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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
PubMed1995

Metabolism of carbamazepine and co-administered anticonvulsants during pregnancy.

Urinary excretions of carbamazepine, carbamazepine-10,11-epoxide, carbamazepine-10,11-trans-diol, 9-hydroxyacridan and 2- and 3-hydroxycarbamazepine were measured at various stages of pregnancy, and in the post-natal period, in ten epileptic women, six of whom took no other enzyme-inducing anticonvulsant and four of whom took such co-medication. Mean plasma carbamazepine apparent clearance was increased in pregnancy, but only by virtue of the increased clearance in the anticonvulsant co-medicated women. Alterations in the proportions of the carbamazepine dose cleared via the various excretion pathways studied were quantitatively minor, but there was evidence consistent with impaired conversion of carbamazepine-10,11-epoxide to carbamazepine-10,11-trans-diol during all pregnancies studied. Clearances of carbamazepine to the various excretory products studied were consistent with there being (i) increased urinary excretion of unmetabolised drug in pregnancy, possibly related to the increased glomerular filtration rate, (ii) increased formation of oxidative metabolites of the drug, particularly in women co-medicated with enzyme-inducing anticonvulsants, this effect being offset, in full (in non-co-medicated women) or in part (in co-medicated women) by (iii) inhibition of the epoxide-diol pathway in pregnancy, an inhibition to which folate intake may have contributed.

Adult↗
PubMed1995

The role of therapeutic drug monitoring in improving the cost effectiveness of anticonvulsant therapy.

When monitoring of the plasma concentrations of anticonvulsant drugs first came into use 25 years ago, it appeared to have a major impact on improving the effectiveness and safety of anticonvulsant therapy. However, as time has passed, prescribers have absorbed many of the lessons to be learned from the monitoring, and now apply this knowledge without necessarily monitoring plasma anticonvulsant concentrations as frequently as in the past. Therefore, the effect of the drug concentration monitoring on the cost effectiveness of anticonvulsant therapy is probably not as significant now as it originally was. In theory, drug concentration monitoring is often unlikely to decrease the cost of contemporary anticonvulsant drug therapy, but it may enhance the efficacy of the therapy. Thus, monitoring may reveal unrecognised under- or overdosage, detect failure of compliance or drug-drug interactions, or indicate when there is little point in persisting with a particular anticonvulsant drug. Despite a good deal of anecdotal testimony, surprisingly little has been published demonstrating the benefits of anticonvulsant therapeutic drug monitoring in epileptic populations. However, one study did show better rates of seizure control rates in patients monitored in the first 6 months of their epileptic disorder; but not if the monitoring began later than this.(ABSTRACT TRUNCATED AT 250 WORDS)

Anticonvulsants↗
PubMed1995

Treatment of Parkinson's disease.

Early stage Parkinson's disease may be better left untreated if it does not limit motor function. Once limitation of function is present levodopa-dopa decarboxylase inhibitor combinations are the most effective therapy, although amantadine may be satisfactory for a time in milder cases. The optimal independent roles of the ergot derivatives bromocriptine and pergolide, and the MAOb inhibitor selegiline, are not yet generally agreed although they are accepted as useful in supplementing the effects of levodopa. With prolonged levodopa use various late-stage treatment problems may appear. The pathogenesis of these is poorly understood and no completely satisfactory ways of managing them are available.

Antiparkinson Agents↗
PubMed1994

Early stage autoinduction of carbamazepine metabolism in humans.

Six healthy young adult male volunteers were given two 600 mg (2540 mu moles) oral doses of carbamazepine (CBZ) 5 days apart. Serial concentrations of CBZ and its 10,11-epoxy (CBZ-epoxide) and 10,11-dihydro-10,11-trans-dihydroxy (CBZ-diol) metabolites in plasma, and daily excretions of these substances and the 2-hydroxy (2-OH-CBZ), 3-hydroxy (3-OH-CBZ) and 9-hydroxymethyl-10-carbamoylacridan (acridan) metabolites in urine were followed for 5 days after each dose. Pharmacokinetic analysis showed that autoinduction of CBZ metabolism was present within 6-10 days of the initial drug dose. The mean oral clearance of CBZ increased from 1.48 to 1.74 l.h-1 (difference 0.26 l.h-1, 95% confidence interval 0.11 to 0.41 l.h-1) and the mean percentage urinary recovery of the amount of CBZ eliminated increased from 41.8% to 44.6% (difference 2.8%, 95% confidence interval 0.5 to 5%) between the two studies 5 days apart. The data for daily clearance to metabolite and the time-courses of the plasma CBZ-epoxide to CBZ and CBZ-diol to CBZ concentration ratios suggested that autoinduction had begun by the second day after CBZ intake, and involved not only the epoxide-diol pathway but, to a lesser extent, the oxidations to phenolic derivatives.

