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Biomedical subjects

C M Lander

Publications and source records attributed to C M Lander.

18 recordsLinked to original sources
PubMed1992

Phenytoin metabolism during pregnancy.

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

Epilepsy↗
PubMed1989

The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin.

1. To investigate the mechanism of the fall in steady-state plasma phenytoin concentration relative to drug dose that occurs during pregnancy, single dose pharmacokinetic studies with stable isotope labelled phenytoin were carried out at different stages of pregnancy, and 2 to 4 months post-natally, in five epileptic women receiving regular oral therapy with the drug. 2. Steady-state apparent plasma clearances of phenytoin (dose/steady-state concentration) correlated closely with simultaneous plasma clearances of the intravenous stable-isotope drug (measured as dose/AUC) suggesting that the patients were complaint with therapy when their phenytoin dosage requirement increased during the pregnancy, and that the oral drug was fully bioavailable. 3. In retrospect, two of the five subjects were probably studied too early post-natally for phenytoin elimination kinetics to have returned to non-pregnant values. Despite this, (i) the mean +/- s.d. t 1/2 for phenytoin was statistically significantly shorter in pregnancy than post-natally (31 +/- 14 vs 39 +/- 28 h), (ii) the mean +/- s.d. whole plasma clearance was also statistically significant greater (0.025 +/- 0.012 vs 0.021 +/- 0.013 kg-1 h-1) and (iii) the mean +/- s.d. Vmax for phenytoin elimination was statistically significantly greater in pregnancy (1170 +/- 600 mg day-1) than post-natally (780 +/- 470 mg day-1). Although the mean +/- s.d. apparent Km was higher in pregnancy (18.2 +/- 8.4 mg l-1, expressed in terms of whole plasma drug concentrations, compared with 10.2 +/- 7.4 mg l-1 post-natally), the difference was not statistically significant. However, if the apparent Km value was expressed in terms of plasma water phenytoin concentrations the difference (pregnant 2.50 +/- 0.85 mg l-1: post-natally 1.16 +/- 0.65 mg l-1) was statistically significant. 4. Human pregnancy appears to result in an increased capacity to eliminate phenytoin.

Adult↗
PubMed1989

Minocycline-induced benign intracranial hypertension.

Four cases of benign intracranial hypertension (BIH) associated with minocycline therapy are described. All subjects were young women being treated for acne. The durations of therapy from the onset of minocycline treatment until the diagnosis of BIH was made were 25 days, 4 weeks, 4 months and 18 months. Headache was severe in all cases. Two had intermittent visual obscurations. Papilloedema was present in each case. CT brain scans did not show any focal abnormalities other than the presence of small ventricles. Cessation of minocycline reversed the disease process though the resolution was much slower in the patient with the longest history of minocycline intake. One subject still had persisting lower nasal quadrantic field loss 6 months after cessation of minocycline. In each case the diagnosis of benign intracranial hypertension related to minocycline was not made by the primary referring doctor, indicating the need for increased awareness of this cause of headache.

Acne Vulgaris↗
PubMed1979

Tiapride in levodopa-induced involuntary movements.

Tiapride, a substituted benzamide derivative closely related to metoclopramide, reduced levodopa-induced peak dose involuntary movements in 16 patients with idiopathic Parkinson's disease. However, an unacceptable increase in disability from Parkinsonism with aggravation of end-of-dose akinesia led to its cessation in 14 patients. Tiapride had no effect on levodopa-induced early morning of "off-period" segmental dystonia. These results fail to support the notion that levodopa-induced dyskinesias are caused by overstimulation of a separate group of dopamine receptors.

Aged↗
PubMed1979

Oscillations in performance in levodopa-treated parkinsonians: treatment with bromocriptine and L-deprenyl.

Fluctuations in performance in levodopa-treated Parkinsonians pose frequent and difficult problems of managment. Controlled trials with two recently introduced drugs, bromocriptine and L-deprenyl, have been performed in an attempt to clarify their use in Parkinsonian oscillations. Bromocriptine, partially substituted for levodopa, was helpful in 4 of 6 patients with early morning dystonia, but did not benefit 9 patients with end-of-dose deterioration and 5 patients with "on-off changes. L-Deprenyl 10mg daily gave substantial benefit to 19 of 39 patients with end-of-dose deterioration, but to only 1 of 10 patients with "on-off' phenomena. Neither L-deprenyl nor bromocriptine helped patients disabled by freezing episodes or levodopa-induced involuntary movements.

Bromocriptine↗
PubMed1979

Some aspects of the clinical use of clonazepam in refractory epilepsy.

Sodium valproate and clonazepam were given in combination to 17 refractory epileptic patients and their progress was reviewed clinically and by EEG's. Even though plasma concentrations of sodium valproate and conventional anticonvulsants were monitored and adjusted according to individual requirements, combination therapy consisting of valproate and clonazepam was ineffective in controlling seizures in the majority of patients. A further 40 patients receiving clonazepam were reviewed in relation to adverse reactions. 22 patients in this group suffered from undesirable effects attributable to clonazepam. These effects were managed by cessation of the drug or a reduction in the dose. The commonest side effects were drowsiness, loss of concentration, irritability and aggression.

