Hypoxanthine-arabinoside pharmacokinetics after adenine arabinoside administration to a patient with renal failure.

Hypoxanthine arabinoside pharmacokinetics were measured during an adenine arabinoside continuous intravenous infusion and during hemodialysis in a patient with renal failure. Therapeutic guidelines for adenine arabinoside in renal failure are provided based on an elimination half-life of 4.7 h and a plasma clearance of 87.9 ml/min for the hypoxanthine metabolite.     

Pharmacology, tolerance, and antiviral activity of vidarabine monophosphate in humans

Vidarabine (adenine arabinoside) is a purine nucleoside useful in humans for therapy of herpes simplex virus encephalitis and herpes zoster virus infections in immunocompromised patients. However, the potential usefulness of vidaribine is limited by its poor solubility, which requires continuous infusion in relatively large volumes of intravenous fluid. Vidarabine 5′-monophosphate is highly soluble and has the advantage that it can be administered intermittently intramuscularly or intravenously. In a clinical, pharmacokinetic study, plasma levels and urinary excretion of vidarabine 5′-monophosphate were determined after intravenous and intramuscular administration in 29 immunosuppressed patients with herpes simplex or zoster virus infections at dosages of 15 to 30 mg/kg per day administered for 5 days. As determined by high-pressure liquid chromatography, vidarabine 5′-monophosphate was metabolized in a fashion comparable to the metabolism of vidarabine and its major metabolite in plasma was arabinosyl hypoxanthine. After administration, 40 to 50% of the vidarabine 5′-monophosphate was recovered from the urine as arabinosyl hypoxanthine, and 3 to 4% was recovered as vidarabine. Determinations of areas under the curve for arabinosyl hypoxanthine were not statistically different by dosage for intramuscular or intravenous routes of administration. At all dosages studied, viral clearance appeared to occur with therapy. The advantage of increased solubility will lead to controlled clinical investigations in which vidarabine 5′-monophosphate is administered by intramuscular or intravenous routes against targeted human herpesvirus infections.     

Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits.

We studied the plasma pharmacokinetics and tissue penetration of cilofungin (LY121019), a new echinocandin antifungal compound, by intermittent and continuous infusion in rabbits. Following a single intravenous dose of 50 mg/kg of body weight, the maximum concentration in plasma was 297 +/- 39 micrograms/ml, the area under the curve was 30.1 +/- 6.7 micrograms.h/ml, clearance was 30 +/- 10 ml/min/kg, volume of distribution was 0.85 +/- 0.23 liters/kg, half-life in distribution phase was 3.7 +/- 0.2 min (first 12 min postdose), and half-life in elimination phase was 12.9 +/- 0.7 min. When rabbits received cilofungin by continuous infusion (CI) at 10 mg/kg/h over 6 days, sustained concentrations in plasma of 290 +/- 56 micrograms/ml were seen, more than 50-fold higher than predicted if kinetics were linear. Similarly, at 5 mg/kg/h, high levels were also obtained. Such elevated levels in plasma would not have been predicted from the pharmacokinetic characteristics of cilofungin given as a single intravenous dose. Further pharmacokinetic study at several rates of CI suggested that cilofungin elimination follows Michaelis-Menten kinetics. Simultaneous cilofungin levels in plasma and tissue were then determined for rabbits receiving six intravenous, intermittent doses (ID) of cilofungin at 15 mg/kg every 4 min and for rabbits receiving CI as described above. After ID, the mean of the ratios of cilofungin levels in tissue to those in plasma were highest for liver and bile but very low for cerebrum and cerebellum. After CI, ratios were as much as 89 times higher than for ID and significantly greater in the brain, choroid, kidney, and bile (P less than 0.05). We conclude that following a single dose of cilofungin, the compound is rapidly cleared via first-order kinetics and does not penetrate into the central nervous system, whereas following CI, cilofungin exhibits nonlinear saturable kinetics, is slowly cleared, and significantly penetrates into central nervous system tissues.     

