[Teratogenic and oncogenic effects of central nervous system drugs].
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Biomedical subjects
Publications and source records attributed to P Loiseau.
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Phenobarbital and diphenylhydantoin were estimated in treated epileptics. An initial measurement was made in 457 patients. 96% were taking phenobarbital and 53% diphenylhydantoin. Only 37% of the phenobarbital levels and 18% of the diphenhlhydantoin levels were in a therapeutic range. Correlations between the levels, the stability of the epilepsy and signs of overdosage are discussed. Intolerance to phenobarbital reported in some patients, which appears to be real, is not reflected by "normal" or even low blood levels. By contrast, high levels of phenobarbital appear to be well tolerated. Signs of overdosage were quasi-constant when levels of diphenylhydantoin were greater than 15 mg/1. Doses of phenobarbital and of diphenylhydantoin were altered, levels assessed and the clinical condition evaluated in 134 patients. Bringing levels to within the therapeutic range resulted in the disappearance of attacks in 55% of cases for phenobarbital and 30% for diphenylhydantoin. Reduction of doses responsible for excessively high blood concentrations (overdosage) was practically never associated with an increase in the number of attacks. This adjustment is easy for phenobarbital though much more difficult for diphenylhydantoin. In this study, therapeutic levels were 15 to 25 mg/1 for phenobarbital, and 7 to 15 mg/1 for diphenylhydantoin.
Two hundred epileptics presenting with partial epileptic attacks were subjected to investigation by Acta-Scanner. Results were normal in 100 cases. Also found were 20 tumours (13 of them astrocytomas), 7 epileptogenic softenings, 41 cerebral atrophies, 8 of which were porencephalies, 5 calcifications (3 isolated, 2 multiple, connected with Bourneville's disease), 5 post-operative lesions and 22 dubious conditions. Various correlations between the results of scanning, the clinical findings and the E.E.G. are considered. The value of scanning in screening for tumours developing under the cloak of isolated epilepsy is emphasized and attention is drawn to certain difficulties of interpretation.
It is no longer acceptable to prescribe anticonvulsants on the basis of empirical rules. Pharmacological studies have made it possible to measure the absorption, distribution and excretion of these drugs. Complete understanding of this data is neccessary if anticonvulsant prescribing is to be fully effective and to avoid iatrogenic disease.
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Since the beginning of 1974, we have studied 17 cases of iatrogenic encephalopathy due to the ingestion of bismuth taken for the treatment of chronic digestive disorders. More than 100 similar cases have been reported in France within the same period. The clinical picture is remarkably consistent: there is a relatively long prodromal phase with difficulties in gait and writing, followed by a phase characterised by four signs, namely a severe confusional syndrome, myoclonus, astasia-abasia and sisorders of language. In our cases, after withdrawal of bismuth, recovery invariably began within 2 to 3 weeks but fatal cases have been described. All our patients had taken, for periods of between 3 weeks and 20 years, bismuth subnitrate. The levels of bismuth in the blood and urine in these patients were between 10 and 100 times as great as those in patients who had taken the same treatment without ill effect. The exact mechanism by which bismuth causes this complication, described only recently, is totally unknown.
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The authors report some basic notions on the pharmacokinetics of antiepileptic drugs, and the informations given by serum level determinations of anticonvulsants. It is not conceivable to treat epileptics without taking into account these facts. But it is neither necessary nor desirable to measure blood levels of antiepileptic drugs in every patient.
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Dipropylacetate is absorbed rapidly and attains a maximum concentration in serum 1 to 3 hr after ingestion. Since its half-life is on the order of 8 to 10 hr, it must be prescribed three times a day, every 8 hr. It reaches a stable concentration in blood within 48 hr after treatment is begun (by contrast with diphenylhydantoin and phenobarbital) and might therefore be useful when seizures must be controlled quickly. The serum concentration can be altered by some other anticonvulsant drugs, but these interactions should be studied in more detail. The serum concentration varies considerably in the course of a day and from one day to the next in the same subject, which makes it difficult to adjust the blood level. Depamide is rapidly transformed in vivo to dipropylacetate.
Three male siblings in a gypsy family presented with congenital Addison's disease. The youngest showed neurological signs at the age of ten and deteriorated rapidly. The eldest had convulsive symptoms and the third an irregular E.E.G. Investigation of the youngest by means of cerebral biopsy revealed rarefaction of myelin with perivascular sudanophil deposits. An ultrastructural study showed frequent liposfuscin deposits in the astrocytes and oligodendrocytes. In the peripheral nerve there were signs of re-myelinization associated with hypertrophy of Schwann cells. These various aspects have led to these cases of demyelinization associated with adrenal deficiency being classified among the leukodystrophies while some authors have interpreted these lesions as characteristic of Schilder's disease. The fact that in thirty or so cases published, almost half of which are familial, only boys are affected supports the theory of an enzymopathy at the root of both leukodystrophy and adrenal atrophy.
The results of serum level determination in 250 epileptics confirm previous papers. Phenobarbital: --Is a "safe" anticonvulsant: steady serum level during 24 hours periods in chronic treatment and rather stable relationship between ingested dose and serum level. It can therefore be given as in the past, without blood level control. --Must always be prescribed according to the patient's weight, because serum level and therefore cerebral concentration depends on the dose per kilogram and not on the absolute dose. --Must be given in relatively higher dosage to children on account of a faster catabolism. --Is interfered with in its kinetics by other anticonvulsants and this fact must be taken into consideration for drugs associations. --Has no predetermined blood level for the control of every epilepsy. Some patients no longer have seizures with a theoretically too low serum level, while others still have seizures in spite of very high serum levels.
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