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Biomedical subjects

W J Keller

Publications and source records attributed to W J Keller.

At least 19 recordsLinked to original sources
PubMed2006

Cardiovascular monkey telemetry: sensitivity to detect QT interval prolongation.

INTRODUCTION: Preclinical evaluation of delayed ventricular repolarization manifests electrocardiographically as QT interval prolongation and is routinely used as an indicator of potential risk for pro-arrhythmia (potential to cause Torsades de Pointes) of novel human pharmaceuticals. In accordance with ICH S7A and S7B guidelines we evaluated the sensitivity and validity of the monkey telemetry model as a preclinical predictor of QT interval prolongation in humans. METHODS: Cardiovascular monitoring was conducted for 2 h pre-dose and 24 h post-dosing with Moxifloxacin (MOX), with a toxicokinetic (TK) evaluation in a separate group of monkeys. In both studies, MOX was administered orally by gavage in 0.5% methylcellulose at 0, 10, 30, 100, 175 mg/kg. Each monkey received all 5 doses using a dose-escalation paradigm. Inherent variability of the model was assessed with administration of vehicle alone for 4 days in all 4 monkeys (0.5% methylcellulose in deionized water). RESULTS: MOX had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOX produced significant dose-related increases in QTc at doses of 30 (Cmax=5.5+/-0.6 microM), 100 (Cmax=16.5+/-1.6 microM), and 175 (Cmax=17.3+/-0.7 microM) mg/kg with peak increases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively (p<or=0.05; compared to vehicle). DISCUSSION: In conclusion, we have developed a reproducible, sensitive and reliable primate telemetry model in rhesus monkeys, which exhibits low inherent intra-animal variability and high sensitivity to detect small but significant increases in QT/QTc interval (approximately 4%) with MOX in the same range of therapeutic plasma concentrations attained in humans. Therefore, the primate telemetry model should be considered an important preclinical predictor of QT prolongation of novel human pharmaceuticals.

Algorithms↗
PubMed1995

Identification of 3-hydroxy-3-methylglutaric acid (HMG) as a hypoglycemic principle of Spanish moss (Tillandsia usneoides).

Bioactivity-directed fractionation, using brine shrimp lethality and murine hypoglycemia, of an ethanol extract prepared from Tillandsia usneoides, led to the isolation of four apparently bioactive compounds from the water-soluble fraction. The compounds were identified as citric acid, succinic acid, 3-hydroxy-3-methylglutaric acid (HMG), and 3,6,3',5'-tetramethoxy-5,7,4'-trihydroxyflavone-7-O-beta-D-g lucoside. The brine shrimp lethality of the acids was simply due to acidity; however, HMG elicited significant hypoglycemic responses in fasting normal mice. Ethyl and methyl esters of citric acid were prepared and tested in the murine hypoglycemic assay. Five of the predominant sugars were identified by tlc. Free thymidine was also isolated. Further evaluation of HMG and other potential inhibitors of HMG CoA lyase, in the treatment of symptoms of diabetes mellitus, is suggested.

Animals↗
PubMed1992

Exploration of head injury without medical attention.

In surveys of prison inmates and four other populations, 1,055 subjects reported having a history of 489 head injuries, with 31% of these "unattended" by a physician and 60% "undocumented" in that they were not hospitalized. The prison inmates did not have a history of more unattended injuries or undocumented injuries than the other groups of subjects as was predicted. However, the inmates reported more permanent effects from their unattended and undocumented injuries. Also, the inmates had more permanent effects and longer unconsciousness than did the other groups for their attended and documented head injuries.

Accidents↗
PubMed1990

New mammalian metabolites of sparteine.

Sparteine is reportedly metabolized in mammals with the formation of an N-oxide which undergoes dehydration to delta 2 and delta 5-dehydrosparteine. In our studies male Sprague-Dawley rats were found to metabolize sparteine and alpha-isosparteine to lupanine and alpha-isolupanine respectively in vivo. Metabolic conversion of sparteine in vitro in the presence of microsomal and 9000 x g supernatant fractions of the rat liver homogenate did not produce detectable lupanine. The in vivo studies were conducted by pretreating rats with inducers and inhibitors of microsomal enzymes. Inducers did not increase levels of lupanine in the rat urine but a significant decrease was observed in the presence of the inhibitor SFK 525A. Disulfiram reduced lupanine levels in the urine. The bioconversion of sparteine to lupanine appears to be mediated by microsomal enzymes and may proceed via an aldehyde intermediate. The conversion of sparteine to lupanine may parallel the mammalian metabolism of nicotine to cotinine.

Alkaloids↗
PubMed1984

[14C]normacromerine fate in the rat.

The biological fate of [14C] normacromerine , a dimethoxylated phenethylamine derivative with putative hallucinogenic properties, was evaluated in male Sprague-Dawley rats at 100 mg/kg po. Urine was the primary elimination route accounting for 50% of administered carbon-14 after 24 h. Of this urine radioactivity, normacromerine comprised 30% at 8 h decreasing to nondetectable levels at 24h. Carbon-14 in feces represented less than 10% of the administered dose at 24 h, and 14CO2 expiration was not detected. Studies of normacromerine fate in comparison with previously studied phenethylamines may enhance evaluation of hallucinogenic potential of normacromerine .

Alkaloids↗
PubMed1984

Period analysis of the EEG in early putative Alzheimer's disease.