Piperacillin pharmacokinetics in subjects with chronic renal failure

The pharmacokinetic parameters of piperacillin sodium were studied in eight volunteer subjects with chronic renal failure. Subjects were given a single 30-min intravenous infusion of 70 mg/kg (lean body weight) on their off-dialysis day. Blood was drawn from the contralateral arm at 15 and 30 min and 1, 3, 6, 9, and 12 h from the start of the infusion. Kinetic parameters were determined during the elimination phase with a one-compartment open model for linear kinetics. The following pharmacokinetic parameters (mean +/- standard deviation) were determined for the eight subjects: elimination half-life = 3.33 +/- 0.99 h, elimination rate constant = 0.22 +/- 0.06 h-1, apparent volume of distribution = 0.18 +/- 0.05 liters per kg, and total body clearance = 0.041 +/- 0.019 liters per kg/h. The mean peak serum concentration was 372 +/- 125 microgram/ml, and mean trough at 12 h was 39 +/- 27 microgram/ml. A dose of 70 mg/kg (lean body weight) or a dose of 4 g appears to provide adequate serum concentrations against susceptible organisms for a 12-h interval. No adverse reactions were noted in any subject throughout the study.     

Pharmacokinetics of Isepamicin during Continuous Venovenous Hemodiafiltration

The objective of this study was to analyze the pharmacokinetics of isepamicin during continuous venovenous hemodiafiltration. Six patients received 15 mg of isepamicin per kg of body weight. The mean isepamicin concentration peak in serum was 62.88 +/- 18.20 mg/liter 0.5 h after the infusion. The elimination half-life was 7. 91 +/- 0.83 h. The mean total body clearance was 1.75 +/- 0.28 liters/h, and dialysate outlet (DO) clearance was 2.76 +/- 0.59 liters/h. The mean volume of distribution was 19.83 +/- 2.95 liters. The elimination half-life, DO clearance, and volume of distribution were almost constant. In this group of patients, the initial dosage of 15 mg/kg appeared to be adequate, but the dosage interval should be determined by monitoring residual isepamicin concentrations in plasma.     

Metabolism of Fibrinogen in Cirrhosis of the Liver

The metabolism of human fibrinogen labeled with radioactive iodine was studied in 50 patients with documented cirrhosis of the liver and in 35 healthy control subjects. Results in cirrhotic subjects were the following: plasma volume 47 +/- 10 ml/kg; plasma fibrinogen concentration 250 +/- 102 mg/100 ml; total plasma fibrinogen pool 118 +/- 59 mg/kg, representing 0.73 +/- 0.10 of the total body pool; fibrinogen half-life 2.99 +/- 0.59 days; fractional catabolic rate 0.34 +/- 0.09 of the plasma pool per day; absolute catabolic rate 39 +/- 20 mg/kg per day; fractional transcapillary efflux rate 0.82 +/- 0.30 of the plasma pool per day. Results in the control subjects were the following: plasma volume 42 +/- 7 ml/kg; plasma fibrinogen concentration 284 +/- 71 mg/100 ml; total plasma fibrinogen pool 119 +/- 40 mg/kg, representing 0.72 +/- 0.07 of the total body pool; fibrinogen half-life 4.14 +/- 0.56 days; fractional catabolic rate 0.24 +/- 0.04 of the plasma pool per day; absolute catabolic rate 28 +/- 9 mg/kg per day; fractional transcapillary efflux rate 0.60 +/- 0.26 of the plasma pool per day.A significant difference between cirrhotics and controls was observed for plasma volume, fibrinogen half-life, fractional and total catabolic rates, and transcapillary efflux rate. During heparinization of 10 cirrhotic patients the fibrinogen half-life was prolonged from 3.15 +/- 0.69 to 4.59 +/- 0.79 days. This was associated with a rise in plasma fibrinogen in six out of eight patients. Heparinization did not influence the fibrinogen half-life in five control subjects. Inhibition of the fibrinolytic system in 17 patients resulted in prolongation of the plasma radioactivity half-life of more than 1 day in only three patients, an incidence comparable with that in five control subjects.These results strongly support the concept of accelerated fibrinogen consumption by a process of disseminated intravascular coagulation in cirrhosis of the liver.     

