Biomedical subjects
M J Brodie
Publications and source records attributed to M J Brodie.
Nicotinylalanine increases cerebral kynurenic acid content and has anticonvulsant activity.
1. Nicotinylalanine is an analogue of kynurenine which has been reported to inhibit the enzymes kynurenine hydroxylase and kynureninase. 2. In the present study rats were given a tryptophan load together with nicotinylalanine two hours before killing, and the brain, liver and kidneys analysed by HPLC for their kynurenic acid content. 3. Tryptophan alone produced a significant elevation of kynurenate but with the additional administration of nicotinylalanine, levels rose dramatically, including a 19-fold increase in brain. 4. In mice the same dose of nicotinylalanine reduced the incidence of seizures induced by leptazol or electroshock treatment. 5. Since kynurenic acid is an antagonist at excitatory amino acid receptors the results may herald a new approach to producing a pharmacological blockade of amino acid receptors in the brain.
Interictal HM-PAO SPECT: a routine investigation in patients with medically intractable complex partial seizures?
Single photon emission computed tomography (SPECT) is increasingly being used as an adjunctive technique in the localisation of epileptogenic foci prior to surgery. As yet, few studies have been undertaken to establish the clinical associations of areas of reduced cerebral perfusion. Sixty-three consecutive patients (15 male, 48 female; median age 30 years, range 14-57 years) with medically intractable complex partial seizures (median/month 8, range 1-36) were investigated as outpatients. All had normal high resolution computerised X-ray tomography (CT) of brain. Twenty-seven (47%) exhibited significant perfusion defects on SPECT scanning with a rotating gamma camera system using Tc-99 HM-PAO. There were no significant differences between patients with normal and abnormal scans in terms of age at scanning or at onset of epilepsy or number of seizures. Patients with perfusion defects did, however, have longer median histories of epilepsy than those with normal scans (normal: 10 years, abnormal: 22 years; P = 0.01). Patients with abnormal scans were no more likely to have suffered febrile convulsions in early childhood. The correlation of abnormal SPECT scans with routine surface EEG recordings was poor with only 41% of cases showing clear agreement between the site of hypoperfusion and focal epileptic activity. It is not yet possible to predict clinically those patients who will exhibit perfusion defects on interictal TC-99 HM-PAO SPECT scanning.
Variability and clinical relevance of the interaction between sodium valproate and carbamazepine in epileptic patients.
Twenty-four epileptic patients (16 females, 8 males; aged 13-62 years) were studied before and after the addition of sodium valproate (VPA) 500 mg twice daily for 5 days. All had been established previously on carbamazepine (CBZ) as monotherapy (300-1600 mg daily in divided doses). Sixteen of these patients undertook a battery of cognitive function tests before and after VPA introduction. VPA had no effect on total or free CBZ concentrations. However, median concentrations of the active metabolite, CBZ 10,11 epoxide (CBZ-E), were significantly increased (CBZ-E before VPA 1.3 mg/l, after VPA 2.1 mg/l, P less than 0.01). The median rise was 25%, although the extent of the interaction ranged from a 25% decrease to an increase of 123% in CBZ-E concentrations. This was related to the marked inter-individual variation in circulating VPA (mean 25-69 mg/l), as CBZ-E concentrations correlated significantly with total (r = 0.5, P less than 0.05, 95% CI 0 to +0.08) and free (r = 0.7, P less than 0.001, 95% CI +0.09 to +0.25) VPA levels in individual patients. Although uncontrolled, no deterioration in performance of any of the cognitive function tests was observed following the addition of VPA. This study does not support immediate clinical relevance for this drug interaction between VPA and CBZ.
Central and peripheral benzodiazepine receptors in rat brain and platelets: effects of treatment with diazepam and clobazam.
