[Methotrexate pharmacology]. / Pharmacologie du méthotrexate.

Methotrexate is a folic acid analog, which is a thymidylate synthetase and dihydrofolate reductase inhibitor. It is used in oncology, dermatology and rheumatology and off labelling in the treatment of ectopic pregnancies. This paper is a review of methotrexate pharmacology with focus on data concerning ectopic pregnancies.

Identification of a novel mutation in the dihydropyrimidine dehydrogenase gene in a patient with a lethal outcome following 5-fluorouracil administration and the determination of its frequency in a population of 500 patients with colorectal carcinoma.

OBJECTIVES: Life-threatening toxic side-effects following 5-FU exposure have been related to deficiency of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in its catabolism. We presently report a new DPYD gene SNP in a Spanish woman who died from multivisceral 5-FU-induced toxicity. DESIGN AND METHODS: We looked for 22 known SNPs by Pyrosequecing. Then, we sequenced the whole 23 exons of DPYD, along with adjacent intronic sequences. PCR was carried out to determine whether or not exons were deleted in the DPYD. To determine whether the predicted stop codon indeed resulted in a truncated protein, a bacterial expression vector was employed to generate the predicted protein. 500 patients were genotyped to determine allele frequency. RESULTS: A novel mutation 464 T>A was identified in DPYD gene exon 5, resulting in the replacement of leucine 155 by a stop codon in the protein. We confirmed this mutation by Pyrosequencing and its involvement by a protein truncation test. We genotyped the patient's family and the allele frequency was 0.2%. CONCLUSION: The involvement of this variant in 5-FU life-threatening toxicity supports its inclusion in pretherapeutic genetic screening.

Hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil.

Here we report on a case of hepatotoxicity associated with the use of a fixed combination of chloroquine and proguanil. Alternative causes of liver injury were excluded. The pathophysiological mechanism remains unclear, with a possibility of allergic reaction. In view of the widespread use of both drugs, clinicians should be aware of this drug-induced liver injury.

Inquiry into the distribution of drugs in a diabetic clinic.

The aim of this study was to investigate possible discrepancies between the drug prescribed and that recorded in the patient's file. A prospective open blind study was conducted with 178 patients included consecutively. We analysed 1011 prescriptions (the median (range) number of drugs per patient was 5 (1-37)) and identified 49 discrepancies (5 per cent of cases). In 18 cases, the drug given to the patient by a nurse was not the drug initially prescribed but the drug recorded in the patient's file was the drug actually given to the patient. In another 31 cases, the drug given to the patient was not the drug initially prescribed, but the drug recorded was that prescribed. This inquiry shows that there may be a discrepancy between the drug initially prescribed and that actually administrated and suggests that poor traceability may affect pharmacological surveillance surveys.

[Retrospective study of adverse drug reactions in the elderly: experience of regional center for pharmacovigilance]. / Etude rétrospective de la iatrogénie médicamenteuse chez le sujet âgé: expérience d'un centre régional de pharmacovigilance.

Cases of adverse drug reactions which occurred in the elderly, and were notified to the Regional Centre of Pharmacovigilance of Angers between 1995 and 1998, were analysed in two subgroups: from 75- to 84-years-old and older than 84 years. Among the 263 cases recorded in the elderly, there was no significant difference between the 75- to 84-year-old patients (180 cases) and the patients older than 84 years (83 cases) concerning past medical history, severity of effects or medication. Side-effects in patients over 74 were mainly cutaneous, haematological and neuropsychiatric, involving in decreasing order of frequency cardiovascular, neuropsychiatric, antibiotic, analgesic and anti-inflammatory drugs. In comparison with patients under 75, adverse drug reactions are more frequent and more serious, notably overdose and drug interactions, in elderly people. The occurrence of some avoidable side-effects justifies the strengthening of information about therapeutic safety in the elderly.

Study of haemostasis in depressive patients treated with fluoxetine.

The object of this study was to investigate a possible pharmacological effect of fluoxetine on haemostatic function, with special attention on primary haemostasis, in order to explain haemorrhagic complications reported in some treated, depressed patients. The haemostatic function of depressive patients, who required fluoxetine therapy, was studied before and after 1 month of treatment with fluoxetine 20 or 40 mg daily. Exclusion criteria were: pregnancy, initial abnormal haemostatic function, history of coagulation abnormalities, treatment with drugs that interfere with haemostasis, and recent fluoxetine therapy. The following tests were performed: prothrombin time, partial thromboplastin time, thrombin time, plasma fibrinogen, platelet counts, bleeding time, platelet aggregation induced by ADP, epinephrine, ristocetin, collagen, arachidonic acid, and plasma determination of fluoxetine and norfluoxetine levels. Statistical analysis was performed by Wilcoxon paired sample, one-tailed test (alpha=0.05). Among 18 patients included, only eight completed the trial. The single statistically significant difference was a decreased velocity in platelet aggregation induced by epinephrine without increased bleeding time. The results failed to demonstrate any compromised haemostatic function after 20 mg daily fluoxetine therapy in patients with initial haemostatic function. However, the results suggest possible effects of fluoxetine on platelet adrenoreceptors.