Pharmacokinetics of Ceftriaxone in Pediatric Patients With Meningitis

Pharmacokinetics of ceftriaxone after a single dose of 50 or 75 mg/kg were determined in 30 pediatric patients with bacterial meningitis. Data for doses of 50 and 75 mg/kg, respectively, were as follows (mean +/- standard deviation): maximum plasma concentrations, 230 +/- 64 and 295 +/- 76 mug/ml; elimination rate constant, 0.14 +/- 0.06 and 0.14 +/- 0.04 h(-1); harmonic elimination half-life, 5.8 +/- 2.8 and 5.4 +/- 2.1 h; plasma clearance, 51 +/- 24 and 55 +/- 18 ml/h per kg; volume of distribution, 382 +/- 129 and 387 +/- 56 ml/kg; mean concentration in cerebrospinal fluid 1 to 6 h after infusion, 5.4 and 6.4 mug/ml. A dosage schedule of 50 mg/kg every 12 h for bacterial meningitis caused by susceptible organisms is suggested for pediatric patients over 7 days of age.     

Intravenous administration of prostacyclin in rabbits: elimination kinetics and blood pressure response

Prostacyclin (PGI2) has been used extensively in human clinical trials and animal studies, but because of its instability, knowledge of its pharmacokinetics has progressed slowly. We assayed plasma PGI2 concentrations with a quantitative chromatographic method following bolus intravenous injection and during continuous infusion in rabbits. Blood pressure response was correlated with plasma PGI2 concentrations and compared with the concentrations necessary to inhibit platelet aggregation in vitro. A two-compartment model was used to analyze the elimination kinetics for PGI2 after a single injection. The half-life of the terminal elimination phase was 2.7 minutes. The calculated systemic clearance and whole body volume of distribution were 93 ml/kg/min and 357 ml/kg, respectively. During continuous infusion, steady-state plasma concentrations were reached within 15 minutes and increased linearly with increasing infusion rate from 4.2 to 604 ng/kg/min, which resulted in PGI2 concentrations of 0.06 +/- 0.01 to 7.6 +/- 2.1 ng/ml, respectively. At steady-state plasma concentrations of PGI2 greater than 0.1 ng/ml, the mean arterial blood pressure decreased in a concentration-dependent manner, reaching a decrease of 45 mm Hg when the plasma concentration was 7.6 ng/ml. Prostacyclin caused a concentration-dependent inhibition of adenosine diphosphate-induced platelet aggregation in vitro with 10% inhibition at 0.4 ng/ml. These results indicate that in the rabbit the level of PGI2 at which the onset of hypotension occurs coincides with the inhibition of platelet aggregation.     

Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients.

The effects of a 48-hour 0.5 mg/kg/hr infusion of the thromboxane synthase inhibitor pirmagrel were studied in 10 renal allograft recipients with cyclosporine nephrotoxicity. Plasma concentrations reached a mean steady-state plasma level of 1798 +/- 481 ng/ml. Biphasic, rapid elimination of pirmagrel was observed with a distribution half-life of 6.7 minutes and a terminal half-life of 73 minutes. Plasma clearance and the volume of distribution of the drug were 300 +/- 87 ml/hr/kg and 497 +/- 232 ml/kg, respectively. The pharmacodynamic effects of pirmagrel were marked by a mean 96% suppression of serum thromboxane B2 (TXB2), which coincided with a suppression of urinary excretion of TXB2, 2,3-dinor-TXB2, and 11-dehydro-TXB2 of 85% +/- 8%, 91% +/- 5%, and 89% +/- 9%, respectively. Urinary excretion of all thromboxane metabolites measured at the end of 1 week after termination of infusion was returned to the baseline. In conclusion, pirmagrel caused effective and sustained suppression of all thromboxane derived metabolites in plasma and urine during continuous infusion in kidney transplant patients receiving cyclosporine.     

Pharmacokinetics of intravenous amdinocillin in healthy subjects and patients with renal insufficiency.

Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocillin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis.     

