Lack of effect of citalopram on the steady-state pharmacokinetics of carbamazepine in healthy male subjects.

Carbamazepine, a drug used in the treatment of seizure disorders, and citalopram, a highly selective serotonin reuptake inhibitor used for the treatment of depression and other psychiatric disorders, are both metabolized predominantly by the cytochrome P4503A4 isozyme. In this study, the effect of subchronic administration of citalopram on the steady-state pharmacokinetics of carbamazepine was evaluated in 12 healthy male subjects. Carbamazepine was administered orally twice daily as a 100-mg dose from days 1 to 3, as a 200-mg dose twice a day from days 4 to 6, and as a 400-mg dose once a day from days 7 to 35. Citalopram, 40 mg, administered once daily, was added to the carbamazepine-dosing regimen on days 22 to 35. The steady-state plasma concentration profiles of carbamazepine and its active metabolite, carbamazepine 10,11-epoxide, on day 35 (in the presence of steady-state levels of citalopram) were compared to the corresponding carbamazepine and epoxide metabolite profiles on day 21 (in the absence of citalopram). No significant differences were found between mean steady-state values for maximal drug concentration, area under the curve, or time of maximal concentration values for carbamazepine and its epoxide metabolite before and after the addition of citalopram to the daily carbamazepine dosing regimen (p > 0.05). These results suggest that the use of citalopram in patients stabilized on carbamazepine should not produce clinically significant changes in carbamazepine plasma concentrations.

Effect of citalopram on plasma levels of oral theophylline.

BACKGROUND: Citalopram and theophylline may be prescribed together to treat patients with depression and asthmatic disease. Because theophylline has a low therapeutic index, small changes in plasma levels may result in therapeutic failure or adverse effects. Both citalopram and theophylline are metabolized by cytochrome P450 (CYP) isozymes. Theophylline is metabolized by CYP1A2; however, the extent to which citalopram interacts with this isozyme in vivo is not known. OBJECTIVE: This study was conducted to investigate whether citalopram alters plasma levels of oral theophylline. METHODS: In an open-label, multiple-dose study, healthy nonsmoking volunteers 18 to 45 years of age were administered a single oral dose of theophylline (300 mg) on day 1. Beginning on day 3, citalopram 40 mg was administered daily through day 24 to achieve steady-state plasma levels. On day 23 a single oral dose of theophylline 300 mg was coadministered with citalopram 40 mg. Fasting plasma levels of theophylline were measured on day 1 (in the absence of citalopram) and on day 23 (in the presence of steady-state plasma concentrations of citalopram) periodically for 36 hours. RESULTS: Thirteen subjects (8 men and 5 women) participated; all completed the study. One subject was not included in the pharmacokinetic calculations. Citalopram treatment had no effect on the pharmacokinetic characteristics of theophylline. CONCLUSIONS: Citalopram dosing to steady state did not inhibit or induce the metabolism of theophylline in this population of healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with citalopram.

Effects of ordinary meals on plasma concentrations of 3,4-dihydroxyphenylalanine, dopamine sulphate and 3,4-dihydroxyphenylacetic acid.

1. Plasma concentrations of 3,4-dihydroxyphenylalanine (DOPA), dopamine sulphate (DA-S), and 3,4-dihydroxyphenylacetic acid (DOPAC) in humans have been claimed to be indexes of sympathetic nervous activity, but the source and significance of plasma DOPA, DOPAC and DA-S have not been completely elucidated. 2. The effects of ordinary meals on plasma concentrations of total dopamine, mainly DA-S, DOPAC and DOPA were studied in seven healthy subjects. Venous blood was collected every hour for 25 h, while subjects were either fasting or received three meals at 9.00 hours, 13.00 hours and 18.00 hours. Catecholamines and metabolites were determined by reverse-phase HPLC with electrochemical detection. Neutral amino acids were measured by ion-exchange chromatography with photometric detection. 3. The food contained relatively little DOPA as compared with phenylalanine, tyrosine, isoleucine and tryptophan. The content of DA and DA-S varied considerably, with the greatest amount in the evening meal of open sandwiches. 4. Plasma DOPA decreased significantly after the meals at 13.00 hours and 18.00 hours, whereas concentrations of the other amino acids increased as expected. 5. Plasma DA-S increased significantly after meals and especially after the evening meal. Increments in DA-S above basal values after a meal were closely related to the content of DOPA+DA+DA-S in the meal. Plasma DOPAC increased significantly after the evening meal. 6. The decrease in plasma DOPA observed after a meal was probably due to uptake of DOPA by muscle tissue. Changes in plasma DA-S and DOPAC during this 25-h study reflected to a large extent the content of DOPA, DA and DA-S in the meals.

