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Biomedical subjects

C M Lander

Publications and source records attributed to C M Lander.

At least 19 recordsLinked to original sources
PubMed1996

Tetraphenylphosphonium chloride induced MR-visible lipid accumulation in a malignant human breast cell line.

The effect of the cationic lipophilic phosphonium salt tetraphenylphosphonium chloride (TPP) on a human malignant breast cell line, DU4475, was monitored with proton nuclear magnetic resonance (1H MRS). TPP caused a dose- and time- dependent increase in resonances arising from MR-visible lipid as measured by the CH2/CH3 ratio in the 1-dimensional 1H MR spectrum. Two-dimensional MRS identified increases in the glycerophosphocholine/lysine cross-peak ratio and corresponding decreases in the phosphocholine/lysine ratio in a dose- dependent fashion in TPP-treated cells. Lipid metabolic changes are discussed in the light of other MR experiments, and the data indicate that accumulation of MR-visible lipids may arise from the rearrangement of phospholipids accompanying mitochondrial destruction or from the catabolism of phospholipids associated with early events in the cytotoxic process.

Antineoplastic Agents↗
PubMed1996

Modulation of MR-visible mobile lipid levels by cell culture conditions and correlations with chemotactic response.

A transformed murine fibroblast cell line has been used to assess which criteria govern the appearance of a lipid pool that is mobile on the MR time scale. A high-resolution proton MR signal arising from neutral lipids, including triglyceride and cholesteryl esters, has previously been associated with membrane events in stimulated, transformed and malignant cells. We report that the attenuation of cellular proliferation by confluence or low pH caused significant increases in MR-visible lipid and that the lipid signal could be amplified at high density by the removal of serum. A significant decrease in chemotactic response accompanied the culture of cells at high density, but chemotactic response was not generally linked to alteration of the lipid signal. The appearance of the signal was also not correlated with the proportion of cells in any phase of the cell cycle. Significant changes in the MR-visible pools of the lipid metabolites choline, phosphocholine and glycerophosphocholine were measured under the culture conditions employed with 2D MRS and suggest that MR-visible lipid may arise from the catabolism of phospholipids.

Animals↗
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↗
PubMed1984

Bioavailability and pharmacokinetics of phenytoin during pregnancy.

Five epileptic women needing to commence phenytoin therapy during pregnancy received a single intravenous and a single oral dose of phenytoin several days apart before starting regular intake of the drug. Plasma phenytoin concentration - time data were analysed by three different pharmacokinetic techniques. However assessed, the mean oral bioavailability of the drug proved to be about 90% of the intravenous bioavailability. This finding makes it unlikely that impaired bioavailability accounts for the increase in oral phenytoin dosage necessary in pregnancy to maintain plasma phenytoin concentrations at pre-pregnancy values. Phenytoin clearance in the pregnant subjects was approximately double the published values for phenytoin clearance in non-pregnant persons. This suggests that increased (metabolic) clearance accounts for the increased phenytoin dosage requirement of pregnancy.

Aging↗
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

Akinetic freezing and trick movements in Parkinson's disease.

The clinical features of akinetic freezing occurring in a group of 85 patients with idiopathic Parkinsonism and the individual methods used to overcome immobility are described. Frequency and severity of attacks are related to duration of disease and are not amenable to currently available medications. The pathogenesis and therapeutic implications are briefly discussed.

Adult↗
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↗