Evaluation of the nocturnal levels of urinary biogenic amines in men exposed overnight to 50-Hz magnetic field.

The aim of this study was to determine whether exposure to magnetic fields might affect human health and to look for possible effects of acute exposure (9 hours) to 50-Hz magnetic fields (10 microT) on the urinary concentration of biogenic amines. Thirty-two young men (20-30 years old) were divided into two groups (sham-exposed and exposed group) of 12 to 16 subjects each. All subjects participated in two 24-hour experiments to evaluate the effects of both continuous and intermittent exposure to magnetic fields. The subjects were exposed to the magnetic field from 2300 to 0800, while lying down. Total urine (from 2300 to 0800) was collected at 0800. The results (expressed as a ratio of biogenic amine excretion to creatinine excretion (nmol/mmol)) did not differ significantly between sham-exposed and exposed men for any of the parameters measured: adrenaline, noradrenaline, dopamine, dihydroxyphenylalanine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid. These results suggest that nocturnal exposure to either continuous or intermittent 50-Hz magnetic fields of 10 microT does not affect, at least under our experimental conditions, the nocturnal excretion of biogenic amines in healthy young men.

Influence of social isolation and 6-OHDA lesion on the effects of quinelorane.

The sensitivity of the response to the preferential dopaminergic D3 (DAD3) receptor agonist, quinelorane, was compared in mice housed socially and in mice isolated for 4 weeks. Quinelorane (1, 5, 10, 50 and 100 microg/kg) was administered intraperitoneally. Motor activity was measured for 60 min posttreatment. Rectal temperature was measured prior to and 1 h following the administration of quinelorane (10, 50 and 100 microg/kg i.p.). Quinelorane significantly and dose-dependently decreased locomotor activity in social and in isolated mice. The locomotor activity of isolated mice was significantly lower than that of social mice, but isolation had no effect on quinelorane-induced hypomotility. Quinelorane decreased dose-dependently rectal temperature in isolated and social mice, but isolation had no effect on quinelorane-induced decrease in rectal temperature. The lesions of dopaminergic terminals with intracerebroventricular administration of 6-OHDA decreased the dopamine (DA) level by 93% in the nucleus accumbens and by 91% in the corpus striatum; these lesions impaired neither the hypolocomotion nor the hypothermia induced by quinelorane. Thus, it may be concluded that social isolation has no influence on the quinelorane-induced decreases in rectal temperature and in locomotor activity and that the DA receptors involved in these effects of quinelorane are located postsynaptically.

Weight loss and changes in energy metabolism in massively obese adolescents.

OBJECTIVE: To investigate the energy metabolism modifications induced by energy restriction and weight loss in massively obese adolescents. SUBJECTS: Ten massively obese girls (179 +/- 31% of ideal body weight; age, 13.3-16.4 y) after 2-5 weeks on a low-energy diet and 4.5-11.5 months later, that is, after a substantial weight loss, and eight controls. MEASUREMENTS: Resting energy expenditure (REE) and carbohydrate-induced thermogenesis (CIT) after a sucrose load (by indirect calorimetry), plasma glucose and insulin before and after the sucrose load. RESULTS: After 2-5 weeks on a low-energy diet, REE (7415 +/- 904 kJ/d) was lower than the expected value calculated from the regression equation of REE on fat free mass in controls (P = 0.005). After a 37 +/- 17% reduction in excess weight, REE decreased (6405 +/- 613 kJ/d) and remained lower than the expected value (P = 0.005). At the early stages of weight loss, the area under the plasma glucose response curve was negatively correlated with CIT (r = -0.80, P = 0.01) and was higher in the six obese adolescents with low CIT than in the four with normal CIT (396 +/- 52 vs 283 +/- 26 mmol.l-1.min-1, P = 0.01). After substantial weight loss, the area under the plasma insulin response curve decreased by 32% (P = 0.02), and both CIT and the area under the plasma glucose response curve became similar in obese patients with low and normal CIT prior to weight loss. CONCLUSION: These results indicate that in massively obese adolescents, REE for fat-free mass is decreased at the very beginning of the process of losing weight and remains decreased as long as energy restriction and weight reduction carry on. They also indicate that the impaired CIT sometimes observed returns to normal after weight reduction suggesting that it is secondary to a decrease in glucose uptake induced by obesity-associated insulin resistance.

