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Biomedical subjects

J T Slattery

Publications and source records attributed to J T Slattery.

At least 55 records · Page 3Linked to original sources
PubMed1996

Teratogenicity of carbamazepine-10, 11-epoxide and oxcarbazepine in the SWV mouse.

The mechanism of carbamazepine (CBZ)-related teratogenicity was investigated in the SWV mouse by contrasting the effects of CBZ-10, 11-epoxide (CBZE) and oxcarbazepine (OXC) treatments. Dietary CBZE administration was initiated 2 weeks before mating and continued through day 18 of gestation. OXC was administered to pregnant dams by gavage on day 6 of gestation and continued through day 18 of gestation. Maternal plasma concentrations of CBZE ranged from 1.4 to 17.7 micrograms/ml and OXC ranged from 6.1 to 15.9 micrograms/ml. In comparison, clinical plasma concentrations of CBZE ranged from 1 to 2 micrograms/ml and OXC plasma concentrations were 1 microgram/ml or less. The incidence of malformation were 14%, 27% and 26% after daily CBZE doses of 300, 600 and 1000 mg/kg, respectively, compared with a 6% incidence in no-drug control mice, P < .05. The incidence of malformation was 8% after exposure at the highest tolerable dose of OXC (1100 mg/kg/day), compared with a 5% incidence in no-drug controls, P > .05. Phenobarbital cotreatment (45 mg/kg/day) with OXC (1100 mg/kg/day) did not lead to changes in the incidence of malformation when compared with OXC (1100 mg/kg/day) dosed alone. These data are consistent with a teratogenic CBZ metabolite, possibly CBZE, or with oxidation of CBZE or CBZ at positions on the aromatic ring leading to the formation of reactive intermediates such as arene oxides or quinones.

Animals↗
PubMed1995

Effect of treatment with phenobarbital and stiripentol on carbamazepine-induced teratogenicity and reactive metabolite formation.

A model using SWV mice was developed to investigate the mechanistic basis of carbamazepine (CBZ)-related fetotoxicity. Drug administration was initiated prior to conception and continued until day 18 of gestation. The incidence of malformation was 33% following CBZ exposure (1,500 mg/kg/day), compared with a 5% incidence in pair-fed control animals (P < 0.05). Coadministration of nonteratogenic doses of phenobarbital (PB; a cytochrome P-450 inducer) (45 mg/kg/day) and CBZ (1,000 mg/kg/day) increased the frequency of malformation from 10% to 26% (P < 0.05), compared with mice dosed with CBZ alone (1,000 mg/kg/day). Coadministration of stiripentol (STP; a cytochrome P-450 inhibitor) (300 mg/kg/day) decreased the incidence of malformations produced by CBZ (1,500 mg/kg/day) from 33% to 16.7% (P < 0.05). The effect of PB administration on the binding of 14C in maternal and fetal tissue was assessed in dams that received CBZ (1,000 mg/kg/day) with or without PB (45 mg/kg/day) or STP (300 mg/kg/day) chronically and a single i.p. dose of 14C-CBZ on day 12 of gestation. In all instances, binding was greatest in maternal liver, then in the placenta, fetal head and body, and maternal thigh muscle. In all tissues, PB caused a two-to threefold increase in binding, compared with binding in mice exposed to CBZ alone. STP administration decreased protein adduct formation only in maternal liver. The binding of 14C was also assessed in hepatic microsomes prepared from female mice exposed to CBZ and PB or STP as in the in vivo study of 14C binding. The extent of irreversible binding was 67% greater in microsomes prepared from mice pretreated with PB and CBZ than with CBZ alone, while STP resulted in only 21% inhibition of 14C adduct formation (P < 0.05). The results are consistent with the formation of a chemically reactive teratogenic metabolite of CBZ in mice by cytochrome(s) P-450.

Abnormalities, Drug-Induced↗
PubMed1995

Metabolism of dapsone to its hydroxylamine by CYP2E1 in vitro and in vivo.

