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Biomedical subjects

J Nicoletti

Publications and source records attributed to J Nicoletti.

8 recordsLinked to original sources
PubMed1997

Biotransformation of clozapine in humans.

The metabolic pathways of clozapine (CZ, Clozaril (Novartis Pharmaceuticals Corporation, East Hanover, NJ), 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b,e][1,4]diazepine, a tricyclic benzodiazepine neuroleptic which has a reduced risk of unwanted neurological effects, were determined in normal male volunteers after a single oral dose of 50 mg of [14C]CZ. There was no radio-activity in exhaled breath, and excretion of total radioactivity was approximately 50% in urine and 30% in feces; parent CZ was a minor component in the excreta. The metabolic profiles were determined in urine and feces using HPLC coupled with radioactivity monitoring. The major metabolic pathways were demethylation, oxidation of the aromatic ring in the 7- and 8-positions, and conjugation. The major urinary components were 8-hydroxy-deschloro-DCZ (desmethylCZ) and its glucuronide, 7-hydroxy-8-chloro-DCZ sulfate and CZ-NO (clozapine N-oxide). Minor amounts of CZ, 7-hydroxy-8-chloro-CZ glucuronide and DCZ were also present. In feces the major component was CZ-N-glucuronide. Urinary excretion of CZ-NO was more rapid than the products of aromatic ring hydroxylation and conjugation.

Adult↗
PubMed1995

Metabolic pathways of 4-[(3-methoxyphenyl)methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride, a silicon-containing xenobiotic, in rat, dog, and man.

1. The metabolic pathways of Sandoz compound 58-112, 4-[(3-methyoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane (MPSC) hydrochloride were evaluated in rat, dog, and man after a single oral dose. 2. In rat, dog and man the major route of elimination was renal. In the dog, renal excretion of unchanged MPSC represented a substantial portion of the dose whereas in rat and man MPSC was completely metabolized prior to excretion. 3. In rat and man, the major end-product metabolite was 3'-[((hydroxydimethylsilyl)-methylamino)methyl]-phenol glucuronide; 4-[(3-hydroxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2,6- disilacyclohexane and 4-[(4-hydroxy-3-methoxyphenyl)-methyl]-2,2,6,6-tetramethyl-1-oxa-4-aza-2 ,6- disilacyclohexane and their conjugates were also present. In dog, the major end-product metabolites were the hippurate of 3-methoxybenzoic acid and 3-hydroxybenzoic acid.

Animals↗
PubMed1987

Metabolism of three trichothecene mycotoxins, T-2 toxin, diacetoxyscirpenol and deoxynivalenol, by bovine rumen microorganisms.

The three trichothecene mycotoxins T-2 toxin, diacetoxyscirpenol (DAS) and deoxynivalenol (DON) were incubated in vitro for 12, 24 and 48 h with rumen microorganisms obtained from a fistulated dairy cow. Gas chromatographic and gas chromatographic-mass spectrometric analyses of extracts indicated all three toxins were biotransformed to a variety of deepoxy and deacylated products. DON was partially converted to a product identified as deepoxy DON. DAS was rapidly converted to four products including 15-monoacetoxyscirpenol (MAS), scirpentriol and two new compounds identified as 15-acetoxy-3 alpha,4 beta-dihydroxytrichothec-9,12-diene (deepoxy MAS) and 3 alpha,4 beta,15-trihydroxytrichothec-9,12-diene (deepoxy scirpentriol). T-2 toxin was also completely biotransformed to the products HT-2, T-2 triol and two new metabolites identified as 15-acetoxy-3 alpha,4 beta-dihydroxy-8 alpha-(3-methylbutyryloxy) trichothec-9,12-diene (deepoxy HT-2) and 3 alpha,4 beta,15-trihydroxy-8 alpha-(3-methylbutyryloxy)trichothec-9,12-diene (deepoxy T-2 triol).

Animals↗
PubMed1981

Anxiolytic effects of low dosage nitrous oxide-oxygen mixtures administered continuously in apprehensive subjects.

