PubMed Health⌕ Search

Biomedical subjects

R T Coutts

Publications and source records attributed to R T Coutts.

At least 91 records · Page 5Linked to original sources
PubMed1990

Ring-substituted analogues of tranylcypromine as monoamine oxidase inhibitors.

4-Fluorotranylcypromine and 4-methoxytranylcypromine, in which the 4-position of the phenyl ring is protected from metabolic ring hydroxylation, were tested for their ability to inhibit, relative to tranylcypromine, monoamine oxidase (MAO) -A and -B in rat brain after administration of low doses (1.2 and 3.7 mumol/kg) of the drugs. One hour after intraperitoneal injection of the lower dose, tranylcypromine was weaker than 4-fluorotranylcypromine and 4-methoxytranylcypromine at inhibiting MAO-A. After long-term (28 day) administration of a dose of 3.7 mumol/kg/day (administered via osmotic minipumps), 4-fluorotranylcypromine had a slightly stronger inhibitory effect on MAO-B than did the other two drugs. At the same time and dose both 4-substituted analogues were slightly more potent inhibitors of MAO-A than was tranylcypromine. After 28 days of administration at a daily dose of 1.2 mumol/kg/day, both analogues produced greater inhibition of MAO-A and -B than did tranylcypromine. 4-Methoxytranylcypromine and 4-fluorotranylcypromine were similar in their extent of inhibition of MAO-B but the former was more potent than the latter at inhibition MAO-A.

Animals↗
PubMed1990

Recent studies on the MAO inhibitor phenelzine and its possible metabolites.

Although N2-acetylphenelzine (N2AcPLZ) appears to be only a minor metabolite of phenelzine (PLZ), other investigations have demonstrated that it may be worthy of study as an antidepressant in its own right. In the present report, the possibility of ring hydroxylation as a metabolic route for PLZ was investigated in the rat. Indirect evidence for such a route was obtained using iprindole, a drug known to block ring hydroxylation. Treatment of rats with iprindole followed by PLZ was demonstrated to result in increased brain levels of PLZ and beta-phenylethylamine (control rats were treated with vehicle and then PLZ). The possibility that hydroxylation in the para-position might be a metabolic route for PLZ has led to interest in the possible use of analogues in which this position is blocked with a substituent. In preliminary acute studies at a dose of 0.1 mmol/kg p-chloro-PLZ was found to have a similar effect to PLZ on the inhibition of MAO and to lead to an elevation of catecholamines and 5-hydroxytryptamine (5-HT) in rat whole brain.

Animals↗
PubMed1990

A rapid procedure for the analysis of phenylalanine in brain tissue utilizing electron-capture gas chromatography.

A rapid procedure has been developed for the analysis of phenylalanine in brain tissue. Perchloric acid extracts of brain tissue were made basic, and benzoyl chloride was added to derivatize the amine function. The aqueous layer was retained and made slightly acidic. To derivatize the carboxylic acid group, a solution of pentafluorobenzyl alcohol was added in the presence of the coupling agent dicyclohexylcarbodiimide and chloroform. After shaking for 15 min, the organic phase was retained and taken to dryness. The residue was taken up in toluene, washed, and an aliquot used for analysis on a gas chromatograph equipped with an automatic injector, a capillary column and an electron-capture detector. The procedure has been utilized for analysis of phenylalanine in brains of rats treated with vehicle or phenylalanine.

Animals↗
PubMed1990

Long-lasting elevation of alanine in brain produced by the antidepressant phenelzine.

Time- and dose-response studies were conducted to determine the effects of the antidepressant and antipanic drug phenelzine (a monoamine oxidase inhibitor) on whole brain levels of the aliphatic amino acid alanine. At a dose of phenelzine of 15 mg/kg IP, there was a significant increase in brain levels of alanine up to 16 hr after drug administration. Dose studies at 4 hr indicated that the alanine elevation after phenelzine was a dose-dependent effect.

Alanine↗
PubMed1990

Hydralazine pharmacokinetics and interaction with food: an evaluation of the dog as an animal model.

The intravenous and oral dose-dependent pharmacokinetics of hydralazine and the effect of concurrent administration of food with hydralazine in dogs were evaluated for comparison with published human data. Four dogs were given intravenous and oral doses of hydralazine at 0.25, 1.0, 2.5, and 4.0 mg/kg. In addition, the oral 2.5 mg/kg dose was given with a meal. Blood samples were collected at appropriate intervals and analyzed for hydralazine. Pharmacokinetic analysis showed that AUCoral/dose (5552 to 13218 mg-min/ml) and F (0.36 to 0.77) increased significantly with dose, indicating saturation of first-pass metabolism, as is seen in humans. Total-body clearance (70 ml/min/kg) and steady-state volume of distribution (9 L/kg) were similar to human values. The bioavailability of hydralazine in the dog was decreased by 63% when the dose was given with a meal, which is comparable to some human data. It was concluded that the dog may be a useful model in which to study mechanisms of the hydralazine-food interaction.