Mechanisms of the inhibition of human erythrocyte pyridoxal kinase by drugs.

The aim of this study was to investigate the interaction between drugs chosen for their clinical neurotoxicity or chemical structure and vitamin B6 metabolism. After a preliminary screening of drugs to determine their potential inhibitory effect on erythrocyte nonpurified pyridoxal kinase (PLK) (EC 2.7.1.35), additional investigations, including kinetic studies and detection of chemical reactivity between the inhibiting drugs and pyridoxal (PL) or pyridoxal-5'-phosphate (PLP), using UV-visible spectrophotometry and mass analysis, were carried out to specify the mechanism of PLK inhibition. Depending on the results, the inhibiting drugs were divided into three groups. The first group included theophylline and progabide and inhibited PLK using either PL or pyridoxamine (PM) as substrate and thereby were true inhibitors. Moreover, they did not form covalent complexes with PL or PLP. The second group, which included cycloserine, dopamine, isoniazid, and thiamphenicol glycinate, inhibited PLK using PL, but not PM, as substrate. They were able to react with PL or PLP to form covalent complexes, and kinetic studies suggested that the observed PLK inhibition was due to these formed complexes. A third group, which consisted of levodopa, D-penicillamine, and muzolimine, inhibited PLK using PL, but not PM, as substrate. They formed, with PL or PLP, chemical derivatives that probably had no inhibitory effect on PLK. These results and the clinical consequences of such interactions are discussed and compared with results of previous studies.

Kinetic studies of the effects of K+, Na+ and Li+ on the catalytic activity of human erythrocyte pyridoxal kinase.

Kinetic studies were conducted to examine the effects of K+, Na+ and Li+ on human erythrocyte pyridoxal kinase (PK) activity. A dialyzed hemolysate served as the PK source. The substrates used were pyridoxal (PL) and ATP. Determination of the enzymatic activity was based on HPLC separation and fluorimetric detection of PL and pyridoxal 5'-phosphate as semicarbazone derivatives. In comparison to the poor activity of PK assayed without monovalent cation, all tested cations are activators. Among them, K+ is the most effective, improving both PK affinity for the substrates and maximal velocity. Na+ increases maximal velocity and PK affinity for ATP but decreases it for PL. Li+ is a poor activator which seems to modify the enzymatic mechanism from a random to an ordered sequential pattern with ATP bound before PL. Results suggest that K+ and Na+ bind to PK on the same site while Li+ binds on another site. This hypothesis and the mechanism of monovalent cation-PK interaction are compared to other well-known K(+)-activated enzymes.

[Uncontrolled retrospective study of 75 pregnancies in women treated for epilepsy]. / Etude rétrospective non contrôlée de 75 grossesses chez des femmes épileptiques traitées.

OBJECTIVE: Our purpose was to study pregnancies and birth outcomes in a population of women treated for epilepsy. STUDY DESIGN: A retrospective uncontrolled study of 75 pregnancies in 55 epileptic women under treatment was conducted in the nursery of CHU Angers. The course of pregnancies and deliveries, the frequency of congenital malformations and the clinical state of the neonates during the first 6 days of life were recorded. RESULTS: There was a high rate of prematurity (15%) especially in patients treated by phenobarbital, a 10.5% rate of intra-utero growth retardation, a 11% rate of major congenital malformations and a 9% rate of isolated minor congenital malformations. Congenital malformations were mainly facial dysmorphia, cardiopahties, urogenital tract abnormalities. The neonatal symptomatology was associated with a high level of antiepileptic drugs in neonates or to a withdrawal syndrome or to hypovitaminosis. CONCLUSION: Overall results justify implementing prevention and detection measures.

Use of plasma iodine assay for diagnosing thyroid disorders.