Pharmacoclinical strategy in neuroleptic resistant schizophrenic patients treated by clozapine: clinical evolution, concentration of plasma and red blood cell clozapine and desmethylclozapine, whole blood serotonin and tryptophan.

1. The aim of the study was to determine if a more rational therapeutic approach could be devised for neuroleptic resistant psychotic patients treated for months and years with clozapine. Clozapine is an atypical antipsychotic medication, but its therapeutic benefit has been limited by a high incidence of agranulocytosis and seizures. 2. The study has been performed in an open setting and included 12 patients. Some of them developed a secondary depression and were treated with fluoxetine. 3. Pharmacokinetic analysis were conducted at the same time as clinical evaluations, grading using the BPRS, the PDS, and QLS, and determinations of plasma and red blood cell clozapine and desmethylclozapine, plasma and RBC fluoxetine and norfluoxetine, whole blood serotonin and tryptophan. 4. A positive linear correlation was found only between RBC concentration and the evolution of the QLS. 5. Clozapine is efficacious both on positive and negative symptoms but its mechanism of action remains unclear. Positive symptoms disappear more quickly, sometimes followed by a post psychotic depression. Negative symptoms improve more slowly but regularly. They seem to be correlated with serotoninergic mechanisms. For whole blood 5HT, an important increase was seen about 4 weeks after Cloza administration, and then a decrease. 6. Therapeutic drug monitoring (on the same sample drawn for haematological monitoring providing) could play a useful role in the management of patients treated by clozapine: compliance, lowest dose, possible toxicity, drug interaction, lack of efficacy, relapse predictivity.

The cortical serotonin2 receptors studied with positron-emission tomography and [18F]-setoperone during depressive illness and antidepressant treatment with clomipramine.

BACKGROUND: Changes in serotonin (5-HT)2 receptor densities were reported in depression by postmortem studies and following treatment with tricyclic antidepressants in animal studies. Here, 5-HT2 receptors were studied in vivo in depressed patients. METHODS: Cortical 5-HT2 receptors were investigated prospectively using positron-emission tomography and [18F]-setoperone in 7 depressed patients, before and after at least 3 weeks of clomipramine (CMI), 150 mg daily. They were compared to 7 age-matched controls. RESULTS: There was no significant difference between the untreated patients and the controls, except in the frontal region, where the [18F]-setoperone specific binding was slightly lower in patients. After CMI treatment, depression scores significantly improved and [18F]-setoperone specific binding decreased in cortical regions, suggesting receptor occupancy and/or receptor regulation, by CMI; however, no clinical score correlated with the 5-HT2 receptor measurements either in the untreated or in the treated conditions. CONCLUSIONS: These data substantiate the view that tricyclic antidepressants such as clomipramine significantly interact with cortical 5-HT2 serotoninergic receptors in actual therapeutic situations.

Evolution of plasma homovanillic acid (HVA) in chronic schizophrenic patients treated with haloperidol.

In a 4-week study of 14 drug-free schizophrenic patients (according to DSM-III-R), free and conjugated fractions of plasma homovanillic acid (pHVA) were repeatedly measured. Free HVA levels decreased during the first 2 h of haloperidol intake (P < 0.03). Conjugated HVA levels slowly decreased during the following weeks (P < 0.05), while free HVA levels remained stable. After 4 weeks, free HVA levels remained unchanged 2 h after morning haloperidol intake, but conjugated HVA levels tended to increase. In haloperidol responders, at baseline the free/total HVA ratio was significantly higher than that in non-responders (P < 0.01). Tolerant patients, i.e. those whose post-treatment free HVA levels decreased below pre-treatment levels, were not found to respond better to haloperidol than non-tolerant patients. The balance between free and conjugated pHVA may be a better reflection of the action of haloperidol than free pHVA levels and it may be of prognostic value in terms of drug response.

Enantioselective high-performance liquid chromatography determination of methadone enantiomers and its major metabolite in human biological fluids using a new derivatized cyclodextrin-bonded phase.