Administration, Oral↗
PubMed1990

Quantification of three lidocaine metabolites and their conjugates.

A method has been developed to quantify three lidocaine metabolites, N-ethylglycyl-2,6-xylidide (MEGX), glycyl-2,6-xylidide (GX), and 4-hydroxy-2,6-xylidine (4-OH-XY), and their conjugates in pooled human urine using enzymic hydrolysis. The commonly used enzymes, pure beta-glucuronidase, sulfatase, and a mixture of the two, were tested for their efficiencies in hydrolyzing the conjugates. Initially, it was found that 4-OH-XY was highly unstable after it was released from conjugates by beta-glucuronidase and the enzyme mixture. This problem was corrected by purging the sample with nitrogen prior to incubation. It has been determined that 4-OH-XY is present in human urine exclusively as its glucuronide. The percentage of MEGX in free and in conjugated forms (glucuronide, sulfate, and others) are 44.9 +/- 6.8, 16.6 +/- 4.5, 6.6 +/- 1.8, and 31.9 +/- 4.4, respectively. GX was present mostly in the free form (90.6 +/- 10.5%).

Acetaminophen↗
PubMed1990

Lack of acute effect on lidocaine pharmacokinetics from parenteral nutrition.

We tested the hypothesis that amino acids in a parenteral nutrition (PN) solution would result in the decreased metabolism of a model compound, lidocaine. One bolus infusion of lidocaine HCl (1 mg/kg) was administered to seven healthy subjects in association with each of three nutrient regimens: (a) a standard PN solution, (b) 10% dextrose water (D10W), and (c) a meal (control) containing similar fluid volume and caloric, protein, and sodium content as the PN solution. Intravenous nutrients were infused consecutively in a random order at 1 L/12 h. Intravenous and control studies were performed 28 days apart. There was no significant difference in the means (+/- SEM) of total body clearance [7.70 +/- 0.70 (PN) versus 6.78 +/- 0.79 (D10W) versus 7.86 +/- 0.93 (control) ml/min kg], half-life [74.0 +/- 12.2 (PN) versus 89.6 +/- 4.35 (D10W) versus 79.2 +/- 7.22 (control) min], volume of distribution [0.82 +/- 0.15 (PN) versus 0.88 +/- 0.13 (D10W) versus 0.78 +/- 0.13 (control) L/kg], and the fraction of unbound lidocaine in the serum [0.34 +/- 0.025 (PN) versus 0.36 +/- 0.019 (D10W) versus 0.33 +/- 0.020 (control)] among the three nutrient regimens. The concentration-time course of the active metabolite, N-ethylglycyl-2,6-xylidide, did not differ significantly regardless of the nutritional regimen used. Our study indicates that amino acids used for PN do not have any acute effect on lidocaine pharmacokinetics in healthy subjects.

Adult↗
PubMed1990

Effects of parenteral nutrition on hepatic elimination of lidocaine: a study using the isolated perfused rat liver.

The effects of acute and a short-term (7 days) parenteral nutrition (PN, consisting of 24.2% dextrose and 5.2% amino acids) on hepatic lidocaine elimination were studied using an isolated perfused rat liver preparation. In the acute study, lidocaine was coinfused with PN solution or normal saline at 0.123 ml/min for 80 min. There was no significant difference in hepatic lidocaine elimination between control and PN-treated groups (six per group). In the post-PN study, only lidocaine was infused for 80 min. Lidocaine hepatic clearance and extraction ratio were reduced by 29.8 and 31.1% (P less than .05), respectively, compared to what occurred in livers isolated from control animals with free access to standard laboratory rat-chow and water (six per group). Mass balance at steady state showed that recovery was higher for lidocaine (46.58 +/- 7.28% vs. 25.56 +/- 5.59%) and lower for N-(N,N-diethylglycyl)-2-hydroxymethyl-6-methylaniline (0.21 +/- 0.01% vs. 2.75 +/- 0.58%) in the PN group compared to chow-fed controls. Recoveries of other lidocaine metabolites: N-(N-ethylglycy)-2,6-xylidine, 3-hydroxylidocaine, 3-hydroxy-N-(N-ethylyglycyl)-2,6-xylidine and N-(N-ethylglycyl)-2-hydroxymethyl-6-methylaniline were similar in the PN- and chow-fed group. These findings suggest that acute PN infusion has no effect on lidocaine metabolism, and that the impaired hepatic lidocaine elimination after 7-days of PN occurs as a result of selective inhibition of hepatic enzyme activities such as those involved in aryl methyl hydroxylation and in other unidentified metabolic pathway(s).

