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Biomedical subjects

J T Slattery

Publications and source records attributed to J T Slattery.

At least 19 recordsLinked to original sources
PubMed1992

The maturation of morphine clearance and metabolism.

OBJECTIVE: To determine how early in childhood the clearance of morphine sulfate reaches that in adults. DESIGN: Patient series. SETTING: Children's Hospital and Medical Center, Seattle, Wash. PARTICIPANTS: Forty-nine children aged 1 day to 2.5 years with normal renal and hepatic function. All children were receiving a constant rate intravenous infusion of morphine for postoperative analgesia for greater than 24 hours. INTERVENTIONS: Blood and urine samples were collected during infusion and immediately after discontinuation of the morphine infusion. MEASUREMENTS: Morphine concentrations were determined and clearance was calculated using the infusion data. Half-life and volume of distribution were calculated using the postinfusion data. The formation of metabolites was evaluated using the urine data. Morphine clearance increased with age, median clearances ranging from 5 mL/kg per minute in neonates aged 1 to 7 days to 21 mL/kg per minute in infants aged 6 months and older. This change in clearance correlated with age. The formation clearance of morphine glucuronide was correlated with age, whereas the formation clearance of morphine sulfate and the renal clearance of morphine were independent of age. CONCLUSIONS: Morphine clearance reaches adult values by age 6 months to 2.5 years. In contrast to previous reports on the maturation of sulfate conjugation, it does not appear that morphine sulfate clearance is enhanced relative to glucuronidation in early infancy.

Analgesia↗
PubMed1992

Saturable tissue binding and imirestat pharmacokinetics in rats.

To investigate the hypothesis that the pharmacokinetics of imirestat, an aldose reductase inhibitor, are influenced by saturable binding to tissues, three experiments were done. (1) The nature of the dose dependence was characterized in rats. Two groups of nine adult male Sprague-Dawley rats received iv 14C-imirestat at doses of 2 or 8 mg/kg. Serial blood samples were obtained over 15 days. Volume of distribution at steady-state was significantly different between the high- and the low-dose groups (0.744 +/- 0.103 l and 1.10 +/- 0.228 L, respectively). Clearance was independent of dose over this fourfold range (approximately 15 ml/hr). (2) The effect of either statil or AL3152, both aldose reductase inhibitors and potential competitors for aldose reductase binding, on the pharmacokinetics of a single 0.2-mg/kg iv dose of imirestat was assessed. A 2.4-mg/kg loading dose of statil was administered and a constant-rate infusion (56 micrograms/hr/kg) was begun 16 hr before imirestat. A 2-mg/kg loading dose of AL3152 and a constant-rate infusion (115 micrograms/kg/hr) were also administered 16 hr before imirestat. The infusions were maintained throughout the study. AL3152 administration decreased the imirestat steady-state volume of distribution by a mean of 63%. Statil administration decreased it by a mean of 39%. (3) The dosing regimen of the second study was repeated and, at two sampling times, nine tissues and plasma were obtained from four rats per sampling time for determination of imirestat tissue-to-plasma concentration ratio. The tissue/plasma imirestat concentration ratio in the adrenals 24 hr after imirestat administration was 56.9 +/- 20.0 in the imirestat group, 17.7 +/- 1.27 in the statil-coadministered group, and 12.3 +/- 2.59 in the AL3152-coadministered group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldehyde Reductase↗
PubMed1991

Dose-dependent pharmacokinetics of the aldose reductase inhibitor imirestat in man.