Intravenous N-acetylprocainamide disposition kinetics in coronary artery disease

N-Acetylprocainamide (NAPA) disposition kinetics was studied in eight patients with coronary artery disease. NAPA was given over a 45-min period by intravenous infusion, and blood samples were drawn at specified times for 24 hr. NAPA plasma levels were determined by a specific high-pressure liquid chromatography (HPLC) procedure and the concentration-time data were fit to a three-compartment model. Mean (+/- SD) values for the elimination half-life, the total body clearance, and the steady-state volume of distribution were 9.53 +/- 3.22 hr, 1.98 +/- 0.40 ml/min/kg, and 1.30 +/- 0.18 1/kg. There was moderate intersubject variability in disposition. The data reported here differ from those reported for normal subjects.     

Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.     

Moxalactam kinetics during continuous ambulatory peritoneal dialysis after intraperitoneal administration.

Moxalactam kinetics during continuous ambulatory peritoneal dialysis (CAPD) was followed in eight patients after a single intraperitoneal dose of 1 g. Approximately 60% of the dose was absorbed after a dwell time of 4 h. Dialysis solutions were exchanged at 4-h intervals with an overnight dwell of 8 h. The mean (+/- standard deviation) elimination half-life was 13.2 +/- 2.9 h, and the mean apparent volume of distribution was 0.22 +/- 0.08 liters/kg. Mean total clearance was 11.5 +/- 2.4 ml/min, with a mean dialysis clearance of 2.3 +/- 0.5 ml/min. The maximum concentration in plasma ranged from 24.5 to 54.1 micrograms/ml. Moxalactam concentrations in the peritoneal dialysis fluid were above 80 micrograms/ml during the first exchange and above 2 micrograms/ml for a further three exchanges. A suggested intraperitoneal dose regimen for patients undergoing CAPD is 1 g initially, followed by 15 to 25% of the recommended dose for normal patients given at the same time intervals, or 30 to 50% of the recommended dose at twice the usual intervals. Moxalactam is suggested for initial treatment of peritonitis in CAPD patients who do not have ready access to the antibiotic of choice.     

Pharmacokinetics of enoxacin and its oxometabolite following intravenous administration to patients with different degrees of renal impairment.

Enoxacin is a fluorinated quinolone with potential clinical use in the treatment of serious infections. Twenty-three patients (age, 19 to 87 years) with different degrees of renal function, including a group undergoing chronic hemodialysis, received enoxacin (400 mg) by intravenous infusion (1 h). Blood samples were collected before infusion; at the end of infusion; and at 5, 10, 20, 30, 45, 60, 90, and 120 min and 3, 4, 6, 12, 18, 24, 48, and 72 h after infusion. Enoxacin and oxoenoxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters (mean +/- standard deviation) were calculated by using a noncompartmental PK model according to creatinine clearances (in milliliters per minute). Total clearance of enoxacin decreased from 4.95 +/- 1.16 ml/min per kg in the group with normal creatinine clearance to 0.76 +/- 0.21 ml/min per kg in the patients with severe renal failure (creatinine clearance, less than 15 ml/min), whereas the elimination half-life increased from 4.5 +/- 1.0 to 20 +/- 5 h, respectively. The elimination of oxoenoxacin (the main metabolite of enoxacin) in urine was markedly decreased when creatinine clearance was less than 15 ml/min. Hemodialysis removed an insignificant amount of enoxacin and oxoenoxacin. These data indicate that as creatinine clearance falls below 30 ml/min, the daily enoxacin dose should be reduced by half. During prolonged administration of enoxacin to patients with creatinine clearances of less than 30 ml/min, the accumulation of oxoenoxacin might lead to unexpected side effects.     

Pharmacokinetics of a fluoronaphthyridone, trovafloxacin (CP 99,219), in infants and children following administration of a single intravenous dose of alatrofloxacin

