A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats.

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50 degrees C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.

The relevance of searching for effects under a clinical-trial lamppost: a key issue.

In economic evaluations of new medical technologies, analysts often need to use data from randomized controlled trials. Trials are designed to achieve high internal validity; however, their selected populations and often highly artificial environments may imply low external validity. Thus, the use of trial data in an economic evaluation may bias the results, since economic evaluation is concerned not with theoretical capability in a trial but with likely performance in the practice environment.

Comparative toxicokinetics of methanol in the female mouse and rat.

The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or i.

Disposition and covalent binding of ibuprofen and its acyl glucuronide in the elderly.

Ibuprofen is an over-the-counter nonsteroidal anti-inflammatory drug with a low incidence of severe adverse reactions. It is metabolized by oxidation to carboxyibuprofen and hydroxyibuprofen and by conjugation to an acyl glucuronide. In vitro studies have indicated that ibuprofen glucuronide is labile and reactive, forming covalent adducts with proteins.

Disposition and reactivity of ibuprofen and ibufenac acyl glucuronides in vivo in the rhesus monkey and in vitro with human serum albumin.

The disposition of ibuprofen and ibufenac, an analog of ibuprofen with a history of severe adverse reactions, was investigated in Rhesus monkeys after oral administration. Plasma concentrations of the parent drugs and their glucuronides were measured by a direct HPLC method. Ibuprofen and ibufenac were rapidly absorbed and metabolized to their acyl glucuronides.

Covalent binding of suprofen to renal tissue of rat correlates with excretion of its acyl glucuronide.

1. Dosing rat with suprofen produces suprofen equivalents that are covalently bound to plasma and tissue proteins in vivo. 2.

Age-dependent intestinal hydrolysis of valproate glucuronide in rat.

1. Age-dependent differences in the intestinal hydrolysis of the glucuronide conjugate of valproic acid were evaluated in the Fisher-344 rat at 14 and 40 days, and 24 months of age. 2.

Age-dependent intestinal absorption of valproic acid in the rat.

The absorption of valproic acid (VPA) across isolated perfused segments of jejunum, ileum and colon was examined in situ in 14-day- to 24-month-old Fischer-344 rats. Within each age group, the intrinsic absorptive clearance (Cla) of VPA at a perfusate concentration of 1 mg/ml was highest in the jejunum, lowest in the colon, and intermediate in the ileum. When intestinal Cla was normalized for the dry weight of the segment, within-group variability decreased.

Acute hemodynamic effects of the prostacyclin analog 15AU81 in severe congestive heart failure.

This multicenter, open-label study provides the first assessment of the safety and acute hemodynamic effects of a short-term infusion of 15AU81, a chemically stable analog of prostacyclin, in patients with New York Heart Association class III or IV heart failure. Twelve patients underwent sequential dose escalation by increasing the rate of the infusion at 15-minute intervals until the drug was no longer tolerated. Patients then received a 90-minute infusion at their maximum tolerated dose.

Synthesis of novel water-soluble 7-(aminoacylhydrazono)-formyl camptothecins with potent inhibition of DNA topoisomerase I.

Eighteen new water-soluble 7-(aminoacylhydrazono)-formyl camptothecins were synthesized and evaluated for their ability to cause protein-linked DNA breaks and to inhibit topoisomerase I activity. Compared with camptothecin, five of the compounds were as potent or more potent in these tw assays but were less toxic in several cancer cell lines. The results suggest that the 7 position in the B ring is a suitable location for introducing a polar moiety into camptothecin producing analogues with enhanced topoisomerase I inhibiting activity.

Overview of current development in patient-controlled analgesia.

Over the past two decades, numerous trials have assessed the safety and efficacy of patient-controlled analgesia (PCA). Advantages over conventional parenteral narcotics reported from these trials include equivalent to superior pain relief, superior patient satisfaction, decreased sedation and anxiety, faster return to normal functional status, and reduction in nursing time and hospitalization. The majority of these trials have been conducted in the postoperative patient population.

Oral torsemide in patients with chronic congestive heart failure: effects on body weight, edema, and electrolyte excretion. Torsemide Investigators Group.

Study Objective: To assess the effects of torsemide on the primary end point of change in body weight from baseline, and the following secondary end points: urinary sodium, potassium, and chloride excretion, and urine volume after the first dose of drug.

Design: Randomized, parallel, double-blind, multicenter study in patients treated with torsemide 5 mg (n = 19), 10 mg (n = 18), or 20 mg (n = 14), or placebo (n = 15) for 7 days.

Patients: Sixty-six patients with New York Heart Association class II or III congestive heart failure and edema.

Effects of probenecid on the pharmacokinetics and pharmacodynamics of adinazolam in humans.

The effects of probenecid (2 gm) on the pharmacokinetics, pharmacodynamics, and uricosuric effects of adinazolam and N-desmethyladinazolam were assessed after single dose administration of adinazolam mesylate sustained-release tablets (60 mg) in a randomized, four-way crossover, double-blind study involving 16 healthy male volunteers. Probenecid decreased adinazolam oral clearance, renal N-desmethyladinazolam clearance, and the amount of N-desmethyladinazolam excreted in the urine. Probenecid increased the N-desmethyladinazolam/adinazolam AUC ratio, adinazolam maximum concentration (Cmax), N-desmethyladinazolam Cmax, and N-desmethyladinazolam time to reach Cmax.

