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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.

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.

The time courses of plasma metoclopramide concentrations were followed in six subjects after oral and intravenous single dose administration. Plasma concentration-time data following i. v. administration in each subject were found to fit a two compartment model with a mean terminal half-life of 4.55 h +/- 0.80 h and a mean distribution half-time of 0.35 h +/- 0.09 h. Volumes of distribution were high (3.43 +/- 1.181 . kg-1), and clearances (0.53 +/- 0.191 . kg-1 h-1) approached liver plasma flow. This suggests that metoclopramide occurs at higher concentrations in tissues than in plasma, and that its clearance is probably limited by liver blood flow rather than liver metabolic capacity. The postabsorption decline in metoclopramide plasma levels after oral administration was also biexponential in each subject. The terminal half-life was 5.17 h +/- 0.98 h. Mean volume of distribution and mean clearance were similar to intravenous values (after adjustment for bioavailability). Oral absorption was rapid with peak plasma concentrations being reached at a mean time of 0.93 h. A mean bioavailability of 0.77 was calculated for the six subjects, and it was postulated that this incomplete availability is due to a first-pass effect. The inter-individual variation in the degree of "first-pass' was considerable (0.47--1.14).

The pharmacokinetics of propranolol (P) and its major metabolites, propranolol glucuronide (PGLUC), 4-hydroxypropranolol (4OHP), 4-hydroxypropranolol glucuronide (4OHPGLUC) and naphthoxylactic acid (NLA), (Walle et al. 1972) were determined, whenever possible, in the first, second and third trimesters of pregnancy in thirteen patients and also when these patients were at least three months post-partum. No correlations were found between the mean arterial blood pressure (post-therapy) or the fall in blood pressure as a result of the P therapy (p much greater than 0.05) and P dose, peak P plasma concentrations, peak 4-hydroxypropranolol (4OHP) plasma concentrations or peak (P plus 4OHP) plasma concentrations. However, a positive nonlinear relationship was found between the daily P dose (independent variable) and peak P plasma concentrations over the daily dose range 30-160 mg/day. The elimination half-lives of NLA for patients in the third trimester of pregnancy were significantly shorter (p = 0.072, df = 13) than those when the patients were at least three months post-partum. Also, the areas under the plasma level-time curves of NLA were significantly less (p less than 0.05, df = 13) for patients in the third trimester of pregnancy than when these patients were at least three months post-partum. The results of this study indicate that the pharmacokinetics of P, PGLUC, 4OHP and 4OHPGLUC are not significantly altered by pregnancy. However, the kinetics of NLA do appear to be altered. The formation of NLA by N-dealkylation of P and further oxidation, appears to be competitively inhibited by unidentified substances, perhaps endogenous steroids, especially in the third trimester when compared to at least three months post-partum.

Steady-state plasma carbamazepine levels were correlated with carbamazepine dose, expressed on a body weight basis, in 217 patients (some of whom were taking other anticonvulsants). Although there was a linear relation between plasma carbamazepine level and drug dose in the whole population studied, no such relation was found for patients taking carbamazepine alone. The factors responsible for this difference could not be identified in full, but interactions between carbamazepine and phenytoin were partly responsible.

The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.

As part of a comparative bioavailability investigation, the steady-state pharmacokinetics of the anticonvulsant valproate (given as the sodium salt and the free acid) were studied in 8 epileptic patients who had received long term therapy with the drug. Mean elimination half-life was 8.21 +/- 3.13 hours, mean apparent volume of distribution 0.1868 +/- 0.0641 L/kg and mean plasma clearance 0.0177 +/- 0.0099 L/kg/hour. The magnitudes of these parameters are similar to those reported for single dose studies in patients at the start of valproate therapy. Thus, long term therapy with valproate does not appear to be associated with significant alterations in the human body's disposition of the drug, unlike the situation with certain other anticonvulsants, e.g. carbamazepine.

In Australia intermittent carbamazepine intoxication that occurs around the expected time of the peak post-dose plasma drug concentrations has been seen more frequently in recent years than in the past. Reworking of pharmacokinetic data from earlier studies of the drug suggests that, between 1977 and 1980, there was a change in the absorption profile of carbamazepine in the most widely used oral Australian preparation of the drug. The drug's absorption rate increased and its peak plasma levels occurred earlier. The reason for this altered absorption profile cannot now be traced, but it seems a possible explanation for the clinical problem that has emerged subsequently in a number of patients.

