Biomedical subjects

J T Slattery

Publications and source records attributed to J T Slattery.

At least 73 records · Page 4Linked to original sources

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↗

PubMed1988

Resistance to atracurium in thermally injured rats. The roles of time, activity, and pharmacodynamics.

Thermal injury induces resistance to nondepolarizing muscle relaxants in patients. Because the mechanism of the resistance is unknown, the authors have sought to establish thermally injured rats as a suitable model for subsequent detailed studies of mechanisms. Two hundred twenty-five- to 250-g rats sustained a 30% total body surface area thermal injury while anesthetized with pentobarbital. Another group had sham injury. Animal activity was monitored both by periods of direct observation and by use of activity cages. At 10, 20, 30, 40, 60, and 90 days after injury, rats were anesthetized and ventilated and the strength of contraction of their gastrocnemius produced by supramaximal stimulation of the sciatic nerve was measured before and after a bolus of atracurium (2.0 mg/kg) was administered. The plasma concentration required to diminish contraction to 50% of the preceding value (Cp50) was determined by atracurium infusion. Animals displayed the greatest resistance to atracurium at 40 days. The Cp50 value was also greatest at this time. The protein binding of atracurium was identical for both sham and injured groups. Activity for thermally injured resistant rats and for sham animals was not different. It appears that pharmacodynamic mechanisms are involved, and inactivity and disuse atrophy are not necessary in rats for development of resistance to nondepolarizing muscle relaxants after thermal injury.

Animals↗

PubMed1988

Percutaneous absorption of retinoids: influence of vehicle, light exposure, and dose.

The percutaneous absorption characteristics of isotretinoin, etretinate, tretinoin, and acitretin were investigated in vitro to assess the feasibility of their topical application for dermatological disorders. The influence of vehicle, photodegradation, and dose was examined. Retinoid absorption through monkey skin was highly vehicle dependent and followed the order: propylene glycol = isopropyl alcohol greater than mineral oil greater than diisopropyl adipate greater than polyethylene glycol 400. Peak flux of etretinate (an ester) was less than 50% that of the acid retinoids in both human and monkey skin. Exposure to light caused a 60% degradation of isotretinoin on the surface of the skin, but did not change the amount of drug which penetrated the epidermis. In accord with this result, the amount of isotretinoin and acitretin which penetrated epidermis did not increase in proportion to dose over a 25-fold range of dose in human skin. Dermal concentration at doses of 10 micrograms/cm2 of isotretinoin and acitretin were greater than that reported for shave biopsies of human skin following treatment for several months with clinically effective doses of isotretinoin and etretinate (the parent ester of the acid acitretin).

Absorption↗

PubMed1988

Contribution of menthofuran to the hepatotoxicity of pulegone: assessment based on matched area under the curve and on matched time course.

In recent years it has become increasingly evident that the toxicity produced by a variety of compounds can be attributed to their metabolites. Simple dose-toxicity studies of a metabolite will help to elucidate its toxic effect, but it is not possible to quantify its role in the toxicity produced by the parent compound unless the disposition of the preformed and endogenously formed metabolite is taken into account. We assessed the contribution of the metabolite, R-(+)-menthofuran (MF), to the hepatotoxicity observed after i.p. administration of R-(+)-pulegone (PUL) to rats. As the major constituent of pennyroyal oil, PUL has been linked to the deaths of several young women over the past several years. After i.p. administration of PUL and MF to separate groups of rats at doses selected to match the area under the curve of generated and synthetic MF, plasma alanine transferase was comparable between groups. Although the area under the curve was matched, the peak concentration in plasma of MF formed in vivo is 4.5 times higher and occurs much earlier than after the administration of MF itself. When the exposure of rats to preformed and synthetic MF is matched with respect to time course in plasma, PUL produces more than twice the increase in plasma alanine transferase and hepatocellular necrosis than does MF. The results suggest that events other than those associated with the disposition of MF contribute to the hepatotoxicity observed after ingestion of PUL, and they emphasize the importance of time course in assessing the role of a metabolite in the toxicity of a given compound.

Alanine Transaminase↗

PubMed1988

Mechanism by which ethanol diminishes the hepatotoxicity of acetaminophen.