Bile flow but not enterohepatic recirculation influences the pharmacokinetics of ranitidine in the rat.

Secondary peaks in oral concentration-time profiles following ranitidine administration may be due to discontinuous absorption along the gastrointestinal tract, postabsorptive storage and release, and/or enterohepatic recirculation (ER). The suitability of the rat as an animal model for studying mechanisms of the double peaks, and the relationship between ER and the occurrence of secondary peaks in ranitidine concentration-time profiles, were examined in the present investigation. Male Sprague-Dawley rats received ranitidine by oral gavage (50 mg/kg), and blood was collected at various times for 6 hr after dosing.

Venous irritation related to intravenous administration of phenytoin versus fosphenytoin.

Study Objective: To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug.

Design: Randomized, double-blind, two-period, crossover study.

Setting: University hospital clinical research unit.

Site-dependent intestinal hydrolysis of valproate and morphine glucuronide in the developing rat.

A previous pharmacokinetic study in developing rats suggested that enterohepatic recirculation of valproic acid was absent prior to weaning. One explanation for this observation is that the rate, extent, and/or primary site of glucuronide hydrolysis in the gastrointestinal tract changes during postnatal development. To test this hypothesis, the hydrolysis of two model glucuronide conjugates, valproate glucuronide and morphine-3-beta,D-glucuronide, was examined in vitro in homogenates of small and large intestine obtained from rats at 5-60 days postpartum.

Disposition and protein binding of valproic acid in the developing rat.

The disposition of valproic acid (VPA) in serum and brain tissue was examined in developing rats (5, 10, 20, and 60 days postpartum) following both single and multiple intraperitoneal doses of VPA. The binding of VPA to proteins in serum was determined ex vivo by ultrafiltration for each age group in pooled serum at various time points following VPA administration, as well as after in vitro addition of VPA (8-2400 micrograms/ml) to pooled rat serum from naive animals of each age. Concentration-time data for VPA in serum and brain tissue were fit simultaneously, assuming first-order absorption from the peritoneal injection site and first-order transfer of drug between serum and brain tissue.

Pharmacokinetics and pharmacodynamics of valproate analogues in rats. IV. Anticonvulsant action and neurotoxicity of octanoic acid, cyclohexanecarboxylic acid, and 1-methyl-1-cyclohexanecarboxylic acid.

We examined the pharmacodynamics of valproate (VPA) and three structural analogues, octanoic acid (OA), cyclohexanecarboxylic acid (CCA), and 1-methyl-1-cyclohexanecarboxylic acid (MCCA) in rats. A pentylenetetrazol (PTZ) infusion seizure model was used to determine threshold convulsive doses of PTZ; the increase in PTZ threshold dose after administration of test compound was taken as an index of anticonvulsant activity. Each of the compounds investigated antagonized PTZ-induced seizures, with MCCA evidencing the highest potency.

Assessment of valproic acid serum-cerebrospinal fluid transport by microdialysis.

The systemic disposition and serum-cerebrospinal fluid (CSF) translocation of valproic acid (VPA) were examined in rats after administration of VPA as a bolus, as a continuous infusion, or with probenecid. VPA in CSF was monitored continuously by in vivo microdialysis. Both prolonged VPA infusion and probenecid pretreatment increased the Km for saturable VPA elimination and decreased intrinsic hepatic clearance, perhaps due to competition of probenecid or accumulated VPA metabolites for glucuronidation or depletion of hepatic UDP-glucuronic acid.

Acute phenobarbital administration alters the disposition of acetaminophen metabolites in the rat.

The effects of acute phenobarbital (PB) administration on the disposition of acetaminophen (APAP), acetaminophen glucuronide (AG), and acetaminophen sulfate (AS) were examined in serum, bile, and urine of rats after a 100 mg/kg iv bolus dose of APAP. PB was administered intravenously as either an acute low (12 mg/kg) or high (60 mg/kg) dose to achieve PB serum concentrations equivalent to, or 5-fold higher than, PB concentrations in previous studies where impaired biliary excretion of AG and AS was noted after PB pretreatment for 5 days. Acute high-dose PB administration decreased the formation clearance of AG by 36% (from 3.

Effect of phenobarbital and p-hydroxyphenobarbital glucuronide on acetaminophen metabolites in isolated rat hepatocytes: use of a kinetic model to examine the rates of formation and egress.

Conventional analysis of initial uptake and egress rates in isolated hepatocytes is limited in the ability to distinguish between rates of metabolite formation and egress, and to separate basolateral and canalicular transport processes. The present study examined the applicability of kinetic modeling in describing acetaminophen glucuronide (AG) and acetaminophen sulfate (AS) formation and egress in hepatocytes after acute exposure to phenobarbital or p-hydroxyphenobarbital glucuronide (p-OHPBG) in vitro, or in vivo phenobarbital pretreatment. A significant pretreatment effect on AG and AS disposition was seen based on initial rates of egress.