The simultaneous determination of methadone (Mtd) enantiomers and its major metabolite, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), in human urine and serum by enantioselective HPLC using a new Cyclobond 1-2000 RSP column is described. After alkaline extraction from urine or serum with estazolam as an internal standard, Mtd enantiomers and its metabolite (EDDP) are separated on the previous column with reversed-mobile phase and detected at 210 nm. Peak resolutions are about 2.0 for Mtd enantiomers. The relative standard deviations (R.S.D.) of Mtd and EDDP standards are between 0.5 and 4.5%. Most drugs of abuse are shown not to interfere with this technique. The method has been applied to study the levels of each Mtd enantiomer and of its racemic metabolite in urine and serum of patients under maintenance treatment for opiate dependence. In urine, R-(-)-Mtd levels are always higher (about 2+/-0.5-fold) than those of S-(+)-Mtd and in most cases, metabolite concentrations are greater than those of global Mtd enantiomers. However, the R-(-) enantiomer levels of residual drug in serum of some patients were lower than those of its antipode. This method is suitable for pharmacokinetic and toxicological studies of Mtd enantiomers and its major metabolite in biological fluids.

Neuroleptic-resistant schizophrenic patients treated by clozapine: clinical evolution, plasma and red blood cell clozapine and desmethylclozapine levels.

The aim of this open study was to determine a more rational therapeutic approach for psychotic patients treated with clozapine for several months, using measurement of plasma and red blood cell levels (P, RBC) of clozapine (cloza) and N-desmethylclozapine (descloza), the major metabolite of clozapine, which has been reported to be less active but more toxic (agranulocytosis) than clozapine itself. The RBC concentration may be considered as more representative of the free fraction drug. The study concerned 7 patients suffering from chronic paranoid schizophrenia according to the DSM-IV criteria. All of them were treatment-refractory schizophrenic inpatients (4 men, 3 women, mean age +/- SD: 38.2 +/- 8.4 years; mean duration of illness +/- SD: 14.4 +/- 5.1 years). They had received at least two different neuroleptics, for 6 weeks, before entering the study. Treatment started in our hospitalization unit with clozapine 25 mg up to a maximum of 900 mg/d (mean stabilized daily dose +/- SD: 507 +/- 211 mg and mean daily dose per kg: 6.91 +/- 3.08 mg). Clinical evaluations (Quality of Life Scale: QLS), regular blood monitoring and biological samples were conducted at the same time, weekly for 18 weeks and then monthly (duration of the study: 4 to 38 months; mean +/- SD: 12.9 +/- 11.5 months). Plasma and RBC (after lysis) levels were determined by reversed phase HPLC and UV detection after extraction with hexane. All the patients improved very quickly after the first week of treatment and six were able to leave the hospitalization unit and start outpatient care such as daily hospitalization, returning home or in sheltered accommodation. With the following plasma (P) and RBC levels: mean cloza +/- SD: (P = 294 +/- 146 ng/ml; RBC = 110 +/- 82 ng/ml) and mean descloza +/- SD: (P = 173 +/- 106 ng/ml; RBC = 76 +/- 54 ng/ml); none of the seven patients developed agranulocytosis. The blood levels, ensuring better surveillance, have a predictive value for clinical improvement. A linear pharmacoclinical correlation was only found between RBC cloza concentrations and the evolution of the QLS scores. Clozapine fulfils the criteria for therapeutic drug monitoring, and determination of plasma, and more particularly RBC, cloza and descloza levels may help to find the lowest effective dose with the fewest side effects.

[Pharmaco-clinical correlations during fluoxetine administration in patients with depressive schizophrenia treated with haloperidol decanoate]. / Corrélations pharmacocliniques lors de l'administration de fluoxétine chez des patients schizophrènes déprimés traités par halopéridol décanoate.

