Search PubMed⌕ Search

Biomedical subjects

J Dow

Publications and source records attributed to J Dow.

At least 55 records · Page 3Linked to original sources
PubMed1983

A monoamine oxidase-B inhibitor, MD 780236, metabolized essentially by the A form of the enzyme in the rat.

In-vivo studies on the metabolism of [14C]MD 780236 a short-acting selective type B MAO inhibitor in the rat showed the acid to be the major metabolite in plasma and urine, whereas it was minor in brain, where the alcohol was the major metabolite. Pretreatment with SKF 525-A did not modify the metabolite profile in brain, but benserazide decreased the alcohol. Pretreatment with (-)-selegiline had no effect, but clorgyline or clorgyline with (-)-selegiline significantly decreased the alcohol and increased the primary amine metabolite in brain. In-vivo results suggest that MAO-A is the enzyme responsible for the metabolism of MD 780236. This was confirmed by in-vitro studies. Rat brain homogenates extensively metabolized the drug, with the aldehyde being the major metabolite formed (28% of the total radioactivity in the incubation mixture after 60 min incubation). The acid (12%) was more important than the alcohol (4%) in-vitro. The addition of all metabolites originating from possible MAO activity gave 46% when the incubation was carried out at pH 7.4 and 82% at pH 8.8. The presence of NADPH or NAD+ did not alter the relative amounts of metabolites formed. Total metabolites originating from MAO activity in the presence of (-)-selegiline accounted for 40% of total radioactivity, whereas in the presence of clorgyline they accounted for 8% and in the presence of both clorgyline and (-)-selegiline they were reduced to 3%, compared with 45% in controls. As a further proof of the importance of MAO-A in the metabolism of MD 780236, rats were pretreated with clorgyline 1 h before the drug and MAO-B inhibition measured at different times ex-vivo in brain and liver. The short-lasting phase of inhibition of MAO-B disappeared after pretreatment with clorgyline, and inhibition at 24 h was as high as that at 1 h. These results demonstrate the importance of the A form of MAO for the metabolism of MD 780236.

Animals↗
PubMed1982

Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias.

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. keO, a measure of the lag time of pharmacological response behind changes in plasma concentration, and Ce (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.

Animals↗
PubMed1982

The effect of niaprazine on the turnover of 5-hydroxytryptamine in the rat brain.

Niaprazine (60 mg/kg i.p.) increased rat brain 5-hydroxyindole acetic acid (5-HIAA) concentrations 30 min after treatment, and reduced them at 3-8 hr after treatment. Rat brain 5-hydroxytryptamine (5-HT) levels were unchanged. Niaprazine also produced a short-lasting depletion of rat brain noradrenaline (NA) and dopamine (DA). Pretreatment with alpha-phenyl-alpha-propyl-benzeneacetic acid, 2-(diethylamino) ethyl ester hydrochloride (SKF 525A) (75 mg/kg i.p.) potentiated the increase in 5-HIAA and depletion of catecholamines produced 1 hr after niaprazine, but abolished the reduction in 5-HIAA produced 8 hr after the drug. This suggested that a metabolite might be responsible for the delayed reduction in 5-HIAA levels. A potential metabolite, p-fluoro-phenylpiperazine (FPP) (5-40 mg/kg i.p.) reduced rat brain 5-HIAA and 3,4-dihydroxyphenyl acetic acid (DOPAC), and inhibited 5-HT and NA uptake in vitro. Unlike niaprazine, FPP produced no behavioural sedation, but in large doses produced a behavioural syndrome indicative of serotonergic stimulation. Studies of the metabolism of 14C-niaprazine in rats indicated the presence of a urinary metabolite with the same chromatographic characteristics as FPP. These results suggest that niaprazine itself depletes brain catecholamines and increases 5-HT turnover, while a metabolite, FPP, subsequently reduces the turnover of 5-HT and DA.

Animals↗
PubMed1982

Disposition of 2,3-dihydro-8-[2-hydroxy-3-[4-[1-oxo-3-(3,4, 5-trimethoxyphenyl)-2-propenyl]-1-piperazinyl]-propoxy]-1, 4-benzodioxin-5-carboxylic acid, isopentyl ester (TPBE) in rat and dog, and its hydrolysis in vitro in rat, dog and man.