Acridines↗
PubMed1994

Urinary excretion of phenobarbitone and its metabolites in chronically treated patients.

The elimination of phenobarbitone (PB) was studied in 14 chronically treated epileptic patients under steady state conditions. PB, [S]-PB-N-glucoside ([S]-PB-N-G) and p-hydroxy-PB (p-OH-PB) were assayed in urine by a HPLC method. Some 57% of the daily dose was recovered in urine, 14% as [S]-PB-N-G, 16% as p-OH-PB (conjugated plus non-conjugated) and 27% as unaltered PB. Thus PB-N-G formation contributed significantly to the elimination of PB during long-term administration of the drug, and there was reason to suspect that some of the PB-N-G formed may have already been degraded to untraced products before excretion from the body.

Adult↗
PubMed1994

Epileptic seizures in 1902 patients: a perspective from a consultant neurological practice (1961-1991).

Over a 30 year period, a total of 1902 persons with at least one epileptic seizure was referred to a consultant neurological practice. The type of seizure that was present was not determined in 10.6%, was generalised in 33.3%, partial in 53.9%, infantile convulsions in 1.1%, and 'generalised-partial' in 1.2%. The latter category probably represented the coincidence of generalised seizures (overt or as an EEG trait) and partial seizures in occasional individuals. At presentation, 13.9% of the series had experienced only a solitary seizure (80% of these a tonic-clonic fit). Compared with the rest of the series, solitary seizure sufferers more often went at least 1 year seizure free (78.6% v. 40.2%, for those with known outcomes), and were known to have been able to cease therapy after 3-5 years without seizures (26.5% v. 12.5%). Established seizure disorders (first seizure more than 1 year earlier, at least three tonic-clonic fits and/or at least 10 less severe seizures) were already present at referral in 996 persons (52.4%). Of these persons, a minimum of 9.1% were able to cease therapy after 3-5 years seizure free. In the whole series, at least 274 persons (14.4%) ceased therapy after a mean of 4.72 +/- SD 3.05 years without seizures. The outcome was unknown in 50: seizures recurred in 20.5% of the remaining 224 who were followed for at least 1 year (in 70% the recurrence was within 1 year of withdrawing therapy). Even one tonic-clonic fit at any time increased the chance of a failed withdrawal of therapy, while seizure control with anticonvulsant monotherapy, earlier age at first seizure and earlier age at seizure control correlated with a successful withdrawal of therapy.

Anticonvulsants↗
PubMed1994

Plasma antiepileptic drug monitoring in a neurological practice: a 25-year experience.

Rates for being free of all epileptic seizures for at least 1 year and for ceasing therapy after 3-5 years of full seizure control were similar in 548 treated epileptic patients referred from 1962 to 1970, during which period plasma antiepileptic drug concentration monitoring became available (32.7 and 17.0%, respectively), in 960 patients referred from 1971 to 1979, when such monitoring was used increasingly (29.6 and 14.9%, respectively), and in 348 patients referred from 1980 to 1989, when this monitoring was widely available (30.5 and 10.1%, respectively). However, monitoring was associated with higher rates of full seizure control in patients seen within 6 months of their first seizure, even when patients with only a solitary seizure were excluded. Possibly, monitoring then helped achieve early complete suppression of not yet established seizure processes, but had less effect on already entrenched seizure mechanisms. Plotting cumulative percentages of patients with fully controlled seizures versus plasma antiepileptic drug concentrations yielded data that were broadly in keeping with conventional 'therapeutic' ranges for phenytoin, carbamazepine, phenobarbital, and ethosuximide monotherapy. With a given plasma phenobarbital (but not phenytoin or carbamazepine) concentration, rates of full seizure control were appreciably higher for generalized onset than for partial onset seizures. Use of a second antiepileptic drug was associated with improved full seizure control in both generalized onset and partial onset seizures, which had not been controlled by monotherapy; adding a third drug yielded little further benefit.

Anticonvulsants↗
PubMed1994

Inhibition of phenobarbitone N-glucosidation by valproate.