The study concerned 7 patients suffering from schizophrenic disorder according to the DSM III R criteria, treated with a stable dose of haloperidol decanoate (Haldol décanoas) added with fluoxetine (Prozac) from 20 mg to 40 mg/day because of major depression. Patients were assessed at baseline and weekly during the first cycle, and then once a month before each haloperidol decanoate injection, using the brief psychiatric rating scale (BPRS), the general clinical impression scale (CGI) and the Montgomery and Asberg depression rating scale (MADRS). Extrapyramidal and anticholinergic side-effects, blood pressure and pulse were noted. Determinations of plasma and red blood cells concentrations of haloperidol and reduced haloperidol, and of fluoxetine and norfluoxetine, were conducted at the same time than clinical evaluations. For all patients, we observed an improvement by the end of the first week, which became significant at the end of the second week, and continued in subsequent weeks (more than 30 per cent). Two weeks after the addition of fluoxetine, a very significant increase in haloperidol concentrations (more than 100 per cent) was noted; fluoxetine seems to have pharmacokinetic interactions with haloperidol, either by inhibiting its hepatic metabolism (inhibition of cytochrome P450 isoenzyme) or/and by displacing it from protein binding sites.

Pharmacoclinical correlations in schizophrenic patients treated with haloperidol decanoate: clinical evaluations, concentrations of plasma and red blood cell haloperidol and its reduced metabolite, and plasma homovanillic acid.

1. The aim of this open study was to determine whether a more rational therapeutic approach could be devised for psychotic patients (n = 11) treated for long periods with long-acting (LA) haloperidol. The mean multiplication factor for the transition from the oral formulation to the long-acting one was 12.8 (10.4, standard deviation), lower than the theoretically recommended factor of 20. 2. The best dose (mg/kg)-concentration correlations were found for haloperidol (HAL) and reduced HAL (RHAL) in the red blood cells (RBC) (representative of the free drug fraction) rather than in the plasma of patients that had attained the steady state (at the third cycle and afterwards) 3. Pharmacokinetic analyses were conducted at the same time as clinical evaluations, grading using the BPRS and determinations of plasma levels of total, free and conjugated homovanillic acid (HVA), a marker of central dopaminergic activity. 4. A between groups comparison at the steady state (patients (n = 20) with oral administration and the above patients (n = 11) with long-acting form of HAL), showed that the plasma and RBC RHAL/HAL ratios of long-acting HAL decreased significantly (p < 0,005) in comparison with oral administration, at least by half. 5. Plasma HVA values complete the information provided by plasma and more especially RBC HAL and RHAL levels. All these results taken together, as substantiated by the clinical assessment scales (BPRS), assure a better pharmacoclinical surveillance and can be predictive of a patient's response.

Effect of pyridoxine and magnesium on stress-induced gastric ulcers in mice selected for low or high blood magnesium levels.

Gastric ulcers were induced by immobilization in adult female mice with genetically low (MGL) or high (MGH) blood magnesium levels, obtained by selective breeding at the CSAL-CNRS (Orléans, France). All animals, fed with the same standard diet rich in magnesium, were divided into four groups of 20 animals and injected subcutaneously every 2 days for 10 days with isotonic saline (group 1), pyridoxine chlorhydrate 1.11 mg/kg in saline (group 2), magnesium lactate 149 mg/kg in saline (group 3) or both pyridoxine and magnesium (group 4). Subsequently, animals were submitted to a complete fast and an immobilization stress for 17 h. Then, they were sacrificed and the gastric mucosa was dissected for ulcer count. Among the controls (group 1), the mean number of gastric ulcers per mouse was significantly larger in the MGL than in the MGH line (p = 0.0003). In the MGH line, no significant differences were observed between control and treated groups. In the MGL line, pyridoxine associated or not with magnesium (groups 2 and 4) significantly reduced the mean number of ulcers. Magnesium treatment alone (group 3) had little effect. These results can be compared with the greater vulnerability to stress previously observed in Swiss mice fed with a magnesium-deficient diet. However, in this latter group, the number of stress ulcers was reduced not only by pyridoxine but also by the sole magnesium treatment, contrary to our present findings in MGL mice.

Determination of 5-hydroxytryptamine and tryptophan by liquid chromatography in whole blood. Its interest for the exploration of mental disorders.