1. 14C-Labelled 2,3-dihydro-8-[2-hydroxy-3-[4-[1-oxo-3-(3,4, 5-trimethoxyphenyl)-2-propenyl]-1-piperazinyl]propoxy]-1, 4-benzodioxin-5-carboxylic acid, isopentyl ester (TPBE) was administered orally and intravenously to rats and dogs and excretion in urine and faeces studied. Large amounts of radioactivity were present in faeces after i.v. drug administration, indicating that biliary excretion was important. 2. Biliary excretion in bile-duct cannulated rats and dogs showed that within one hour after i.v. dosage, greater than 50% dose was excreted in the bile of both species. Much lower amounts of radioactivity were excreted in bile after oral administration, indicating that absorption was incomplete. 3. T.l.c. of urine, bile and faeces showed that the hydrolysis product of TPBE was the major metabolite in urine and bile of the rat, but was less predominant in dog. 4. Incubation of TPBE in rat whole blood, and with homogenates of liver and small intestine, demonstrated hydrolysis of the drug. Hydrolysis by small intestine and colon contents was low. In the dog, only liver homogenates were capable of extensive hydrolysis of the drug. Hydrolysis also occurred in human blood in vitro; hydrolysis was most rapid in blood of rat then man and finally dog. 5. Experiments in vitro indicate that hydrolysis of TPBE in dog in vivo is likely to be mainly hepatic, whereas in rat hydrolysis in vivo is likely to be both hepatic and extrahepatic (blood and intestines). Results from rat, dog and man indicate that man is likely to be similar to the rat in hydrolysis of TPBE.

Animals↗
PubMed1976

Ethanol oxidizing enzyme activites in liver disease.

1 The activites of hepatic alcohol dehydrogenase, catalase and the reduced nicotinamide adenine dinucleotide phosphate (NADPH) dependent ethanol oxidizing system were determined in liver biopsies from nine patients with liver disease and seven control subjects with non evidence of liver disease. 2 Alcohol dehydrogenase and catalase activites were significantly lower in the patients with liver disease. 3 The activity of the NADPH dependent ethanol oxidizing system was significantly greater in the patients with liver disease, when its activity was expressed in terms of mg protein or g wet weight liver. 4 It is suggested that the greater activity of the NADPH dependent system may compensate for the low alcohol dehydrogenase activites found in patients with liver disease and maintain normal rates of ethanol metabolism.

Alcohol Oxidoreductases↗
PubMed1975

Relation between hepatic alcohol dehydrogenase activity and the ascorbic acid in leucocytes of patients with liver disease.

1. Hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content was measured in thirty-five patients with liver disease and in ten control subjects with duodenal ulcer. The patients with liver disease were divided into three groups consisting of non-drinkers, moderate drinkers and alcoholic/heavy drinkers. 2. There was no significant difference in hepatic alcohol dehydrogenase activity between the groups with liver disease, but all patients had less than half the hepatic alcohol dehydrogenase activity of the control subjects (P less than 0-001). 3. The ascorbic acid in leucocytes was significantly lower in the alcoholic/heavy drinker group than that in the control subjects (P less than 0-02) when the Student's t-test was applied, but no significant difference was found when the Mann-Whitney U-test was used. 4. A correlation coefficient of r = 0-77 (P less than 0-001) was observed among the thirty-five patients with liver disease when hepatic alcohol dehydrogenase activity was compared with leucocyte ascorbic acid content. An insignificant correlation (r = 0-332) was found in the control subjects with no liver disease. 5. This comparison was also significant among non-drinkers with liver disease (r = 0-873; P less than 0-001), moderate drinkers (r = 0-739; P less than 0-02) and alcoholic/heavy drinkers (r = 0-702; P less than 0-005). 6. The addition of ascorbic acid in vitro (0-5-10 mmol/1) had no effect on the activity of alcohol dehydrogenase. 7. The relation between hepatic alcohol dehydrogenase activity and leucocyte ascorbic acid content is probably a consequence of liver disease, as opposed to any specific effect of ascorbic acid deficiency of alcohol consumption on alcohol dehydrogenase activity.

Alanine Transaminase↗
PubMed1975

Fate of coronary collateral circulation after aorto-coronary saphenous vein bypass grafts.

The pre- and postoperative patterns of coronary artery collateral circulation have been studied in 34 patients who had saphenous vein bypass grafting. When the graft remained patent homocoronary collaterals could not be visualized after operation, but new intercoronary anastomoses frequently developed to other diseased arteries. When the graft and the bypassed artery were both obstructed there was a high incidence (5 out of 11) of myocardial infarction despite good preoperative collaterals.

Aorta, Thoracic↗