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Biomedical subjects

J H Tyrer

Publications and source records attributed to J H Tyrer.

At least 19 recordsLinked to original sources
PubMed1985

Valproate hepatotoxicity: a review and report of two instances in adults.

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.

Adolescent↗
PubMed1984

Pharmacokinetics of midazolam in the aged.

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)

Administration, Oral↗
PubMed1984

Cortisol production during high dose dexamethasone therapy in neurological and neurosurgical patients.

Simultaneous plasma dexamethasone and cortisol levels were followed at intervals over 8 hour periods on 40 occasions in 19 subjects who received regular high dosage dexamethasone therapy (rarely less than 12 mg a day) for various neurological and neurosurgical conditions. Lower dexamethasone doses (for example 2 mg daily for 2 days) normally suppress adrenal cortical production of cortisol to below 50 micrograms/l for at least 8 hours. However, in 12 of the 35 studies that did not take place at the first steroid dose or in subjects taking second daily bolus steroid dosage such suppression was not present 8 to 12 hours after dexamethasone intake, though it was shown that dexamethasone could suppress cortisol production in all these cases. Failure of maintained suppression despite the high steroid dose appeared to be related to rapid elimination of dexamethasone. These findings may help explain the relative rarity of adrenal failure in clinical neurological practice after high dosage steroid therapy is ceased.

Adult↗
PubMed1984

Dexamethasone: pharmacokinetics in neurological patients.

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.

Adult↗
PubMed1983

Bioavailability of oral dexamethasone during high dose steroid therapy in neurological 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.

Administration, Oral↗
PubMed1983

Steady-state valproate pharmacokinetics during long term therapy.

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.

Adolescent↗
PubMed1982

Aspirin treatment of migraine attacks: plasma drug level data.

Plasma aspirin and salicylate levels were measured at intervals over a two hour period during migraine attacks in 10 subjects given 900 mg oral aspirin alone, in 10 subjects given 900 mg oral aspirin plus 10 mg oral metoclopramide, and in 10 subjects given 900 mg oral aspirin plus an intramuscular injection of 10 mg metoclopramide. Higher peak aspirin and salicylate levels occurred in patients given aspirin with metoclopramide. Aspirin tended to appear in plasma earlier in patients given aspirin with oral metoclopramide than in patients given aspirin alone, or aspirin with intramuscular metoclopramide. Patients given aspirin with oral metoclopramide tended to obtain better early pain relief than the other two treatment groups, though by one hour from dosage use of injected metoclopramide was also associated with better pain relief.

Adolescent↗
PubMed1982

Aspirin treatment of migraine attacks: clinical observations.

A retrospective study of the efficacy of soluble aspirin in migraine has been carried out. Data were available for 61 patients. These patients differed in only relatively minor ways from the remainder of the population of migraine sufferers referred to a neurological consultative practice. Soluble aspirin usually or always relieved migraine attacks in 44% of these patients, and sometimes relieved the disorder in another 25%. Adverse effects mainly nausea and vomiting, were reported by 16% of patients only, and in some cases nausea and vomiting may have been due to migraine rather than to the drug. Response to aspirin was unrelated to factors such as the patient's age, sex and duration of migraine history, and to the severity of migraine or occurrence of nausea and vomiting during attacks. However, the presence of a migraine aura appeared to improve the chances of a response to aspirin. The aura may have permitted earlier recognition that migraine was present, and thus allowed earlier aspirin intake at a stage when it had a better chance of influencing migraine mechanisms.

Adolescent↗
PubMed1981

How worthwhile is plasma primidone level measurement?

Simultaneous steady-state plasma levels of primidone and phenobarbitone were studied in 43 patients receiving primidone therapy. Primidone and phenobarbitone levels in the individual appeared to be linearly related but steady-state plasma phenobarbitone levels correlated better with primidone dose than did steady-state plasma levels of primidone itself. This pattern of correlation is probably due to primidone being more rapidly eliminated than the phenobarbitone that is derived from it. Steady-state plasma primidone levels showed more inter-dosage fluctuation than steady-state plasma phenobarbitone levels in the same patients. In the subjects studied age, sex, and concurrent anticonvulsant therapy did not alter the relation between plasma levels of primidone or phenobarbitone and primidone dose. The study suggested that knowledge of steady-state plasma primidone levels adds little to knowledge of plasma phenobarbitone levels in guiding the therapy of epilepsy with primidone.

Adolescent↗
PubMed1981

Factors influencing simultaneous concentrations of carbamazepine and its epoxide in plasma.

Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10, 11-epoxide were measured by high performance liquid chromatography in 295 patients. Plasma carbamazepine epoxide correlated more closely with carbamazepine dose than did plasma levels of the drug itself. Plasma carbamazepine epoxide levels tended to the higher, relative to drug dose, in children than in adults, whereas age did not seem to influence the relationship between plasma carbamazepine level and drug dose. Simultaneous phenytoin intake lowered the plasma carbamazepine levels relative to drug dose but left plasma carbamazepine epoxide levels largely unaltered. However, simultaneous valproate intake was associated with raised plasma carbamazepine epoxide levels relative to carbamazepine dose, whereas plasma carbamazepine epoxide levels were unaltered. The amount of conversion of carbamazepine to its epoxide thus appears to vary in different circumstances in human.

Adolescent↗
PubMed1981

The clearance of anticonvulsant drugs in pregnancy.

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.

Adult↗
PubMed1980

Electron-capture gas chromatographic assay for metoclopramide in plasma.

An original electron-capture gas chromatographic assay has been developed for the quantiation of metoclopramide in human plasma. The method involves derivatization with heptafluorobutyryl imidazole after alkaline extraction, acid backwash, and a further alkaline extraction. Plasma levels of metoclopramide as low as 5 micrograms/l can be measured using 1 ml of plasma, and no interference from related substances or commonly prescribed drugs has been found. The percentage recovery of drug from plasma ranges from 88% to virtually 100%, and the between-run variation in the assay is 4.3%. The assay has been used for the study of metoclopramide pharmacokinetics in man following intravenous single-dose administration. The resultant plasma concentration vs. time curve was biexponential, with a terminal half-life of 5.0 h, and a distribution half-time of 0.3 h.

Acetylation↗
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↗
PubMed1978

Preliminary observations on the pharmacokinetics of methylphenobarbitone.

The pharmacokinetics of methylphenobarbitone and phenobarbitone were studied following the administration of methylphenobarbitone on a chronic basis in 77 patients, and after a single dose to each of 4 subjects who had received no other drugs and 4 subjects who had been pretreated with various anticonvulsants and other agents. At steady-state, plasma phenobarbitone concentrations correlated better with methylphenobarbitone dose than did plasma methylphenobarbitone concentrations. In this group the ratio of plasma phenobarbitone level to plasma methylphenobarbitone level was in the range of 7 to 10:1. In the single dose studies, mean values of elimination rate constant (0.0155h) and clearance (1.85L/h) for untreated subjects were different from those for the pretreated subjects (0.0375h and 5.10L/h), while the apparent volumes of distribution did not differ significantly between the two groups (120.3L vs 140.8L). The data are interpreted as most probably indicating induction of hepatic microsomal enzymes in the pretreated group.

Adult↗