citalopram Celexa
Distribution of citalopram in the blood serum and in the central nervous system of rats after single and multiple dosage.

Melzacka M, Rurak A, Adamus A, Daniel W.

Distribution in rat tissues of citalopram, a potent and specific inhibitor of neuronal 5-HT uptake was uneven. The blood serum level of the drug did not reflect its distribution in the brain tissue and in the spinal cord. Prolonged administration of citalopram enhanced its blood serum, brain and spinal cord AUC values and slowed down its elimination from all investigated tissues. In contrast to imipramine, citalopram penetrated easily to the spinal cord.

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citalopram Celexa
Antagonism of fenfluramine-induced hyperthermia in rats by some, but not all, selective inhibitors of 5-hydroxytryptamine uptake.

Sugrue MF.

The injection of fenfluramine (7.5 mg kg-1,i.p.) to rats housed at 27-28 degrees C was associated with an elevation of core body temperature which peaked at approximately 1 h post-injection. One h pretreatment with citalopram (20 mg kg-1, i.p.), chlorimipramine (10 mg kg-1, i.p.), femoxetine (10 mg kg-1, i.p.) and fluoxetine (20 mg kg-1, i.p.) resulted in an attenuated response to fenfluramine. In contrast, Org 6582 (20 mg kg-1) and zimelidine (20 mg kg-1) were devoid of an effect on fenfluramine-induced hyperthermia. The response to fenfluramine was was also blocked by i.p. injections of metergoline (0.2 mg kg-1), methysergide (5 mg kg-1) and mianserin (0.5 mg kg-1). Rectal temperature was unaltered by both the 5-hydroxytryptamine (5-HT) uptake inhibitors and the 5-HT receptor antagonists. The IC50 values (nM) for in vitro inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes were for citalopram 2.4, chlorimipramine 8.8, femoxetine 14, fluoxetine 16, Org 6582 75 and zimelidine 250. The injection of all six compounds (20 mg kg-1, i.p.) 1 h before death was associated with an inhibition of [3H]-5-HT uptake into rat hypothalamic synaptosomes which ranged from 47.2% for chlorimipramine to 83.3% for citalopram. Rat hypothalamic 5-HT levels were decreased by approximately 50% 3 h after the injection of fenfluramine (15 mg kg-1, i.p.). This effect was blocked by a 1 h pretreatment with fluoxetine, Org 6582 and zimelidine (all 20 mg kg-1, i.p.). Ki values for displacement of specifically bound [3H]-5-HT (1 nM) to rat hypothalamic membranes were for metergoline 26 nM, methysergide 1.1 microM, mianserin 3.6 microM, chlorimipramine 9.2 microM and fluoxetine 32.7 microM. Values for citalopram, femoxetine, Org 6582 and zimelidine were in excess of 65.4 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

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citalopram Celexa
Citalopram, a selective serotonin reuptake inhibitor: clinical antidepressive and long-term effect--a phase II study.

Pedersen OL, Kragh-Sorensen P, Bjerre M, Overo KF, Gram LF.

In a phase II study the antidepressive effect of citalopram, a selective and potent serotonin reuptake inhibitor, was examined in 20 endogenously and three non-endogenously depressed hospitalized patients. Four endogenously depressed patients dropped out due to deterioration early in the treatment period. The remaining 19 patients completed a 4-6 week treatment schedule. Of 16 endogenously depressed patients 11 responded, one was a partial responder and four did not respond. Of three patients with non-endogenous depressions, two responded and one did not respond. No correlation between plasma citalopram concentration and therapeutic outcome was found. Fourteen patients were given maintenance treatment for 8-113 weeks. One patient developed depression when the dose was reduced from 60 to 40 mg and one patient became manic. After discontinuation of treatment seven patients had a depressive relapse and six of these who again were treated with citalopram responded completely. Side effect rating scores of symptoms usually associated with depression or treatment with tricyclic antidepressants declined during treatment. Three patients complained of increased need of sleep for a period after several weeks of treatment. Apart from an unspecific, transient rise in liver enzymes in two patients, detailed biochemical laboratory tests were all normal. There were no effects on blood pressure, pulse rate, orthostatic reaction, or electrocardiogram. One patient took an overdose of citalopram resulting in plasma levels about six times higher than the average therapeutic level, but there were no signs of severe toxicity. In particular no change in consciousness, electrocardiogram or blood pressure occurred. Pharmacokinetic variables such as dose schedule, steady state kinetics, and metabolism are discussed.

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citalopram Celexa
Effect of a specific 5HT uptake inhibitor (citalopram) on drug accumulation by rat lung slices.

Drew R, Siddik ZH.

Rat lung slices were used to examine the effects of citalopram, a compound reported to be a specific inhibitor of neuronal uptake of 5-hydroxytryptamine (5HT), on the pulmonary accumulation of 5HT, noradrenaline (NA), imipramine (IP) and paraquat (PQ). 5 X 10(-9) mol/l citalopram inhibited 5HT uptake by 30-40% but NA uptake was not affected at any of the concentrations of citalopram studied. At the highest concentrations of citalopram (10(-5) to 10(-4) mol/l) the accumulation of IP and PQ was reduced by25-30%. It is concluded that at low concentrations, citalopram is a specific and potent inhibitor of 5HT uptake by rat lung slices.