AIMS: To examine the advantage of systematic plasma iodine assays in establishing the thyroid function of patients with thyroid disorders. METHODS: Iodine was determined by inductively coupled plasma mass spectrometry (ICPMS) in the plasma of 799 patients consulting for possible thyroid disorders, indicated by FT4 and TSH assays. RESULTS: Plasma iodine was below 40 micrograms/l in 57 (7%) patients, most of whom had hypothyroidism; 40-80 micrograms/l in 439 (55%) patients, most of whom had normal thyroid hormone function; 80-250 micrograms/l in 240 (30%) patients, most of whom had hyperthyroidism; and above 250 micrograms/l in 63 (8%) patients, almost all of whom had iodine overload caused by iodinated drugs, particularly amiodarone, resulting in euthyroidism (24%), hyperthyroidism (36%), and hypothyroidism (16%). Sixty five (7%) had been treated with amiodarone and 27 (3%) with other iodinated drugs. More than 10% of patients with thyroid disorders therefore had an iodine overload. CONCLUSIONS: The determination of total plasma iodine using the simple, accurate ICPMS technique, should be carried out in patients consulting for thyroid disorders, particularly for the detection of an iodine overload.

[Evaluation of drug side effects over a year in a cardiology service]. / Bilan des effets indésirables médicamenteux recueillis au cours d'une année dans un service de cardiologie.

An intensive pharmacovigilance survey was carried out over the course of 1 year in cardiology department which revealed 64 reports of adverse drug reactions among 61 hospitalised patients, giving an overall incidence of 2.3%. Most of the patients in whom adverse drug reactions were recorded were elderly and female. The most common adverse events were cardiovascular (72%) and haemorrhagic (9%), and related to drugs given for the treatment of cardiovascular disorders. The symptoms originating from drug therapy were dominated by sinus arrhythmias (25 cases), linked to drugs co-administered that have potentially similar cardiac pharmacodynamic effects. Seven cases of "torsades de pointe" were also observed.

Inhibition of cholinesterases by histamine 2 receptor antagonist drugs.

Many studies have demonstrated that histamine 2 receptor antagonists (H2RA) have in vitro anticholinesterase effects, but discrepancies about type and potency of this inhibitory effect exist among published results. Moreover, cholinesterase inhibition has not been shown in patients receiving H2RA. These discrepancies led us to study the in vitro antibutyryl- and in vitro antiacetylcholinesterase activities of ranitidine, cimetidine, nizatidine comparatively to pyridostigmines. Plasma cholinesterase activity (PCEA), erythrocyte cholinesterase activity (ECEA) and plasma ranitidine levels were measured in six patients before and during continuous IV infusion (150 or 200 mg/d) of ranitidine. Our in vitro results confirm the weak anticholinesterase activity of H2RA. Ranitidine is the most potent inhibitor of butyrylcholinesterase (Ki = 61 microM). Ranitidine and nizatidine are the most potent inhibitors of acetylcholinesterase (Ki' = 2.1 microM, Ki' = 5.1 microM, respectively) but one thousand times less effective than pyridostigmine (Ki = 0.003 microM). The results in patients show no statistically significant difference between PCEA and ECEA measured before and during ranitidine infusion (plasma ranitidine levels between 0.31 and 1.25 microM).

[Severe anaphylactoid reactions after intravenous corticosteroids. Report of a case and review of the literature]. / Réactions anaphylactoïdes graves après corticoïdes intraveineux. A propos d'un cas et revue de la littérature.

We report a case of fatal anaphylactic reaction to intravenous methylprednisolone succinate therapy developed in a 51 year old asthmatic man with aspirin intolerance and undetermined myocarditis. 14 similar cases were found in literature and analysed: asthma and aspirin intolerance seem to be risk factors; the organism reacts against either unconjugated corticoid or esterified corticoid principally its succinate salt; the mechanism of these reactions remains not clear; it may be either a true allergic reaction or a non specific reaction.

Automated determination of cholinesterase activity in plasma and erythrocytes by flow-injection analysis, and application to identify subjects sensitive to succinylcholine.

This automated spectrophotometric method for determination of cholinesterase activity in erythrocytes and plasma is based on measurement of the choline produced at 30 degrees C by the hydrolysis of acetyl-, butyryl-, or succinylcholine. Blanks, standards, and samples are prepared by a Gilson robotic unit. Use of flow-injection analysis for detection allows use of smaller volumes of reagent and sample. We applied this method to the study of 91 healthy subjects and members of two families with succinylcholine sensitivity. Results with use of the three different substrates for determination of activity in plasma correlated well (r greater than 0.94). Results for plasma and erythrocytes from healthy subjects are lower in women less than 50 years old than in women greater than 50 years or men. Values for plasma obtained with succinylcholine substrate (range: 31 to 100 U/L) allow detection of very sensitive subjects--AA phenotypes (less than 10 U/L)--but do not distinguish the UA from the UU phenotype.