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Biomedical subjects

G E Mawer

Publications and source records attributed to G E Mawer.

At least 19 recordsLinked to original sources
PubMed2001

A pharmacoepidemiologic study of factors influencing the outcome of treatment with lamotrigine in chronic epilepsy.

PURPOSE: To identify prognostic factors for freedom from seizures and long-term retention of treatment in patients receiving lamotrigine (LTG). METHODS: A multicenter, retrospective, case record study of 1,050 patients with chronic epilepsy was carried out. Logistic regression and Cox regression analyses were used to identify clinical features associated with freedom from seizures and retention of treatment, respectively. Long-term retention rates of LTG therapy were estimated using Kaplan-Meier survival analysis. RESULTS: The 1,050 patients with chronic epilepsy were included in the study. Patients with generalized epilepsy (p = 0.01), who were not receiving carbamazepine (CBZ; p = 0.02) were more likely to become seizure-free. Sixty percent of patients continued on LTG therapy >1 year and estimated retention at 8 years was 38%. Patients with generalized epilepsy (p = 0.002), patients receiving concurrent sodium valproate (VPA; p < 0.0001), those not previously exposed to gabapentin and vigabatrin (p < 0.0001), and those in whom the starting dose was lower (p < 0.0012), were more likely to remain on long-term treatment with LTG. The relationships with exposure to other antiepileptic drugs remained significant in patients with focal and with generalized epilepsy when considered separately. CONCLUSIONS: The best results from LTG treatment in terms of freedom from seizures and long-term retention of treatment were obtained in patients with generalized epilepsy. Retention of treatment was enhanced by VPA not only in generalized but also in focal epilepsy. The importance of a low starting dose of LTG was again confirmed. The apparent negative effect of CBZ in patients taking LTG merits further investigation.

Anticonvulsants↗
PubMed2001

Adverse event monitoring in lamotrigine patients: a pharmacoepidemiologic study in the United Kingdom.

PURPOSE: This postmarketing surveillance study of lamotrigine (LTG) was performed to provide complementary data to large-scale Prescription-Event Monitoring study with a retrospective case records survey in five tertiary referral epilepsy centres in the United Kingdom. METHODS: Adverse events were recorded and compared with those of two other new antiepileptic drugs (AEDs), gabapentin (GBP) and vigabatrin (VGB). All deaths were followed up and standardised mortality ratios (SMRs) were calculated. Serious adverse events were assessed individually. RESULTS: A total of 2,701 patients was identified as being exposed to LTG and/or the comparators. It was necessary to exclude 1,326 patients because LTG and/or comparators had been commenced outside the study centres. The adverse events with LTG reported by this study were similar to those reported in the literature. Skin rash was the major adverse event. Life-threatening hepatic failure, acute exacerbation of ulcerative colitis, disseminated intravascular coagulation, and renal failure were reported. No death could be directly attributed to the use of LTG. The SMR was slightly higher than that reported in the literature; this probably reflects severity of epilepsy in the study population. CONCLUSIONS: The safety profile of LTG was similar to that in the large-scale Prescription-Event Monitoring study and generally acceptable. Life-threatening adverse reactions were rare.

Acetates↗
PubMed2000

Medical students' errors in pharmacotherapeutics.

OBJECTIVES: This study analysed the errors made by 16 final-year medical students in a classroom prescribing exercise. The aim was to gain greater understanding of the reasons for non-optimal prescribing and of how to improve basic training in pharmacotherapeutics. METHODS: The task was to adjust a patient's phenytoin sodium dosage to achieve better control of seizures. It was based on a real-life case, and was presented as a written exercise. Process-tracing and think-aloud techniques were used to study the students' performance. RESULTS: The results suggest that the root cause of the errors was lack of a knowledge base which integrated scientific knowledge with clinical know-how. Three different clinical reasoning strategies were observed. Students who followed an incremental strategy demonstrated superior scientific knowledge and this resulted in less hazardous errors. Those who followed gambling or backward-reasoning strategies appeared to possess inferior scientific knowledge and this resulted in more hazardous errors. CONCLUSIONS: The results support current trends towards integrating basic medical science into a foundation of clinical know-how, as in the problem-based curriculum. They also emphasize the importance of a thorough grounding in medical science as a means of minimizing error.