Adolescent↗
PubMed1977

The pharmacokinetics of carbamazepine.

The time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters: kabs = 0.176 +/- 0.209 h-1; k = 0.0203 +/- 0.0055 h-1; T1/2 = 37.5 +/- 13.1 h; VD = 0.825 +/- 0.1041 . KG-1; Clearance = 0.0163 +/- 0.0061 1 . kg-1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.

Adult↗
PubMed1977

Factors influencing plasma phenobarbitone levels in epileptic patients.

1 Various statistical techniques were used to study the effects of age, sex and concurrent therapy with other anticonvulsants on the relation between plasma phenobarbitone levels and doses of (i) phenobarbtione, (ii) methylphenobarbitone or (iii) primidone, in epileptic patients. 2 Methylphenobarbitone and primidone are converted to phenobarbitone in the body. The mean doses of phenobarbitone, methylphenobarbitone and primidone which produced the same plasma phenobarbitone level (15 microgram/ml) were, respectively, 1.75,2.75 and 7.75 mg kg-1 day-1. 3 For both phenobarbitone and methylphenobarbitone dose requirement to achieve a given plasma phenobarbitone level fell progressively with age. Sex influenced the relation between plasma phenobarbitone level and phenobarbitone or methylphenobarbitone dose. Interactions were detected between primidone and both phenytoin and carbamazepine. 4 In individual patients, within the limits of dosage studied, the relation between plasma phenobarbitone level and drug dose was not rectilinear if phenobarbitone itself was taken, but was rectilinear if methylphenobarbitone was taken.

Adolescent↗
PubMed1977

Plasma anticonvulsant concentrations during pregnancy.

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.

Epilepsy↗
PubMed1977

Factors influencing plasma carbamazepine concentrations.

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.

Adolescent↗
PubMed1976

Hereditary motor peripheral neuropathy predominantly affecting the arms.

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.

Adolescent↗
PubMed1976

The effects of phenobarbitone dose on plasma phenobarbitone levels in epileptic patients.

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.

Adolescent↗
PubMed1975

Interactions between anticonvulsants.

Anticonvulsant drug interactions have been investigated using multiple linear regression analyses. The one statistically significant interaction found was that in which phenytoin dosage decreased plasma carbamazepine concentrations. There was a suggestion that carbamazepine and phenobarb dosage tended to increase phenytoin levels. No interaction was detected between phenytoin and sulthiame. Studies in individuals suggested that ethosuximide may increase plasma phenytoin concentration and that clonazepam tends to decrease carbamazepine and phenytoin concentrations.

Anticonvulsants↗
PubMedDate not supplied

Antiepileptic drug intake during pregnancy and malformed offspring.

Possible associations between the presence of malformations in the offspring and various factors related to epilepsy were studied in 134 pregnancies in 105 epileptic women who had plasma antiepileptic drug concentrations measured on multiple occasions during pregnancy. No statistically significant associations could be detected between the malformations and maternal age, the number of the pregnancy, the type, duration or activity of the maternal seizure disorder, and the nature, dose or maximum recorded plasma concentration of the antiepileptic drugs used in the first 16 weeks of pregnancy. However, there was a statistically significant association between the malformations and maternal intake of antiepileptic drugs in combination. No particular combination of agents could be shown responsible for the association, which has been noted previously in the literature. It seems that a much larger study will be needed to clarify the matter.

Abnormalities, Drug-Induced↗
PubMedDate not supplied

Plasma antiepileptic drug concentrations during pregnancy.

Steady-state plasma antiepileptic drug (AED) concentrations were measured at intervals throughout pregnancy and during the postnatal period in 105 women who underwent 134 pregnancies. Phenytoin (PHT) dosage had to be increased in 85% of pregnancies in which the drug was received, carbamazepine (CBZ) dosage in 70%, and phenobarbital (PB) or methylphenobarbital (MPB) dosage in 85%, in an attempt to prevent or correct a fall in plasma concentrations of the respective drugs as pregnancy progressed. The altered disposition of the AEDs usually began in the first 10 weeks of pregnancy (often before epileptic pregnant women are referred for neurological supervision), and had returned to baseline value within 4 weeks of childbirth in two thirds of the women receiving PHT. The return to the nonpregnant situation appeared to be slower for CBZ, PB, and MPB. In women studied during more than one pregnancy, the changes in AED dosage to plasma concentration ratios tended to be greater in the first than in the subsequent pregnancies. Full seizure control prior to pregnancy was associated with a more favorable outcome for freedom from seizures during pregnancy. However, the plasma level monitoring-dosage adjustment policy produced no marked improvement in overall seizure control in pregnancy. This may have occurred because some patients were seen too late in their pregnancies for the policy to have been applied optimally.

Adolescent↗
PubMedDate not supplied

Plasma drug level monitoring in pregnancy.

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.

Anticonvulsants↗