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Biomedical subjects

A K Cho

Publications and source records attributed to A K Cho.

At least 73 records · Page 4Linked to original sources
PubMed1982

Conversion of N-hydroxyamphetamine to phenylacetone oxime by rat liver microsomes.

These in vitro studies indicate that N-oxidation of N-hydroxyamphetamine (NOHA) by rat liver homogenates yields phenylacetone oxime (PAOx) as the major metabolite. This oxidation was NADPH and oxygen dependent but was not appreciably increased in microsomes from phenobarbital-pretreated animals. The addition to microsomal incubations of superoxide dismutase (SOD), catalase (CAT), azide or mannitol did not alter the rate of oxidation, suggesting that O2-, H2O2, or OH' are not involved in this process. The reaction was minimally inhibited by a 2:1 ratio of CO/O2, and there was no significant reduction in the formation of product by the presence of diethylaminoethyl diphenylvalerate (SKF-525A) or 2,4-dichloro-6-phenylphenoxyethylamine (DPEA) in micromolar concentrations. Thus, although this NADPH-dependent N-oxidation pathway was catalyzed by rat hepatic microsomes, the data suggest that is was not a cytochrome P-450 mediated monooxygenase reaction.

Amphetamines↗
PubMed1982

N-oxidation of phentermine to N-hydroxyphentermine by a reconstituted cytochrome P-450 oxidase system from rabbit liver.

Previous studies in our laboratory have indicated that the cytochrome P-450 system is involved in the oxidation of phentermine (2-methyl-1-phenyl-2-aminopropane) to N-hydroxyphentermine by liver microsomal preparations. In the present study, a reconstituted system which consisted of cytochrome P-450 and NADPH cytochrome P-450 reductase purified from liver microsomes of phenobarbital-induced rabbits was found to oxidize phentermine to N-hydroxyphentermine. The reaction was NADPH-dependent and required the presence of both the cytochrome P-450 and reductase preparations. N-Hydroxyphentermine was formed 3 times more rapidly in incubation mixtures which contained dilauroyl phosphatidylcholine than in those without added phospholipid. The reaction was inhibited several-fold by octylamine. It is concluded that the cytochrome P-450 system is able to catalyze the oxidation of phentermine to N-hydroxyphentermine.

Animals↗
PubMed1982

Inhibition of [3H]norepinephrine uptake in organ cultured rat superior cervical ganglia by xylamine.

The superior cervical ganglia (SCG) of the rat, when maintained in organ culture, show an increase in [3H]norepinephrine (NE) uptake in the first 2 days and then a leveling off of this activity through 6 days of culture. The [3H]NE uptake in cultured SCG is Na+ - and temperature-dependent and is inhibited by cocaine, desipramine and benztropine with potencies similar to those reported for uptake inhibition into noradrenergic nerve terminals. The preparation also accumulates [3H]dopamine (DA), but, in contrast to NE and DA uptake in the brain, desipramine and benztropine show no specificity for a particular catecholamine, inhibiting both [3H]NE and [3H]DA uptake with potencies similar to those shown for NE uptake in brain. Thus, observed DA uptake and SCG appears to occur mostly via the NE uptake system, not a specific DA uptake system. Xylamine (N-2-chloroethyl-N-ethyl-2-methylbenzylamine) at 10 microM irreversibly inhibits [3H]NE uptake in cultured SCG by 85% in 30 min, uptake being measured after washing away unbound drug. The IC50 for inhibition is about 0.3 microM. When SCG are again cultured after xylamine exposure, [3H]NE uptake recovers after 2 days. This recovery is partially blocked by cycloheximide, indicating that the synthesis of new uptake sites may be involved.

Animals↗
PubMed1982

Chemical transformations of xylamine (N-2'-chloroethyl-N-ethyl-2-methylbenzylamine) in solution. Pharmacological activity of the species derived from this irreversible norepinephrine uptake inhibitor.

Xylamine (N-2'-chloroethyl-N-ethyl-2-methylbenzylamine), a nitrogen mustard that irreversibly inhibits norepinephrine uptake, cyclizes in solution to form an aziridinium ion. The first-order rate constants for cyclization at 23 degrees and 37 degrees are 0.12 min-1 and 0.40 min-1, respectively. The aziridinium ion is relatively stable at 23 degrees but hydrolyzes at 37 degrees with a half-time of 70 min. A dimeric compound was indirectly shown to form at 1 mM xylamine through a reaction between the parent mustard and its aziridinium ion. A similar reaction between the 2-hydroxyethylamine and the aziridinium ion does not take place at pH 7.4. The aziridinium ion, its hydrolysis product, and the dimer were synthesized to evaluate directly their effects on norepinephrine uptake in rabbit thoracic aorta. The aziridinium ion was as potent as xylamine as an irreversible uptake inhibitor, and the effects of both compounds were sodium-dependent. The dimer was a weak competitive inhibitor of norepinephrine uptake, with an IC50 of about 10 microM. The 2-hydroxyethylamine, at 100 microM, competitively inhibited only 20% of control norepinephrine accumulation. These results demonstrate that the aziridinium ion is responsible for xylamine's uptake blocking activity and that the other xylamine derivatives do not influence this action.