Clinical Competence↗
PubMed1999

The long-term use of gabapentin, lamotrigine, and vigabatrin in patients with chronic epilepsy.

PURPOSE: To compare the long-term retention of gabapentin (GBP), lamotrigine (LTG), and vigabatrin (VGB) by patients with chronic epilepsy and the reasons for treatment discontinuation. To assess the likelihood of seizure freedom, seizure-related injury/hospital admission and mortality after these drugs were commenced. METHODS: This was a retrospective case-records survey in five tertiary referral epilepsy centres in the U.K. The retention times on treatment (from initiation to discontinuation) for the different antiepileptic drugs (AEDs) were compared by using Kaplan-Meier survival analysis and Cox regression. Incidences of seizure freedom and seizure-related injury/hospital admissions and standardised mortality ratios were calculated. RESULTS: There were 1,375 patients with chronic epilepsy included; 361 were taking GBP, 1,050 LTG, and 713 VGB. The retention of GBP, LTG, or VGB was <40% at 6 years. Fewer than 4% of patients become seizure free while taking one of the drugs. There was no reduction in mortality or seizure-related injury/admission. CONCLUSIONS: The impact of these new AEDs on chronic epilepsy can be described only as modest. This view may be revised, however, as more experience is gained with new drugs in previously untreated patients.

Acetates↗
PubMed1999

Adjustment of carbamazepine dose to offset the effects of the interaction with remacemide hydrochloride in a double-blind, multicentre, add-on drug trial (CR2237) in refractory epilepsy.

PURPOSE: The efficacy of remacemide hydrochloride (REM) as an antiepileptic drug (AED) was tested in a double-blind, add-on trial in patients with refractory epilepsy. Concurrent drugs included carbamazepine (CBZ). The interfering effects of the pharmacokinetic interaction between REM and CBZ were offset by the monitoring of plasma CBZ concentration and the appropriate reduction of CBZ dose by an unblinded observer. METHODS: Patients taking CBZ entered a 4-week run-in period to stabilise their dosage regimen to Tegretol tablets and blinded capsules containing Tegretol tablets. They then entered an 8-week baseline period during which variation of plasma CBZ concentration was used to derive an individual Shewart Control Chart for each patient. These charts were used to define the threshold for CBZ dose reduction after the addition of trial drug. Where necessary the unblinded observer adjusted that portion of the daily dose of CBZ concealed in the opaque capsules, thereby maintaining the blind for the investigator and the patient. RESULTS: CBZ dosage reductions ranging from 14 to 50% were required by 63% of patients who received REM. Substantial increases in plasma CBZ concentration, which would have confounded the results of the trial, were thus avoided. The small increases in CBZ concentration that occurred in spite of this procedure were of similar magnitude in responders (patients who experienced > or =50% reduction in seizure frequency during treatment) and nonresponders, and in both groups the mean increase was <1 mg/L. CONCLUSIONS: The method is offered as a model solution for problems caused by pharmacokinetic interactions in add-on trials.

Acetamides↗
PubMed1999

Factors influencing the incidence of lamotrigine-related skin rash.