The pharmacokinetics of trovafloxacin following administration of a single intravenous dose of alatrofloxacin, equivalent to 4 mg of trovafloxacin per kg of body weight, were determined in 6 infants (ages 3 to 12 months) and 14 children (ages, 2 to 12 years). There was rapid conversion of alatrofloxacin to trovafloxacin, with an average +/- standard deviation (SD) peak trovafloxacin concentration determined at the end of the infusion of 4.3 +/- 1.4 microg/ml. The primary pharmacokinetic parameters (average +/- SD) analyzed were volume of distribution at steady state (1.6 +/- 0.6 liters/kg), clearance (151 +/- 82 ml/h/kg), and half-life (9.8 +/- 2.9 h). The drug was well tolerated by all children. There were no age-related differences in any of the pharmacokinetic parameters studied. Less than 5% of the administered dose was excreted in the urine over 24 h. On the basis of the mean area under the concentration-time curve of 30.5 +/- 10.1 microg. h/ml and the susceptibility (< or =0.5 microg/ml) of common pediatric bacterial pathogens to trovafloxacin, dosing of 4 mg/kg/day once or twice daily should be appropriate.     

Kinetics of alpha-difluoromethylornithine: an irreversible inhibitor of ornithine decarboxylase

We gave alpha-difluoromethylornithine (DFMO), a selective, irreversible inhibitor of ornithine decarboxylase, to six health men in single intravenous doses of 5 and 10 mg/kg body weight and oral doses of 10 and 20 mg/kg. Plasma concentrations were monitored during the 24 hr after each dose. Urine was collected from 0 to 24 hr after drug and amount of unchanged drug excreted was determined. Peak plasma concentrations were reached within 6 hr after oral doses. The decay of the plasma concentrations followed first-order kinetics with a mean half-life (t 1/2) for all four doses studied of 199 +/- 6 min (+/- SD). Mean total body clearance (ClT) for the four doses was 1.20 +/- 0.06 ml . min-1 . kg-1. Mean renal clearance was determined as 0.99 +/- 0.03 ml . min-1 . kg-1, accounting for 83% of drug elimination. Mean apparent volume of distribution (aVD) was 0.337 +/- 0.031 l/kg-1, corresponding to 24 l for 70 kg of body weight. The amount of unchanged drug in 24-hr urine samples was 47 +/- 7% and 40 +/- 11% after 10 and 20 mg/kg orally, and 78% and 81 +/- 8% after 5 and 10 mg/kg intravenously. Bioavailability of the 10 mg/kg dose was estimated as 58% from the urinary recoveries and as 54% from the areas under the plasma concentration curves (AUC 0 leads to infinity). Since doubling of the dose resulted in a doubling of the mean AUC 0 leads to infinity and since other kinetic parameters, such as aVD, t 1/2, ClT, and the urinary recovery of unchanged drug, were essentially the same at all doses, DFMO kinetics follow a dose-linear model.     

Cardiovascular actions and pharmacokinetics of desethyl-N-acetylprocainamide in the dog

The pharmacokinetic profile and the cardiovascular actions of desethyl-N-acetylprocainamide (NAPADE) were studied in chloralose-urethane anesthetized dogs. NAPADE was given as a 15-min i.v. infusion in doses of 12 and 60 mg/kg. In all cases, the plasma concentration vs. time curve could be resolved into two exponential components, and the distribution and elimination of NAPADE were analyzed with a two-compartmental model. Total apparent volume of distribution was 0.4153 +/- 0.0301 liters/kg (mean +/- S.E.M.) for the 12-mg/kg group and 0.4946 +/- 0.0691 liters/kg for the 60-mg/kg group (P greater than .05). Elimination clearance was 0.0061 +/- 0.0006 liters/min/kg for the 12-mg/kg group and 0.0086 +/- 0.0013 liters/min/kg for the 60-mg/kg group (P greater than .05). The elimination phase half-life (T1/2 beta) was 57.0 +/- 4.1 and 53.1 +/- 3.2 min for the 12- and 60-mg/kg groups, respectively (P greater than .05). Thus, NAPADE exhibited first-order kinetics of distribution and elimination in the dose range studied. Renal clearance of unchanged NAPADE amounted to 45.9 +/- 4% of total plasma clearance. NAPADE had a dose- and concentration-related positive inotropic effect, as measured with a Walton-Brodie gauge sutured to the right ventricle. A 12-mg/kg infusion caused a peak increased in myocardial force of 18.4 +/- 3.6% over base line, whereas a 60-mg/kg infusion caused a peak increase in myocardial force of 48.9 +/- 10% over base line. The positive inotropic effect of NAPADE was sustained for 50 to 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of intravenous cefetamet and oral cefetamet pivoxil in patients with renal insufficiency.

