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Biomedical subjects

M J Eadie

Publications and source records attributed to M J Eadie.

At least 19 recordsLinked to original sources
PubMed1992

Phenytoin metabolism during pregnancy.

The steady-state 72 h urinary excretion of various phenytoin metabolites has been measured in 10 epileptic women, whose plasma phenytoin concentrations relative to the phenytoin dose fell during pregnancy and rose again post-partum. In later pregnancy and post partum, a mean of 61.3% and 48.9%, respectively, of the total daily phenytoin dose was eliminated as 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Even though p-HPPH accounts for not much more than half the total daily phenytoin dose, increased excretion of this metabolite sufficed to account for the elimination of the entire increase in the dose of phenytoin required during pregnancy. There was no definite increase in the excretion of any other (minor) metabolite measured. Thus pregnancy seems not to enhance uniformly the capacity of the various metabolic pathways of phenytoin.

Epilepsy↗
PubMed1992

Vigabatrin--plasma enantiomer concentrations and clinical effects.

Plasma concentrations of the [R]- and [S]- enantiomers of the new anticonvulsant vigabatrin were measured by an enantiospecific gas-liquid chromatographic assay in a group of therapy-resistant epileptic patients in whom racemic vigabatrin was added to their existing antiepileptic drug regimens. The peak plasma concentrations of the biologically active [S]-enantiomer of vigabatrin were correlated with those of the [R]-enantiomer, with drug dose, seizure frequency and change in score on various tests of psychological function administered prior to and when the subjects were under steady-state conditions following vigabatrin therapy. Plasma [S]-vigabatrin concentrations correlated with drug dose, [R]-vigabatrin concentration and change in score of certain psychological tests reflecting verbal memory, recall and speed of information processing. No definite pharmacokinetic interactions were detected, though plasma phenobarbitone concentrations tended to fall during vigabatrin administration. There were too few data to assess the relation between [S]-vigabatrin concentrations and seizure frequency.

Adolescent↗
PubMed1992

XIXth century pre-Jacksonian concepts of epileptogenesis.

By the beginning of the XIXth Century the old belief that epilepsy was due to demonic possession or to malevolent influences emanating from a variety of sources had largely given way to an acceptance that the disorder was a physical illness which arose in the brain, though in some not very precisely defined way. No even reasonably satisfactory hypotheses about epileptogenesis were available till Marshall Hall (1790-1857), from 1836 onwards, popularised the concept of reflex action which had earlier been described by Robert Whytt (1714-1776) under the name 'sympathy'. Marshall Hall interpreted epilepsy as due to abnormal irritability in the afferent limb or central section of what later came to be called the reflex arc, loss of consciousness in the seizures being the result of secondary cerebral venous congestion. This concept of epileptogenesis was refined by Brown-Séquard, who in 1858 ascribed a more important role to overt or occult peripheral afferent nerve irritability, considered that the central element of the relevant reflex mechanism involved the medulla oblongata, and believed that reflex cerebral vasospasm, rather than cerebral venous congestion, caused loss of consciousness in the seizures. Almost contemporaneously, Schroeder van der Kolk placed considerably greater emphasis on the medullary element in causing the increased excitability of the reflex arc that produced epileptic seizures. These ideas of exaggerated reflex activity as the mechanism of epilepsy were made redundant by the work of Hughlings Jackson (1837-1911), who from 1860 onwards demonstrated that epilepsy arose in the cerebrum itself, rather than from altered function at lower levels of the nervous system.

Epilepsy↗
PubMed1992

The influence of other anticonvulsants on the plasma concentration of E-2-en-valproate.

E-2-en-valproate is a major metabolite present in the blood of humans treated with valproate. In animals it is a potent anticonvulsant. We have measured concentrations of valproate and E-2-en-valproate in 102 plasma samples obtained from 75 adult patients (20 taking valproate only; 55 taking valproate and other anticonvulsants) under steady-state conditions. The two groups' mean ages and weights were comparable. The average valproate daily dose was lower (p < 0.002) in the monotherapy group (1152 +/- S.D. 661 mg/d) than in the polypharmacy group (1902 +/- S.D. 874 mg/d). Despite this, the mean plasma levels of valproate and E-2-en-valproate were significantly higher (p < 0.05, p < 0.0001, respectively) in the monotherapy group (60.0 +/- S.D. 22.6 micrograms/ml; 3.00 +/- S.D. 1.40 micrograms/ml, respectively) than in the polypharmacy group (49.5 +/- S.D. 24.8 micrograms/ml; 1.73 +/- S.D. 0.95 microgram/ml). While the mean plasma valproate level was 17.5% lower in the polypharmacy group, the mean plasma E-2-en-valproate level was 42% lower. The co-administration of other anticonvulsants significantly reduced the concentration of valproate and, more so, of E-2-en-valproate in plasma.

Adult↗
PubMed1992

Salivary concentrations of antiepileptic drugs, oestradiol and progesterone throughout pregnancy in epileptic women.