The effect of 5 mM ethanol, maintained by a constant infusion, on the hepatotoxicity and disposition of acetaminophen was examined in 3-methylcholanthrene-induced rats. Ethanol infusion, which began 1 hr before acetaminophen and was maintained for 9 hr, resulted in a 2.8-fold higher hepatic glutathione concentration 6 hr after acetaminophen than did saline infusion. Ethanol infusion also diminished the rise in the 24 hr postacetaminophen plasma alanine transferase concentration by approximately 46%. Ethanol (5 mM) had only a modest effect on the oxidation of acetaminophen in rat liver microsomes, 7 to 14% inhibition over a range of acetaminophen concentration of 0.1 to 3 mM, whereas a 30 to 40% decline of covalent binding of acetaminophen-derived material was observed in vivo (peak acetaminophen concentration approximately 3 mM). Thus, a mechanism other than direct inhibition of cytochrome(s) P-450 by ethanol is invoked to account for the protective effect of ethanol. Ethanol infusion increased the ratio of total hepatocellular NADH/NAD+, and the ratio of free NADH/NAD+ in cytosol and mitochondria as a consequence of sequential oxidations of ethanol producing acetaldehyde and acetic acid in the respective compartments. The toxic electrophile produced by cytochrome P-450 oxidation of acetaminophen, N-acetyl-p-benzoquinoneimine, is reduced rapidly by NADH in aqueous solution. However, acetaminophen alone also increased free NADH/NAD+ in cytosol, and there was no indication that N-acetyl-p-benzoquinoneimine consumed NADH generated by the oxidation of ethanol. Ethanol infusion also increased the ratio of total hepatocellular NADPH/NADP+, apparently through transhydrogenation of NADP+ by NADH in mitochondria.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1987

Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans.

The time course of excretion of acetaminophen and its metabolites in urine was determined in eight healthy adults (seven men and one woman) who ingested 1 gm of the drug and collected timed urine samples for 24 hours. The mean time of peak excretion rate was 1.3 to 3.7 hours for acetaminophen, its glucuronide, sulfate, cysteine, mercapturate, and methoxy metabolites but 13.5 hours for methylthioacetaminophen. The mean half-life of acetaminophen was 3.1 hours and the mean half-life of the metabolites other than methylthioacetaminophen ranged from 4.1 to 5.7 hours. The half-life of methylthiometabolite could not be determined because of its very late peak time. In a second study the effect of dose on the clearance of acetaminophen was determined in nine healthy adult subjects (eight men and one woman) who received doses of 0.5 and 3 gm acetaminophen on separate occasions, separated by 4 to 10 days. The renal clearance of acetaminophen and the formation clearances of the sulfate, glutathione, and catechol metabolites were lower (by 38%, 41%, 35%, and 46%, respectively) at the higher dose. The renal clearance of acetaminophen sulfate and glucuronide conjugates were not different between doses. In a third study (10 men), 10 gm N-acetylcysteine was found to increase the formation clearance of the sulfate conjugate by 27% and that of the glutathione conjugate by 10%. The data suggest that the hepatic supply of reduced glutathione and 3'-phosphoadenosine 5'-phosphosulfate begins to be depleted over the range of 0.5 to 3 gm acetaminophen and that the depletion is overcome by the administration of N-acetylcysteine.

Acetaminophen↗

PubMed1987

Propranolol reduces bupivacaine clearance.

Propranolol reduces the clearance of lidocaine by both reducing hepatic blood flow and inhibiting lidocaine metabolism. The authors investigated the possibility that propranolol reduces the clearance of bupivacaine as well. Bupivacaine, 30-50 mg, was administered intravenously to six normal human volunteers, over 10-15 min on two occasions, at least 2 weeks apart. Propranolol, 40 mg orally every 6 h, was used on one occasion, beginning 24 h prior to the bupivacaine administration. The sequence of the sessions was randomized. Twenty-two venous blood samples were obtained over 36 h in order to determine bupivacaine clearance, terminal elimination rate constant, and volume of distribution. All subjects experienced mild CNS toxicity, consisting of tinnitus, facial tingling, or subtle visual disturbances, associated with peak venous plasma concentrations of 0.81 to 2.7 micrograms/ml. Mean bupivacaine clearance was 0.33 +/- 0.12 l/min for the control session and 0.21 +/- 0.12 l/min during propranolol use, a significant 35% reduction (P less than 0.01). The terminal elimination rate constant (beta) was 0.27 +/- 0.16 h-1 for the control session and 0.14 +/- 0.069 h-1 with propranolol (P less than 0.05); terminal elimination half-lives were 2.6 and 4.9 h, respectively. Volume of distribution was unchanged. Because bupivacaine clearance should be relatively insensitive to hepatic perfusion, it appeared that propranolol caused a substantial inhibition of bupivacaine metabolism at the level of the hepatocyte. These data suggest that concomitant use of propranolol could result in the accumulation of a toxic concentration of bupivacaine.

Adult↗

PubMed1987

Morphine pharmacokinetics in early infancy.