The pharmacokinetics of cefetamet after a short intravenous infusion of cefetamet (515 mg) and oral administration of 1,000 mg of cefetamet pivoxil were studied in 9 healthy subjects and in 38 patients with various degrees of renal impairment. The results showed that cefetamet elimination was dependent on renal function. After intravenous dosing, total body (CLS), renal (CLR), and nonrenal (CLNR) clearances were linearly related to creatinine clearance (CLCR; r = 0.95, 0.92, and 0.59, respectively). Elimination half-life (t1/2 beta) was prolonged from 2.46 +/- 0.33 h in normal subjects to 29.1 +/- 13.9 h in patients with CLCR of less than 10 ml/min per 1.73 m2. Correspondingly, CLS and CLR decreased from 1.77 +/- 0.27 and 1.42 +/- 0.25 ml/min per kg to 0.14 +/- 0.04 and 0.04 +/- 0.03 ml/min per kg, respectively. The volume of distribution at steady state (0.298 +/- 0.049 liter/kg) for cefetamet was not altered by renal insufficiency (P greater than 0.05). After oral administration, the elimination parameters, t1/2 beta and CLR, were insignificantly different from the intravenous data (P greater than 0.05). Furthermore, the bioavailability (F) of cefetamet pivoxil (45 +/- 13%) was not altered by renal failure (P greater than 0.05). However, maximum concentration in plasma and the time to achieve this value were significantly increased (5.86 +/- 0.74 versus 14.8 +/- 6.14 micrograms/ml and 3.9 +/- 1.1 versus 8.4 +/- 1.7 h, respectively; P less than 0.05). Based on these observations, it is recommended that patients with CLcr of <10 ml/min per 1.73 m2 and between 10 and 39 ml/min per 1.73 m2 be given one-quarter of the normal daily dose either once or twice daily. Patients with CLcr between 40 and 80 ml/min per 1.73 m2 should receive one-half of the normal dose twice daily. For patients with CLcr of <10 ml/min per 1.73 m2, it would be recommended that they receive a normal standard dose as a loading dose on day 1 of treatment.     

Pharmacokinetic-pharmacodynamic relationships of morphine in neonates.

Morphine pharmacokinetics and pharmacodynamics (analgesia and sedation) were evaluated after continuous intravenous infusion of morphine in 19 neonates, both preterm and term, whose lungs were ventilated to relieve respiratory distress. Elimination half-life, total plasma clearance, and volume of distribution (mean +/- SD) were 9.6 +/- 3.0 hours, 2.55 +/- 1.65 ml/min/kg (area analysis) or 2.09 +/- 1.19 ml/min/kg (steady-state data), and 2.05 +/- 1.05 L/kg, respectively, and were not significantly different in preterm and term neonates. In neonates with adverse effects of morphine, the plasma clearance was decreased twofold. Mean morphine concentration required to produce adequate sedation in 50% of patients was found to be 125 ng/ml, but concentrations above 300 ng/ml may be associated with adverse effects of morphine. Morphine-6-glucuronide was not detected in the plasma of any neonate, which may explain why neonates require high plasma concentrations of unchanged morphine for sedation.     

Midazolam kinetics

The effect-kinetics of the new benzodiazepine midazolam was evaluated in six subjects after single oral (7.5 and 15 mg) and intravenous (0.075 mg/kg) doses and infusion programs. The drug is bound to plasma proteins by 94%, and less than 0.5% is excreted unchanged in urine. Hepatic elimination is rapid: t1/2 beta is 2.4 +/- 0.8 hr (mean +/- S.D) and total body clearance is 283 +/- 43 ml/min (plasma) or 502 +/- 105 ml/min (blood). This substantial first-pass effect leads to bioavailability of only 44%, despite very rapid absorption (t1/2abs = 0.23 +/- 0.37 hr) after oral dosing. There is good intraindividual linear correlations (r between 0.68 and 0.97) between plasma levels and dynamic effects, as assessed by the d2 letter cancellation test and a sedation index formed from visual analogue scales.