1. 5-Hydroxytryptamine (5-HT) is a well known neurotransmitter implicated in mental disorders, tryptophan (Trp) as amino acid precursor may be interesting. 2. A rapid and simple reversed-phase (mu Bondapac C18 as stationary phase) liquid chromatographic method with fluorimetric detection (excitation: 302 nm, emission: 340 nm) is described for the quantitation of 5-hydroxytryptamine (5-HT) and free tryptophan (Trp), in whole blood. 5-fluoro-dl-tryptophan (5-FdlT) was used as internal standard. The mobile phase was 0.01 M phosphate buffer (pH = 4.5) with 0.0025 M 1-heptane sulfonic acid and 15% methanol. 3. In blood of healthy subjects (n = 30), the concentrations were, for 5-HT: 258 +/- 68 ng/ml and for Trp: 5.7 +/- 1.02 micrograms/ml. 4. The assay was used to follow the effect of antidepressant drugs, as a 5-HT reuptake inhibitor (clomipramine) and a monoamine oxidase inhibitor (moclobemide). After 4 week treatments, we observed, with clomipramine by 7 patients (150 mg/day) a highly significant reduction (p < 0.01) in 5-HT levels (77% +/- 12) and with moclobemide by 8 patients (300 or 450 or 600 mg/day) a highly significant increase in 5-HT levels (from 16% to 300% according to the drug dosage). These two drugs did not influence blood Trp concentrations. 5. Assays on whole blood present various advantages: (i) the simplicity for clinical departments (ii) the absence of sample pretreatment and (iii) the assurance that the entire platelet population is assayed since all of the 5 HT in blood is bound to platelets.

Brain weight and noradrenaline content in mice selected for low (MGL) and high (MGH) blood magnesium.

Brain noradrenaline content was determined by high performance liquid chromatography in adult male mice from three different strains: 40 mice with genetically low (MGL) or high (MGH) blood magnesium levels, obtained by selective breeding and 20 outbred Swiss albino mice. Brain wet weight and noradrenaline levels were significantly higher in MGL than in MGH and Swiss mice. Few or no differences were found between MGH and Swiss mice. MGL and MGH animals had a similar mean body weight, were raised in identical conditions, and were fed with a normal diet, rich in magnesium. These results together with the higher urinary noradrenaline excretion previously observed in the MGL line, indicate that the mere selection for genetic traits inducing low blood magnesium levels entails an increased catecholamine production. This phenomenon most probably accounts for the higher sensitivity and/or reactivity of MGL animals to stress. The possible role of magnesium-controlling genetic factors in the regulation of brain growth is also suggested.

Rapid determination of 5-hydroxytryptamine in whole blood by liquid chromatography with fluorimetric detection.

A rapid and simple reversed-phase (using muBondapak C18 as the stationary phase) liquid chromatographic method with fluorimetric detection is described for the quantitation of 5-hydroxytryptamine in whole blood. The rapidity and simplicity of the method are explained by the absence of a pretreatment. 5-Fluoro-dl-tryptophan was used as internal standard. The mobile phase was 0.01 M phosphate buffer (pH 4.5) with 0.0025 M 1-heptanesulfonic acid and 20% methanol. The detection wavelength were 302 nm for excitation and 340 nm for emission. Analysis time was 10 min with retention times for 5-hydroxytryptamine of 9 min and for 5-fluoro-dl-tryptophan of 7 min. This method is proposed for biological exploration of psychiatric disorders involving 5-hydroxytryptamine and would be useful for tryptophan.

Effect of controlled-release carbidopa/levodopa on motor performance in advanced Parkinson's disease.

Twenty parkinsonian patients were treated with controlled-release carbidopa/levodopa (Sinemet CR). All were affected by therapeutic response fluctuations related to the timing of drug administration. The daily dosage after 1 year, 766 mg +/- 250 mg, was increased by 23% compared with standard Sinemet dosage, without additional secondary effects. Parkinsonian scores improved by 43%; the prolongation of "on" periods was 63%. Nevertheless, 7 patients withdrew from this study during the 1st month of treatment. Only 1 withdrew due to an adverse reaction to the formulation, a recurrence of hallucinations. The progressive effect of the 1st morning dose and the often unpredictable time at which the product first takes effect were found to be frustrating for the other patients who withdrew. We believe that this disappointment can be avoided by giving new patients the controlled-release formulation from the start of therapy.

