Biomedical subjects
Publications and source records attributed to B Vandel.
The biotransformation modification of amitriptyline by phenothiazines has been studied in 65 depressive inpatients. Thirty-four of them were treated with oral amitriptyline and 31 with a combination of amitriptyline and phenothiazine. Urinary and plasmatic results showed a decrease in hydroxylated metabolites of amitriptyline (OHAMTc and OHAMT) in patients with added phenothiazine.
A number of treatment failures occurring during antidepressant treatment may be related to the pharmacokinetics of the drug used. In fact, numerous factors are able to modify the fate of the antidepressant in the body. These factors may involve the absorption, distribution, biotransformation or elimination of the drug. The reality of these problems is illustrated by a number of clinical case reports. Such modifications lead to a variation in the quantity of drug available to exert its antidepressant action at the sites responsible for the pharmacodynamic effects. This raises the possible value of defining, and then using in practice, the therapeutic zone of the plasma concentrations of the antidepressant used, below and above which a poor therapeutic response is likely. Modern analytical techniques actually allow the routine analysis of plasma concentrations of a number of antidepressants, resulting in a more rational approach to drug therapy and a decrease in the number of depressions resistant to antidepressant treatments.
Urinary elimination of HVA, MHPG and 5-HIAA was studied in 22 depressed inpatients before and after 28 days of antidepressant treatment. Mean values did not change significantly during treatment, and were not related significantly to recovery in patients. Some marked changes in urinary metabolite levels were, however, observed in individual patients, and could be related to changes in their depression. The direction of change in urinary monoamine metabolites during treatment was associated with pretreatment levels, in that high pretreatment values tended to decrease whereas low pretreatment levels tended to increase.
Results of a study in nine alcoholic patients designed to investigate the effects on wakefulness of tiapride combined with alcohol are presented. Each patient was given successively alcohol, tiapride, and both. Changes in certain psychomotor performances during each of these three periods are described. In the study patients, the tiapride-alcohol combination produced no detrimental effect on wakefulness; on the contrary, results of one of the tests were improved.
The metabolism of amitriptyline (AMT) has been studied in two groups of depressed in-patients on long term AMT therapy: 11 patients with no other major disease and 8 patients with chronic renal failure, who were being dialysed. The patients with renal insufficiency had decreased concentrations of AMT, nortriptyline (NT) and their unconjugated hydroxymetabolites compared to patients with normal kidney function. The plasma levels of conjugated products were extremely high in the uraemics. The latter metabolites are probably inert. The reduced concentration of unconjugated hydroxymetabolites , which are active compounds, may decrease the clinical effectiveness of the drug.
The biotransformation of amitriptyline (AMT) during steady state conditions was studied in plasma and urine from 11 nonalcoholic and 10 alcoholic depressive inpatients treated with oral AMT. The 2 groups of patients had a different pattern of biotransformation. The Demethylation of AMT was lower in alcoholic than in nonalcoholic depressive patients, and conjugation and hydroxylation of AMT were also more marked in the former group. The results may be of clinical relevance since the conjugates of AMT are inactive.
The clinical importance of pharmacokinetic studies of psychotropic drugs is described. First, definitions of the main pharmacokinetic parameters which allow accurate evaluation of the fate of a drug in the organism are given. Secondly, two important points are considered: the variability of drug plasma concentrations from one patient to another with identical doses makes "standard dosages" worthless; current data evidences correlations between the therapeutic effect of a drug and it's plasma concentrations. Clinical implications of the above points are as follows: adjustment and prediction of dosages; definition of rational precepts of prescription; definition of principles for monitoring treatment. These implications are exemplified by clinical cases reported in the medical literature or seen in the department of psychiatry at the university hospital in Besançon.
The urinary excretion of amitriptyline (AMT) and seven of its metabolites was studied by mass spectrometry in 10 depressive in-patients treated to steady-state condition with oral amitriptyline. An average of 68.3% of the dose was recovered in the urine, of which 68.6% was present as conjugates. Hydroxynortriptyline and its conjugate represented 54% of the total recovery. There was marked variation in metabolite pattern between patients. The variations were not due to concomitant medication with benzodiazepines. There was no correlation between the plasma and urine concentrations of AMT and its metabolites, except for amitriptyline conjugates. Two groups of patients could be distinguished - low and high excretors, who displayed alternative routes of metabolism. The disappearance rate of AMT from plasma was determined by the metabolic clearance of AMT to its metabolites. It varied considerably between patients.
Thirty one in-patients suffering from depression were treated orally with clomipramine (C1) at various dosage, for 28 days, after a "wash-out" period of three days. In 17 patients receiving 75 mg per day of C1, steady state plasma levels of C1 were reached at Day 14, and steady state plasma levels of its active metabolite, desmethylclomipramine (DMC1), were reached at Day 21. In contrast, in 7 other patients receiving a dosage increasing to 150 mg per day at Day 7, mean plasma levels of C1 and DMC1 continued to rise during the entire treatment period. At the steady state, a correlation was found between C1 dosage expressed as mg kg body weight and the plasma concentration of C1 and DMC1. Factors such as tobacco and alcohol consumption seem to modify the C1/DMC1 ratio. A comparison of clinical response with plasma levels of C1, DMC1 and C1 + DMC1 showed a significant negative linear correlation.
