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Biomedical subjects

S Wilk

Publications and source records attributed to S Wilk.

At least 127 records · Page 7Linked to original sources
PubMed1978

Thiethylperazine; clinical antipsychotic efficacy and correlation with potency in predictive systems.

A one-to-one relationship between clinical antipsychotic potency and pharmacologic dopaminergic antagonism is implicit in the dopamine hypothesis of neuroleptic action. Thiethylperazine maleate, a classical antiemetic phenothiazine, displays dopaminergic antagonism in behavioral, neurochemical, and neuroendocrine systems, but is paradoxical insofar as it is thought not to possess clinical neuroleptic activity. In three tests of dopaminergic antagonism--elevation of levels of CSF homovanillic acid in monkeys, striatal dihydroxyphenylacetic acid in rats, and prolactin in man--as well as in a clinical trial of neuroleptic efficacy in schizophrenics, thiethylperazine was fully active and approximately three times as potent as chlorpromazine. Differences in efficacy between this and earlier clinical studies can be accounted for on the basis of dosage.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1978

gamma-Glutamyl dopa: a kidney-specific dopamine precursor.

gamma-Glutamyl derivatives of amino acids and peptides are selectively accumulated in the kidney and introduced into the metabolism of kidney cells. gamma-Glutamyl L-3,4-dihydroxyphenylalanine (gamma-glutamyl dopa) was synthesized both chemically and enzymatically. Injection of this derivative into mice led to a selective generation of dopamine in the kidney as a consequence of the sequential action of gamma-glutamyl transpeptidase and aromatic L-amino acid decarboxylase, two enzymes which are highly concentrated in the kidney. The concentration of dopamine in the kidney after gamma-glutamyl dopa was almost 5 times higher than that after an equivalent dose of L-dopa. Infusion of 10 nmol/g/30 min of gamma-glutamyl dopa to rats produced a 60% increase in renal plasma flow. By contrast the same dose of L-dopa had no effect on renal plasma flow. Only a small pressor effect was observed after the infusion dose of gamma-glutamyl dopa was increased 20-fold indicating that the systemic effects of this pro-drug slight. The results suggest that the pro-drug gamma-glutamyl dopa can be used as a specific renal vasodilator.

Animals↗
PubMed1977

The effect of antipsychotic drugs and their clinically inactive analogs on dopamine metabolism.

Changes in dopamine metabolite levels in the rat striatum and tuberculum olfactorium, following the administration of three non-antipsychotic butyrophenones (AL-499, AHR-1900 and U-25,927) and a non-antipsychotic benzazepine (SCH-12,679), were compared to the effects seen following the antipsychotics haloperidol, chlorpromazine and clozapine. The non-antipsychotics, although clinically ineffective, were reported as active in a variety of animal screening tests. Haloperidol, chlorpromazine and clozapine produced a dose-dependent increase in 3,4-dihydroxyphenylacetic acid (DOPAC) levels in both regions. Of the non-antipsychotic drugs only AHR-1900 significantly elevated the level of DOPAC, however, the slope of its dose-response curve was atypically flat in comparison to the dose-response curves of drugs with known antipsychotic efficacy. Moreover, the maximal effect of AHR-1900 observed at a dose of 40 mg/kg was less than the ED50 effect of haloperidol which occurs at a 250 fold lower dose. It is concluded that the dose-dependent elevation of DOPAC in the striatum and tuberculum olfactorium of the rat is a good predictor of antipsychotic efficacy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1977

Perlapine and dopamine metabolism: prediction of antipsychotic efficacy.

A model for the prediction of antipsychotic efficacy based on the dose-dependent increase in levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and tuberculum olfactorium of the rat is presented. The effect of perlapine, a sleep-promoting and sedative agent reported to lack antipsychotic efficacy, was compared in this system to haloperidol, chlorpromazine and clozapine. All four drugs produced a dose-dependent increase in DOPAC in the two dopamine-rich structures. The potency of perlapine was similar to that of chlorpromazine. Dopamine, assayed in the striatum and tuberculum olfactorium by a new gas chromatographic procedure was not altered by perlapine. The time--action curves for perlapine and clozapine were virtually identical both in the striatum and in the tuberculum olfactorium. All four drugs also elevated homovanillic acid to a similar extent. These results indicate that perlapine should be re-evaluated clinically. We predict that such trials will reveal that perlapine does possess antipsychotic efficacy.

Animals↗
PubMed1976

Metabolism of gamma-glutamyl amino acids and peptides in mouse liver and kidney in vivo.