Cerebrospinal fluid from amyotrophic lateral sclerosis has no effect on intracellular free calcium in cultured cortical neurons.

The data from the literature regarding the presence of a neurotoxic factor in amyotrophic lateral sclerosis (ALS) plasma or cerebrospinal fluid (CSF) remain controversial. As a new approach to this question, we have studied the effect of CSF from ALS patients on the temporal dynamics of the intracellular free calcium concentration ([Ca2+]i) of murine cortical neurons in cultures using Fura-2 fluorescence videomicroscopy and single-cell imaging. CSF from seven ALS patients and controls was added at dilutions up to 20% to cortical neuronal cultures. The in vitro inhibition of CSF on [3H]kainic acid binding showed that the CSF did not contain any substances other than glutamate itself in larger amounts. At the concentrations used, the CSF did not have any effect on [Ca2+]i or on the neuronal responsiveness as defined by the ability of the cells to respond with a transient increase in [Ca2+]i to depolarization induced by KCl. The disturbance of the intracellular calcium homeostasis is one of the key mechanisms of action of excitotoxic compounds mediating delayed neuronal cell death by stimulation of glutamate receptor subtypes. In this study, CSF from ALS patients did not induce immediate rises in [Ca2+]i or disturbances of the intracellular calcium homeostasis when measured over a period of 2 h.

Aggression and personality: association with amino acids and monoamine metabolites.

Associations in 52 normal individuals were examined between plasma and cerebrospinal fluid (CSF) concentrations of tryptophan (Trp) and tyrosine, and concentrations of monoamine metabolites in the CSF, and scores on an aggression questionnaire, the Kinsey Institute Reaction List II, and the Eysenck Personality Questionnaire. There was a significantly positive correlation between CSF 5-hydroxyindoleacetic acid (5-HIAA) levels and extroverted aggression scores, and a significantly negative correlation between CSF 5-HIAA levels and introverted aggression scores. Males showed higher plasma Trp concentrations than females, and significantly positive correlations between plasma Trp concentrations and scores on extroverted aggression and the Eysenck E scale. Males, furthermore, showed a significantly negative correlation between CSF Trp levels and scores on the Eysenck P scale, and a significantly positive correlation between concentrations of 3-methoxy-4-hydroxy-phenylglycol in CSF and scores on moral aggression. These results suggest that central serotonin influences aggression in normal individuals through effects on personality.

Long-term effect of dexfenfluramine on amino acid profiles and food selection in obese patients during weight loss.

In depressive disorders an association between basal pre-treatment plasma ratios of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA) and the clinical efficacy of serotonergic acting drugs have been established. In order to clarify whether a similar relation exists in obesity and to elucidate the long-term effect of dexfenfluramine (dF) on plasma amino acid profiles and macronutrient selection, we examined 29 obese patients participating in a 12 months double-blind weight loss trial with either dexfenfluramine (dF) (30 mg/day) or placebo (PL) in conjunction with 4.2-5.0 MJ/d diet. Maximum weight loss was obtained after 6 months (dF 12.8 +/- 5.4 kg; PL 13.8 +/- 9.2 kg, x +/- s.d., ns). Plasma Trp/LNAA and Tyr/LNAA were found to be lower than in normal weight controls and were further reduced during treatment (p < 0.05), but without differences between dF and PL groups. Macronutrient selection was not affected by the dF treatment. In the placebo group weight loss was associated with a high pre-treatment energy intake and a high carbohydrate-protein ratio (p < 0.05). A decrease in dietary fat and increase in protein intake (%) and age was found to explain 82% of the variation in weight loss (p < 0.0005), whereas no correlation could be shown in the dF group. Pre-treatment plasma Trp/LNAA or Tyr/LNAA and weight loss were not correlated. In conclusion, neither food selection nor basal plasma amino acid profiles were predictors of weight loss during long-term treatment with dF as an adjuvant to energy restriction, and they were not affected by the drug treatment.