The pharmacokinetics and oral biovailability of dexamethasone were studied in 6 patients with neurological disease being treated with high dosages of the drug. A specific high performance liquid chromatographic assay was used to measure dexamethasone concentrations. Unlike the previously published mean figure of 0.78 for the oral bioavailability of the drug given in single doses to healthy volunteers, the mean bioavailability of dexamethasone in the patients studied was 0.53 +/- SD 0.40. It appeared more likely that this incomplete bioavailability was due to presystemic elimination than to poor absorption. The intravenous clearance of the drug was relatively high (0.4902 +/- SD 2291 1 kg-1, approximately 65% of expected hepatic plasma flow), the oral clearance higher (2.5804 +/- SD 3.2181 1 kg-1 h-1) while the absorption rate constant (4.8729 +/- 8.4998 h-1), suggested rapid absorption after oral administration. Prior phenytoin and possibly prior dexamethasone therapy is likely to have contributed to the higher clearance values of the drug in these patients than the values reported in healthy volunteers after single dose studies.

The diagnosis of the cause of facial pain can be made clinically in the great majority of cases, if the physician is aware of the gamut of manifestations of the various disorders which may produce the symptom. Therapeutic tests are sometimes helpful in diagnosis, but extensive ancillary investigation often is unnecessary. The management of facial pain is one area of medicine in which the knowledgeable clinician can more than hold his own with the contemporary proliferation of specialized investigational tools.

A clinical and pharmacokinetic study was carried out progressively substituting a new anticonvulsant oxcarbazepine for its congener carbamazepine in a group of patients with refractory epilepsy. Although oxcarbazepine showed possible though not statistically significant advantages of better seizure control and was probably less sedating, its use was associated with a dose-dependent reduction in plasma sodium levels in 12 of 15 patients. The mean plasma sodium level fell from 137.5 +/- 5.2 (s.d.) to 128.5 +/- 6.1 mE/l. Imposed restriction of fluid intake may have minimized the degree of hyponatraemia. This adverse effect may limit the role of the drug as an anticonvulsant or necessitate special precautions when it is used. However, the possibility of employing the drug in diabetes insipidus may be worth exploring.

The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg-1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (+/- SD) elimination half-life (2.14 +/- 1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (+/- SD) clearance value (0.30 +/- 0.19 l kg-1h-1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean +/- SD) did not differ to a statistically significant extent between the aged subjects (0.77 +/- 0.47 l kg-1) and the young subjects studied previously (1.09 +/- 0.58 l kg-1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F = 0.59 +/- 0.15, mean +/- SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34 +/- 0.17, (mean +/- SD), with an appreciable but variable lag time (0.74 +/- 0.40 h, mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

An original, highly sensitive and specific high performance liquid chromatographic method has been developed for the measurement of aspirin and salicylate in plasma. Minimum concentrations of 10 micrograms/L (aspirin) and 0.5 mg/L (salicylate) can be measured using 1 ml of plasma. After collection, plasma is first treated with physostigmine sulfate to inhibit enzymatic hydrolysis of aspirin to salicylate. Maximal recovery is achieved using an acid extraction into anhydrous diethyl ether with a subsequent drying-down step in an iced water bath. Aspirin and salicylate are separated by elution with a mixture of methanol, 1-butanol, orthophosphoric acid, and water on a reversed-phase octadecyl silane column at 47 degrees C and detected at 234 nm by ultraviolet absorption. Quantitation is achieved using the peak height ratio of aspirin and salicylate to internal standard (m-anisic acid). The assay has been used for the study of simultaneous aspirin and salicylate pharmacokinetics after a single oral dose of 100 mg soluble glycinated aspirin for platelet antiaggregatory therapy in six subjects, one of whom was also studied after receiving a 600 mg dose.

The rate of disappearance of ergotamine from the mouth after buccal administration has been studied in seven subjects. Allowance has been made for non-absorptive losses of the drug due to experimental technique. The absorption of ergotamine across the buccal mucosa appears to be a passive process, pH-dependent but independent of ergotamine concentration or the simultaneous presence of caffeine. Because of the low solubility of ergotamine at the pH of saliva, it is unlikely that therapeutically useful amounts of the drug would have absorbed across the buccal mucosa even after the drug had been in the mouth for five minutes.