The EEG of patients with presumptive diagnoses of mild-to-moderate dementia of the Alzheimer type (DAT) and still residing in the community was examined using period analytic techniques. DAT patients were found to have significantly slower major and intermediate period EEG activity as compared to controls. Furthermore, one DAT patient, whose clinical EEG was read as normal, had period analytic EEG descriptors that were greater than one standard deviation below the mean of the control group. Results suggest that EEG activity, as quantified by period analysis, can be detected very early in the course of DAT.

Aged↗
PubMed1983

(-)-alpha-Isosparteine from Lupinus argenteus var. stenophyllus.

Combined GLC-mass spectrometry revealed that an unidentified sparteine isomer was the major component of an alkaloid extract of the aboveground portions of Lupinus argenteus Pursh. var. stenophyllus (Rydb.) Davis (Leguminosae). After isolation, this alkaloid was characterized as the least common of the known sparteine isomers, (-)-alpha-isosparteine. A preliminary pharmacological study showed (-)-alpha-isosparteine to have a more rapid onset and a shorter duration of action when compared with (-)-sparteine on rat myocardium.

Chemical Phenomena↗
PubMed1980

Catecholamine metabolism in a psychoactive cactus.

The Dona Ana cactus, Coryphantha macromeris (Engelm.) Br. and R. and its runyonii (Br. and R.) L. Benson variety are being promoted as natural and legal psychedelic agents with about one-fifth potency of peyote [Lophophora williamsii (Lem.) Coult.]. Like peyote, Dona Ana produces and accumulates various methylated catecholamine derivatives. Of these phenethylamines, normacromerine (N-methyl-3,4-dimethoxy-beta-hydroxyphenethylamine) is by far the most abundant and has been shown to affect animal behavior in such a way as to suggest psychoactivity. It has been demonstrated that the catecholamines epinephrine and norepinephrine occur naturally in C. macromeris var. runyonii and serve as biosynthetic intermediates in normacromerine biosynthesis. Catecholamine precursors and derivatives have also been shown to be part of the metabolic pathway leading to the formation of normacromerine in Dona Ana. Normacromerine appears to be the end product of catecholamine metabolism since recent studies have revealed that very little of this compound is metabolized once it has been formed by the cactus. Completed research of this type has allowed the comparison of catecholamine metabolism leading to the formation of a mind-altering drug in a cactus plant and the metabolism of catecholamines in humans. These data together with evidence from future research will allow biochemical analogies which may suggest etiologies for certain types of mental illness.

Alkaloids↗
PubMed1979

Macromerine and normacromerine biosynthesis in Coryphantha macromeris var. runyonii.

The biosynthetic conversion of epinephrine to normacromerine in Coryphantha macromeris (Engelm.) Br. and R. var. runyonii (Br. and R.) L. Benson (Cactacae) has been studied. Metanephrine, which has been isolated from this cactus and is a normal metabolite of epinephrine in mammalian systems, appeared to be the likely intermediate between epinephrine and normacromerine. Normacromerine turnover studies suggested a 16-day interval between metanephrine administration and harvest of the cacti. During this incubation period, the cacti specifically converted 4.77% of the administered DL-7-3H-metanephrine to normacromerine. Based on biochemical precedents, the postulated metabolic fate of normacromerine in the cactus was an enzymatic N-methylation to give macromerine. However, radiolabeled normacromerine was a very ineffecient precursor to macromerine.

Alkaloids↗
PubMed1978

Alkaloids from Lupinus argenteus var. stenophyllus.

TLC and GLC of an alkaloid extract of the aboveground portions of Lupinus argenteus Pursh. var. stenophyllus (Rydb.) Davis (Leguminosae) suggested the presence of sparteine, beta-isosparteine, delta5-dehydrolupanine, alpha-isolupanine, lupanine, thermopsine, and anagyrine. GLC-mass spectrometry confirmed these preliminary findings. Preparative TLC was used to isolate sparteine, and this alkaloid was further characterized by IR spectral analysis and derivatization.

Alkaloids↗
PubMed1977

Effects of 3,4-dimethoxyphenethylamine derivatives on monoamine oxidase.

The cactus alkaloid 3,4-dimethoxyphenethylamine and its naturally occurring N-methylated homologs inhibited the deamination of tyramine and tryptamine by rat brain monoamine oxidase. In contrast, the beta-hydroxylated derivatives of this series failed to inhibit the action of monoamine oxidase on both tyramine and tryptamine.

Animals↗
PubMed1976

Selectivity of 4-methoxyphenethylamine derivatives as inhibitors of monoamine oxidase.

It has been established that the oxidative deamination of tyramine by monoamine xodase is inhibited by (+/-)-4-methoxy-beta-hydroxyphenethylamine and its N-methylated derivatives. This particular series of compounds does not inhibit the action of monoamine oxidase when tryptamine is used as the substrate. In contrast, 4-methoxyphenethylamine and its N-methylated homologs inhibit the monoamine oxidase-catalyzed deamination of both tyramine and tryptamine.

Animals↗
PubMed1975

Monoamine oxidase inhibiting activity of a series of (+/-)-4-methoxy-beta-hydroxyphenethylamines.

The synthesis and selected pharmacological testing of (+/-)-4-methoxy-beta-hydroxyphenethylamine [1-(4-methoxyphenyl)-2-aminoethanol] and its N-methylated derivatives are presented. Members of this series were found to exert partial prevention of reserpine-induced hypothermia in mice and to inhibit monoamine oxidase in Warburg studies. Activity was essentially dose dependent. The secondary amine was the most active member of the series. The tertiary amine was least active, and the primary amine exhibited intermediate activity.

Animals↗