The pharmacokinetics of morphine in ten infants less than or equal to 10 weeks of age who were receiving morphine infusions were determined. Infants 1-4 days of age (newborns) showed longer elimination half-lives than the older infants (6.8 vs. 3.9 h). Clearance in the newborns is less than one-half that found in older infants (6.3 vs. 23.8 ml X min-1 X kg-1). The combination of lower clearance and longer elimination half-life in newborns (0-7 days) may well explain a prolonged duration of action for morphine in very young infants, but other etiologies are needed to explain the respiratory sensitivity believed to persist in older infants.

Female↗

PubMed1987

Correction for bacterial loss in in vitro dilution models.

A new method to correct for bacteria lost to dilution in in vitro kinetic models is presented which includes the influence of the stationary bacterial growth phase. The method imposes an upper limit on bacterial density, in contrast to previous methods.

Bacteria↗

PubMed1986

Pharmacokinetics of ethanol in pigtailed macaques: intersubject variability and effect of subchronic administration.

The pharmacokinetics of IV ethanol (0.6 g/kg) were examined in 11 male colony-bred pigtailed macaques (Macaca nemestrina) aged 3 to 13 years. The animals were either chaired during blood sampling (4 hr) or connected to a tether system that allowed injections and blood sampling while the animal moved freely about its cage. In all instances, ethanol pharmacokinetics could be described by a single Michaelis-Menten function; inclusion of a parallel first-order rate constant to account for non-alcohol dehydrogenase elimination of ethanol did not improve the fit. Volume of distribution was 0.802 +/- 0.054 L/kg (mean +/- SD), Km (the apparent in vivo Michaelis constant) was 0.063 +/- 0.022 micrograms/ml, and Vmax was 0.199 +/- 0.039 g/kg/hr. The pharmacokinetic parameter values of chaired and tethered monkeys did not differ. Three of the tethered monkeys received 3 g/kg of ethanol daily for two weeks by IV infusion (subchronic administration). Ethanol pharmacokinetics, determined on five occasions before and five occasions after subchronic ethanol administration, showed that the treatment did not alter the volume of distribution or Km in any of the three monkeys. The value of Vmax increased approximately 23% in one of the three monkeys that received subchronic ethanol; this increase may have been due to a single, inadvertent administration of a 4.5-g/kg dose over a 20-min period. Vmax did not change in the other two monkeys.

Animals↗

PubMed1986

Effects of food, mild stress, and distributed intake on the absorption and plasma concentration-time profile of orally ingested ethanol in pigtailed macaques.

To evaluate the possibility of estimating ethanol plasma level from a record of voluntary intake, the effects of food, mild stress, and distributed dosing on the fraction of ethanol absorbed and the relative exposure to circulating blood ethanol were determined in four adult male pigtailed macaques (Macaca nemestrina). The animals received 0.6 g/kg ethanol IV and orally after an 18-hour fast, after a small meal, and under mild stress; distributed dosing was evaluated for the oral route only. The concentration-time profile for the oral/fasting condition was very similar to that following an IV dose. The dose was completely absorbed and peak plasma level occurred about 30 min after ingestion. Peak plasma concentration was reduced by 42% following a small meal, 29% following mild stress, and 18% following distribution of the dose over 60 min. The time to peak concentration was more than doubled by distributed dosing. Relative exposure was reduced by 18 to 27% by all conditions of oral administration except feeding, which caused a 52% reduction. The fraction of ethanol absorbed was influenced only by feeding, which caused a reduction of 20%. The magnitude of changes in concentration-time profile produced by such factors precludes accurate estimation of blood levels from records of voluntary intake. Furthermore, the effects of social factors on voluntary ethanol consumption may be mediated by centrally controlled changes in gastrointestinal function that alter the rate and extent of absorption of the drug.

Animals↗

PubMed1985

Analysis of oxidized and reduced pyridine dinucleotides in rat liver by high-performance liquid chromatography.

NADP+, NAD+, NADPH, and NADH were assayed by selective extraction and isocratic reversephase HPLC. Sample preparation involves freeze clamping and powdering liver under liquid nitrogen, extraction of dinucleotides with basic (reduced species) or acidic (oxidized species) cold ethanol, and injection onto the HPLC for quantitation at 340 nm (reduced) and 254 nm (oxidized). The mobile phase for the oxidized species is pH 5.25, 0.2 M ammonium phosphate/methanol, and for the reduced species is pH 6.0, 0.2 M ammonium phosphate/methanol/tributylamine. The method is linear over the range 0.016 to 2.0 nmol for the reduced species, and from 0.005 to 0.8 nmol for the oxidized pyridine dinucleotides. The recoveries were from 94.5% for NAD+ to 99.3% for NADPH, with standard deviations of approximately 2.5% for all species other than NADP+, which had a standard deviation of 10.4%. The coefficients of variation for repeated determinations of standards over 3 months were less than 4%.

Animals↗