Effects of oral contraceptives on plasma neutral amino acids and cholesterol during a menstrual cycle.

OBJECTIVE: Concentrations of plasma neutral amino acids, i.e. threonine, serine, asparagine, glycine, alanine, citrulline, alpha-aminobutyric acid, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine, and tryptophan, and serum cholesterol, were determined at the follicular (Day 4), mid-cycle (Day 16) and luteal (Day 25) phases of the menstrual cycle in 15 users of the new generation of combined oral contraceptives (OC), 11 on multiphase combined OC, and 17 controls. RESULTS: The controls showed a decrease in the sum of amino acids to 95% at mid-cycle and 90% in the luteal phase relative to the follicular phase, and a significant decrease in the tyrosine level at the luteal relative to the follicular phase. Since there was no significant difference between the two OC subgroups in the levels of the specified variables at either of the phases, the two groups were considered together. The sum of amino acids in the OC group decreased to 89% at mid-cycle and 91% at the luteal phase relative to the follicular phase, indicating less metabolic effect than reported for older OC formulations. Compared to the controls, the OC group showed significant increased threonine level at the luteal phase, decreased glycine levels at mid-cycle and the luteal phases, decreased citrulline level at mid-cycle, and markedly decreased tyrosine levels at the mid-cycle and luteal phases. Neither total nor high density lipoprotein (HDL) cholesterol differed significantly between the control and OC groups. CONCLUSION: The results suggest that the metabolic effects of the new generation combined OC on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible subjects.

PIP: Concentrations of plasma neutral amino acids and serum cholesterol were determined at the follicular (day 4), mid-cycle (day 16), and luteal (day 25) phases of the menstrual cycle in 15 users of the new generation of combined oral contraceptives (OCs), 11 on multiphase combined OCs, and 17 controls. The controls showed a decrease in the sum of amino acids to 95% at mid-cycle and 90% in the luteal phase relative to the follicular phase and a significant decrease in the tyrosine level in the luteal relative to the follicular phase. Since there was no significant difference between the two OC subgroups in the levels of the specified variables at either of the phases, the two groups were considered together. The sum of amino acids in the OC group decreased to 89% at mid-cycle and 91% in the luteal phase relative to the follicular phase, indicating less metabolic effect than reported for older OC formulations. Compared to the controls, the OC group showed significant increased threonine levels in the luteal phase, decreased glycine levels at mid-cycle and in the luteal phase, decreased citrulline levels at mid-cycle, and markedly decreased tyrosine levels at mid-cycle and in the luteal phase. Neither total nor high-density lipoprotein (HDL) cholesterol differed significantly between the control and OC groups. The results suggest that the metabolic effects of the new generation combined OCs on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible individuals.

Effects of branched-chain amino acids on plasma amino acids in amyotrophic lateral sclerosis.

Although the cause of amyotrophic lateral sclerosis (ALS) remains unknown, biological findings suggest that the excitatory amino acid glutamate contributes to the pathogenesis of ALS. In previous studies of ALS, the therapeutic effect of the branched-chain amino acids (BCAAs) leucine, valine and isoleucine has been evaluated. The present study aimed at investigating the acute effect of BCAAs on plasma glutamate levels in ALS patients. Following two oral doses of BCAAs, significantly increased plasma levels were seen for valine (500%), isoleucine (1,377%) and leucine (927%), however the plasma level of glutamate was not affected. The plasma level of several other amino acids (tryptophan, tyrosine, phenylalanine and methionine) were found decreased after oral BCAAs, which may indicate a diminution in the rate of degradation of muscle protein and/or an increase in tissue disposal of amino acids.

Effect of branched-chain amino acids on glutamate metabolism in amyotrophic lateral sclerosis.

Data from the literature about glutamate metabolism remain controversial. To refine such analysis we have studied plasma glutamate and aspartate levels after glutamate loading (60 mg/kg) in 6 fasting controls and ALS patients, before and after at least 2 weeks treatment with branched-chain amino acids. ALS patients showed no difference from age-matched controls in basal plasma glutamate or aspartate levels, but significantly elevated levels of glutamate and aspartate at 30 and 45 min after loading, and an increased area under the curve in plasma for glutamate following oral glutamate loading. Two weeks BCAAs treatment did not affect plasma glutamate metabolism in ALS patients.

