C.A. Korduba

Effect of dexamethasone on monoamine oxidase inhibition by iproniazid in rat brain

Chronic (6 days) dexamethasone administration caused a slight decrease of rat brain MAO enzyme activity which was reflected by lower levels of 14C-homovanillic acid (HVA) and increased levels of 14C-3-methoxytyramine (3MT) following intracisternal injections of 14C-dopamine (DA). Opposite results with dexamethasone were obtained in iproniazid (MAO-inhibited)-treated rats. In these animals, brain MAO enzyme activity was significantly increased by dexamethasone. This effect increased with the duration of dexamethasone treatment and appeared to be dose dependent. In the brain areas tested (hypothalamus, midbrain, cerebellum, pons and medulla, olfactory, rest of brain) increases of MAO enzyme activity were also indicated by lower levels of 14C-3MT and increased levels of 14C-HVA formed from intracisternally injected radiolabeled DA. Treatment with other glucocorticoids (16alpha-methyldichlorisone, 16beta-methylprednisone and prednisolone) had a similar effect on 14C-DA metabolism. On the other hand, desoxycorticosterone, progestone, estradiol and testosterone, did not exhibit this property. The data indicate that chronic glucocorticoid treatment may have a slight inhibitory effect on brain MAO and also has the ability to partially reverse or antagonize the inhibition of MAO caused by iproniazid.

Inhibition of dopamine uptake into synaptosomes of rat corpus striatum by chlorpheniramine and its structural analogs.

Abstract Pheniramine and its structural analogs were evaluated for their ability to inhibit dopamine uptake into synaptosomes of rat corpus striatum. A structural activity relationship has been observed. A chlorine or bromine substitution greatly facilitates the inhibitory activity of pheniramine which is further enhanced by demethylation or addition of another halogen. There was no appreciable difference in activity between d- and l- optical isomers of chlorpheniramine or brompheniramine. There was also no correlation between the antihistaminic potency of the compounds and their inhibitory activity on dopamine uptake.

The effect of amantadine on radiolabeled biogenic amines in the rat brain

Abstract Intracisternally (i.ci.) administered radiolabeled dopamine, l-dopa or norepinephrine were used to study the mode of oction of amantadine as an anti-Parkinson agent. The data show thatpretreatment with amantadine resulted in higher radioactivity concentration in all brain areas investigated when radiolabeled dopamine was administered i.ci. This increase in the brain radioactivity was reflected in higher levels of dopamine and its metabolites. Amantadine had no effect on the brain radioactivity concentration in experiments in which radiolabeled l-dopa or norepinephrine were administered i.ci. Amantadine also did not affect MAO activity in rat brain and liver, and was shown to be a very weak inhibitor of dopamine or serotonin uptake into synaptosomes of rat corpus striatum. Possible modes of action of amantadine are discussed.

The effect of pheniramine and its structural analogues on 5-hydroxytryptamine in rat and mouse brain

Abstract A series of pheniramine analogues was tested for the ability to inhibit 5-HT uptake by synaptosomes of rat corpus striatum. A chlorine or bromine substitution on the aromatic ring greatly facilitated the inhibitory activity of pheniramine. 3,4-dichlorpheniramine was found to be the most active in this series and was also more effective than desipramine or amphetamine. In mice treated with 3,4-dichlorpheniramine, the rate of 5-HT synthesis in brain tissue was considerably reduced when compared to controls.

Analysis of isepamicin in human plasma by radioimmunoassay, microbiologic assay, and high-performance liquid chromatography.

Plasma concentrations of isepamicin, a new aminoglycoside antibiotic, were determined by radioimmunoassay (RIA), microbiological assay (MA), and high-performance liquid chromatography (HPLC) in healthy volunteers after administration of 7.5 mg/kg intramuscular dosages once daily for 10 days. Plasma samples were collected on days 1, 7, and 10. The limit of quantitation (LOQ) was 0.1 microg/ml for HPLC and RIA and 0.5 microg/ml for MA. The HPLC and RIA yielded superimposable plasma concentration-time curves, whereas the plasma concentrations obtained with MA appeared to be 20% to 30% lower. Regression analysis indicated good correlations among the three assays, with coefficients of correlation measuring 0.935 to 0.960 for RIA compared with HPLC, 0.925 to 0.945 for MA compared with HPLC, and 0.920 to 0.945 for RIA compared with MA.