Dapsone toxicity is putatively initiated by formation of a hydroxylamine metabolite by cytochromes P450. In human liver microsomes, the kinetics of P450-catalyzed N-oxidation of dapsone were biphasic, with the Michaelis-Menten constants of 0.14 +/- 0.05 and 0.004 +/- 0.003 mmol/L and the respective maximum velocities of 1.3 +/- 0.1 and 0.13 +/- 0.04 nmol/mg protein/min (mean +/- SEM). Troleandomycin (40 mumol/L) inhibited hydroxylamine formation at 100 mumol/L dapsone by 50%; diethyldithiocarbamate (150 mumol/L) and tolbutamide (400 mumol/L) inhibited at 5 mumol/L dapsone by 50% and 20%, respectively, suggesting that the low-affinity isozyme is CYP3A4 and the high-affinity isozymes are 2E1 and 2C. Disulfiram, 500 mg, 18 hours before a 100 mg oral dose of dapsone in healthy volunteers, diminished area under the hydroxylamine plasma concentration-time curve by 65%, apparent formation clearance of the hydroxylamine by 71%, and clearance of dapsone by 26%. Disulfiram produced a 78% lower concentration of methemoglobin 8 hours after dapsone.

Adult↗
PubMed1995

Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics.

We have determined the relationships between busulfan average concentration at steady-state and (1) rejection of graft, and (2) regimen-related toxicity, and have evaluated the dependence of busulfan clearance/F on body size and age. Patients received 16-30 mg/kg of busulfan followed by cyclophosphamide in doses of 120, 150, 174, or 200 mg/kg or 8 g/m2 in preparation for autologous, syngeneic or allogeneic grafts varying in compatibility from HLA-matched siblings to HLA-partially-matched unrelated donors. In a multivariate Cox time-to-rejection analysis, only busulfan concentration remained a significant determinant of rejection, P = 0.0154. An average concentration of busulfan at steady-state of at least 200 ng/ml was needed to avoid rejection of a matched-sibling graft, while 600 ng/ml was needed to avoid rejection of HLA-partially-matched related or HLA-matched unrelated donor grafts. The toxicity of the cytoreductive regimen correlated with busulfan average concentration at steady-state (rs = 0.717). Busulfan clearance/F expressed relative to body weight, ideal body weight or surface area declined with age during the first decade of life. Over the entire span of age, the coefficient of variation in clearance/F for all ages was similar when clearance/F was expressed in absolute terms (ml/min) and when adjusted for body surface area; the coefficient of variation was greater for clearance/F when expressed relative to total or ideal body weight. We conclude that busulfan concentration in plasma is an important determinant of graft survival and regimen-related toxicity, and that the variability of busulfan pharmacokinetics with age precludes the use of a fixed dose for all ages and indications.

Adolescent↗
PubMed1994

Phase Ib trial of pentoxifylline and ciprofloxacin in patients treated with interleukin-2 and lymphokine-activated killer cell therapy for metastatic renal cell carcinoma.