1. The bioavailabilities of carbamazepine in 100 mg and 200 mg tablets have been compared in a cross-over study of six subjects after two 600 mg doses of the drug, the different preparations being taken at 3 week intervals. 2. Areas under the plasma level curves, absorption rate constants and times to achieve peak plasma levels showed little difference between the two preparations. These findings suggest similar rates and extents of bioavailability of carbamazepine in the two preparations. 3. Calculated mean absorption and elimination parameters for carbamazepine were as follows: kabs = 0.1081 h-1, (s.d. = 0.0289); Tmax = 23.39 h, (s.d. = 8.66); k = 0.0191 h-1, (s.d. = 0.0033); VD = 0.989 1/kg, (s.d. = 0.159); and clearance = 0.0185 1/kg h, (s.d. = 0.0015).

Plasma anticonvulsant levels were followed during pregnancy in 11 epileptic women taking phenytoin and/or phenobarbital or a drug metabolized in the body to phenobarbital. As judged from the relationship between plasma level and drug dose, phenytoin requirement increased in all 10 women taking this drug during pregnancy. The requirement fell again in the puerperium. Plasma phenobarbital levels decreased during pregnancy in all five women taking a constant daily dose of phenobarbital or a congener. These findings should be borne in mind if epileptics are to be protected against seizures during pregnancy and against anticonvulsant overdosage during the puerperium.

The term "degenerative disease" is one which is rather widely used in relation to the nervous system and yet one which is rarely formally and carefully defined. The term appears to be applied to disorders of the nervous system which often occur in later life and which are of uncertain cause. In the Shorter Oxford Dictionary the word degeneration is defined as "a change of structure by which an organism, or an organ, assumes the form of a lower type". However this is not quite the sense in which the word is applied in human neuropathology, where it is conventional to restrict the use of the word to those organic disorders which are of uncertain or poorly understood cause and in which there is a deterioration or regression in the level of functioning of the nervous system. The concept of degenerative disorder is applied to other organs as well as to the brain, and as disease elsewhere in the body may affect the nervous system, it seems reasonable to include within the topic of degenerative disorder affecting the nervous system those conditions in which the nervous system is involved as a result of primary degenerations in other parts of the body., (Copyright © 1974 Australian Physiotherapy Association. Published by . All rights reserved.)

Plasma concentration-time data after oral and intravenous administration of dexamethasone have been subjected to pharmacokinetic analysis in six neurological or neurosurgical patients taking the steroid with phenytoin, and in nine patients (one studied twice) taking dexamethasone without phenytoin. An additional patient was studied before and during phenytoin intake. Apparent volume of distribution was similar in the two groups, but the group treated with phenytoin had an almost statistically significantly shorter dexamethasone mean terminal half-life, an approximately trebled mean plasma clearance, and a mean oral bioavailability of the steroid of only 33%, compared with a mean 84% oral bioavailability in those not receiving phenytoin. To achieve a given plasma dexamethasone concentration, patients treated with the steroid and phenytoin may need oral dexamethasone doses several times those required by patients not receiving phenytoin.

Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1-2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25-0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37 +/- 0.45 h) did not differ significantly ('t' = 2.04, df = 10, p greater than 0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74 +/- 0.45 h). The terminal half-life, (t 1/2), of midazolam in plasma was 1.77 +/- 0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383 +/- 0.0941 . kg-1 . h-1. The first pass effect, F, determined experimentally (0.36 +/- 0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%-0.028%).

Single doses of effervescent tablets (1200 mg) and enteric coated (EC) tablets (1300 mg and 650 mg) of acetylsalicylic acid (aspirin, ASA) were given to healthy volunteers in random order. Plasma ASA and salicylic acid (SA) levels were measured and concurrent in vitro measurements of the volunteers' platelet aggregation were carried out. The effervescent preparation resulted in peak ASA concentrations of 17-40 mg/l, achieved 20 to 30 min after a 1200 mg dose, whereas peak ASA levels of 0.01-0.37 mg/l were observed 4-6 h after a 650 mg dose of the EC preparation. With all the aggregating agents that were added to the test system maximum inhibition of platelet aggregation (about 50% of pre dose levels) was seen 1.0 h after the effervescent ASA dose, and persisted to at least 24 h, but with the EC preparation not until 24 h, at which time the degree of inhibition was also about 50% of pre-dose levels. A 1.0 g dose of sodium salicylate had no effect on in vitro platelet function. It was concluded that mean plasma levels of ASA of less than 0.25 mg/l are sufficient to depress aggregation by approximately 50%. A low dose of ASA taken daily either as effervescent ASA or EC ASA, significantly inhibits platelet aggregation and so may reduce the risk of ischaemic episodes in susceptible patients.

