Search PubMed⌕ Search

Biomedical subjects

E T Mellerup

Publications and source records attributed to E T Mellerup.

At least 19 recordsLinked to original sources
PubMed1997

An affinity-modulating site on neuronal monoamine transport proteins.

The dissociation rates of [3H]nisoxetine, [3H]GBR 12935 and [3H]citalopram from, respectively, the rat brain noradrenaline, dopamine and 5-HT transporters were found to be markedly affected by several drugs. Sertraline strongly attenuated the rate of dissociation of [3H]nisoxetine from the noradrenaline transporter, while citalopram strongly attenuated that of [3H]citalopram from the 5-HT transporter. The effect of both drugs were stereospecific. Less potent affinity-modulating drugs were identified with regards to [3H]GBR 12935 dissociation from the dopamine transporter. All three neuronal monoamine transporters may thus have specific affinity-modulating sites which change the function of the transporters with possible implication for the reuptake of monoamines released during synaptic activity.

1-Naphthylamine↗
PubMed1996

Double-blind comparison of the side-effect profiles of daily versus alternate-day dosing schedules in lithium maintenance treatment of manic-depressive disorder.

The side-effect profiles of daily vs. alternate-day lithium carbonate dosing schedule were compared in a double-blind study of 50 manic-depressive patients. Following a 3-month period on daily lithium maintenance treatment the patients were randomly allocated to daily or alternate-day lithium dosing aiming at maintaining the same 12-h serum concentration as prior to allocation (median 0.7 mmol/l). The daily and alternate-day median lithium doses were 700 mg and 1200 mg, respectively. There was no significant correlation between changes in the side-effect scores on the UKU side-effect rating scale and lithium dosing schedule (ordinal logistic regression), although analysis revealed a trend in favour of alternate-day dosing with respect to polyuria/polydipsia and diarrhoea (loose stool). The study thus lends no support to the hypothesis that lithium-related side-effects can be diminished by extending the interval between lithium doses from 1 to 2 days.

Adult↗
PubMed1996

Twelve-hour brain lithium concentration in lithium maintenance treatment of manic-depressive disorder: daily versus alternate-day dosing schedule.

The 12-h brain lithium concentration was measured by lithium-7 magnetic resonance spectroscopy in ten manic-depressive patients receiving daily or alternate-day lithium carbonate treatment. The median dose of lithium carbonate was 800 mg in the daily treatment group and 1200 mg in the alternate-day group. Median 12-h serum lithium concentration in the two groups was 0.86 mmol l-1 and 0.55 mmol l-1, respectively, while the corresponding concentration in brain was 0.67 mmol l-1 and 0.52 mmol l-1, respectively. The 12-h brain lithium concentration was independent of lithium dosing schedule (multiple linear regression), but correlated significantly with the 12-h serum lithium concentration (P = 0.003; B = 0.53, 95% c.l. 0.24-0.82; beta = 0.83). Thus at identical 12-h serum lithium concentrations the 12-h brain lithium concentration is similar with both treatment regimes. As the risk of manic-depressive relapse during alternate-day lithium treatment is in our experience 3-fold greater than with daily treatment (at similar mean 12-h serum lithium concentration), the findings suggest that the difference in the prophylactic efficacy of the two dosing schedules is unrelated to differences in the 12-h brain lithium concentration.

Adult↗
PubMed1995

Lithium prophylaxis of manic-depressive disorder: daily lithium dosing schedule versus every second day.

The prophylactic efficacy of lithium carbonate given every second day versus daily intake was compared in a double-blind study including 50 manic-depressive patients. The patients met the DSM-III-R criteria for bipolar disorder or depressive disorder; according to ICD-8 the patients fulfilled criteria for manic-depressive disorder: All patients had experienced at least 3 episodes of mania or major depression, and all had been euthymic for at least 4 months. The median doses of lithium carbonate given were 800 mg/day or 1200 mg/every second day corresponding to median 12-h serum lithium concentrations of 0.6 mmol/l or 0.7 mmol/l, respectively. Manic or depressive relapse was defined as DSM-III-R criteria for mania or major depression, and a score > or = 10 on the Bech-Rafaelsen Mania Scale or the Bech-Rafaelsen Melancholia Scale, respectively. The two treatment schedules were allocated at random. Using the Cox proportional hazard model for statistical analysis, the lithium dosing schedule of every second day did not maintain its prophylactic efficacy against recurrent episodes of manic-depressive disorder. The risk of relapse increased 3 times when the interval between intake of lithium was extended from 1 to 2 days.