The pharmacokinetics of imirestat were studied in healthy volunteers following single and multiple oral doses. After single doses of 20 to 50 mg, imirestat plasma concentrations declined with an apparent elimination half-life of 50 to 70 hr over the 168 hr in which levels were measured. However, with lower doses (2 to 10 mg), an initial rapid decline in drug concentration was followed by a very slow terminal elimination phase with plasma concentrations decreasing little over the 1 week of sampling. This resulted in a decrease in apparent t 1/2 with increasing dose, from 272 +/- 138 hr at 2 mg to 66 +/- 30 hr at 50 mg. During once-daily dosing of 2 to 20 mg/day for 4 weeks, mean steady-state imirestat concentration appeared to be dose proportional, although the time required to achieve steady state decreased with increasing dose. The mean effective half-life for accumulation ranged from 54 to 98 hr, suggesting that the very slow elimination of drug at low concentrations did not produce disproportionate accumulation of drug at these doses. Mean oral clearance was independent of dose, ranging from 30 to 45 ml/min. At the 2-, 5-, and 20-mg doses, one subject in each group had steady-state concentrations two- to fourfold greater than any of the other five subjects at the same dose, although the reason for this was not apparent from these data. The overall kinetic profile of these data was suggestive of dose-dependent pharmacokinetics resulting from nonlinear tissue binding of imirestat.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Disposition of drugs in cystic fibrosis. III. Acetaminophen.

The disposition of acetaminophen after oral administration was investigated in adults with cystic fibrosis (n = 5) and in age-matched healthy control subjects (n = 5). The total plasma clearance of acetaminophen was found to be greater (p less than 0.025) in subjects with cystic fibrosis (0.362 +/- 0.081 L/hr/kg) than in control subjects (0.247 +/- 0.022 L/hr/kg). This difference in clearance was found to be primarily attributable to a greater metabolic clearance of acetaminophen to acetaminophen sulfate (0.080 +/- 0.023 L/hr/kg for subjects with cystic fibrosis and 0.045 +/- 0.008 L/hr/kg for control subjects; p less than 0.05) and to a greater metabolic clearance of acetaminophen to acetaminophen glucuronide (0.189 +/- 0.051 L/hr/kg for subjects with cystic fibrosis and 0.114 +/- 0.017 L/hr/kg for control subjects; p less than 0.05) in persons with cystic fibrosis. Of the mechanisms that may be responsible for these differences, the most likely is enhanced activity (in subjects with cystic fibrosis) of the transferases that mediate the metabolism of acetaminophen to acetaminophen sulfate and acetaminophen glucuronide, respectively.

Acetaminophen↗
PubMed1991

Inhibition of the metabolism of paracetamol by isoniazid.

1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non-oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre-isoniazid values.

Acetaminophen↗
PubMed1991

Age-dependent morphine partitioning between plasma and cerebrospinal fluid in monkeys.

Steady-state partitioning of morphine between blood and cerebrospinal fluid (CSF) was evaluated in pigtailed monkeys at three ages: 2-3 days, 1 month and 1 year. Protein binding of morphine to serum proteins was assessed by ultrafiltration. Newborns showed a higher CSF to plasma ratio than the 1-month- or 1-year-old monkeys (0.506 vs. 0.369 or 0.374, respectively). Protein binding of morphine was 11% in newborns, and 17% at 1 year of age, not explaining the increased morphine penetration into CSF in newborns. Increased CSF morphine is a transient finding in infant macaques, which appears to reach young adult values by 1 month of age.

Aging↗
PubMed1991

Pharmacokinetics and pharmacodynamics of morphine in infant monkeys.

We report the pharmacokinetics of morphine administered as intravenous boluses in newborn (less than 7 days) and 3- to 4-month-old macaque monkeys. Morphine was administered in a series of bolus doses until PaCO2 was elevated greater than 50 mm Hg. In newborns less than 7 days of age, a mean dose of 1.4 mg/kg was required (range 0.75-2.8 mg/kg), and in the 3-month-olds, a mean dose of 1.88 mg/kg was required (range 1.5-2.5 mg/kg). The respiratory effects measured by PaCO2 and respiratory rate did not correlate with declining serum or cerebrospinal fluid morphine levels. Both newborn and 3- to 4-month-old macaque monkeys show only mild respiratory depression after intravenous morphine, at serum concentrations as high as 300-400 ng/ml. Infant and young macaque monkeys appear to be less sensitive to the respiratory depressant effect of morphine than humans.

Aging↗
PubMed1990

Effect of methylxanthines on acetaminophen hepatotoxicity in various induction states.