We observed the effect of low doses of nitrous oxide on the cardiovascular and respiratory systems, the cortisol output in blood and saliva, and the degree of sedation and analgesia of 20 volunteers. A psychologic screening inventory was also performed. We found nitrous oxide, at low dosage, to be primarily an anxiolytic and not an analgesic or amnesic agent. The nasally inhaled concentrations necessary to induce an anxiolytic effect varied from subject to subject, ranging from 30% to 65% and averaging 35% to 40%. This finding justifies the use of the gas to relieve anxiety instead of nonvolatile parenterally administered psychosedatives and narcotics. Nitrous oxide is preferable because its action is established within several minutes, it is rapidly eliminated at the conclusion of a procedure, and the sensorium is clear after five or six minutes. The gas is simply and safely administered with fail-safe apparatus designed specifically for this purpose. The technic is admirably suited for use in ambulatory care units where minor surgical or dental procedures are performed.

Adolescent↗
PubMed1975

A community-oriented program for training and using volunteers.

Eleven women volunteers from the Arvada, Colorado, community were provided intensive training in communication and other variables related to effective functioning in a community mental health center. Volunteers were then provided various placements within the center. Results indicated that the volunteers' communication effectiveness levels increased significantly from pretest to posttest and as compared to a control group of students going through a mental health program. Volunteers also received favorable evaluation rating from their practicum supervisors. The paper will discuss the procedures, benefits, and considerations involved in developing and utilizing volunteers.

Adult↗
PubMedDate not supplied

Disposition of fluvastatin, an inhibitor of HMG-COA reductase, in mouse, rat, dog, and monkey.

The physiological disposition of fluvastatin, a potent inhibitor of hydroxymethylglutaryl-CoA reductase and thus cholesterol synthesis, has been studied in the mouse, rat, dog, and monkey using 14C- or 3H-labeled drug. Oral doses of fluvastatin were absorbed at a moderate to rapid rate. The extent of absorption was dose-independent and was essentially complete in all four species studied. However, the drug was subject to extensive presystemic hepatic extraction followed by direct excretion via the bile, thus minimizing the systemic burden and yielding high liver/peripheral tissue concentration gradients for fluvastatin and its metabolites. Only at high doses far exceeding the intended human daily dose of ca 0.6 mg kg-1 did fluvastatin bioavailability approach unity, apparently due to saturation of the first-pass effect. Dose-normalized blood levels of fluvastatin and total radioactivity were higher in the dog than in the other species, suggesting a smaller distribution volume in the former. Fluvastatin was partially metabolized before excretion, the extent of metabolism being smallest in the dog and greatest in the mouse. The half-life of intact fluvastatin ranged from 1-2h in the monkey to 4-7h in the dog. Regardless of the dose or dose route, the administered radioactivity was recovered predominantly in feces, with the renal route accounting for less than 8 per cent of the dose. No tissue retention of radioactivity was observed, and material balance was essentially achieved within 96h after dosing.

Administration, Oral↗
PubMedDate not supplied

Biotransformation of fluvastatin sodium in humans.

The metabolic pathways of fluvastatin sodium (FV; Lescol, Sandoz compound XU 62-320), [R*,S*-(E)]-(+-)-sodium-3,5-dihydroxy-7-[3- (4-fluorophenyl)-1-(1-methylethyl)-1H-indole-2-yl]-hept-6-enoate, a potent inhibitor of hydroxy-methylglutaryl-CoA reductase (HMG-CoA reductase)--the rate-limiting enzyme in cholesterol biosynthesis--were determined in normal male volunteers at steady state. The metabolite profiles were determined in pooled human blood/plasma, urine, and feces obtained from healthy male volunteers after a single dose of 2 and 10 mg of [3H]FV and at steady state after a single 40 mg daily dose of [3H]FV for 6 sequential days utilizing HPLC coupled with radioactivity monitoring. The two major components in plasma were FV and the desisopropylpropionic acid (4) derivative of FV, the latter a result of oxidative removal of the N-isopropyl group and beta-oxidation of the side chain. Minor amounts of the 4,5-pentenoic acid derivative of FV, the threo-isomer of FV, the trans-lactone of FV, and conjugates of 5-hydroxy FV and 6-hydroxy FV were also present in plasma. Parent FV was not present in feces, the major excretory route, or in urine. In urine, 4 and conjugates of 5-hydroxy FV, and 6-hydroxy FV were present, and each represented < 1% of the dose. In feces 5-hydroxy FV, 6-hydroxy FV, and desisopropyl-FV represented the only peaks of significance. The metabolism of FV leading to the 5-hydroxy FV and 6-hydroxy FV was not stereospecific.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