Tyrosine metabolism in users of oral contraceptives.

Brain noradrenaline takes part in the regulation of several brain functions. The formation of brain noradrenaline depends on brain tyrosine (Tyr) levels, which associates with the ratio in plasma of Tyr to other large, neutral amino acids (LNAA). Tyr metabolism has been studied in users of the new generation combined oral contraceptives (OC) and comparable controls at the follicular, mid-cycle, and luteal phases of the menstrual cycle. OC users showed significantly increased plasma Tyr transaminase activity, and significantly decreased plasma Tyr and Tyr/LNAA levels at mid-cycle and luteal phase, whereas plasma total 3-methoxy-4-hydroxyphenylglycol (MHPG) was not affected. Following an oral protein load, the area under the curve in plasma of Tyr and Tyr/LNAA in OC users at the luteal phase were 43% and 29%, respectively, of control levels. The results suggest that the decreased Tyr availability to the brain in OC users may result in a substrate-limited reduction of brain noradrenaline formation, which, secondarily, may contribute to disturbances of mood, coping mechanisms, and appetite in susceptible subjects.

Quantification of physiological amino acids by gradient ion-exchange high-performance liquid chromatography.

A single-column gradient lithium ion-exchange chromatographic method with post-column derivatization and fluorimetric detection for the quantification of physiological amino acids is described. The method runs automatically, requires a minimum of sample preparation, separates all amino acids in plasma and cerebrospinal fluid, and most compounds in brain extract, in addition to some amino acids used therapeutically and in pharmacological studies. About 40 compounds can be quantitated within a run time of 3 h. The within-assay and between-assay coefficients of variations for principal amino acids in plasma samples are satisfactory. The system has performed conveniently and with high stability in the daily routine work and is cost-saving based on laboratory-prepared buffers.

Plasma amino acid profiles in relation to clinical response to moclobemide in patients with major depression. Danish University Antidepressant Group.

With the aim of identifying predictors of treatment response, plasma levels of tryptophan (Trp) and tyrosine (Tyr) pretreatment and during treatment, and their ratios in plasma to the sum of the other large neutral amino acids (LNAA), were determined in 26 inpatients with major depression. The subjects were treated double-blind on a fixed-dose schedule for 4 weeks with the monoamine oxidase (MAO) inhibitor moclobemide. The study took place at 4 clinical centers. Endogenous and nonendogenous depressives were comparable in all biochemical variables and were therefore analysed together. The levels of plasma Trp/LNAA were decreased pretreatment and during treatment in the depressives compared with healthy controls. No significant correlation between plasma amino acid levels or ratios, or plasma moclobemide level, and clinical improvement was found, and there were no indications of a specific plasma amino acid profile associating with a favourable clinical response. Endogenous depressives showed significantly greater improvement than nonendogenous depressives; however, neither subgroup showed significant correlations between biochemical and clinical variables. The findings are at variance with a series of studies, which showed significant correlations between plasma amino acid ratios and clinical improvement on a variety of antidepressant treatments.

Serotonin, carbohydrates, and atypical depression.

At least three categories of atypical depression have been described. The hysteroid dysphoria is characterized by repeated episodes of depressed mood in response to feeling rejected, and a craving for sweets and chocolate. Two other issues are characterized by a cyclical occurrence of changes of mood and appetite, i.e., the late luteal phase dysphoric disorder (DSM-III-R, appendix), or "the premenstrual syndrome" (PMS), and the major depression with seasonal pattern (DSM-III-R), or seasonal affective disorder (SAD). The reactive mood changes are frequently accompanied by features as hypersomnia, lethargy and increased appetite, particularly with a preference for carbohydrates. Central serotonin pathways participate in the regulation of mood and behavioural impulsivity, and modulate eating patterns qualitatively and quantitatively. Depressives with PMS og SAD benefit, in general, from treatments with serotonin potentiating drugs, suggesting that brain serotonin plays a role in the pathophysiology. Ingestion of carbohydrates increases the plasma ratio of tryptophan to other large neutral amino acids in man and animal, and the serotonin synthesis in the rat brain. Based on these findings it has been suggested that the excessive carbohydrate intake by patients with PMS and SAD reflects a self-medication that temporarily relieves the vegetative symptoms via an increased central serotonergic activity.

Paroxetine and imipramine treatment of depressive patients in a controlled multicentre study with plasma amino acid measurements.