Amino Acids↗
PubMed1990

A rapid, sensitive assay for gamma-aminobutyric acid in brain using electron-capture gas chromatography.

A rapid, sensitive procedure has been developed for the assay of gamma-aminobutyric acid (GABA) in brain tissue. The method involves sequential reaction with isobutyl chloroformate and pentafluorophenol under aqueous conditions and subsequent separation and quantitation of the derivative on a gas chromatograph equipped with a capillary column and an electron-capture detector. The method produces a derivative with good stability and provides for simultaneous analysis of GABA and five other aliphaticamino acids in very small volumes of supernatant from brain homogenates.

Amino Acids↗
PubMed1990

Synthesis and pharmacological evaluation of acyl derivatives of phenelzine.

Acyl derivatives of phenelzine were required for pharmacological evaluation. Eight mono- and di-acyl derivatives were synthesized and characterized by gas chromatography, mass spectrometry, nuclear magnetic resonance and infrared spectrophotometry. Selective acylation was observed with both acetic anhydride and ethyl chloroformate. In aqueous medium, monoacylation yielded N1-acetyl- and N1-(ethoxy-carbonyl)-phenelzine exclusively, whereas in non-aqueous medium only N2-acetyl and N2-(ethoxycarbonyl) products were obtained. NMR temperature studies were conducted to ascertain the presence of rotational isomers and their ratios. At room temperature, one ethoxy-carbonyl and four phenelzine acetate derivatives were present as mixtures of rotamers. Preliminary evaluations of the MAO-inhibiting properties of acylated phenelzines indicate that a hydrogen atom on the N1-position of phenelzine and its derivatives is essential for activity.

Acylation↗
PubMed1989

Chronic effects of tranylcypromine and 4-fluorotranylcypromine on regional brain monoamine metabolism in rats: a comparison with clorgyline.

A regional analysis of brain amine and acid metabolite levels was conducted after chronic administration of the antidepressant tranylcypromine (0.5 mg/kg/day), of a novel fluorinated analog of this compound, and of clorgyline (1.0 mg/kg/day). These compounds were administered to male Sprague-Dawley rats for 28 days by subcutaneous infusion using osmotic minipumps (Alzet 2002). Levels of noradrenaline, 5-hydroxytryptamine, dopamine, and of the acid metabolites 5-hydroxyindole-3-acetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were measured in the frontal cortex, nucleus accumbens, caudate nucleus, hippocampus, and hypothalamus. After 28 days of drug administration, sustained increases in amines and decreases in their acid metabolites were observed. Regional differences in these effects were minimal. These results are consistent with reports of sustained increases in brain amine concentrations following prolonged administration of other monoamine oxidase inhibitors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1989

Implications of chirality and geometric isomerism in some psychoactive drugs and their metabolites.

Many drugs contain a chiral centre, or such a centre is introduced during metabolism of the drug in man and in animals. If a single chiral centre is present, the drug will normally exist as a mixture of two enantiomers, of which one may have quite different pharmacologic and/or toxic effects than the other. Chiral drugs that are used in psychiatry, and some other pharmacologically related drugs are identified, and the implications of the presence of one or two chiral centres in these drugs are discussed. Differences in pharmacologic properties of drug and metabolite enantiomers are identified and discussed. Also reviewed are the properties of some drugs used in psychiatry that both are chiral and display geometric isomerism.

Animals↗
PubMed1989

Metabolism of monoamine oxidase inhibitors.

1. Despite the fact that monoamine oxidase inhibitors have been used clinically and in animal experiments for many years, much still remains unknown about their metabolism. An overview of the metabolic aspects of several monoamine oxidase inhibitors, including phenelzine, tranylcypromine, pheniprazine, pargyline and deprenyl, is presented. 2. There is still considerable controversy surrounding the role of acetylation in the metabolism of phenelzine. The possibility of ring hydroxylation as well as the formation of beta-phenylethylamine, phenylacetic acid and rho-hydroxyphenylacetic acid from phenelzine is explored. 3. Tranylcypromine has been shown to undergo acetylation and ring hydroxylation. Opening of the cyclopropyl ring is also possible, although this still remains a matter of debate. The pharmacological activity and pharmacokinetic properties of the enantiomers of tranylcypromine are discussed. Chemical substitution in the 4-position of the phenyl ring has been utilized in the design of tranylcypromine analogues with potential antidepressant activity. 4. The formation of amphetamine from pheniprazine and the metabolism of the N-propargyl drugs pargyline and deprenyl are discussed.