Epileptic women may experience an increase in seizure frequency during pregnancy. To explore the relationship between seizures, simultaneous antiepileptic drug and sex hormone concentrations, 8 pregnant epileptic women collected saliva each week throughout their pregnancies and for up to 6 weeks after delivery. The ratio of the drug dose to the drug's body fluid concentration at steady state (dose:Css), as measured by high performance liquid chromatography (HPLC), increased throughout pregnancy and fell in the 3rd to 4th week postpartum. There was no correlation between the dose:Css ratio and the salivary oestradiol concentration, nor between the number of seizures and the antiepileptic drug or sex hormone concentrations, and there was only a weak positive correlation between the dose:Css ratio and the salivary progesterone concentration. The possible interactions between sex hormone concentrations, antiepileptic drug concentrations and seizures are complex, and warrant further study in a greater number of pregnant subjects.

Adult↗
PubMed1991

Single oral dose pharmacokinetics and comparative bioavailability of danazol in humans.

A comparative bioavailability study was conducted with two capsule formulations of danazol (200 mg) in 16 healthy adult male volunteers. Fasting subjects received single doses (400 mg) of each formulation on separate occasions 1 week apart. Blood samples were drawn at specified times up to 32 h after the dose and danazol concentrations in plasma were determined by a specific and sensitive HPLC method. The results for one subject were excluded as outlier values. The data from the other 15 subjects showed small differences, which did not achieve statistical significance between the formulations with respect to Cmax, Tpeak and AUC0-infinity. The mean elimination half-life for danazol was 9.44 +/- SD 2.74 h and the mean apparent total body clearance was 710 +/- SD 2161 h-1. These data differed from previously published results, probably as a result of the more sensitive and specific assay method used in the present work. It is likely that a high proportion of the oral dose of danazol is eliminated by presystemic metabolism.

Administration, Oral↗
PubMed1991

Lack of a pharmacokinetic interaction between phenobarbitone and gabapentin.

Twelve subjects received a single oral dose (300 mg) of gabapentin and serial blood and urine samples were collected for drug measurements. Oral phenobarbitone (30-90 mg/day) was then administered to steady-state, and the gabapentin single dose study was repeated on day 42. Gabapentin was administered from days 49 to 52 to achieved steady-state, and further blood and urine samples were collected for drug measurements. Trough plasma phenobarbitone concentrations were monitored at frequent intervals. No statistically significant differences were observed in gabapentin Cmax, tmax, AUC, t1/2 or urinary drug recovery following single doses of gabapentin alone or combined with phenobarbitone. Phenobarbitone did not alter the disposition of gabapentin at steady state. Mean trough steady-state phenobarbitone concentrations were not significantly affected by concomitant gabapentin administration.

Acetates↗
PubMed1991

Formation of active metabolites of anticonvulsant drugs. A review of their pharmacokinetic and therapeutic significance.

All of the commonly used anticonvulsants drugs, except possibly primidone, are cleared from the human body mainly by metabolism. The metabolites of phenytoin, phenobarbital and ethosuximide have so far not been shown to possess significant pharmacological activity. However, carbamazepine-10,11-epoxide, derived from carbamazepine, has anticonvulsant activity comparable with that of its progenitor, while oxcarbazepine, a new anticonvulsant congener of carbamazepine, is essentially a prodrug for its 10-hydroxy derivative. Valproic acid forms numerous metabolites through a variety of pathways; 2-en valproic acid, a beta-oxidation derivative, probably contributes to its anticonvulsant action, though the extent of the contribution is uncertain. Another metabolite, 4-en-valproic acid, has been considered a possible hepatotoxin and teratogen. N-Methyl-phenobarbital and primidone, though both anticonvulsants in their own right, are metabolised to phenobarbital, which probably mediates much of their antiseizure effect. Primidone also yields the weaker anticonvulsant phenylethylmalonamide. The various benzodiazepine anticonvulsants form numerous metabolites, some of which possess both antiseizure and other forms of pharmacological activity. As yet, there is little understanding of how best to interpret simultaneous plasma concentration measurements of anticonvulsant drug and its active metabolite (or metabolites) in the clinical situation, and the possible roles of anticonvulsant metabolites in the idiosyncratic toxicity of these drugs remain largely unexplored.

Anticonvulsants↗
PubMed1990

Possible roles for frequent salivary antiepileptic drug monitoring in the management of epilepsy.

Salivary levels of phenytoin, phenobarbitone, carbamazepine and carbamazepine-epoxide correlate with the simultaneous plasma water levels of these substances, after correcting for the effects of pH differences between saliva and plasma in the case of phenobarbitone. Saliva is easy and painless to collect, and salivary levels of the drugs are conveniently measured. Frequent (often daily) monitoring of pre-dose morning anticonvulsant drug concentrations in saliva over periods of weeks or months in 3 groups of epileptic subjects showed that (i) in some but not all poorly controlled epileptic patients seizures tended to occur on days when salivary anticonvulsant levels were lower than on non-seizure days, (ii) in such subjects it was possible to estimate an anticipated optimal drug concentration and dose to minimize seizure activity from the plot of seizure frequency against drug concentrations, (iii) in women with 'catamenial' epilepsy, salivary anticonvulsant levels were lower on perimenstrual days than at mid-cycle in half of the subjects studied, and (iv) in pregnant epileptic women the time course of the change in drug levels relative to dose could be followed more closely throughout pregnancy and the post-natal period than was practicable when using blood level measurements. Frequent measurement of salivary anticonvulsant concentrations appears a promising and inexpensive adjunct to the investigation and management of certain problem areas in epilepsy.

