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Biomedical subjects

J P O'Donnell

Publications and source records attributed to J P O'Donnell.

At least 19 recordsLinked to original sources
PubMed2001

Assessing adult ADHD using a self-report symptom checklist.

The self-ratings of DSM-IV ADHD symptoms by adults reporting a previous ADHD diagnosis were contrasted with ratings by controls matched for age and sex. Adults previously diagnosed with ADHD endorsed significantly more symptoms of inattention and of hyperactivity-impulsivity. Specifically, 13 of the 18 DSM-IV ADHD symptoms were endorsed more frequently by the group previously diagnosed with ADHD than by the control group. Predictive power analysis showed that persons endorsing ADHD symptoms were highly likely to have reported a prior ADHD diagnosis. Finally, the data suggested that the DSM-IV diagnostic criteria of 6 symptoms of inattention or 6 symptoms of hyperactivity-impulsivity could be appropriately applied during adult ADHD assessment.

Adolescent↗
PubMed2000

(R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.

Fluoxetine is one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs) that is marketed worldwide. However, details of its human hepatic metabolism have been speculative and incomplete, possibly due to the sensitivity of analytical techniques and selectivity of specific in vitro probes and reagents used. Studies with (R)-, (S)-, and racemic fluoxetine were undertaken to determine the stereospecific nature of its metabolism and estimate intrinsic clearance contributions of each CYP for fluoxetine N-demethylation. Measurable fluoxetine N-demethylase activity was catalyzed by CYP1A2, -2B6, -2C9, -2C19, -2D6, -3A4, and -3A5. All enzymes catalyzed this reaction for both enantiomers and the racemate, and intrinsic clearance values were similar for the enantiomers for all CYP enzymes except CYP2C9, which demonstrated stereoselectivity for R- over the S-enantiomer. Scaling the intrinsic clearance values for the individual CYP enzymes to estimate contributions of each in human liver microsomes suggested that CYP2D6, CYP2C9, and CYP3A4 contribute the greatest amount of fluoxetine N-demethylation in human liver microsomes. These data were corroborated with the examination of the effects of CYP-specific inhibitors quinidine (CYP2D6), sulfaphenazole (CYP2C9), and ketoconazole (CYP3A4) on fluoxetine N-demethylation in pooled human liver microsomes. Together, these findings suggest a significant role for the polymorphically expressed CYP2D6 in fluoxetine clearance and are consistent with reports on the clinical pharmacokinetics of fluoxetine.

Cytochrome P-450 Enzyme System↗
PubMed1999

Metabolism of CP-195,543, a leukotriene B4 receptor antagonist, in the Long-Evans rat and Cynomolgus monkey.

1. The fate of [14C]CP-195,543, a novel leukotriene B4 receptor antagonist, was studied following oral administration to the Long-Evans rat and Cynomolgus monkey. 2. Most of the radioactivity was primarily excreted in the faeces, and urine was a minor route of excretion. 3. CP-195,543 was extensively metabolized in the two species, primarily by two metabolic pathways: glucuronidation of unchanged CP-195,543 and oxidative metabolism, presumably by cytochrome P450. 4. The sites of glucuronidation were the carboxylic acid moiety and the hydroxy group. The ester glucuronide was the predominant glucuronide conjugate detected in the rat, whereas the monkey generated the ether as well as the ester glucuronide. 5. The structures of oxidative metabolites were elucidated using mass spectrometry (in the positive- and negative-ion mode) and 1H-NMR. The sites of hydroxylation were the benzylic group and the 3-position of the benzopyran ring. 6. This study has indicated that CP-195,543 was mainly eliminated by Phase II metabolism in both species.

Animals↗
PubMed1998

Characterization of polar urinary metabolites by ionspray tandem mass spectrometry following dansylation.

The present report illustrates the application of dansyl chloride coupled with ion spray tandem mass spectrometry (IS-MS/MS) in identifying polar urinary metabolites. In the course of the metabolism studies of a drug that is currently in development, the urine from rats and dogs was collected following oral administration of radiolabelled compound. Urinary metabolic profiles of the rat and dog indicated the presence of four major peaks and one major peak, respectively, in the radiochromatogram. Since all attempts to identify the peaks by conventional MS/MS techniques failed, the metabolites were isolated by fraction collection and dansylated. Derivatization of the metabolites resulted in the formation of more hydrophobic, readily ionizable species which were more sensitive in IS-MS/MS analysis than the underivatized metabolites. Examination of the molecular ions and the product ion mass spectra of these derivatives revealed the structures of all the urinary metabolites. The metabolites in the rat and the dog were 4-hydroxyphenylpiperazine glucuronide (M1), 1,4-dihydroxyphenyl glucuronide (M2), 1,4-dihydroxyphenyl sulfate (M3) and phenylpiperazine (M4). Thus, derivatization with dansyl chloride in conjunction with tandem mass spectrometry is a useful tool in identifying polar urinary metabolites.