OBJECTIVE: To determine the incidences of serious and nonserious lamotrigine-related rash, determine the risk factors for lamotrigine-related rash, and evaluate the impact on the incidence of rash of the manufacturer's recommendation to reduce the starting dose of lamotrigine. METHODS: This was a retrospective case record survey at five tertiary referral epilepsy centers in the UK. The risk factors for lamotrigine-related rash were identified by logistic regression. The independent factors tested were gender, age, epilepsy type, concurrent medication, and starting dose of lamotrigine. The incidences of rash before and after the recommendation of reduction in starting dose were compared by chi2 analysis. RESULTS: A total of 1050 patients were included. The incidences of serious and nonserious rash were 1.1% (95% CI 0.5% to 1.8%) and 7% (95% CI 5.5% to 8.6%), respectively. Females were at higher risk of developing rash than were males, with a relative risk of 1.8 (95% CI 1.2 to 2.8). The starting dose of lamotrigine was reduced in response to the manufacturer's recommendation, and there was a significant reduction (p = 0.045) in the incidence of serious rash, from 1.5% (12/805) to 0% (0/245). However, there was no reduction in the overall incidence of lamotrigine-related rash, with 63/805 (8%) before and 23/245 (9%) after the recommendation. CONCLUSIONS: Failure to detect a reduction in the incidence of lamotrigine-related rash since the new (reduced) recommended starting dose of lamotrigine may arise from failure to reduce the starting dose below a critical threshold level, incomplete compliance with current recommendations, or insufficient sample size. The results of this and other studies show that the starting dose of lamotrigine is a significant factor affecting the incidence of rash; furthermore, this study also shows that significant reduction in the incidence of serious rash can be achieved by reducing the starting dose. Therefore, clinicians should not deviate from the recommendations.

Adolescent↗
PubMed1995

Interactions involving new antiepileptic drugs.

The advent of new antiepileptic drugs (AED) has increased the opportunities for interaction. Clinicians seek therapeutic interactions in which two AED together have greater efficacy than either drug alone; there are case reports of such, but few prospective studies. Interactions must also be suspected when the adverse effects of a new AED differ according to the co-medication. The basis can be pharmacodynamic, but more frequently it is pharmacokinetic. Inhibition of cytochrome P450 enzymes by the new drugs is more common than induction. There are important implications for the design of clinical trials and the planning of treatment changes in patients.

Anticonvulsants↗
PubMed1993

Impairment of psychomotor function at modest plasma concentrations of carbamazepine after administration of the liquid suspension to naive subjects.

1. The influence of pharmaceutical formulation on the plasma drug concentration-time curve and the psychomotor responses to 400 mg carbamazepine has been assessed in 12 healthy male volunteers; three formulations and placebo were compared in a randomised, blind, crossover study. 2. The plasma concentration of carbamazepine rose to a maximum of 3-7 mg l-1 by 2-3 h after administration of the liquid suspension. Conventional and controlled release tablet formulations gave lower peaks at about 8 and 32 h, respectively. From 32 h onwards the plasma concentrations from the three formulations were indistinguishable. 3. Significant impairment of psychomotor function was observed after the liquid suspension only; subjective sedation was significant at 1 and 2 h and the critical flicker fusion frequency threshold was lowered at 1-8 h. Digit-symbol substitution, choice reaction time and body sway gave less conclusive evidence of impairment. 4. The results do not support the hypothesis that a psychomotor effect from carbamazepine is a threshold phenomenon with a critical plasma drug concentration at about 8 mg l-1. 5. A second hypothesis that rate of rise of plasma carbamazepine concentration has an important influence on psychomotor effect fits the observations. This interpretation is tentative since the use of a fixed dose of carbamazepine meant that differences due to rate of rise of drug concentration were confounded with differences due to peak height.

Adult↗
PubMed1990

Respiratory and sedative effects of clobazam and clonazepam in volunteers.

1. The respiratory and psychomotor effects of two benzodiazepines used mainly as anticonvulsants were compared in healthy volunteers, using a double-blind placebo controlled design. 2. Clobazam (10 and 20 mg) produced significantly fewer psychomotor side effects than clonazepam (0.5 and 1 mg). Neither drug at either dose affected the ventilatory response to CO2. 3. Although clonazepam produced significant effects on psychomotor performance, these did not correlate with plasma drug concentration. 4. Our studies provide further evidence that at the doses chosen clobazam is considerably less sedating than clonazepam. Further investigation is required into the tolerance profile of both drugs in patients.

Adult↗
PubMed1989

Equivalence of conventional and sustained release oral dosage formulations of acetazolamide in primary open angle glaucoma.

