Biomedical subjects

M Traut

Publications and source records attributed to M Traut.

18 recordsLinked to original sources

PubMed2001

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release.

OBJECTIVE AND DESIGN: It has been proposed that the anti-obesity agent, phentermine, may act in part via inhibition of monoamine oxidase (MAO). The ability of phentermine to inhibit both MAO(A) and MAO(B) in vitro has been examined along with that of the fenfluramine isomers, a range of selective serotonin reuptake inhibitors and sibutramine and its active metabolites. RESULTS: In rat brain, harmaline and lazabemide showed potent and selective inhibition of MAO(A) and MAO(B), their respective target enzymes, with IC(50) values of 2.3 and 18 nM. In contrast, all other drugs examined were only weak inhibitors of MAO(A) and MAO(B) with IC(50) values for each enzyme in the moderate to high micromolar range. For MAO(A), the IC(50) for phentermine was estimated to be 143 microM, that for S(+)-fenfluramine, 265 microM and that for sertraline, 31 microM. For MAO(B), example IC(50)s were as follows: phentermine (285 microM), S(+)-fenfluramine (800 microM) and paroxetine (16 microM). Sibutramine was unable to inhibit either enzyme, even at its limit of solubility. CONCLUSION: We therefore suggest that MAO inhibition is unlikely to play a role in the pharmacodynamic properties of any of the tested drugs, including phentermine. Instead, the lack of potency of these drugs as MAO inhibitors is contrasted with their powerful ability either to inhibit the uptake of one or more monoamines (fluoxetine, paroxetine, sertraline, sibutramine's active metabolites) or to evoke the release of one or more monoamines (S(+)-fenfluramine, S(+)-norfenfluramine, phentermine). These differences in mode of action may be linked to the adverse cardiovascular events experienced with some of the releasing agents.

Animals↗

PubMed1999

Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy.

The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3, 4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3, 4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy.

Animals↗

PubMed1999

Effects of LU-111995 in three models of disrupted prepulse inhibition in rats.

LU-111995 is a novel antipsychotic drug in clinical development. It has a clozapine-like receptor profile and affinities for dopamine D(4) and 5-hydroxytryptamine(2A) receptors. The effects of LU-111995 were examined in three models of disrupted prepulse inhibition (PPI) in rats. The first model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the dopamine agonist apomorphine. LU-111995 significantly reduced the effect of apomorphine on PPI but also slightly increased PPI by itself. Thus, the increases in PPI were not specific to the animals treated with apomorphine but reflected an effect of LU-111995 on PPI. LU-111995 also attenuated the apomorphine-induced increase in startle reactivity. The second model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by rats treated with the psychotomimetic phencyclidine (PCP). LU-111995 significantly blocked the PCP-induced increase in startle reactivity but did not alter the PPI-disruptive effects of PCP. The third model tested the hypothesis that LU-111995 would normalize the deficit in PPI exhibited by isolation-reared rats tested as adults. Isolation rearing of rats produced deficits in PPI. LU-111995 reversed the isolation rearing-induced deficit in PPI without having any significant effect on PPI in socially reared rats. In summary, LU-111995 exhibits potential antipsychotic-like activity in two models of disrupted PPI. It remains to be elucidated whether its effects on PPI can be attributed to a blockade of single dopamine and 5-hydroxytryptamine receptor subtypes, especially D(4) and 5-hydroxytryptamine(2A), or a combination of both.

Acoustic Stimulation↗

PubMed1997

MAO-A inhibition in brain after dosing with esuprone, moclobemide and placebo in healthy volunteers: in vivo studies with positron emission tomography.

OBJECTIVE: The aim of the study was to investigate whether or not esuprone binds substantially to MAO-A in the human brain. METHODS: In a randomised double-blind placebo-controlled study 16 male healthy volunteers were examined with positron emission tomography (PET) with [11C]harmine. Eight of the volunteers were given daily doses of 800 mg esuprone, four were given bi-daily doses of 300 mg moclobemide, and four volunteers were given placebo tablets. PET was performed before initiation of a 7-day treatment period. On day 7, one investigation was made immediately before administration of the drug, representing 23 h after the previous day's treatment for esuprone and 11 h after the last tablets of moclobemide. Further investigations were made 4 h and 8 h after the morning dose on day 7. RESULTS: PET showed a high degree of binding of [11C]harmine, a high-affinity ligand for MAO-A, before the start of treatment, and a marked and similar reduction after treatment with esuprone and moclobemide. A slight tendency for normalisation of enzyme binding was observed at the last time point. In the placebo group no change was observed. Plasma kinetics of esuprone showed a rapid elimination with a half-life of about 4 h. CONCLUSION: The study demonstrates that esuprone was comparable to moclobemide in its effect on MAO-A inhibition in the brain at the doses given. This is an illustration of the potential of PET to monitor drug effects directly on target biochemical systems in the brain in human volunteers, and the possibility of using these data, rather than pharmacokinetic data, for the determination of dosing intervals.