Tolerance to the effects of benzodiazepines (BZ) may be mediated by changes in benzodiazepine receptors (BZRs). Peripheral BZRs (in brain and platelets) and central BZRs (in brain) were measured in rats following intraperitoneal administration of diazepam and clobazam each for 4 and 12 days. BZRs were measured by binding assays using [3H] PK 11195 (peripheral) and [3H] flunitrazepam (central) as radioligands. Diazepam, but not clobazam, increased peripheral BZR numbers in platelets (both P < 0.005), but not in brain, after 4 and 12 days' treatment compared with appropriate controls. Neither drug altered central BZR affinities or numbers in rat brain. BZ effects on peripheral BZRs in platelets cannot be extrapolated to predict changes in brain receptors, either peripheral or central.
Therapeutic drug monitoring improves seizure control and reduces anticonvulsant side-effects in patients with refractory epilepsy.
The benefit to patients of an on-site antiepileptic drug monitoring service, in which physicians' decisions were recorded before and after the concentration became available, have been assessed retrospectively. In 109 patients with refractory epilepsy monitored on three (n = 61) or four (n = 48) occasions between 1986 and 1990, one or more assay result was rated as 'unexpected' by the consulting doctor. In 51 of these, revision of the dose was undertaken as a consequence (active group). Their clinical outcomes were compared with those of the other 54 patients in whom the initial management plan was left unchanged (passive group). Median seizure frequency decreased in both groups, but this was statistically significant only for the actively treated patients [active group: first visit 1 (0 to 26) seizures/month, last visit 0 (0 to 19) seizures/month, P < 0.01, 95% CI -2 to -0.5; passive group: first visit 2.5 (0 to 57) seizures/month, last visit 1.5 (0 to 44) seizures/month, NS, 95% CI -1 to +10]. The number of patients reporting one or more episodes of drug-related toxicity also favoured the actively managed patients (active group 25%, passive group 56%, P < 0.01). Within this selected group of patients, the anticonvulsant concentration was a better guide to clinical management than the physician's assessment.
Rapid tolerance to acute psychomotor impairment with carbamazepine in epileptic patients.
Thirteen patients with newly diagnosed epilepsy performed a battery of psychomotor function tests before and during the first 12 weeks of carbamazepine (CBZ) therapy. Movement time (P less than 0.025), total choice reaction time (P less than 0.025), finger tapping rate (P less than 0.005) and number cancellation (P less than 0.05) were all significantly impaired after 1 week's treatment, but had returned to baseline by 4 weeks. Mean (+/- s.d.) serum CBZ concentrations and those of its active metabolite CBZ 10,11 epoxide (CBZ-E) were comparable at 1 (CBZ: 8.5 +/- 2.1 mg l-1, CBZ-E: 1.1 +/- 0.68 mg l-1) and 4 weeks (CBZ: 8.1 +/- 4.4 mg l-1, CBZ-E: 0.93 +/- 0.27 mg l-1). These results suggest the rapid development of tolerance to the acute deleterious psychomotor effects of CBZ.
Drug interactions in epilepsy.
The abolition of seizures using a single antiepileptic agent can be expected in more than 80% of patients, although not necessarily with the first drug tried. The remainder often receive polypharmacy, and current evidence suggests that perhaps only around 10% of these benefit significantly in terms of improved seizure control. Many more experience complicated drug interactions. Carbamazepine, phenytoin, phenobarbital, and primidone (metabolized in part to phenobarbital) all induce the synthesis of hepatic monooxygenase and conjugating enzymes. This will result in an acceleration in the metabolism of other lipid-soluble drugs with likely attenuation of their pharmacological effects. Valproate, on the other hand, is a minor enzyme inhibitor. Pharmacokinetic interactions are almost invariable when more than one antiepileptic drug is coprescribed. The extent and direction of interactions with combinations of these drugs are varied and unpredictable. Discontinuation of an enzyme inducer or inhibitor will influence the concentrations of the remaining drug(s). Pharmacodynamic interactions also cause problems in epileptic patients. A number of commonly prescribed psychoactive drugs, such as tricyclic antidepressants and neuroleptics, can worsen seizure control by reducing the convulsion threshold. In addition, there seems little doubt that ethanol abuse and withdrawal can precipitate seizures in susceptible patients. Antiepileptic polypharmacy is more likely to impair cognitive function than the same drugs used singly. In addition, the more antiepileptic drugs received by a patient in the first trimester of pregnancy, the higher the risk of teratogenesis in the exposed infant. Drug interactions prolong and complicate the process of new drug assessment, particularly when introduced in treated patients with refractory epilepsy. The candidate antiepileptic drug may alter the concentration of concomitant therapy, or its own breakdown may be influenced by coprescribed enzyme inducers or inhibitors. Even if the new drug is excreted unchanged by the kidney, unexpected interactions can be uncovered. Pharmacodynamic interactions need not always be detrimental. Currently, there is no rational approach to the treatment of intractable epilepsy. As more new drugs with single mechanisms of action become available, the potential exists for combining these synergistically. This approach may revolutionize the pharmacological management of the epileptic patient in the 21st century.