Animals↗
PubMed1982

The opposing effects of N-hydroxyamphetamine and N-hydroxyphentermine on the H2O2 generated by hepatic cytochrome P-450.

The effects of N-hydroxyphentermine (NOHP) and N-hydroxyamphetamine (NOHA) on hydrogen peroxide generated by rat liver microsomes and reconstituted preparations in the presence of NADPH were compared. In microsome incubations, NOHP caused an increase in H2O2 levels and NOHA caused a substantial decrease. When the substances were compared for cytochrome P-450-dependent H2O2 generation in reconstituted preparations, NOHA at mM blocked generation and NOHP had no effect. NOHP appears to be an uncoupler of the cytochrome P-450 system in microsomes whereas NOHA is a potent inhibitor, presumably because of its ability to form a metabolic intermediate complex. During the course of their effects on O2 reduction, NOHP and NOHA are themselves undergoing oxidation, NOHP to 2-methyl-2-nitro-1-phenylpropane and NOHA to phenylacetone oxime. The enzymatic natures of these oxidations differ. Thus, two closely related arylalkylhydroxylamines differ substantially in their interaction with cytochrome P-450 systems.

Amphetamines↗
PubMed1981

Computer analyzed EEG in amphetamine-responsive hyperactive children.

Electroencephalographic (EEG) frequency analysis and evoked potentials (EPs) of 27 hyperactive children were examined to determine which, if any, of these electrophysiological parameters might be useful for the selection of those children likely to respond to stimulant medication. The children were treated with placebo, d-amphetamine, and l-amphetamine in double-blind fashion and in random order. EEGs for frequency analysis, visual EPs, and auditory EPs were obtained before and during treatment. Off medication, hyperactive responders to amphetamine had higher predominant beta frequency and shorter latencies of some EP waves than did nonresponders. Although the findings reported here would not select all responders, they would allow the exclusion of most nonresponders.

Adolescent↗
PubMed1981

Compartmental analysis of tyramine-induced norepinephrine depletion.

Tyramine-dependent depletion of norepinephrine was shown to occur from a single kinetically defined compartment. The kinetics of depletion were related to the tyramine concentration and were independent of the amount of norepinephrine within the neuron. Tyramine depleted equivalent amounts of norepinephrine from cytoplasmic, biosynthetic, stable and labile intraneuronal storage compartments by a cocaine-sensitive process. The norepinephrine specific activity of the thoracic aorta remained constant even after greater than 80% depletion due to tyramine. The results show no evidence for a tyramine-resistant pool(s) of norepinephrine within adrenergic neurons.

Animals↗
PubMed1981

Sympathomimetic amine-induced release of norepinephrine-3H from different intraneuronal storage compartments.

The effects of different loading procedures on norepinephrine-3H (NE-3H) efflux induced by a structurally analogous group of indirectly acting sympathomimetic amines was examined in rabbit vas deferens. (+)-Amphetamine was ineffective in releasing 3H from tissues with intact intraneuronal storage granules but was an effective depletor of (a) non-granular intraneuronal compartment(s) following in vivo treatment with reserpine. (+/-)-p-Hydroxynorephedrine was a less effective depletor of non-granular NE-3H. These experiments provide further evidence in support of multiple intraneuronal storage compartments which can be pharmacologically differentiated by utilizing indirectly acting sympathomimetic amine agents.

Animals↗
PubMed1981

The actions of xylamine on central noradrenergic neurons.