Adult↗
PubMed1995

Differences in brain 5-HT transporter dissociation rates among animal species.

The potential of using receptor-ligand dissociation rates as a model for investigating molecular changes in receptors was tested using the dissociation of [3H]citalopram, [3H]paroxetine and [3H]imipramine from the brain 5-HT transporter of four different species (mouse, rat, pig and man). Since the dissociation rates of each of the three ligands differed in most of the species investigated, receptor-ligand dissociation rate constants would seem to be a sensitive measure of receptor conformation. The model could be useful in the search of structural variation in receptors whether attributable to genetic factors or to posttranslational modification.

Adrenergic Uptake Inhibitors↗
PubMed1994

24-hour lithium concentration in human brain studied by Li-7 magnetic resonance spectroscopy.

Brain and serum lithium concentrations were measured every second hour during a 24-hr period following lithium intake, and again 48-hr later in two normal subjects in steady state lithium treatment receiving lithium carbonate (Priadel Synthelabo) once every evening. The brain-lithium concentration was measured by 7Li magnetic resonance spectroscopy (MRS). The brain lithium level was found to undulate in a peak-trough pattern that followed the serum lithium profile, although in an attenuated form. The brain/serum lithium concentration ratio varied considerably during the 48-hr period, ranging from 0.5 to 1.3, but the ratio was independent of the serum-lithium concentration. The median half-life for lithium was 28 hr in the brain, and 16 hr in serum. The brain lithium concentration in the morning was about 75% of the clinically relevant standard 12-hr serum lithium concentration. The finding that brain lithium undulates during the day means that MRS measurements of brain lithium can only be compared if carried out under standard conditions that include a fixed interval following lithium intake and an identical treatment regimen.

Adult↗
PubMed1994

[Winter depression and light therapy].

Winter depression (Seasonal Affective Disorder, SAD) is a depressive illness, which starts in the autumn and disappears in the spring. The depression is, in contrast to the typical endogenous depression, characterized by increased appetite with carbohydrate craving, and increased sleep. There is an increase in the frequency of the illness towards the geographical poles. About 80% of the patients are women. The most remarkable aspect of the depression is however, that it can be effectively treated with bright light, given two hours daily for one to two weeks. A number of biological functions are currently under investigation in relation to winter depressions; among these are the metabolism of melatonin, various diurnal rhythms and the serotonergic system.

Circadian Rhythm↗
PubMed1993

Platelet paroxetine binding and light therapy in winter depression.

The effect of light therapy on serotonin uptake capacity in patients suffering from winter depressions (seasonal affective disorders) was examined indirectly by using [3H]paroxetine binding to determine the number of platelet serotonin transporters. In patients who responded to light therapy the number of platelet serotonin transporters decreased significantly following treatment. In contrast, patients who did not respond to light therapy were found to have a relatively low number of serotonin transporters prior to treatment, and the number did not change significantly following treatment.

Adult↗
PubMed1992

Lithium treatment regimens induce different changes in [3H]paroxetine binding protein and other rat brain proteins.

Rats were treated with lithium administered either via the food or by intraperitoneal injection. Lithium administration via the food results in a rather stable serum lithium concentration, whereas lithium injection results in a varying serum lithium concentration whereby a sharp increase shortly after the injection is followed by an exponential decline until the next injection (Plenge et al. 1981). After 5 months of lithium treatment the 5HT transport protein, the beta-adrenergic receptor and several other brain proteins were determined. The 5HT transport protein, labelled with [3H]paroxetine, was found to be decreased in the lithium-injected rats (Bmax = 347 fmol/mg protein) but was unchanged in the lithium-fed rats (Bmax = 389 fmol/mg protein), as compared with control rats (Bmax = 396 fmol/mg protein), and therefore probably is a specific effect only seen with varying lithium concentration. In contrast, the neuronal membrane marker protein D3 was decreased in the lithium-fed rats (88% of the control value), and showed a trend towards decrease in the lithium-injected rats. The decrease in D3 in the lithium-fed rats may indicate some neuronal damage due to the continuous presence of lithium. This damage may be more pronounced than in rats, where periods of low lithium concentration enable repair to take place. The beta-adrenergic receptor and the neural cell adhesion molecule NCAM were unaffected by the different lithium treatment regimens. Lithium has been reported to inhibit the 5HT1B receptor (the serotonin autoreceptor).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Platelet paroxetine binding in alcoholics.