A rapid, sensitive and accurate high-performance liquid chromatographic method for the simultaneous quantitation of phenobarbitone, phenytoin, carbamazepine and carbamazepine-10,11-epoxide in saliva is described. Only small volumes of saliva (100 microliters) are required. Separation of the drugs is achieved by reversed-phase chromatography on a Nova-Pak C18 column, with a mobile phase of acetonitrile-phosphate buffer at a flow-rate of 2.0 ml/min. Detection is effected by ultra-violet absorption at 215 nm. The total run time is under 12.5 min per assay. A precipitation but no extraction step is involved, simplifying the assay method. Salivary concentrations in the range 0.25-25 micrograms/ml for carbamazepine, 0.5-20 micrograms/ml for phenytoin and phenobarbitone and 0.4-20 micrograms/ml for carbamazepine-10,11-epoxide can be measured. Recovery varies from 94 to 108%. The method has been used for routine measurements of anticonvulsants in saliva collected daily from patients with intractable epilepsy.

During pregnancy a number of continuously changing circumstances exist which might be expected to modify the relation between plasma drug levels and drug dosage. Alimentary tract motility may be decreased, the distribution of many drugs may be altered, glomerular filtration rate is greater and biotransformation capacity may be changed as pregnancy advances. However, relatively little has been published on the monitoring of plasma drug levels during pregnancy. It has been established that, in the presence of constant drug doses, plasma levels of phenytoin, phenobarbitone and certain other anticonvulsants tend to fall during pregnancy and rise again during the puerperium. Plasma lithium and possibly digoxin levels also fall relative to drug dose as pregnancy progress, and rise again in the puerperium. While the changes in lithium and digoxin levels are probably chiefly due to increased rate of glomerular filtration during pregnancy, the altered anticonvulsant requirement is more likely to depend mainly on an increased rate of biotransformation. Anticonvulsant plasma levels should be monitored regularly from the outset of pregnancy and more frequently after birth.

The concepts underlying the notion of a risk-benefit ratio for anticonvulsant therapy have determined the development of the drug treatment of epilepsy over many years. The risk element in the ratio arises from the various possible physical and psychological adverse effects of anticonvulsant therapy; the benefit is derived from the capacity of therapy to prevent seizures and thus reduce the disadvantages which result from having epilepsy. The physical adverse effects of anticonvulsant therapy may involve many tissues and organs. The drugs tend to depress cerebral, cerebellar and brain stem function, and may slow peripheral nerve conduction. Prolonged intake may cause hypocalcaemia and osteoporosis, folate depletion, various haematological and immunological abnormalities, and overgrowth of subcutaneous and gingival tissues. Idiopathic reactions may involve the skin, lymph nodes, liver, pancreas, kidney and thyroid, and cause electrolyte disturbances, while maternal anticonvulsant intake during pregnancy may be associated with an increased incidence of fetal malformations. Local reactions may occur at drug administration sites, and anticonvulsants may interact pharmacokinetically and pharmacodynamically with co-administered drugs. The taking of anticonvulsants sometimes has undesirable psychological effects on both the patient and his or her family. Epilepsy itself often results in adverse psychological consequences which emanate from the uncertainty and insecurity that is imposed by the unpredictable occurrence of seizures, from the limitations epilepsy sets on the patient's lifestyle and employment prospects, and from unfavourable community attitudes towards the disorder. Contemporary anticonvulsant therapy is not fully effective in all patients, but to the extent that it can control seizures it may help alleviate these emotional burdens that are a result of epilepsy. The consensus of present day medical opinion is that, in the great majority of clinical situations, the benefits of anticonvulsant therapy outweigh the disadvantages. However, to provide optimal management for individual patients, the risk-benefit ratio of therapy must be repeatedly assessed at all stages of a patient's treatment, and therapeutic decisions taken in the light of the ratio as it applies to the individual.