The effect of caffeine, theophylline and theobromine on acetaminophen-induced hepatotoxicity was evaluated in uninduced, 3-methylcholanthrene- and phenobarbital-induced adult male Sprague-Dawley rats. The methylxanthines themselves did not cause hepatotoxicity in any induction state. In 3-methylcholanthrene-induced rats, each methylxanthine afforded protection (in varying degrees) against acetaminophen-induced hepatotoxicity as reflected by serum alanine aminotransferase and liver histopathology determined 24 hr after acetaminophen administration. However, in phenobarbital-induced rats, caffeine and theophylline substantially potentiated the hepatotoxicity of acetaminophen whereas theobromine had no effect. Hepatic glutathione (GSH) was determined in rats that received caffeine 4 hr after acetaminophen or vehicle. Acetaminophen alone substantially depleted hepatic GSH in each induction state, whereas caffeine depleted hepatic GSH in uninduced and phenobarbital-induced, but not in 3-methylcholanthrene-induced rats. In rats that received both caffeine and acetaminophen together, hepatic GSH depletion was greater than in rats that received acetaminophen only. The effect of caffeine on hepatic GSH is most likely due to a decrease in core body temperature. The most likely mechanisms for the effects observed are 1) inhibition of acetaminophen reactive metabolite formation in 3-methylcholanthrene-induced animals by each of the methylxanthines, and 2) activation of the phenobarbital-inducible forms of cytochrome(s) P-450 toward formation of acetaminophen reactive metabolites by caffeine and theophylline, but not theobromine.

Acetaminophen↗
PubMed1990

Menthofuran-dependent and independent aspects of pulegone hepatotoxicity: roles of glutathione.

Pulegone, a monoterpene that protects source plants against predators, is a hepatotoxic constituent of the folklore abortifacient pennyroyal oil. In the rat, pulegone extensively depleted glutathione measured in both liver tissue and plasma, and its toxicity was markedly enhanced in animals treated with buthionine sulfoximine. The glutathione-depleting effect of pulegone was compromised following inhibition of cytochrome P-450 by piperonyl butoxide. In addition, we found no evidence for conjugation of glutathione to unchanged pulegone in vitro. Administration of menthofuran, a known oxidative and hepatotoxic metabolite of pulegone, only marginally affected glutathione levels in plasma and liver, and toxicity was not augmented by buthionine sulfoximine. These results provide indirect evidence for cytochrome P-450-catalyzed bioactivation of pulegone via at least two independent pathways: 1) the formation and subsequent activation of menthofuran from pulegone; and 2) the formation of reactive intermediate(s) from pulegone, but not menthofuran, which can be detoxified through a mechanism requiring reduced glutathione.

Animals↗
PubMed1989

Effect of ethanol on hepatotoxicity of acetaminophen in mice and on reactive metabolite formation by mouse and human liver microsomes.

The protective effect of a single dose of ethanol with regard to hepatotoxicity caused by acetaminophen (APAP) can be a consequence of either direct or indirect inhibition of APAP oxidation to its hepatotoxic intermediate (N-acetyl-p-benzoquinoneimine, NAPQI), or augmentation of repair mechanisms following the hepatotoxic insult. The mechanism of hepatoprotection appears to be species dependent. By varying the time of ethanol administration relative to APAP in mice (30 min before to 240 min after APAP), it was shown that ethanol must be administered early relative to APAP for hepatoprotection to be maximized. The role of direct inhibition of cytochrome P450 in the hepatoprotective effect of ethanol was evaluated by comparing the hepatoprotection afforded by ethanol and 4-methylpyrazole (4-MP) in vivo to the inhibition of APAP oxidation to NAPQI caused by each in mouse liver microsomes. At their respective peak in vivo concentrations attained following hepatoprotective doses, both ethanol and 4-MP inhibited the oxidation of APAP in microsomes by 25-30%. This result suggests that direct inhibition of cytochrome P450 by ethanol plays a role in the protection against acetaminophen-induced hepatotoxicity in mice. In human liver microsomes the inhibition of APAP oxidation to the hepatotoxic intermediate by 48 mM ethanol is less than half of the apparent inhibition of APAP oxidation reported in clinical studies in which the maximum ethanol concentration would have been 15-20 mM. Thus, in contrast to the mouse, inhibition of APAP oxidation to NAPQI in humans appears to be largely indirect, as has been reported previously in the rat.