Platelet paroxetine binding was analysed in 24 abstinent alcoholics and 18 control persons. The alcoholics had significantly more binding sites than the control persons. Most of the alcoholics showed affective symptoms and the increased platelet paroxetine binding was predominantly observed among those who had the lowest Newcastle score, indicating the presence of non-endogenous depression.

Adult↗
PubMed1991

Affinity modulation of [3H]imipramine, [3H]paroxetine and [3H]citalopram binding to the 5-HT transporter from brain and platelets.

The dissociations of [3H]imipramine, [3H]paroxetine and [3H]citalopram from the 5-HT (serotonin 5-hydroxytryptamine) transporter were found to be markedly influenced by several drugs, although concentrations in the microM range were needed. Most of these drugs attenuated the dissociation rate, i.e. increased the affinity between the ligand and the binding site. A few increased the dissociation rate however. The binding of drugs to the affinity-modulating site was specific, although of low affinity and probably changing the conformation of the high-affinity binding site, thereby changing the fit between the ligand and the interacting amino acid side-chains. Although the drugs usually affected the dissociation rates of the three ligands in the same manner, there were some which had different effects on [3H]imipramine, [3H]paroxetine and [3H]citalopram. For example, 5-HT markedly attenuated the dissociation of [3H]imipramine, had a moderate effect on [3H]paroxetine and very little effect on [3H]citalopram dissociation. This indicates that the three ligands are bound to different domains on the 5-HT transporter. [3H]Citalopram dissociation from human brain and rat brain were differently affected by several drugs. Indalpine augmented the dissociation rate of the [3H]citalopram 5-HT transport complex in human brain but attenuated it in rat brain, thus revealing a species difference of the 5-HT transporter.

Animals↗
PubMed1991

[3H]citalopram binding to brain and platelet membranes of human and rat.

Citalopram, a selective serotonin (5-HT) uptake inhibitor with antidepressant properties, was found to bind with high affinity to the 5-HT transporter from human neuronal and platelet membranes. At 20 degrees C, KD was about 1.5 nM in both tissues. [3H]Citalopram bound to rat neuronal membranes with higher affinity than to human neuronal and platelet membranes; at 20 degrees C KD was about 0.7 nM. The Bmax value for the binding of [3H]citalopram to platelet membranes was close to that found using the 5-HT uptake inhibitors [3H]imipramine and [3H]paroxetine, suggesting that all three 5-HT uptake inhibitors bind to the 5-HT transporter. The dissociation rate of [3H]citalopram increased twofold with each 4-5 degree C increase in temperature in both human and rat membranes, although at any given temperature, the dissociation rate was about four times faster in the human neuronal and platelet membranes than in rat neuronal membranes.

Animals↗
PubMed1990

Inhibitory and regulatory binding sites on the rat brain serotonin transporter: molecular weight of the [3H]paroxetine and [3H]citalopram binding proteins.

Citalopram binds with high affinity to a specific binding site located on the serotonin (5-HT) transporter in 5-HT neurons. The binding affinity of [3H]citalopram was found to increase with increasing concentration of citalopram. This may be a homotropic positive allosteric effect, thus indicating the presence of an allosteric binding site for citalopram. The molecular weight of the proteins containing the high-affinity binding sites for citalopram and paroxetine, as well as the allosteric binding site for citalopram were determined by the irradiation method. The molecular weights of the three binding site proteins were found to be the same, suggesting that all three binding sites are located on the same protein molecule in the 5-HT transporter. The results support a hypothesis that the binding area for [3H]citalopram is located deeper in the transport channel than the [3H]paroxetine binding area. Thus the two high-affinity binding sites probably cover different, but overlapping, parts of the protein molecule. The allosteric binding site may be located elsewhere on the protein where it induces conformational changes of the 5-HT transporter with the result that high-affinity bound ligands get trapped in the transport channel, thereby explaining the increase in affinity.

Animals↗