Animals↗
PubMed1989

Metabolic implications of chiral centres in psychotropic drugs.

1. Various drugs of neuropsychopharmacological importance contain one or more chiral centres, or centres of asymmetry are introduced during drug metabolism. 2. A drug or drug metabolite with one asymmetric centre exists in two enantiomeric forms, of which usually only one possesses the desired pharmacological activity. The other enantiomer may be inert, or possess an undesired activity. 3. In certain circumstances it is appropriate to administer the racemic drug (mixture of enantiomers), while on other occasions only the pure enantiomer which possesses the desired activity should be given. 4. Drugs employed in psychiatry that contain centres of asymmetry, or are metabolized to pharmacologically active chiral products are identified and implications of chirality are discussed.

Animals↗
PubMed1989

Biotransformation of aryl alkylamines by Cunninghamella bainieri.

1. Incubations of phenylethylamine and 11 of its analogues with Cunninghamella bainieri have been performed. 2. Products of all major routes of mammalian metabolism including ring and aliphatic hydroxylation, oxidative deamination, N-oxidation, N-dealkylation, and conjugation were found in extracts of the fungal incubation broths. 3. Metabolism was influenced by the nature and degree of substitution.

Biotransformation↗
PubMed1989

Uptake and biotransformation of 6,7-dimethylquinoline and 6,8-dimethylquinoline by rainbow trout (Salmo gairdneri).

1. 6,7-Dimethylquinoline (6,7-DMQ) is readily taken up by rainbow trout and bioconcentrated in tissue after exposure to ca 1 mg/l for 7.5 h. Mean bioconcentration factors (from water) were 21, 18, 6 and 14 for bile, liver, muscle and carcass respectively. Mean tissue concentrations after 69-96 h depuration were ND, ND, 0.54 and 0.48 micrograms/g for bile, liver, muscle and carcass respectively. 2. Major metabolites, following exposure to 6,7-DMQ, were conjugates (glucuronide or sulphate) of 7-hydroxymethyl-6-methylquinoline and 6-hydroxymethyl-7-methylquinoline. Mean concentration of metabolites in the bile were 500 micrograms/g after 7.5 h exposure to ca 1 mg/l and 1367 micrograms/g after 9.5 h exposure to ca 1 mg/l and 69 h depuration. 3. 6,8-Dimethylquinoline (6,8-DMQ) is also readily bioconcentrated in fish tissue after exposure to ca 1 mg/l. Mean bioconcentration factors (from water) were 23, 20, 13 and 25 for bile, liver, muscle and carcass respectively. Mean tissue concentrations after 7 h exposure to ca 1 mg/l and 63 h depuration were 4.0, 0.67, 0.49, and 3.2 micrograms/g respectively for bile, liver, muscle and carcass. 4. Major metabolites, following exposure to 6,8-DMQ were conjugates (glucuronide or sulphate) of 6,8-dimethyl-5-hydroxyquinoline, 6,8-dimethyl-7-hydroxyquinoline, 6,8-dimethyl-3-hydroxyquinoline and 6-hydroxymethyl-8-methylquinoline. Mean concentration of metabolites in the bile were 1278 micrograms/g after exposure to ca 1 mg/l for 8 h and 1031 micrograms/g after exposure to ca 1 mg/l for 7 h and 63 h depuration.

Acetylation↗
PubMed1988

Determination of polycyclic aromatic compounds in fish tissue.

A method is presented for the analysis of polycyclic aromatic hydrocarbons (PAHs), polycyclic aromatic sulfur heterocycles (PASHs), and basic polycyclic aromatic nitrogen heterocycles (PANHs) in fish. The analytical procedure includes Soxhlet extraction of prepared fish tissue with methylene chloride followed by gel permeation chromatography (GPC) using Bio-beads SX-3. For PAHs/PASHs, further cleanup is performed using adsorption chromatography on Florisil (5% water deactivated) and elution with hexane. For basic PANHs further cleanup of the fish extracts after GPC is achieved using liquid-liquid partitioning with 6 M hydrochloric acid and chloroform and then basifying the aqueous phase and extracting it with chloroform. Analysis of fortified fish samples was performed using capillary gas chromatography with flame ionization detection and capillary gas chromatography-mass spectrometry. Good agreement was observed for both methods of analysis when applied to fish samples fortified with PAHs, PASHs and basic PANHs at 0.1 to 1 microgram/g, suggesting that the method is effective at removing interfering biogenic compounds prior to analysis. Average recovery of PAHs/PASHs from fortified fish tissue was 87% and 70% for fish tissue fortified at 0.24-1.1 and 0.024-0.11 microgram/g, respectively. Average recovery for basic PANHs was 97% for fish fortified at 1.2-1.4 micrograms/g.

Animals↗