Acetaminophen↗
PubMed1989

Lack of effect of cimetidine on acetaminophen disposition in humans.

The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N-Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3-hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect.

Acetaminophen↗
PubMed1989

Acetylcholine receptor density and acetylcholinesterase activity in skeletal muscle of rats following thermal injury.

Thermal injury causes systemic changes that result in altered sensitivity to many drugs including nondepolarizing muscle relaxants. In an effort to identify the mechanism(s) responsible for the resistance to nondepolarizing muscle relaxants, the density of acetylcholine receptors (AChR) and the activity of acetylcholinesterase (AChE) were determined in rats following a 30% total body surface thermal injury at a time when resistance to atracurium is maximum. AChR density in gastrocnemius and diaphragm was unchanged by thermal injury. Furthermore, the ratio of junctional to extrajunctional AChR in diaphragm was unaltered. Total AChE activity was unchanged in thermally injured rats compared with that in sham-injured animals. Separation of the molecular forms of AChE by sucrose gradient centrifugation also showed no changes in the relative proportions of these species. The mechanism of resistance to nondepolarizing muscle relaxants does not appear to be explained by changes in AChR number or changes in the activity of AChE.

Acetylcholinesterase↗
PubMed1989

Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atracurium in humans.

Thermal injury causes resistance to many nondepolarizing muscle relaxants including d-tubocurarine, metocurine, pancuronium, and atracurium. To evaluate the role of pharmacokinetics and pharmacodynamics in this phenomenon, the disposition and effect of atracurium (0.5 mg/kg iv) were studied in thermally injured patients (5 males, 16-43 yr) in comparison with that in nonburned control patients (3 males, 1 female, 24-53 yr). The decline of plasma atracurium concentration with time was biexponential in both groups of patients. There were no significant differences in the mean value of any pharmacokinetic parameter (clearance, V1, V beta, alpha and beta half-lives). The time course of effect was also similar, although the maximum twitch depression was significantly smaller (66.1% vs. 100% maximal twitch depression) and time to recover to 50% of maximal twitch depression was significantly shorter (14.2 vs. 52 min) in thermally injured patients. Patients with thermal injury had an EC50 (plasma concentration of atracurium required for 50% of the maximum possible response) 3.4 times that of control patients. Plasma-free fraction of atracurium in the thermally injured patients was 75% that in controls, and free EC50 (the product of free fraction and EC50) of the thermally injured group was 2.7 times that of controls. The results of this study confirm a pharmacodynamic mechanism for the majority of resistance to atracurium, with a diminished free fraction in plasma also contributing to this effect.

Adolescent↗
PubMed1989

In vitro evaluation of the determinants of bactericidal activity of ampicillin dosing regimens against Escherichia coli.

An in vitro flow model was used to examine the influence of peak concentration (Cmax), the area under the antibiotic concentration-time curve (AUC), the magnitude of AUC above the MIC, and the aggregate time the antibiotic concentration exceeds the MIC (TMIC) on the bactericidal effect of ampicillin against Escherichia coli ATCC 12407. Bacteria in the log phase were exposed to therapeutically realistic drug regimens. Ampicillin concentration and bacterial density (CFU per milliliter) were measured over time. Four parameters reflecting bactericidal activity were quantitated: difference between initial and minimum and initial and final bacterial densities, area under the bacterial density-time curve, and a fourth parameter, sigma, which is a function of these three. Multiple regression analysis confirmed AUC as the major factor in predicting bactericidal activity. An AUC of greater than 70 micrograms.h/ml correlated with the lack of emergence of resistance.

Ampicillin↗
PubMed1979

Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin.

The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.

Adult↗
PubMed1979

Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin.

The purpose of this investigation was to determine whether the anti-inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.

Adult↗