Two patients with severe liver damage induced by sodium valproate are described. Both were adults. One had taken valproate for longer than one year before complications developed. The other, in whom the disorder was fatal, had a predominantly 'hepatic' pattern of liver damage with centrilobular necrosis and he also developed pancreatitis. The first patient, who recovered following cessation of valproate intake, manifested a predominantly cholestatic illness with portal tract inflammation. In addition he had a degree of reversible renal failure. Neither subject had microvesicular steatosis on liver biopsy. This report indicates that valproate hepatotoxicity is not always confined to children, that it may develop much later in the course of valproate therapy than has been previously recognized, that it is not necessarily fatal if valproate intake is ceased early enough, and that it may be associated with reversible renal insufficiency.

Cytophotometric measurements of the activities of 5 enzymes (succinate, malate, and NAD+-linked isocitrate dehydrogenases from the tricarboxylic cycle, lactate dehydrogenase from the Embden-Meyerhof pathway, and NADH dehydrogenase) were correlated with cell volume for neurones in the anterior horn of rabbit lumbar and cervical spinal cord. The data for succinate and isocitrate dehydrogenases indicated that these enzymes were at higher concentrations in the smaller neurones, which consist largely of interneurones. No preferential localization to particular sizes of cell could be assigned to the other enzymes studied. The relationship between enzyme distribution patterns and their possible role in contributing toward susceptibility to ischaemia of particular sizes of neurones is discussed.

A high performance liquid chromatographic assay has been used to measure the time courses of plasma dexamethasone concentrations in patients with various neurological disorders being treated with this steroid. The pharmacokinetics of the drug in these circumstances differed from the kinetics in healthy volunteers. In particular whole body clearances were higher, causing a substantially impaired mean oral bioavailability of the drug with considerable interindividual variation in bioavailability. The clearance of dexamethasone was increased by concurrent phenytoin therapy, and dexamethasone and phenytoin are often given together in neurosurgical practice. The previously unrecognized bioavailability limitation of oral dexamethasone may explain individual instances of apparent steroid-resistant neurological disease, and suggests the desirability of monitoring plasma dexamethasone levels when using the steroid therapeutically. Some preliminary evidence has been obtained suggesting that it may be possible to avoid adrenal suppression from long-term high-dosage dexamethasone therapy, if plasma dexamethasone levels can be allowed to fall to zero between consecutive dexamethasone doses.

30 epileptic patients taking one or more of the anticonvulsants phenytoin, carbamazepine, phenobarbitone, methylphenobarbitone and ethosuximide have been studied during the courses of 34 pregnancies. In all cases the drug dosage requirement to maintain therapeutic range plasma anticonvulsant levels increased during pregnancy and fell again during the puerperium. Calculated plasma drug clearances showed a marked increase during pregnancy, reaching a peak in the third trimester, and declined again in the 3 months following pregnancy to pre-pregnancy values. For the more extensively used drugs the mean ratios of the plasma clearances in the third trimester to those in the pre- or post-pregnancy state were phenytoin 2.5:1 (p less than .001), carbamazepine 1.9:1 (p less than .005), phenobarbitone 1.6:1 (p less than .001). The limitations of the plasma clearance approach for phenytoin, a drug which is eliminated largely by Michaelis-Menten kinetic mechanisms, are discussed.

The pharmacokinetics of oxcarbazepine (a new anticonvulsant which is a congener of carbamazepine) and of its 10-hydroxy metabolite were studied at the outset of therapy in 8 adult epileptics comedicated with other anticonvulsants. The pharmacokinetic study was repeated under steady-state conditions after 3 months of drug intake in 6 of these subjects. The plasma elimination half-life of oxcarbazepine appeared to lie in the range 1.0-2.5 h, and that of its 10-hydroxy metabolite averaged 8.4 h. The apparent oral clearance of the parent drug (averaging 2.51.kg-1.h-1) was high enough to suggest substantial presystemic elimination. The oral clearance fell after 3 months of drug intake, but the half-lives of the drug and metabolite showed no statistically significant change over this time. Steady-state plasma levels of both drug and metabolite were linearly related to drug dose, metabolite levels averaging 9 times those of the parent substance.