1. Outpatients with primary open angle glaucoma uncontrolled on single topical therapy with either pilocarpine or timolol were recruited for a stratified double dummy cross over trial. Once or twice daily sustained release acetazolamide (SRA) was compared with an identical regimen of conventional tablets (CA). 2. During the run in period the patients received 500 mg SRA once or twice daily as needed to control intraocular pressure (IOP). The dose was thereafter kept constant and patients were allocated randomly to 4 weeks treatment with CA followed by 4 weeks SRA or vice versa. IOP and venous plasma concentrations of acetazolamide were measured at weekly intervals. At the end of each 4 week course, patients were admitted for a 24 h profile of IOP and drug concentration measurements. 3. Thirty-five patients were recruited, but eleven were withdrawn during the run in period largely because of adverse effects; these became less troublesome when it was decided to give the once daily dose at 22.00 h. Four were withdrawn during the cross over, two because of inadequate IOP control. Twenty completed the trial. 4. The morning plasma concentration of acetazolamide measured each week showed no tendency to accumulation during the study. The mean swing (maximum minus minimum) in plasma acetazolamide concentration during the 24 h profile was less (P less than 0.005) with the SR formulation (11.6 +/- 4.9; mg l-1) +/- s.d.) than with the conventional (15.5 +/- 4.7) but the mean concentrations over the 24 h profile were indistinguishable (P greater than 0.05; 9.7 +/- 3.8 and 8.6 +/- 2.8 respectively). 5. Satisfactory control of IOP (no more than one reading above 22 mmHg) was maintained despite the changes in formulation in all but two of the patients who entered the cross over study. No close relationship between IOP and plasma concentration of acetazolamide was found. The 24 h IOP profiles whilst receiving each of the formulations were indistinguishable; thus the smoothing of the plasma drug concentration profile achieved by the SR formulation did not reduce the amplitude of swings in IOP. Similarly, no difference was observed between the formulations with respect to adverse effects. 6. It is concluded that the SR and conventional formulations were equivalent with respect to mean plasma acetazolamide concentration, IOP control and adverse effects. The SR formulation did not show practical advantages over the conventional formulation which was equally effective even with dosage intervals of 12 or 24 h.

Acetazolamide↗
PubMed1987

Phenytoin infusion in severe pre-eclampsia.

Intravenous phenytoin sodium was given as a high-dose infusion (10 X 8-18 mg/kg) for anticonvulsive prophylaxis to 2 eclamptic patients and to 24 patients with moderate to severe pre-eclampsia. There were no major maternal or neonatal side-effects. Plasma phenytoin levels were within the therapeutic range (7-20 mg/l) at 30 min and 6 h after the infusion in all patients, and remained at a therapeutic level in 21 patients after 12 h. After a second dose of phenytoin in 19 patients, drug levels were within the therapeutic range at 24 h.

Female↗
PubMed1987

The respiratory effects of oral ethyl loflazepate in volunteers.

A volunteer study was undertaken to assess the respiratory effects of ethyl loflazepate, a new benzodiazepine, and to correlate these with plasma concentrations of the active metabolites. Twelve volunteers were given placebo, 2 mg ethyl loflazepate, and 6 mg ethyl loflazepate on separate occasions. Respiration and plasma metabolite levels were assessed hourly for 8 h and at 24 h. The 6 mg ethyl loflazepate treatment produced a significant decrease (P less than 0.02) in the ventilatory response to carbon dioxide at 5 h. However this did not equate with a peak in plasma metabolite concentrations which were maintained at a plateau level from 4 to 24 h.

Adult↗
PubMed1987

Influence of dosage interval on the therapeutic response to gentamicin in mice infected with Klebsiella pneumoniae.

Without treatment all mice died after receiving 10(3) Klebsiella pneumoniae by intraperitoneal injection. Nevertheless, it was possible to delay treatment for 12 h and still observe a therapeutic response from im gentamicin (5 mg/kg). This gave initial serum concentrations comparable to clinical levels, which fell rapidly (t 1/2 = 15 min) to reach the limit of detection by 90 min. Courses were given of 3 or 6 doses spaced at different intervals. Irrespective of dosage interval there was a marked fall in bacteraemia with each of the first two doses. Between doses separated by 8 or even 12 h there was no evidence of bacterial multiplication but this was obvious by 24 h. Both the bacteraemic responses and the lengths of survival were best with the 12-hour dosage interval. These results are consistent with other reports of the persistence of antibiotic effects despite undetectable serum concentrations and the compatibility of a substantial dosage interval with a successful therapeutic outcome.