The dose of interleukin 2 (IL-2) which can be administered to cancer patients is limited largely by a capillary leak syndrome. Pentoxifylline (PTX) is a methylxanthine which reduces IL-2 toxicity in animals. Ciprofloxacin (Cipro) modifies the metabolism of methylxanthines and, when coadministered with PTX, increases levels of PTX and certain of its metabolites. We conducted a phase Ib trial in patients receiving IL-2 and lymphokine-activated killer cell (LAK) cell therapy for metastatic renal cell carcinoma to identify the maximum tolerated dose of PTX which could be coadministered with Cipro in this setting. Eighteen patients received IL-2 (Roche) by continuous infusion at 6 x 10(6) units/m2/day on days 1-5 and underwent leukapheresis on days 7-9. LAK cells were infused on days 12-14. IL-2 was administered at 2 x 10(6) units/m2/day on days 10-20. Cohorts of patients received PTX at 2.5 (n = 3), 3.1 (n = 6), 3.9 (n = 6), and 4.9 (n = 3) mg/kg by 30 min i.v. infusion every 4 h on days 0-5 and 10-20 and Cipro (500 mg p.o. every 12 h) on days 1-5 and 10-20. Toxicity was compared with that observed in 33 historical control patients who received 37 cycles of an identical regimen of IL-2/LAK without PTX/Cipro. PTX at 2.5-3.9 mg/kg and Cipro were well tolerated. The maximum tolerated dose of PTX was 3.9 mg/kg. Dose-limiting emesis (n = 1) and atrial fibrillation (n = 2) occurred at 4.9 mg/kg and were reversible. Two complete, one partial and one minor, responses were observed. Patients treated with 3.9 mg/kg PTX received 95.0% of the planned dose of IL-2 as compared to 72.8% in the control patients (P < 0.025), primarily due to a lower incidence of azotemia and metabolic acidosis in PTX/Cipro recipients than had been seen in the historical control patients. The results of this study demonstrate that PTX/Cipro can be administered to patients receiving IL-2/LAK without apparent loss of therapeutic efficacy. Moreover, PTX/Cipro recipients exhibited less toxicity than historical controls. Therefore, treatment with PTX/Cipro may allow delivery of higher doses of IL-2, which might induce more responses in IL-2-responsive tumors and regression of tumors unresponsive to conventional doses of IL-2.

Adult↗
PubMed1994

Hepatotoxicity associated with acetaminophen usage in patients receiving multiple drug therapy for tuberculosis.

We report three patients who experienced hepatotoxic reactions in association with acetaminophen ingestion while undergoing treatment for active tuberculosis with isoniazid, rifampin, and other agents. All were young adult women. One patient intentionally took a large amount of acetaminophen and had typical signs and symptoms of acetaminophen overdosage; another took acetaminophen in combination form for a minor upper respiratory illness. She experienced no symptoms. The remaining patient took acetaminophen to ameliorate the symptoms of fever and malaise that were subsequently attributed to tuberculosis. She had the rapid onset of signs and symptoms of isoniazid hepatotoxicity. The patterns of liver function abnormalities were similar: each patient experienced pronounced serum elevations of hepatocellular enzymes with at most only modest rises in those of bilirubin. All antituberculous drugs were withheld until symptoms resolved and laboratory values became normal; then treatment for tuberculosis was resumed without isoniazid and was successfully completed in all three patients. These cases plus similar reports in the literature suggest that isoniazid or rifampin, or both, may potentiate the hepatotoxicity of acetaminophen, perhaps by induction of cytochrome P450 isozymes that oxidize acetaminophen to its toxic metabolites.

Acetaminophen↗
PubMed1993

Oxidation of acetaminophen to N-acetyl-p-aminobenzoquinone imine by human CYP3A4.

We have investigated: (a) the formation of N-acetyl-p-aminobenzoquinone imine (NAPQI) from acetaminophen (APAP) by reconstituted human liver CYP3A4, (b) the kinetics of NAPQI formation in microsomes prepared from four human livers varying in CYP1A2, 2E1 and 3A4 content determined by Western blot analysis, (c) the contribution of CYP3A4 to the total formation of NAPQI from 0.1 mM APAP in human liver microsomes using troleandomycin as a specific inhibitor, and (d) the relationship between the contribution of CYP3A4 to NAPQI formation and relative CYP3A4 content. The Km of CYP3A4 for APAP was found to be approximately 0.15 mM, similar to concentrations observed in humans after therapeutic doses of the drug. The kinetics of formation of NAPQI in human liver microsomes were complex; the lower Km was similar to that found for reconstituted CYP3A4. The contribution of CYP3A4 to total NAPQI formation varied from 1 to 20% among livers, and correlated with the relative CYP3A4 content, r2 = 0.88, P < 0.05. Our findings indicate that CYP3A4, the major P450 isoform in human liver and enterocytes, contributes appreciably to the formation of the cytotoxic metabolite NAPQI at therapeutically relevant concentrations of APAP and suggest that APAP may be a previously unrecognized inhibitor of this enzyme.