The effects of xylamine (N-2-chloroethyl-N-ethyl-2-methylbenzylamine) on catecholamine content and uptake in rat brain were examined after systemic administration. Four hours after doses of 10 to 50 mg/kg i.p. of xylamine, norepinephrine uptake in synaptosomal preparations from cortex was reduced, but dopamine uptake in striatal preparations was unaffected. The levels of norepinephrine in the cortex and hypothalamus were depressed over this dose range, whereas dopamine levels in the striatum again were unaltered. The depletion of norepinephrine from the cortex and hypothalamus was also seen histologically by fluorescence histochemistry. When brain tissue was examined 10 days after a single 25 mg/kg dose, the depletion persisted in cortex and hypothalamus, and although there was a decrease in fluorescence intensity there was no clear evidence of a decreased number of catecholamine-containing processes that would have indicated neurotoxic effects. There was also no gliosis (an indicator of neuronal degeneration) in any of the brain areas or damage to the blood brain barrier. Thus, in contrast to 6-hydroxydopamine, xylamine appears to have selective action on norepinephrine systems and does not appear to be a nonselective neurotoxin.

Brain↗
PubMed1980

Plasma and saliva levels of chlorpromazine and subjective response.

Newly admitted schizophrenic patients (N=48) were given a test does of 2.2 mg/kg of chlorpromazine hydrochloride by mouth. Chlorpromazine was measured in plasma and saliva at 1, 2, 3 (saliva only), 4, 6, 8, 12 (saliva only), and 24 hours by gas chromatography-mass spectography. Subjective response at 4 and 24 hours after test dose was not significantly related to either plasma or saliva level even for dysphoric responders. Dyschoric responses to chlorpromazine appear to be idiosyncratic--rooted perhaps in altered recepter sensitivity or in a patient's very personal interpretation of drug effect.

Adult↗
PubMed1980

The effects of xylamine, a nitrogen mustard on [3H]norepinephrine accumulation in rabbit aorta.

Xylamine (N-2-chloroethyl-N-ethyl-2-methylbenzylamine) irreversibly inhibits [3H]norepinephrine accumulation by rabbit aortic rings in vitro. Inhibition is observed when aortic rings are exposed to xylamine, washed and [3H]norepinephrine accumulation is measured in media free of xylamine. This dose-dependent effect, with an I50 of 10(-7) M, is prevented by coincubation of xylamine with the reversible uptake inhibitors cocaine and amphetamine in the incubation bath during exposure of the tissue to xylamine. The action of xylamine is also sodium dependent, since when tissue was exposed to xylamine in sodium-free Krebs' solution, xylamine had no action. Reduction of potassium ion concentration and the presence of ouabain also protected against xylamine inhibition. These results indicate that xylamine action involves interaction with the neuronal uptake system in a manner very similar to norepinephrine.

Animals↗
PubMed1979

Metabolism of dimethoxymethyl phenobarbital (eterobarb) in patients with epilepsy.

The metabolism of dimethoxymethyl phenobarbital (DMMP) was investigated in 6 epileptic patients using deuterium-labeled drug measured by integrated gas chromatography/mass spectrometry. Following an oral dose of 120 mg, none of the parent compound appeared in serum, urine, or saliva in spite of a measurement sensitivity of less than 0.05 nmol/ml. A metabolite, monomethoxymethyl phenobarbital (MMP), was detected in all patients, with peak serum concentrations averaging 1.96 nmol/ml at 1.3 hours. Phenobarbital was the major metabolite detected, and it reached peak levels in 6 to 12 hours. Two of the patients were continued on DMMP therapy for several months and then administered a pulse dose of deuterated drug. Again no DMMP was detectable. Steady-state drug administration had no effect on the kinetics of metabolism of either MMP or phenobarbital although peak serum concentrations were lower for both metabolites. In the urine of 5 patients an unidentified labeled fragment was detected that does not appear in urine from patients taking phenobarbital. From these pharmacokinetic studies it appears likely that the anticonvulsant activity of DMMP results from its metabolic conversion to phenobarbital.

Adolescent↗
PubMed1979

Inhibition of uptake of catecholamines by benzylamine derivatives.

Eight benzylamine analogues of bretylium were synthesized, including N-(2-chloroethyl)-N-ethyl-2-methylbenzylamine (5), and evaluated as inhibitors of accumulation of norepinephrine and dopamine in rat brain homogenates. All compounds gave an I50 value (concentration of inhibitor that causes 50% reduction in control accumulation) considerably lower against norepinephrine in cortex that against dopamine in striatum. High potency (low I50) and high specificity (preference for inhibition of norepinephrine transport compared to dopamine transport) are associated with a (2-chloroethyl) moiety, tertiary amino center, and ortho substitution of the aromatic function in the benzylamino group. 5 also inhibited the uptake of norepinephrine in rabbit aorta, indicating its effect against the uptake process in general. Cocaine protects against the effects of 5 in coincubation studies when compared to the appropriate controls, indicating that 5 acts at or close to the site of action of cocaine which is thought to be the uptake carrier site.

Amines↗