Clinical trial of Madopar HBS in parkinsonian patients with fluctuating drug response after long-term levodopa therapy.

23 parkinsonian patients, 11 men and 12 women with an average age of 62 +/- 10 years, were recruited for an open substitution study of standard Madopar by Madopar HBS (hydrodynamically balanced system). All patients were presenting fluctuations in efficacy associated or not with abnormal involuntary movements. The patients in this study had been suffering from Parkinson's disease for 16 +/- 6 years and were severely disabled (Hoehn and Yahr grade III-V). The substitution was carried out dose for dose from one day to another. During the first month the dosage titration was aimed at finding the optimal therapeutic effect. After 120 days 13 patients were continuing the treatment while 10 had stopped it because of lack of therapeutic advantage. After 120 days, as compared to the initial state, end-of-dose fluctuations improved by 47%, the parkinsonian symptomatology by 54% and the abnormal involuntary movements improved by 33%. The daily dose of Levodopa had to be increased from 580 +/- 230 to 710 +/- 240 mg. The results obtained were excellent in 5 cases, good in 6 and moderate in 2 cases.

[Controlled release levodopa-benserazide and changes in efficacy during treatment of Parkinson's disease]. / Levodopa-bensérazide a libération contrôlée et fluctuations d'efficacité au cours du traitement de la maladie de Parkinson.

Twenty-five patients, 12 men and 13 women, 42 to 79 years (mean 62) were studied to determine possible interest of a controlled release preparation of L. dopa combined with benserazide. All patients were experiencing fluctuations in efficacy over the last 8 +/- 4 years. Their Parkinson disease was of long duration, (16 +/- 5 years), severe (Hoehn and Yahr's stages III to V) and treated with L. dopa for 12 +/- 4 years. Results were evaluated in the short, medium and long term. During the initial period the new treatment was substituted for previous therapy on a dose for dose basis. Long term (300 days) results showed that "end of dose" fluctuations had been improved in 40 p. 100 of cases without concomitant reduction in therapeutic effects, duration of "ON" periods progressing by 60%. The frequency of drug intake was unaltered but daily dosage could be increased by 30% without increasing severity of abnormal movements to a similar degree. The administration of this new presentation can be recommended, especially when frequent fluctuations compromise long term therapeutic effects.

Vigilance states and cerebral monoamine metabolism in experimental magnesium deficiency.

Correlations between cerebral monoamine metabolism and electrophysiological parameters were compared in 18 male Wistar rats subjected to a magnesium-restricted diet and in 14 normal rats. During the 40-day experimental period, plasma and erythrocyte Mg2+ levels and plasma Ca2+ and phosphorus levels were measured, and electroencephalographic tracings as well as clinical data were recorded at regular intervals. At the end of the study, the animals were killed and cerebral concentrations of monoamines and their metabolites were determined. Cerebral monoamine disorders characterized by a rise of dopamine and 5-hydroxyindole-3-acetic acid levels were observed in the magnesium-deficient group. This rise was accompanied by an increase in wakefulness and a decrease in sleep percent. The role played by magnesium in cerebral monoamine metabolism and sleep cycles is discussed.

[Plasma levels of desmethylclomipramine and clomipramine at steady-state in the morning. Correlative analysis and prediction of theoretical blood clomipramine]. / Taux plasmatiques de desméthylclomipramine et de clomipramine au "steady-state', le matin. Analyse corrélative et prévision d'une clomipraminémie théorique.

Clomipramine (CMI) was administered to eight patients, either as an antidepressive drug or, in two patients, as an antalgic drug (average age: 54 y.; average body surface area: 1,71 m2). These patients were treated with 20 to 150 mg, every day, for various lengths of time: min.; one week: max.; 7 years, till the day before the determination of plasma levels. The samples were drawn on patients, fasting, in the morning. Plasma levels of CMI, Desmethylclomipramine (DCMI) and Cortisol were dosed by means of High Performance Liquid Chromatography with U. V. detection.