Pharmacokinetic optimisation of anticonvulsant therapy.
Changing attitudes towards the use of antiepileptic drugs have led to an emphasis on monotherapy with serum concentration measurement coupled with standard, weight-adjusted starting and maintenance regimens to guide initial therapy and subsequent dosage titration. Currently, the established anticonvulsants are carbamazepine, valproic acid (sodium valproate) and phenytoin. Phenobarbital is now less commonly prescribed due to its propensity to produce sedation and impair cognitive function. The value of pharmacokinetic optimisation with valproic acid is limited by its wide therapeutic index, large fluctuations in the concentration-time profile and concentration-dependent protein binding. Thus, although serum concentrations are often measured, they are rarely subjected to pharmacokinetic interpretation. Carbamazepine has a flatter concentration-time profile than valproic acid. Its target range is more clearly defined and it undergoes autoinduction of metabolism and interacts with other drugs. Pharmacokinetic principles can, therefore, be more readily applied to carbamazepine, although, in general, a simple clinical approach to its use is usually satisfactory. Phenytoin has required the greatest pharmacokinetic input due to its nonlinear pharmacokinetics and narrow target range. Many different graphical methods, equations and computer programs have been reported, some of which demand 2 steady-state, dose-concentration pairs; others function satisfactorily with only 1. Recent attempts have been made to interpret non-steady-state data. In addition, a number of workers have demonstrated the value of altering the population parameter estimates to account for ethnic differences. A pharmacokinetic approach can also be used to tailor the use of phenytoin in the treatment of status epilepticus. Dosage alterations may be needed for specific patient groups. In particular, children generally require higher dosages on a weight-for-weight basis than adults, while equivalently lower dosages should be given to neonates. Most anticonvulsants are principally cleared by hepatic mechanisms, so dosage adjustment is not usually required in renal disease, although care must be taken in interpreting serum concentrations because of changes in protein binding. Close monitoring is required in the elderly and patients with hepatic impairment, while increased dosages may be needed in critically ill patients and during pregnancy. Pharmacokinetic principles can be used in the treatment of treat self-poisoning with anticonvulsants. There are few data available on the pharmacokinetics of vigabatrin, lamotrigine, oxcarbazepine and gabapentin in patients. Due to its mode of action in binding irreversibly to its target enzyme, serum concentration monitoring of vigabatrin plays no role in optimising therapy. The value of applying pharmacokinetic principles with the other 3 drugs remains to be investigated.(ABSTRACT TRUNCATED AT 400 WORDS)
Sudden death in epilepsy: an avoidable outcome?