In a 12-week double-blind study with 36 patients with major depressive episode (DSM-III), paroxetine (Seroxat, Aropax) showed significantly quicker onset of efficacy on the Melancholia Scale, and better tolerance than imipramine. Plasma concentration analyses showed no clear concentration-efficacy correlation in either treatment group. During long-term treatment paroxetine seemed to be superior to imipramine in preventing relapse; both treatments were well tolerated. A significant correlation between baseline plasma tryptophan: large neutral amino acids ratio and final Hamilton Rating Scale for Depression (HRSD) score and a trend towards an inverse correlation between this ratio and percentage reduction in HRSD score were seen in the paroxetine group but not in the imipramine group. In line with previous studies, these results support the hypothesis that paroxetine is an effective and well tolerated antidepressant.

Effect of aspartame and protein, administered in phenylalanine-equivalent doses, on plasma neutral amino acids, aspartate, insulin and glucose in man.

Six human males each received 0.56 g phenylalanine (Phe) in the form of 1.0 g aspartame or 12.2 g bovine albumin in 200 ml water or water alone. Venous blood samples collected before consumption and during the following 4 hr were assayed for plasma levels of large, neutral amino acids (LNAA), aspartate, insulin and glucose. The area under the curve for plasma Phe was 40% greater, although not significant, after aspartame compared with albumin intake. The indicated increased clearance rate of plasma Phe after albumin may be caused by the significant increase of insulin, on which aspartame had no effect. There was a significant main effect of aspartame for plasma tyrosine but not for tryptophan, valine, isoleucine or leucine. Plasma aspartate was significantly increased at 0.25 hr after the aspartame intake. The percentage Phe/LNAA decreased slightly in response to albumin but increased 55% after aspartame and remained significantly increased for 2 hr. Tyrosine/LNAA increased and tryptophan/LNAA decreased modestly after aspartame intake. The study showed that the intake of aspartame in a not unrealistically high dose produced a marked and persistent increase of the availability of Phe to the brain, which was not observed after protein intake. The study indicated, furthermore, that Phe was cleared faster from the plasma after consumption of protein compared with aspartame.

5-HT uptake inhibitors and tricyclic antidepressants: relation between tryptophan availability and clinical response in depressed patients.

The amount of tryptophan (Trp) available for transport from plasma into the brain was estimated in patients with major depression before treatment for 4 weeks with a 5-HT potentiating tricyclic antidepressant (TCA), amitriptyline (n = 21) or clomipramine (n = 17), or a selective 5-HT uptake inhibitor, citalopram (n = 14) or paroxetine (n = 27). The ratio in plasma of Trp to the sum of the other large neutral amino acids (LNAA) was significantly inversely correlated with improvement on TCA, and patients with ratio Trp/LNAA below the mean improved significantly more than patients with a higher ratio but with comparable serum steady-state drug levels. The Trp concentration was a bit stronger inversely correlated with improvement on 5-HT uptake inhibitors than the ratio Trp/LNAA, and patients with Trp level below the mean improved significantly more than those with a higher level but with comparable serum steady-state drug levels. Plasma amino acid variables may be a useful tool for increasing the efficacy of antidepressant treatment.

Plasma ratio tryptophan/neutral amino acids in relation to clinical response to paroxetine and clomipramine in patients with major depression.

The pretreatment plasma ratio of tryptophan (Trp) to other large neutral amino acids (LNAA), thought to reflect brain serotonin formation, was determined in 44 inpatients with major depression, who were subsequently treated double-blind on a fixed-dose schedule for 4 weeks with the selective serotonin uptake inhibitor paroxetine (n = 27) or clomipramine (n = 17). The study took place at four clinical centers. Endogenous and non-endogenous depressives were comparable with respect to the ratio Trp/LNAA and clinical improvement and were therefore analyzed together. The clomipramine group showed a significant inverse correlation between ratio Trp/LNAA and improvement, and patients with a ratio Trp/LNAA below the mean showed a trend towards greater improvement than patients with a higher ratio but with comparable serum drug levels. The improvement in the paroxetine group was significantly inversely correlated with the Trp concentration but not with the ratio Trp/LNAA. The findings accord with previous trials of various antidepressant treatments, in which about 25% of the variance in therapeutic response associates with pretreatment plasma amino acid profiles.