Plasma phenobarbitone concentrations and daily urinary excretion of phenobarbitone and its metabolites p-hydroxyphenobarbitone (conjugated and unconjugated), and [S]-phenobarbitone-N-glucoside were measured under steady-state conditions in two groups of epileptic patients, (i) taking phenobarbitone with or without other drugs, but not valproate (n = 12), and (ii) taking phenobarbitone with other drugs including valproate (n = 8). Mean steady-state plasma phenobarbitone concentrations were 5.9 mg l-1 higher, relative to drug dose, in the patients taking valproate than in those not taking valproate. Urinary excretion of [S]-phenobarbitone-N-glucoside was significantly lower in the group taking valproate (1.9 +/- s.d. 2.0% of phenobarbitone dose vs 16.2 +/- s.d. 9.9%). Urinary excretion of phenobarbitone (23.7 +/- s.d. 9.8% vs 48.2 +/- s.d. 13.6%) and unconjugated p-hydroxyphenobarbitone (5.7 +/- s.d. 3.9% vs 16.0 +/- s.d. 9.1%) was higher in those taking valproate, while conjugated p-hydroxyphenobarbitone excretion was similar in both groups (8.3 +/- s.d. 4.9% vs 6.5 +/- s.d. 2.9%). Valproate appeared to inhibit both the direct N-glucosidation of phenobarbitone and the O-glucuronidation of p-hydroxyphenobarbitone.

Adult↗
PubMed1994

The understanding of epilepsy across three millennia.

The phenomena of epilepsy have been known for at least 3000 years, the earliest recorded account being in an Akkadian text called the Sakikku (written around 1067-1046 BC). Over nearly all the subsequent centuries the popular belief has been that epilepsy is a disorder of supernatural origin, and to some extent such ideas have carried over into medical thought. In Western civilisation, the long dominant belief was that epilepsy was due to possession by a devil or a demon, an interpretation given authoritative support by the miracle story of the cure of the epileptic child which is recorded in all three synoptic Gospels. However, there have been many other interpretations e.g. epilepsy as a consequence of wrong doing or of lunar or magical influences. Such ideas began to die out only in the past 200 years. From Hippocrates (c. 400 BC) onwards, there has been a continuing line of thought that considered epilepsy a medical condition due to natural causes. The hypotheses concerning its pathogenesis have ranged from excess phlegm in the brain, through boiling up of the vital spirits in the brain (Paracelsus), explosion of the animal spirits in the centre of the brain (Willis), heightened reflex activity at a spinal (Marshall Hall) or medullary level (Brown Séquard), to Hughlings Jackson's notion of an occasional, an excessive, and a disorderly discharge' in part of the cerebral cortex. Among thinking men, epileptology in the past century has proved largely to be a matter of exploring the ramifications of Jackson's concepts.

Epilepsy↗
PubMed1993

Plasma vigabatrin enantiomer ratios in adults and children.

The new anticonvulsant vigabatrin (gamma-vinyl-gamma-aminobutyric acid) is normally supplied as a racemate, but its anticonvulsant effect is thought to reside in its [S]-enantiomer only. The plasma concentration ratio of the [R] to [S] enantiomers appears to remain constant across the vigabatrin dosage interval in adult volunteers, and in the present study this has also proved to be the case in 12 chronically treated adult epileptic patients. However, in 8 epileptic children chronically treated with other anticonvulsants and given add-on vigabatrin therapy because of failure to control seizures, plasma [R]:[S]-vigabatrin ratios changed across the drug dosage interval, the [R]-vigabatrin levels tending to be relatively higher soon after intake, and to fall more rapidly than the [S]-vigabatrin concentrations over the next few hours (mean half-lives 2.52 +/- SD 0.49 and 6.53 +/- SD 6.62 hours). The reason for the shorter half-life of [R]-vigabatrin in children remains to be elucidated, but it appears that measurement of racemic vigabatrin plasma concentrations in children, though not in adults, may lead to somewhat misleading conclusions as regards the amount of the circulating anticonvulsant [S]-vigabatrin.

Aged↗
PubMed1993

The explosive Copula of Thomas Willis.

Thomas Willis (1621-1675), arguably the founding father of neurology, devised an interpretation of neurophysiology which involved motor function being mediated by explosions in nerve tissue and muscle, facilitated by the temporary development of an explosive Copula comprising short-lived aggregates of 'nitrous' and 'sulphur' particles i.e. the components of gunpowder. Seen from a modern standpoint, such a concept is manifestly absurd. However, seen from the standpoint of the Paracelsian iatrochemistry to which Willis subscribed, and understood in the spirit of analogy which he probably intended, Willis' interpretation can be regarded as the beginning of the application of bioenergetics to neural function.

England↗
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↗