The relation between plasma phenobarbitone level and phenobarbitone dose was studied in 121 patients. The relation changed with age, the dosage requirement (on a day weight basis) tending to fall as patients grew older. Males under 5 years had a higher dosage requirement than females of the same age, but otherwise sex did not affect the relationship, nor did the concurrent intake of the anticonvulsants phenytoin, carbamazepine or sulthiame. In the individual, plasma phenobarbitone levels tended to increase out of proportion of dosage increases. These findings can provide a basis for prescribing appropriate phenobarbitone doses in epileptics.

The plasma concentrations of anticonvulsant drugs, and of certain of their biologically active metabolites, tend to be proportionate to the antiepileptic effects of these drugs. Consequently, anticonvulsant drug levels in plasma are monitored to help guide the clinician in managing his patients' epilepsies. In making use of the measurements, the clinician needs to know the relation between plasma level and biological effect for the various drugs. He also needs to have some awareness of simple pharmacokinetic principles. These are important in deciding when plasma levels should be monitored in relation to the patients' clinical state, to the dosage interval, and to change in the dosage of anticonvulsant or other drug. The clinician also requires pharmacokinetic knowledge in altering anticonvulsant drug dosage in his patients, and in interpreting plasma anticonvulsant level data, particularly when the patient is concurrently suffering from non-neurological disease. The ability to monitor plasma anticonvulsant levels has appreciably improved the treatment of epilepsy, but to obtain maximum benefits from the method, both pharmacokinetic insight and clinical wisdom are required.

We examined the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in both hypercalcemic and hypocalcemic rat models and the effect of exogenous 25-hydroxyvitamin D3 (25(OH)D3) on serum and tissue aluminum (Al) burdens. Rats fed a 0.2% Al diet received daily subcutaneous injections of either 1,25(OH)2D3 (80.9 ng/kg, n = 5 and 809 ng/kg, n = 8), 25 (OH)D3 (809 ng/kg, n = 4, and 8090 ng/kg, n = 8) or propylene glycol vehicle for 18 days. Rats given 809 ng/kg of 1,25(OH)2D3 were hypercalcemic and when compared with pair-fed controls had higher serum (33.1 vs. 14.3 micrograms/L, P less than 0.01), bone (21.2 vs. 13.2 micrograms/gm, P less than 0.01), and kidney (6.5 vs. 2.0 micrograms/gm, P less than 0.01) but not brain (1.2 vs. 1.5 micrograms/gm) or liver (0.9 vs. 0.8 micrograms/gm dry tissue) Al concentration. The lower dose of 1,25(OH)2D3 had no effect on serum or tissue Al. Treatment with 25(OH)D3 did not increase serum Ca and Al or tissue Al concentration. To dissociate a specific effect of exogenous 1,25(OH)2D3 from the concurrent hypercalcemia, endogenous production of 1,25(OH)2D3 was stimulated. Animals were fed a low Ca diet until hypocalcemia developed and were then divided into four groups: one given low Ca (n = 7) for 21 days, one given low Ca plus 0.2% Al (n = 7) for 21 days, one returned to a normal Ca diet (n = 4) for 30 days, and one returned to a normal Ca diet for 9 days and continued with a normal diet plus 0.2% Al (n = 5) for 21 days. Hypocalcemic rats fed the Al diet, when compared with hypocalcemic controls, had higher serum (143.6 vs. 31.8 micrograms/L, P less than 0.01), bone (16.0 vs. 2.9 micrograms/gm, P less than 0.01), and kidney (8.2 vs. 2.8 micrograms/gm, P less than 0.005) but not brain (3.4 vs. 2.3 micrograms/gm) or liver (3.8 vs. 2.3 micrograms/gm) Al concentrations. Serum, bone, and kidney Al concentration was also significantly higher than that in normocalcemic rats fed the Al diet. These results indicate that pharmacologic doses of 1,25(OH)2D3 and dietary hypocalcemia enhance gastrointestinal Al absorption and serum, kidney, and bone Al concentration.

A kinship is described in which there was slowly progressive wasting and weakness of the muscles of the upper and occasionally of the lower limbs. Some members had hyperreflexia. There were no sensory abnormalities. Electrophysiological study suggested the presence of motor peripheral polyneuropathy. The condition appeared to be inherited as an autosomal dominant. The disorder does not appear typical of any of the known hereditary polyneuropathies and it is possible that it may represent a unique hereditary, dominantly motor, polyneuropathy. The significance of the hyperreflexia is uncertain, but raises the possibility of minor central involvement as well as peripheral neuropathy.