The metabolism in vivo of gamma-glutamyl amino acids and peptides was studied in the mouse after administration of loading doses of L-gamma-glutamyl-2-aminobutyrate and several other gamma-glutamyl compounds, including glutathione. A great and rapid accumulation of glutamate, glutamine, aspartate and pyrrolidone carboxylate was observed in the kidney. Similarly, after administration of a tracer dose of L-gamma-[14C]glutamyl-L-2-aminobutyrate a rapid incorporation of label into kidney glutamate, glutamine and aspartate was found. These results suggest that both the hydrolytic and gamma-glutamyl transfer reactions catalyzed by gamma-glutamyl transpeptidase are active in the renal handling of gamma-glutamyl compounds. Indirect evidence was obtained that L-gamma-glutamyl-2-aminobutyrate is partially taken up by the kidney cell in an intact form. In contrast to the kidney, administration of several gamma-glutamyl derivatives did not cause an increase in liver glutamate, glutamine and pyrrolidone carboxylate. After administration of L-gamma-glutamyl-2-aminobutyrate only a slight increase in liver aspartate and pyrrolidone carboxylate was observed. Experiments with L-gamma-[14C]glutamyl-L-2-aminobutyrate suggest that this derivative is largely first degraded to its component amino acids (probably in the kidney) before entering into the metabolism of the liver cell. gamma-Glutamyl transpeptidase may function in the metabolism and transport of glutathione and other gamma-glutamyl compounds in a manner analogous to the function of dipeptidases and disaccharidases in the metabolism and transport of dipeptides and disaccharides respectively.

Aminobutyrates↗
PubMed1976

Dopamine metabolism in the nucleus accumbens: the effect of clozapine.

Dopamine metabolism in the nucleus accumbens of the rat was studied by gas chromatographic quantitation of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The ratio of DOPAC/HVA in the nucleus accumbens was significantly greater than the same ratio in the striatum. Dose-response curves for the increase in DOPAC and HVA in the nucleus accumbens and striatum 2 h after clozapine were generated. The effect of clozapine on dopamine metabolism was similar in both structures.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1976

Exploration of affective illness.

This report deals with a series of experimental approaches carried out in clinical studies to attempt to examine the role of amines in relationship to affective state and the mode of action of thymoleptic agents. Attempts have been made to examine enzymes, amines and other metabolites in biological fluids to assess the role of catecholamines and indoleamines in these disorders. Synthesis inhibitors were employed in studies where antidepressant drug-induced remission was initiated and the effect of two inhibitors was assessed on the clinical state. The results are presented and discussed in regard to the significance of the role of serotonin in depressive states and the action of thymoleptic agents.

Adult↗
PubMed1975

Intermediates of the gamma-glutamyl cycle in mouse tissues. Influence of administration of amino acids on pyrrolidone carboxylate and gamma-glutamyl amino acids.

GAMMA-Glutamyl transpeptidase, gamma-glutamyl cyclotransferase, L-pyrrolidone carboxylate hydrolase, gamma-glutamylcysteine synthetase and glutathione synthetase, the enzymes of the gamma-glutamyl cycle, were found in mouse brain, liver and kidney. The activity of L-pyrrolidone carboxylate hydrolase was many times lower than the activities of the other enzymes, and thus the conversion of L-pyrrolidone carboxylate to L-glutamate is likely to be the rate-limiting step of the cycle. The specificity of gamma-glutamyl cyclotransferase from mouse tissues was similar to that from rat tissues. The concentration of pyrrolidone carboxylate and gamma-glutamyl amino acids, intermediates of the gamma-glutamyl cycle, was determined by a gas chromatographic procedure coupled with electron capture detection. Administration of L-2-aminobutyrate, an amino acid that is utilized as substrate in the reaction catalyzed by gamma-glutamylcysteine synthetase, led to a large accumulation of gamma-glutamyl-2-aminobutyrate and pyrrolidone carboxylate in mouse tissues. L-Methionine-RS-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, abolished the increase in concentration of pyrrolidone carboxylate. No accumulation of pyrrolidone carboxylate was observed after L-cysteine. The separate administration of several protein amino acids had little effect on the concentration of pyrrolidone carboxylate; however formation of small amounts of the corresponding gamma-glutamyl derivatives (e.g. gamma-glutamylmethionine and gamma-glutamylphenylalanine) was detected. These intermediates are probably formed by transpeptidation between glutathione and the corresponding amino acid, catalyzed by gamma-glutamyl transpeptidase. The concentration of pyrrolidone carboxylate increased significantly after administration of a mixture containing all protein amino acids, the highest increase occurring in the kidney. The results suggest that two separate pathways for the formation of gamma-glutamyl amino acids and pyrrolidone carboxylate exist in vivo. One of these results from the function of gamma-glutamylcysteine synthetase in glutathione synthesis. The other pathway involves the amino-acid-dependent degradation of glutathione, mediatedby gamma-glutamyl transpeptidase. Only very small amounts of free intermediates are apparently derived from the latter pathway, suggesting that the gamma-glutamyl amino acids formed in this pathway are either enzyme-bound or are directly hydrolyzed to glutamate and free amino acid.