Amines↗
PubMed1998

Metabolism of droloxifene in the CD-1 mouse, Fischer-344 rat and cynomolgus monkey.

1. The fate of [14C]droloxifene, a novel non-steroidal anti-oestrogen, was studied following oral administration to the CD-1 mouse, F-344 rat and Cynomolgus monkey. 2. Most of the radioactivity was primarily excreted in the faeces and urine was the minor route of excretion. 3. Droloxifene was extensively metabolized in all three species, primarily by two metabolic pathways; glucuronidation of unchanged droloxifene and oxidative metabolism, presumably by cytochrome P450. 4. In mouse, oxidative metabolism followed by conjugation played a significant role in the elimination of droloxifene. An unusual diglucuronide of 4-hydroxydroloxifene was also identified in this species. 5. In rat, glucuronidation and oxidative metabolism were significant, whereas in monkey glucuronidation of droloxifene was the predominant pathway of elimination.

Administration, Oral↗
PubMed1998

Health plans and state tort liability.

In 1997, Texas enacted legislation expanding state tort liability to health plans. The following article discusses major provisions of the Texas health plan liability law, as well as a recent lawsuit asserting that the statute is preempted by the Employee Retirement Income Security Act and the Federal Employees Health Benefits Act.

Liability, Legal↗
PubMed1994

Construct validity of neuropsychological tests of conceptual and attentional abilities.

In a mixed sample of community-living adults, this study examined the construct validity of five neuropsychological tests: Category Test (CAT), Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Task (PASAT), Visual Search and Attention Test (VSAT) and Trail Making Test: Part B (TMT-B). Principal components analyses showed that PASAT, VSAT, and TMT-B defined an attention factor and that CAT and WCST defined a conceptual factor. The results were discussed in terms of common interpretations of these procedures as well as in terms of Mirsky's (1989) components of attention.

Adolescent↗
PubMed1993

Bioequivalence of two methotrexate formulations in psoriatic and cancer patients.

OBJECTIVE: To compare the bioequivalence of a generic methotrexate (MTX) tablet (Mylan) with that of a brand-name (Lederle) product. DESIGN: A single-dose, randomized, crossover study. SETTING: Clinical Research Center (CRC) at a university hospital. PATIENTS: Men and women who had a diagnosis of malignancy or psoriasis who were at least 21 years old. METHODOLOGY: Two overnight study periods were scheduled at the CRC at least one week, but not more than two weeks apart. Each period consisted of a 10-hour fast prior to and 4 hours following oral MTX 15 mg administered as six 2.5-mg tablets. Blood samples were collected over 48 hours. Plasma MTX concentrations were determined using an HPLC assay. Area under the curve from zero to infinity (AUC0-infinity) was calculated by the log-trapezoidal method. RESULTS: Twenty-two patients (21 psoriasis, 1 colon cancer) aged 23-61 years completed both study periods. Mean values for peak concentration, time to peak concentration, and AUC0-infinity were 0.80 mumol/L, 1.2 hours, and 3.0 mumol.h/L, respectively, for Mylan's MTX tablets and 0.81 mumol/L, 1.4 hours, 3.0 mumol.h/L, respectively, for Lederle's MTX. Normalization for weight or body surface area did not affect interpatient variability. Relative bioavailability of generic MTX was 99.2 percent. Rate and extent of absorption were not significantly different and the confidence intervals were within the range of 80-120 percent required by the Food and Drug Administration. CONCLUSIONS: Mylan's MTX tablet is bioequivalent to Lederle's product.

Adult↗
PubMed1992

Characterization of two forms of cationic peroxidase from cultured peanut cells.

Two forms of cationic peroxidase from peanut cells were differentiated by concanavalin A affinity chromatography. They differed in molecular mass as well as concanavalin A binding, leading to the initial suggestion that they represented two isozymes of peroxidase. However, similar values for the specific activity, Soret absorption, calcium content, and peptide molecular mass were observed for each of the forms. Therefore, the binding and nonbinding fractions most likely represent two molecular forms of cationic peanut peroxidase, rather than two distinct cationic isozymes. The difference between these two forms is discussed in terms of glycosylation. Through the amino acid sequence analysis of the formic acid treated peptide, the cationic isozyme has been shown to be identical in amino acid sequence to the cDNA clone PNC1.