During a carbamazepine (CBZ) relative bioavailability study involving tablets and a syrup preparation, salivary drug concentrations appeared disproportionately high relative to simultaneous plasma drug concentrations in the first 2-3 h after oral drug intake. This raised the suspicion of contamination of saliva by retention of drug in the mouth. In a separate study CBZ was retained in the mouth in tablet form (whole or crushed) or in syrup, for only 5 s before being spat out, and the mouth was carefully rinsed. Despite this, measurable salivary concentrations, sufficient to cause substantial error if extrapolated to simultaneous plasma drug concentrations, were present for at least 2 h after drug administration. CBZ in these studies disappeared from saliva with an apparent mean half-life of 21.0 +/- 4.8 min. This experience suggests that, in therapeutic drug monitoring, salivary CBZ concentrations for at least 2 h after dosage may lead to invalid conclusions about simultaneous plasma CBZ concentrations.

Oxcarbazepine is a new anticonvulsant, currently undergoing clinical trials. Its spectrum of antiepileptic action, and its chemical structure, resemble those of carbamazepine, though the 2 drugs have no pharmacologically active metabolites in common. In a study of 7 adults with poorly controlled partial epilepsy, progressive substitution of oxcarbazepine for carbamazepine left seizure control unaltered in 4 and improved in 3, whilst 5 became more alert and one was rendered ataxic. Three subjects became hyponatraemic. There were no other adverse effects. Plasma levels of the drug and its pharmacologically active 10-hydroxy derivative were measured sequentially over 4 days after a single drug dose at the outset of therapy in 5 subjects. Calculated pharmacokinetic parameter values for the drug, assuming complete oral bioavailability, were: absorption lag time 2.07 +/- 1.61 h: absorption rate constant 8.328 +/- 8.941 h-1: apparent volume of distribution 3.937 +/- 2.222 L kg-1: oral clearance 2.898 +/- 1.439 L kg-1: elimination rate constant 0.609 +/- 0.261 h-1 (half-life 1.26 +/- 0.37 h), while the metabolite had a formation rate constant of 0.593 +/- 0.233 h-1, and an elimination rate constant of 0.082 +/- 0.014 h-1 (half-life 8.74 +/- 1.79 h). Even with a single dose, peak plasma metabolite levels were substantially higher than those of the parent drug. Oxcarbazepine appears to be a promising alternative to carbamazepine as an anticonvulsant, although in view of its rapid elimination it probably serves mainly as a prodrug for its 10-hydroxy metabolite.

In a random cross-over design, six healthy consenting adult volunteers were given on separate occasions single doses of 300-650 mg of 3 different formulations of enteric-coated aspirin. Over various intervals for 48-54 h following dosage, plasma aspirin and salicylate concentrations were measured together with percentage inhibition of platelet aggregation activated by threshold concentrations of sodium arachidonate alone and combined with ADP and collagen. In all subjects each formulation delivered measurable quantities of aspirin to the peripheral circulation, the unchanged drug being detected at various times up to and including 28 h after dosage. Moreover, low aspirin concentrations were found to co-exist with unimpaired platelet aggregation. All 3 formulations yielded statistically significant (P less than 0.01) inhibition of platelet aggregation activated both by arachidonate and by the combination of aggregants when tested 24-29 and 48-54 h after dosage; there were no significant differences (P greater than 0.05) between the 3 formulations in this regard. Two different patterns of delivery of unchanged aspirin to the systemic circulation from these enteric-coated formulations were apparent. These patterns may be important when considering which aspirin formulation might be most appropriate in chronic use for an antiplatelet effect. None of the enteric-coated formulations used in this study may be optimal in this regard.

Twelve cases have been reported in the literature to have developed acute, largely reversible, global amnesic syndromes some hours after ingesting substantial doses of clioquinol. Two of these cases presented again after asymptomatic intervals of some 12 years. Both had recently developed typical clinical and electroencephalographic evidence of partial epilepsy originating in a temporal lobe. The similarity of clinical events in these two subjects, the absence of any other known cause for their epilepsy and the fact that, in mice, acute clioquinol overdosage causes hippocampal and amygdaloid injury, suggest that the drug was responsible for both the acute encephalopathy and the epilepsy of delayed onset.