Acetaminophen↗
PubMed1993

Comparison of the pharmacokinetics and pharmacodynamics of the aldose reductase inhibitors, AL03152 (RS), AL03802 (R), and AL03803 (S).

The pharmacokinetics of AL03152 (RS) and its enantiomers, AL03802 (R) and AL03803 (S), were studied in the Sprague-Dawley rat following intravenous bolus administration. The enantiomers had differing pharmacokinetic profiles, while the racemic compound exhibited pharmacokinetic parameters approximating the mean values of the individual enantiomers. The total clearance (CLT) values of the two enantiomers were similar, but the intrinsic clearance (Cl(int)) was much greater for the S-enantiomer than for the R-enantiomer. The volume of distribution (Vss) for AL03802 (R) was threefold greater than that for AL03803 (S). The stereoselectivity in Vss could not be totally accounted for by the slight difference in serum protein binding of the isomers and resulted in a difference in the half-lives of the enantiomers. Only the R-isomer exhibited a persistent terminal elimination phase, consistent with more extensive tissue binding than the S-isomer. AL03152 enantiomers were equivalent in potency assessed from in vitro IC50 values toward rat lens aldose reductase and rat kidney L-hexonate dehydrogenase and lens EC50 values in diabetic rats.

Aldehyde Reductase↗
PubMed1993

Inhibition and induction of cytochrome P4502E1-catalyzed oxidation by isoniazid in humans.

We studied the effect of isoniazid administration on the cytochrome P4502E1-catalyzed elimination of chlorzoxazone and acetaminophen. Isoniazid, 300 mg daily, was administered for 7 days to a group of 10 volunteer slow acetylators. Acetaminophen, 500 mg, and chlorzoxazone, 750 mg, were administered on separate occasions before isoniazid, during the period of isoniazid administration, and after the discontinuation of isoniazid. Isoniazid inhibited the clearance of chlorzoxazone by 58%, as assessed from plasma data, and inhibited the formation of acetaminophen thioether metabolites (a measure of the formation of the hepatotoxin N-acetyl-p-benzoquinone imine and catechol oxidative metabolites of acetaminophen, as determined from their recovery in urine, by 63% and 49%, respectively. Two days after the discontinuation of isoniazid, the clearance of chlorzoxazone was increased over the value before isoniazid by 56%. Acetaminophen thioether but not catechol metabolites were increased by 56% 1 day after the discontinuation of isoniazid and had returned to the pre-isoniazid value 3 days after the discontinuation of isoniazid. We conclude that the time course of the interaction with regard to chlorzoxazone elimination and formation is compatible with an inhibition-induction effect of isoniazid on cytochrome P4502E1. The mechanism of this biphasic effect is probably induction by protein stabilization, which results in inhibition of catalytic activity while isoniazid is present.

Acetaminophen↗
PubMed1993

Respiratory effects of intravenous morphine infusions in neonates, infants, and children after cardiac surgery.

We evaluated the respiratory effects of intravenous morphine infusions in 30 patients (2 to 570 days old, mean 155 days) after cardiac surgery. PaCO2 during spontaneous breathing and CO2 response curves during rebreathing were obtained on morphine infusions at drug steady state and during drug washout. Steady state morphine serum levels > 20 ng/mL resulted in hypercarbia (PaCO2 > 55 mm Hg) and depressed CO2 response curve slopes (< 10 mL.min-1.mm Hg ETCO2(-1).kg-1) in 67% and 70% of patients, respectively (P < 0.05, compared to those with levels < 20 ng/mL). During washout, morphine levels more than 15 ng/mL resulted in hypercarbia in 46%, whereas levels less than 15 ng/mL were associated with hypercarbia in 13% (P = 0.025). No age-related differences in respiratory effect were seen in these studies at the same serum morphine level. Careful observation of any patient receiving morphine remains necessary, but neonates and young infants seem to have the same respiratory response to morphine infusions as older infants and children at the same blood level.

Cardiac Surgical Procedures↗
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↗