Animals↗
PubMed1986

Enhancement by sodium salicylate of the blood glucose lowering effect of chlorpropamide-drug interaction or summation of similar effects?

The ability of sodium salicylate (3 g) to enhance the blood glucose lowering action of chlorpropamide (200 mg) has been confirmed in healthy male volunteers who received an oral test dose of 50 g glucose. Salicylate raised the plasma concentration of insulin and lowered that of cortisol but did not alter the concentration of chlorpropamide. The area under the blood glucose concentration-time curve was used as the measure of drug response and the significance of drug effects was assessed by analysis of variance. In one study on five volunteers the effect of combining salicylate and chlorpropamide was additive. In a second study on six volunteers 200 mg chlorpropamide, 3 g sodium salicylate and 100 mg chlorpropamide + 1.5 g salicylate were equi-effective. The enhancement of chlorpropamide action by salicylate in this single dose study is consistent with the summation of similar effects. It is not necessary to postulate an interaction.

Adult↗
PubMed1986

Netilmicin in gram-negative sepsis: comparative abilities of a dosage nomogram and clinical microbiologists to predict the preferred individual dose.

The preferred dose of netilmicin was determined in each of 39 patients with severe gram-negative sepsis treated at two centres. The dose was based upon the attainment of recommended serum concentrations. Patient age varied from 18 to 87 years (mean 58), estimated creatinine clearance from 20 to 150 ml/min (mean 71), and the preferred dose from 100 to 750 mg/24 h. The dose generated by a nomogram for netilmicin was compared in retrospect with the initial dose assigned to each patient by the clinical microbiologist concerned. With respect to the preferred dose, the nomogram underdosed, on the average, by 40 mg/24 h, and the microbiologists, by 30 mg/24 h. The correlation with the preferred dose was stronger for the nomogram dose (r = 0.66; p less than 0.001, 37 df) than for the microbiologists' dose (r = 0.47; p less than 0.005, 37 df) but there was no significant difference between the two in the frequency with which they predicted the preferred dose to within 50 mg/24 h (nomogram 19/39; microbiologists 16/39). The prescription of a fixed dose of 450 mg/day to all patients would have had a similar success rate (15/39). The performance of the nomogram was better in patients with serum creatinine concentrations of greater than or equal to 100 microM (r = 0.82; p less than 0.001, 13 df; 10/15 within 50 mg/24 h of preferred dose) than in those with creatinine concentrations less than 100 microM (r = 0.55; p less than 0.01, 22 df; 9/24 within 50 mg/24 h of preferred dose).

Adolescent↗
PubMed1984

Estimation of gentamicin clearance and volume of distribution in neonates and young children.

Gentamicin therapy should be guided by serum level monitoring in all age groups, dosage adjustments depending on age related changes in pharmacokinetics. Population data analysed from two centres (43 infants from Glasgow and 100 infants and children from Manchester) by the computer program NONMEM showed that volume of distribution was related to body weight by a proportionality factor that decreased from the region of 0.41-0.46 l/kg in children less than 3 months to 0.25-0.32 l/kg in older children, a value which merges with that accepted for adults (0.25 l/kg). In both young and older children, clearance was also found to be dependent on body weight. Renal function (creatinine concentrations) provided no further explanatory power. When these results were used prospectively to forecast gentamicin concentrations with a Bayesian kinetic parameter estimation program, trough concentrations were more precisely predicted than peaks when a single concentration measurement was used. In clinical practice, however, two concentration measurements are usually routinely available and these should lead to greater precision of both peak and trough predictions. These results have been incorporated into a simple nomogram which can be used to determine a dose of gentamicin which will achieve target peak concentrations in infants, assuming that troughs should not exceed 2 micrograms/ml.

Age Factors↗