Plasma concentrations of viloxazine were determined in twenty depressed inpatients during 4 weeks of treatment with progressively increasing dosage. Viloxazine plasma levels varied markedly during the day, due to the short half-life of the drug. Plasma levels rose to peak values after 7-10 days of treatment and then decreased, perhaps due to enzymatic induction by viloxazine. A negative linear correlation was found between the plasma concentration of viloxazine and its clinical effect, with the best clinical improvement in patients whose plasma concentration was 20-500 ng/ml at 7 a.m. Performance in psychomotor tests (visual reaction time and ring of Pierron was improved in many patients after treatment and was correlated with the plasma viloxazine level and the Hamilton Rating score. Assessment of viloxazine effects of electroencephalogram showed a decrease in EEG amplitude in the eight clinically improved patients.
Pharmacokinetic can perhaps explain that about 30% of depressed patients do not respond to tricyclic antidepressants. Studies of the relationship between the pharmacokinetic and pharmacological effects of the tricyclic antidepressants are particularly important. Clomipramine is a tricyclic antidepressant widely used. But there are disparities in various findings on relationship between plasma levels of this drug and clinical effect. Forty in-patients, with an endogenous or exogenous depressive syndrome, received clomipramine orally. In 19 patients treated by 75 mg per day of clomipramine, there was a great interindividual variability of the plasma levels at the 28 day treatment. A comparison of clinical response with plasma levels of clomipramine and desmethylclomipramine, showed a significant negative linear correlation at day 28.
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Plasma levels of amitriptyline and nortriptyline were measured twice weekly in 62 patients treated for three weeks with i.m. amitriptyline 120 mg/day. In half the patients the ratio of amitriptyline to nortriptyline was under 1 and in the other half it was greater than 1. 30 of these 62 patients were clinically monitored with the Hamilton Rating Scale and the side effects of the drug were recorded. There was no correlation between plasma level of the drug and its side effects, but there was a statistically significant curvilinear correlation between the plasma levels of amitriptyline plus nortriptyline and nortriptyline alone, and the clinical effect. The practical value of this type of investigation was demonstrated by showing that patients whose drug plasma level was not in the therapeutic range, were clinically improved after adjustment of the dose. The plasma level of amitriptyline plus nortriptyline must lie between 60 to 220 ng/ml, and that of nortriptyline between 60 to 140 ng/ml, to obtain the best clinical effect. Associated treatments, age, weight and sex of patients, and the type of depression did not appear significantly to affect the plasma level of the drug.
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The pharmacokinetic characteristics of a new antidepressant, viloxazine hydrochloride, were investigated in five males and five females to study sex differences. Plasma levels were determined over a period of 9 h after a single dose of viloxazine of 100 mg (expressed as base). The half life of the drug was in the range of 2.19 - 4.21 for females and 2.61 - 4.31 h for males. The maximum plasma levels occurred in 29 - 171 min of the oral dose for females and 54 - 155 min for males. They reached 1382 - 1769 ng/ml-l for females and 1108 - 2932 ng/ml for males. Pharmacokinetic data were not statistically different between males and females.
Voluntary drug intoxications are not systematically recorded. Main aspects of this important problem have been studied in the unit responsible for medico-psychological emergencies in the university hospital of Poitiers. Files of all patients admitted to the unit from January to December 1994 have been analysed and 598 patients were included in our study. Of these, 67 per cent were females. 31 per cent were 20 to 29 years old and for the most part unemployed (62.5 per cent). Drugs most commonly used are benzodiazepines (39 per cent), alone or often associated with alcohol (33 per cent). A fatal outcome was observed in one patient. In many cases (50 per cent) this was not the first episode of voluntary intoxication; 53 per cent of the patients were discharged from hospital after a psychiatric consultation. For many years, voluntary drug intoxication frequency has increased continually. All cases have a specific intention that we have to clarify in order to take effective preventive measures to prevent recidivism.
Hospital admissions resulting from an adverse drug reaction have been studied in the emergency unit of the university hospital in Poitiers during a 27-day period. This prospective study consisted in documenting all observations considered as an ADR by the medical practitioner in charge of the patient. There were 1235 hospital admissions to the emergency unit during the study period. Thirty-one (2.5 per cent) of admissions were considered to be drug-related. Women were more often affected than men. Patients with ADR were classified taking into account the type of pathology and the drug responsible for the effect. Dermatological and gastrointestinal reactions were predominant. Antibiotic and analgesic drugs were the most common drug groups implicated in causing an ADR.