In a retrospective survey of mortality among the first 1000 unselected patients referred to the Epilepsy Research Unit at the Western Infirmary in Glasgow between 1985 and 1990, a total of 18 deaths were identified. Three patients had committed suicide and one each had died of status epilepticus in hospital, a subdural haematoma and a myocardial infarction. The remaining 12 deaths (67%) were sudden (median age 32 years; range 22-68 years). Poor seizure control and poor compliance with antiepileptic drug therapy were recorded in only three (25%) of these patients. There was a change in antiepileptic drug regimen in five (28%) in the month before death. Only two (17%) underwent postmortem examination. In nine of the 12 patients dying suddenly, the primary cause of death was not listed as epilepsy but as asphyxia (3), aspiration (2) and one each of ischaemic heart disease, myocardial infarction, asystole and drowning (in the bath). 'Status epilepticus' was assumed to have been responsible for the other three deaths, two of which were unwitnessed. Sudden death in people with epilepsy is an entity of great concern. Appropriate death certification and mandatory postmortem examination are essential to provide a truer picture of this neglected phenomenon.
Inhaled nebulised fentanyl for postoperative analgesia.
The effects of three concentrations of inhaled nebulised fentanyl citrate solution given for postoperative pain relief were studied. Each of 30 patients inhaled one dose of 3 ml of solution nebulised over 9 min. A combined analysis of pain relief, time to further analgesia and effect on respiratory frequency showed the highest concentration (318 micrograms/ml fentanyl base) to be more effective (p less than 0.01) than the two lower concentrations (159 micrograms/ml and 64 micrograms/ml) which were indistinguishable from each other. There were no major side effects. This study provides evidence for the efficacy and safety of inhaled fentanyl for postoperative analgesia. Estimation of the delivered doses did not support the hypothesis that fentanyl is more effective by this route compared with other parenteral routes. Further studies are required to improve the method of delivery and investigate the pharmacodynamic features of this technique.
Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.
1. Oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2. Serum concentrations of OXC and its active metabolite 10-OH-carbazepine (10-OH-CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4. Elimination half-lives (mean +/- s.e. mean) of 10-OH-CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 +/- 1.1 h; after 13.9 +/- 3 h). Trough plasma concentrations of 10-OH-CZ at steady-state (31 +/- 2.2 mumol l-1) were higher than predicted (16.5 +/- 4 mumol l-1). 5. Antipyrine metabolism, urinary 6-beta-hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6. OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose-concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.
Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.
1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.
Monotherapy with conventional and controlled-release carbamazepine: a double-blind, double-dummy comparison in epileptic patients.
1. Twenty-one epileptic patients completed a double-blind, double-dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, Ciba-Geigy) with a new controlled-release formulation (CBZ-CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2. Peak serum CBZ concentrations (mean +/- s.e. mean) were lower (CBZ 11.4 +/- 0.4 mg l-1; CBZ-CR 10.4 +/- 0.5 mg l-1; P less than 0.01) and times to peak longer (CBZ 3.6 +/- 0.5 h, CBZ-CR 5.2 +/- 0.7 h, P less than 0.01) during CBZ-CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 +/- 0.3 mg l-1; CBZ-CR 9.1 +/- 0.5 mg l-1, P less than 0.05) and this was associated with greater seizure frequency (CBZ 2.8 +/- 1.2, CBZ-CR 3.8 +/- 0.9; P less than 0.05) during the CBZ-CR treatment phase. 3. Diurnal fluctuations (CBZ 41 +/- 3%, CBZ-CR 28 +/- 2%, P less than 0.01) and variations (CBZ 53 +/- 5%, CBZ-CR 33 +/- 3%; P less than 0.01) in serum CBZ concentration were substantially less with CBZ-CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 +/- 3%, variation 42 +/- 5%).(ABSTRACT TRUNCATED AT 250 WORDS)
Myoclonic epilepsy--pitfalls in diagnosis and management.
Three cases of myoclonic epilepsy presenting in adolescence are described. Seizures were uninfluenced by treatment with carbamazepine. Substitution of sodium valproate in early adult life resulted in all becoming seizure-free. A high degree of clinical awareness is required in making the correct diagnosis and in choosing appropriate therapy for this form of epilepsy which can present with generalised tonic-clonic or partial seizures.
New and potential anticonvulsants.
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Management of epilepsy during pregnancy and lactation.
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