Adult↗

PubMed1995

Nyctohemeral rhythm in the levels of S-adenosylmethionine in the rat pineal gland and its relationship to melatonin biosynthesis.

Liquid chromatographic techniques that permit the simultaneous analysis of S-adenosylmethionine, melatonin, and its intermediary metabolites N-acetyl-5-hydroxytryptamine and 5-hydroxytryptamine within individual pineal glands have been developed. S-Adenosylmethionine has been shown to undergo a marked nyctohemeral rhythm in the pineal gland of the rat, with maximal levels occurring during the light period and minimal levels during the dark period. Detailed studies of the temporal relationships between the levels of S-adenosylmethionine and those of melatonin and its intermediary metabolites suggest that an association exists between the levels of S-adenosylmethionine and the status of the biosynthesis of melatonin. Exposure of animals to continuous light and the administration of the beta-adrenoreceptor antagonist propranolol were both found to inhibit the induction of melatonin synthesis and prevent the reduction in the levels of S-adenosylmethionine during the dark period. As a corollary the induction of melatonin biosynthesis following the administration of the beta-adrenoreceptor agonist isoproterenol during the light period was accompanied by a marked decrease in the levels of S-adenosylmethionine in the pineal gland. The significance of the link between the nyctohemeral rhythms in the levels of S-adenosylmethionine and the biosynthesis of melatonin in the pineal gland is discussed in the context of the therapeutic efficacy of S-adenosylmethionine as an antidepressant.

Animals↗

PubMed1981

Determination of amezinium in body fluids.

Possible approaches to the determination in body fluids of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in this study briefly called amezinium, are investigated and the methods developed on the basis of results obtained in pilot experiments described. These methods, which are primarily based on radioactive tracer techniques, allow both labelled and unlabelled amezinium to be determined in urine, bile, blood, and plasma in concentrations down to about 2 n/ml. Relative standard deviations of 0.5%-9% and 96-102% accuracy are obtained. Advantages and disadvantages of individual methods for various types of samples are discussed.

Body Fluids↗

PubMed1981

Pharmacology of amezinium, a novel antihypotensive drug. IV. Biochemical investigations of the mechanism of action.

The possible sites of action of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, were investigated in biochemical experiments. 1. In vivo in mice, amezinium inhibits the uptake of 3H-noradrenaline into heart and adrenals (among other tissues). The Ki for this inhibition determined in vitro with rat atria is 1.3 x 10(-7) mol/l. As is shown with synaptosomes amezinium exhibits a predilection for the noradrenaline transport, the uptake of dopamine and serotonin being also inhibited, but less so. 2. Amezinium itself is taken up into synaptosomes. This transport follows Michaelis-Menten kinetics, showing the same dependence on Na+ and K+ as uptake 1 of noradrenaline, and is also inhibited by desipramine and cocaine. 3. Storage of 3H-amezinium in rat atria in vivo is almost completely inhibited by pretreatment with 6-hydroxy-dopamine and by approx. 50% inhibited by pretreatment with reserpine. This indicates that amezinium is at least partly stored in the neuronal granules. 4. Amezinium inhibits MAO-A in rat heart homogenate with a Ki of 3 x 10(-6) mol/l and MAO-B in liver homogenate with a Ki of 3 x 10(-4) mol/l; the inhibition is reversible. 5. Even high doses of amezinium do not deplete catecholamines in the heart or adrenals of the rat. The role of the various sites of action is discussed and the effect of amezinium interpreted as the result of noradrenaline release with simultaneous inhibition of intraneuronal and extraneuronal MAO-A and of uptake 1.

Animals↗

PubMed1981

Pharmacokinetics of amezinium in rat and dog.