Arachis↗
PubMed1991

Relationship between covalent binding to microsomal protein and the destruction of adrenal cytochrome P-450 by spironolactone.

Previous investigations have demonstrated that guinea pig adrenal microsomes catalyze an NADPH-dependent activation of spironolactone (SL) resulting in the degradation of cytochrome(s) P-450 and decreases in steroidogenic enzyme activities. Studies were done to evaluate the relationship between the destruction of cytochrome P-450 and the covalent binding to microsomal protein by SL and by 7 alpha-thiospironolactone (7 alpha-thio-SL), an obligatory intermediate in the activation pathway. NADPH-dependent irreversible binding to guinea pig adrenal microsomal protein was demonstrable with 22-14C- and with 35S-labelled SL or 7 alpha-thio-SL as substrates. In the absence of NADPH, there was relatively little binding. NADPH-dependent covalent binding was not demonstrable with hepatic microsomal preparations. The amount of covalent binding to adrenal microsomes was far greater with 7 alpha-thio-SL than with SL and also greater with 35S-labelled than with 14C-labelled substrates. The latter results suggest the possibility of more than one reactive metabolite. Time-course experiments revealed a good correlation between covalent binding and P-450 destruction by SL and by 7 alpha-thio-SL. In addition, the 17 alpha-hydroxylase inhibitor, SU-10'603, and the 17 alpha-hydroxylase substrate, progesterone, prevented both the degradation of cytochrome P-450 and the NADPH-dependent covalent binding by 7 alpha-thio-SL. Reduced glutathione also decreased covalent binding but did not diminish P-450 destruction. The latter results indicate that some of the covalent binding is unrelated to the degradation of cytochrome P-450. However, all of the data are consistent with the hypothesis that 7 alpha-thio-SL is a suicide inhibitor of adrenal cytochrome P-450 and that covalent binding to protein is involved in the degradation of cytochrome P-450.

Adrenal Glands↗
PubMed1991

Cosolvency of dimethyl isosorbide for steroid solubility.

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI-PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.

Dexamethasone↗
PubMed1990

A comparison of language deficits in learning-disabled, head-injured, and nondisabled young adults: results from an abbreviated Aphasia Screening Test.

This study used an Aphasia Screening Test (AST) abbreviated to its naming, pronunciation, and sentence interpretation items to compare groups of 60 learning-disabled (LD), 30 head-injured (HI), and 30 nondisabled (ND) young adults matched for FISQ and balanced for gender composition. The LD and HI, who did not differ, made significantly more AST errors than the ND. One-quarter to one-third of the LD and HI subjects exhibited language deficits. For the clinical groups only, AST errors, particularly pronunciation errors, were related negatively to WRAT reading and spelling scores. The Reitan and Wolfson (1988) severity ratings for AST items did not improve group discrimination.

Achievement↗
PubMed1988

Adrenal mitochondrial metabolism of spironolactone. Absence of metabolic activation.

Previous investigations have established that spironolactone (SL) administration to guinea pigs decreases adrenal mitochondrial and microsomal cytochrome P-450 content, and that the latter requires microsomal activation of the drug. Studies were carried out to determine if adrenal mitochondrial metabolism (activation) of SL was similarly involved in the effects of the drug on mitochondrial cytochrome P-450 destruction. Incubation of guinea pig adrenal mitochondria with SL in the absence of NADPH resulted in the formation of 7 alpha-thio-SL as the only metabolite. In the presence of an NADPH-generating system, an unknown polar metabolite was also produced. The mass spectrum of the unknown compound suggested that it was a hydroxylated derivative of SL. Incubation of mitochondrial preparations with 7 alpha-thio-SL also resulted in the formation of a polar metabolite, but the latter had a different HPLC retention time than that of the SL metabolite. Formation of the polar SL metabolite was prevented by metyrapone, an 11 beta-hydroxylase inhibitor, and was greatest in mitochondria from the adrenal zone having the highest 11 beta-hydroxylase activity. Steroid substrates for 11 beta-hydroxylation inhibited the production of the SL metabolite. Mitochondrial incubations with SL or with 7 alpha-thio-SL in the presence or absence of an NADPH-generating system did not affect cytochrome P-450 concentrations. The results indicate that, unlike the microsomal effects of SL, local activation of SL is not responsible for the destruction of adrenal mitochondrial cytochromes P-450. The major adrenal mitochondrial metabolites of SL appear to be 11 beta-hydroxy-SL and 7 alpha-thio-SL.

Adrenal Glands↗