A comparative study of the fate of dopamine-14C in rat and mouse

The metabolism of dopamine-14C was investigated in selected organs of the rat and mouse, by means of a new, rapid, and quantitative assay of tissue catecholamines. Differences were found in the rate of dopamine metabolism in organs of the same species as well as between species. In each species, the rate of norepinephrine formation from dopamine was more rapid in the heart than in the spleen. Dopamine metabolism in mouse spleen was much slower than in the same organ in the rat. Pretreatment of animals with iproniazid resulted in an increased level of radioactive catecholamines in heart and spleen. This monoamine oxidase inhibitor also affected the metabolism of dopamine at early time intervals, but the differences between the control and iproniazid-treated animals greatly diminished with time.

Pharmacokinetics and metabolism of 14C-isepamicin in humans following intravenous administration.

Twelve healthy adult male volunteers received 1 g (base equivalent) of 14C-isepamicin (131 microCi) as an intravenous bolus over 5 min. The areas under the plasma concentration-time curves at infinity for isepamicin (196 micrograms*h/ml) and total radioactivity (164 micrograms*h/ml) were similar, indicating no biotransformation of isepamicin. The disappearance of isepamicin from plasma followed a triexponential decline, with half-lives of 0.17, 2.12, and 34 h for the alpha, beta, and gamma phases, respectively. However, the contribution of the gamma phase to the total area under the concentration-time curve was only 2.6%. There were no detectable metabolites in plasma and urine, confirming that isepamicin was not biotransformed. The cumulative levels of isepamicin and total radioactivity excretion in urine from 0 to 120 h were 97.3 and 92.1% of the dose, respectively, indicating that the drug was excreted mainly as unchanged isepamicin in urine.

Pharmacokinetics of intravenously administered isepamicin in men.

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, were studied in men after intravenous administration. Three groups of six volunteers received isepamicin for 10 consecutive days by 0.5-h intravenous infusions at respective dosages of 7.5 mg/kg of body weight once daily, 7.5 mg/kg twice daily, and 15 mg/kg once daily. Levels of isepamicin in plasma and urine were determined by a specific high-performance liquid chromatography method. For all three groups, steady-state concentrations of the drug in plasma were attained with the first dose. The area under the concentration-time curve for plasma and urinary drug excretion were dose proportional. A half-life ranging from 2.0 to 2.5 h was independent of the dosage regimen. Isepamicin excreted in urine over 24 h accounted for about 100% of the dose. The results show that the pharmacokinetics of isepamicin are linear with these dosage regimens. The drug does not accumulate upon multiple dosing, undergoes no detectable biotransformation, and is cleared solely by urinary excretion.

Pharmacokinetics of Intramuscularly Administered Isepamicin in Man

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, was studied in man after intramuscular administration. Two groups each of 6 volunteers received isepamicin for 10 consecutive days by intramuscular injection at respective doses of 7.5 mg/kg once daily or 7.5 mg/kg twice daily. Plasma and urinary concentrations of isepamicin were determined using a specific HPLC method. In both groups, there was no drug accumulation following multiple administration. The t1/2, which ranged from 2.4 to 2.7 h, was independent of the dosage regimen. Isepamicin excreted into (0-24 h) urine accounted for virtually 100% of the dose. The results show that the pharmacokinetics of isepamicin are similar with these dosage regimens. The drug undergoes no detectable biotransformation, does not accumulate upon multiple dosing, and is cleared solely by urinary excretion.

Norepinephrine biosynthesis in the rat pancreas

Abstract The biosynthesis in vivo of norepinephrine was studied in rat pancreas with 14C-dopamine as precursor. It was shown that after i.m. injection 14C-dopamine was taken up by the pancreatic tissue, where this catecholamine was metabolized. Norepinephrine was the major transformation product found in the pancreas. Dopamine was metabolized faster in the pancreas than in the heart and the spleen. On the other hand, the concentration of the radioactivity at 30-min and 120-min time intervals was higher in the heart and spleen than in the pancreas.