Amino Acids↗
PubMed1975

Assessment of cerebrospinal fluid levels of dopamine metabolites by gas chromatography.

The acid metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in lumbar cerebrospinal fluid (CSF) by a new procedure. After gas chromatographic separation, the pentafluoroprionyl 2,2,3,3,3-pentafluoro-1-propionyl esters of DOPAC and HVA were analyzed by electron capture detection. Normal HVA levels were quantitated in as little as 0.1 ml CSF. No significant amounts of DOPAC (less than 1 ng/ml) were found in any of the drug-free samples analyzed. Levels of DOPAC increased only marginally in the CSF of patients receiving acute or chronic doses of L-Dopa. Baseline HVA levels ranged from 4.5--50 ng/ml with a mean value of 23 ng/ml. These studies demonstrate that HVA is the major dopamine metabolite in human CSF.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Evaluation of dopamine metabolism in rat striatum by a gas chromatographic technique.

Dopamine metabolism in rat striatum was evaluated by gas chromatographic quantitation of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The level of DOPAC (5.21 nmoles/g plus or minus 0.40 S.E.M., n equals 12) exceeded that HVA (3.63 nmoles/g plus or minus 0.25 S.E.M., n equals 12). 2 hr following administration of probenecid (200 mg/kg i.p.) the level of striatal HVA was approximately doubled whereas the level of DOPAC was not significantly elevated. Pargyline (75 mg/kg i.p.) poduced a rapid depletion of DOPAC and HVA. the rate of disappearance of DOPAC (t1/2 equals 10 min) exceeded that of HVA (t1/2 equals 18 min). Rates of metabolite formation were computed assuming steady state kinetics. The rate formation of DOPA (20.5 nmoles/g/hr) was much greater than that of HVA (10.1 nmoles/g/hr). We conclude that DOPAC is the major dopamine metabolite in rat striatum and that its measurement may provide the best index of functional neuronal activity in this species.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Dopamine metabolism in the tuberculum olfactorium.

The occurrence of the major dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the tuberculum olfactorium of the rat was demonstrated by gas chromatography. The ratio of DOPAC to HVA in the tuberculum olfactorium was greater than the ratio of these metabolites in the striatum. The effect of pargyline and probenecid on dopamine metabolite levels was similar for both the tuberculum olfactorium and striatum.

Animals↗
PubMed1975

Differential sensitivity of two dopaminergic structures in rat brain to haloperidol and to clozapine.

The mechanisms underlying the dissociation of the extrapyramidal and antipsychotic properties of haloperidol as compared to clozapine were explored by studying the effects of these drugs on dopamine metabolism in the straitum and tuberculum olfactorium (TO) of the rat. Homovanillic acid and 3,4-dihydroxyphenylacetic acid were simutaneously measured in these regions by a gas chromatographic techinque after treating the rats with different doses of the drugs. Dose-response curves and time-action curves were generated. For both drugs, a higher dose was required to achieve half-maximal metabolite elevation in the TO as compared to the striatum. The apparent differential sensitivity to haloperidol was attributed to differences in time to peak response. The time to peak response to clozapine was similar in both structures. Thus, the striatum appears to be more sensitive to clozapine than the TO with respect to elevation of dopamine metabolites. The effect of haloperidol on dopamine metabolism in the striatum was more persistent than that in the TO. After 4 hours, metabolite levels were still elevated in the striatum, whereas after 2 hours they returned to base line in the TO. The extrapyramidal effects of haloperidol may be due to the persistent action of this drug on dopamine metabolism in the striatum, and the lack of extrapyramidal effects of clozapine may be due to its brief action on dopamine metabolism in the striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1975

Use of synthesis inhibitors in defining a role for biogenic amines during imipramine treatment in depressed patients.

Endogenously depressed patients who showed an antidepressant response to the tricyclic drug imipramine continued to show sustained well being after alpha-MPT was added whereas depression returned when small doses of PCPA were added for brief periods. In one patient the antidepressant response to imipramine occurred after pre- and continued treatment with alpha-MPT. Urinary excretion levels of MHPG in one of the patients studied longitudinally did not correspond to the direction of clinical affective state but did reflect anticipated changes during alpha-MPT treatment. Implications are that serotonergic mechanisms are likely involved in the anti-depressant effects of imipramine in man.

3-Methoxy-4-hydroxyphenylethanol↗