P = 0.0001). The highest displacement factor (DF) was calculated to be 2.8 (+/- 0.6) at the end of drug infusion. Average total serum bilirubin concentrations decreased from a baseline value of 59.6 (+/- 27.0) mumol/l to 55.2 (+/- 27.1) mumol/l (P = 0.026). Sixty minutes after the end of CRO infusion, RAC was 58.3 (+/- 21.7) mumol/l, PBTI regained baseline, but DF was still 1.9 (+/- 0.2). No adverse events were recorded. Our results demonstrate significant competitive interaction of CRO with bilirubin-albumin binding in vivo. Thus, ceftriaxone should not be given to the neonate at risk of developing bilirubin encephalopathy.

Pharmacokinetics of midazolam administered by continuous intravenous infusion to intensive care patients.

OBJECTIVE: To determine the pharmacokinetics of continuously infused midazolam in patients during intensive care. DESIGN: Descriptive trial. SETTING: General ICU in a Swiss hospital. SUBJECTS: Eight critically ill patients requiring mechanical ventilation. INTERVENTIONS: To achieve an appropriate level of long-term sedation, the rate of iv infusion of midazolam in ICU patients was adjusted individually to between 6 and 15 mg/hr. Blood samples were taken during and after the continuous infusion of midazolam. MEASUREMENTS: Measurements included plasma concentration time profiles of midazolam and pharmacokinetic parameters, such as elimination half-life, clearance, and volume of distribution. RESULTS: The elimination half-life was prolonged (mean 5.4 vs. 2.3 hrs) and the volume of distribution was larger (3.1 vs. 0.9 L/kg) in patients vs. healthy volunteers. The clearance did not differ between groups (6.3 vs. 4.9 mL/min/kg in patients vs. volunteers, respectively). CONCLUSIONS: The increased volume of distribution in our critically ill patients is the major determinant for the observed slower elimination of midazolam. It is unlikely that the hepatic metabolism of midazolam was impaired in these patients.