Using 14C-labelled 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), briefly called amezinium, the time course of plasma level in the rat and of blood level and renal excretion rate in the dog has been followed. The distribution of radioactivity in the organism was investigated by autoradiography of whole-animal sections and by quantitative radioactivity determinations in rat tissue as well as by in vitro experiments. From the results we draw the following conclusions: 1. In the two species investigated here, amezinium is almost completely absorbed after enteral administration. In the rat the absorption proceeds with a half-life of 11 min, after a lag phase of 6 min. In the dog, the lag phase is 30-40 min, after which the compound is absorbed with a half-life of 30 min or less. The small intestine appears to be the site of absorption. 2. Amezinium has a high affinity for tissues. Its transport through the cell membrane, in the case of sympathetic neurons and probably also in the case of other chromaffin cells, is mediated by the noradrenaline carrier; in other tissues, for example the liver, a different active transport mechanism, as yet not elucidated, is operating. The placenta and blood-brain barrier are passed only slightly, if at all. In rat blood amezinium distributes between erythrocytes and plasma with a ratio of 2.7:1; the proportion bound to plasma proteins is about 20%. 3. In the rat amezinium is eliminated from the circulation to the extent of about 3/4 by biotransformation; on enteral administration, about 80% is trapped by first-pass metabolism. In the dog biotransformation accounting for about 40% of the elimination is relatively unimportant; the first-pass metabolism is virtually negligible. 4. Amezinium is eliminated by rats about equally with urine and bile, whilst in the dog the predominant proportion is excreted renally. From plasma level curves the terminal half-life t 1/2 (beta) in the rat was found to be 17 h and 21 h after i.v. and p.o. administration, respectively; blood level data and urinary excretion data in the case of the dog gave 5 1/2 (beta) values between 11 h and 20 h. 5. Renal clearance of amezinium in the dog is not constant: initially it is several times greater than the glomerular filtration rate (GFR) decreasing subsequently to about the same magnitude or even below the GFR.

Animals↗

PubMed1981

Pharmacokinetics of amezinium in man.

Pharmacokinetics of 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, was studied in two groups of subjects. The substance was administered i.v. (1 mg and 10 mg) and p.o. (40 mg and 50 mg), resp. In all cases the time course of renal excretion rate was followed; in two studies blood levels were determined additionally. Together with findings from animal experiments the results are used to describe the pharmacokinetic behaviour of amezinium in man at the present state of knowledge: 1. Absorption of amezinium administered p.o. is preceded by a lag phase which depends on the dissolution time of the tablets used. After the lag phase absorption takes place with a half-life of less than 30 min. 2. Absolute bioavailability of the batches used is estimated to be about 50% and 67% resp. 3. Amezinium is distributed rapidly into the tissues. The first distribution phase detectable has a half-life of less than 10 min. Steady state volumes of distribution are calculated to be between 2 and 3 l/kg. 4. Amezinium and its metabolites are excreted predominantly by the kidneys; extrarenal elimination amounts to about 30%. Terminal half-life was determined from blood levels and excretion data after i.v. as well as p.o. administration to be between 9 and 17 h. 5. Renal clearance of amezinium is not constant. Initially it exceeds the glomerular filtration rate (GFR) by a factor of 4, later it decreases to values similar to the GFR. Comparison of the time courses of the renal excretion on the one hand and of the blood level on the other indicates that renal handling of amezinium may be influenced by its own pharmacological action. This anomalous clearance behaviour of amezinium is considered to be favourable with respect to drug safety.

Administration, Oral↗

PubMed1981

The fate of amezinium in humans and animals.

The metabolism of 14C-labelled 4-amino-6-methoxy-1-phenyl-pyridazinium methyl sulfate (ameziniummetilsulfate, LU 1631, Regulton), in the following briefly called amezinium, was studied in 6 animal species (dog, cat, rabbit, guinea-pig, rat, and mouse) and in humans. Two-dimensional thin-layer radiochromatography revealed qualitative and quantitative differences between species. In man, dog, cat, guinea-pig, and mouse unchanged amezinium is the principal excretion product, accounting for 56-89% of the radioactivity in the urine whilst metabolites predominate in the rabbit and particularly in the rat. Since besides unchanged amezinium (I) no radioactive substance from the urine is adsorbed on cation exchanger, the first step of biotransformation is assumed to be the formation of uncharged, pharmacologically inactive 5-amino-2-phenyl-3(2H)-pyridazinone (II). The metabolites excreted by man and dog have largely been identified; apart from small quantities of II, hydroxylated pyridazinones and/or their sulfuric acid conjugates were isolated. The formation of the metabolites is discussed.

Administration, Oral↗

PubMed1980