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citalopram Celexa
Initial, clinical trial of a new, specific 5-HT reuptake inhibitor, citalopram (Lu 10-171).

Gottlieb P, Wandall T, Overo KF.

Ten endogenously depressed inpatients were treated once daily for at least 4 weeks with 40-50 mg citalopram (Lu 10-171) - a specific serotonin reuptake inhibitor. The Hamilton rating scale for depression and global assessment indicated pronounced or moderate response in seven patients and slight or no response in three. Side effects were few, mild and transient and neither anticholinergic nor cardiotoxic effects were observed. No difference was observed between responders and non-responders as regards psychopathology, plasma levels or uptake inhibition. It is concluded, that citalopram seems to possess antidepressant properties and that controlled trials are wanted to evaluate its therapeutic value as well as the underlying hypothesis of serotonin - deficient depressions.

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citalopram Celexa
The kinetics of citalopram: single and multiple dose studies in man.

Kragh-Sorensen P, Overo KF, Petersen OL, Jensen K, Parnas W.

The kinetics of citalopram were studied in a group of volunteers after oral (8 subjects) and intravenous (4 subjects) single doses and repeated oral administration (7 subjects). Inter- and intraindividual variation was limited and linearity of kinetics indicated. Systemic and apparent oral clearance estimates (mean 0.42 l plasma/min.) were similar, indicating roughly complete systemic availability. The presence of unchanged drug in urine, corresponding to 1/7 of the dose, suggests elimination by renal as well as hepatic processes. The data from the intravenous test revealed two compartment kinetics; the total volume of distribution was estimated to about 1150 l and that of the central compartment to 175 l. Upon repeated administration steady-state conditions were generally achieved after one week in agreement with the 33 hrs half-life of elimination. Citalopram peak concentrations were reached within 2-4 hours after the daily dose and maximally two-fold variation was recorded in the 24 hrs dose interval. The levels of a main pharmacodynamically active metabolite were roughly half as high as the drug levels.

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citalopram Celexa
Determination of the antidepressant agent citalopram and metabolites in plasma by liquid chromatography with fluorescence detection.

Oyehaug E, Ostensen ET, Salvesen B.

A high-performance liquid chromatographic method is described for the determination of citalopram [1-(3-(dimethylaminopropyl)-1-(4-fluorophenyl)-5-phthalancarbonitrile] and its two main metabolites (the methylamino and amino derivatives). The compounds were extracted from alkaline plasma with diethyl ether. The combined ether layers were evaporated after addition of 50 microliter of 0.1 N HCl. The residual extracts were purified with diethyl ether and 20 microliter were injected into a Spherisorb ODS 5-micrometer column with acetonitrile--0.6% phosphate buffer pH 3 (55:45, v/v) as the mobile phase. Using a fluorescence detector the detection limits are 1 ng/ml of plasma for citalopram and the methylamino metabolite and 0.5 ng/ml for the amino metabolite.

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citalopram Celexa
Citalopram antagonizes the stimulation by lysergic acid diethylamide of presynaptic inhibitory serotonin autoreceptors in the rat hypothalamus.

Langer SZ, Moret C.

Slices of rat hypothalamus prelabeled with [3H]-5-hydroxytryptamine ([3H]-5-HT) were superfused and the release of the labeled transmitter was elicited either by electrical stimulation or by fenfluramine. Whereas the electrically stimulated release of [3H]-5-HT was completely abolished by removing calcium from the superfusion medium, the fenfluramine-induced release of [3H]-5-HT was calcium-independent. Methiothepin increased, in a concentration-dependent manner, the [3H]-5-HT release induced by electrical stimulation but had no effect on that elicited by fenfluramine. The 3H-transmitter release elicited by electrical stimulation was inhibited by lysergic acid diethylamide (LSD) in a concentration-dependent manner, but the release induced by fenfluramine was not modified by LSD. The reduction by LSD of [3H]-5-HT overflow elicited by electrical stimulation was antagonized by methiothepin, but unaffected by phentolamine or by sulpiride. Low concentrations (10-1000 nM) of citalopram, a 5-HT uptake inhibitor, antagonized the inhibition by LSD of electrically evoked release of [3H]-5-HT. These concentrations of citalopram did not modify by themselves the overflow of [3H]-5-HT elicited by electrical stimulation. It is concluded that the modulation of [3H]-5-HT release by presynaptic serotonin autoreceptors is not operational when the neurotransmitter is released through a calcium-independent mechanism. The potent presynaptic inhibition by LSD of serotonergic neurotransmission may contribute to the central actions of this drug. The interaction between citalopram and LSD at the level of [3H]-5-HT release does not seem to involve a competitive interaction at the same receptor site. The possibility that neuronal uptake of 5-HT and the presynaptic 5-HT autoreceptor may be linked in a functional manner cannot be excluded.

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