Adult↗
PubMed1990

Valproate metabolism during hepatotoxicity associated with the drug.

Plasma concentrations of valproate and certain of its metabolites and their patterns of excretion in urine are described in three adults who developed hepatotoxicity during treatment of epilepsy with sodium valproate. One patient also developed a degree of reversible renal insufficiency, whilst another may have had associated infectious mononucleosis. All three cases showed evidence of impaired mitochondrial beta-oxidation of valproate. In one the impairment was at the stage catalysed by fatty acyl-CoA dehydrogenase, in another at the stage catalysed by 3-hydroxyacyl-CoA dehydrogenase and in the third at the stage catalysed by enoyl-CoA hydratase and possibly also at the next stage catalysed by 3-hydroxyacyl-CoA dehydrogenase. The impaired beta-oxidation meant that valproate metabolism was diverted into various alternative pathways. Plasma concentrations of the suspected hepatotoxic metabolite 4-en-valproate were normal for the valproate-treated population in all cases. By analogy with certain spontaneous and acquired human disorders of branched chain amino acid metabolism, it is suggested that valproate-associated hepatotoxicity may represent the consequences of a valproate overload on a limited mitochondrial beta-oxidation capacity, causing accumulation of a toxic product of endogenous branched chain amino acid metabolism.

Adult↗
PubMed1990

Effect of food on absorption of lomefloxacin.

Twelve subjects participated in an open-label, single-dose, balanced three-way crossover study in which the absorptions of lomefloxacin were compared following (i) an overnight fast, (ii) a carbohydrate meal, and (iii) a high-fat meal. The time to peak concentration of lomefloxacin was delayed, but peak concentration in plasma and amount of drug absorbed were unchanged following both meals.

4-Quinolones↗
PubMed1990

The evolution of J. Hughlings Jackson's thought on epilepsy.

By 1870, and within 5 or 6 years of his beginning to analyse the clinical phenomena of epilepsy and to correlate them with autopsy data, the 35-year-old John Hughlings Jackson had come to a view of the nature of epilepsy that was radically different from that of his contemporaries. He recognized that epileptic seizures arose in the cerebral cortex, and not in the medulla oblongata, as was then thought, and he saw that there was no fundamental difference between so-called 'genuine' epilepsy and epileptiform seizures. His great lecture, 'A study of convulsions', published in 1870, contains the essence of nearly all our modern ideas concerning the nature of epilepsy. While Jackson spent the next 30 years of his life in further interpretation of the phenomena of epilepsy, as he did this he began to back away from many of the more radical implications of his earlier brilliant insights. He seems to have done this to make his views more palatable to his contemporaries, but this also encouraged him to interpret varieties of epilepsy in relation to a conceptual scheme of 2, and later 3, hierarchal levels of nervous system functioning. The result is that today's reader of Jackson's later papers can be left rather bewildered and it is only by reading the whole corpus of his work that his enormous conceptual contribution to present-day epileptology can be appreciated.

Cerebral Cortex↗
PubMed1979

Effects of subjects' sex, and intake of tobacco, alcohol and oral contraceptives on plasma phenytoin levels.

1. Steady state plasma phenytoin levels in 210 epileptic patients were studied by computerized analysis of covariance to determine whether the subject's sex, alcohol intake, tobacco smoking or use of oral contraceptives influenced the relation between plasma drug level and drug dose. 2. Sex, tobacco smoking and alcohol usage had no statistically significant effect. There was a trend towards higher phenytoin levels relative to drug dose in oral contraceptive users. 3. This finding prompted an additional study of plasma phenytoin levels in 40 oral contraceptive users and 135 aged matched non-users. Analysis of covariance again showed higher plasma phenytoin levels relative to drug dose in users of oral contraceptives (P = 0.061). 4. This finding raised the possibility that the relation between plasma phenytoin level and drug dose differed between males and females who did not use oral contraceptives. However, when the relation between plasma phenytoin levels and drug dose was compared in 159 females who did not use oral contraceptives and 101 males (both groups aged 15 to 70 years) no statistically significant difference was found.

Adolescent↗
PubMed1979

The epoxide of carbamazepine.

Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide have been measured by high pressure liquid chromatography in 101 epileptic children and adults taking the drug. There was either no statistically significant correlation, or only a very poor correlation, between drug dose and steady-state plasma levels of a) carbamazepine, b) its epoxide, and c) the sum of drug and epoxide. Plasma concentrations of carbamazepine correlated with those of it epoxide. Plasma carbamazepine levels were lower in patients taking phenytoin with carbamazepine than in patients taking carbamazepine alone. Plasma carbamazepine-10,11-epoxide levels were not definitely altered when carbamazepine and phenytoin were used together. This finding is consistent with the hypothesis that phenytoin enhances the metabolism of carbamazepine to a metabolite other than its epoxide.

Adolescent↗