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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
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 Thirty-five patients were recruited, but eleven were withdrawn during the run in period largely because of adverse effects; these became less troublesome when it was decided to give the once daily dose at 22.00 h. Four were withdrawn during the cross over, two because of inadequate IOP control.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↗
PubMed1979

Comparison of medigoxin and digoxin in the control of atrial fibrillation.

1 Medigoxin (Lanitop) 300 microgram/day and digoxin (Lanoxin) 500 microgram/day were compared in cross-over studies on healthy volunteers and on patients with uncontrolled atrial fibrillation. Serum glycoside concentrations were measured by radioimmunoassay and ventricular rates by ECG. The two regimens appeared to be therapeutically equivalent. 2 The mean serum glycoside concentration in the steady state and the rate at which this state was attained were similar with both drug regimens in the healthy volunteer group. The between-subject variation in serum glycoside concentration was not significantly less during medigoxin administration. 3 The renal clearance of serum glycoside was much lower during medigoxin administration both in healthy volunteers and in patients. This was not due to a difference in serum protein binding. The relatively small dosage requirement for medigoxin was attributed partly to a lower clearance rate and partly to more nearly complete absorption. 4 During the first 2 weeks of the patient study there was a substantial rise in mean serum glycoside concentration and a corresponding fall in ventricular rate. This was attributed to more consistent self-administration of digoxin. The subsequent change to medigoxin had no further effect on mean glycoside concentration, ventricular rate or frequency of ventricular ectopic beats. 5. An attempt to compare the onset of the ventricular rate response to a single oral dose of medigoxin with that to digoxin gave inconclusive results.

Adult↗
PubMed1978

Individual variation in daily dosage requirements for phenytoin sodium in patients with epilepsy.

1 Ninety adult patients receiving phenytoin sodium were studied prospectively in an epileptic centre. Serum concentrations of phenytoin under steady state conditions were measured by gas liquid chromatography. When clinically indicated the daily dosage rate was adjusted by 50 mg steps until a serum concentration of 10--20 mg/l was produced. 2 Concentrations within the above range were obtained in 50 patients; the required dosage rate varied from 200--500 mg/day. Twenty-five clinical, biochemical and haematological attributes were recorded for each patient and tested for correlation with dosage requirement. 3 The dosage requirement correlated most strongly (r = 0.57, P less than 0.001) with body surface area. This relationship (approximately 200 mg/day per m2) accounted however for only one third of the total dosage variance. 4 Amongst 18 patients receiving simultaneous treatment with phenobarbitone, the effective plasma clearance of this drug taken in conjunction with body surface area accounted for a significantly greater proportion of the total dosage variance. Multiple regression analysis failed to reveal other, more widely applicable predictors of individual phenytoin dosage requirements.

Adult↗
PubMed1976

Intravenous injection of gentamicin and tobramycin without impairment of hearing.

The aminoglycoside antibiotics gentamicin and tobramycin were given to six healthy volunteers by intravenous injection. A dose of 80 mg was injected within 1 min. The curves relating serum concentration to time did not differ significantly for the two drugs. The maximal serum concentrations of drug exceeded 10 mug/ml on seven of 12 occasions. Despite these high concentrations, loss of hearing was not significant at any frequency (1,000-8,000 Hz) up to one month after injection. It is suggested that the aminoglycoside antibiotics penetrate into the inner ear lymph very slowly and that the concentration at that site is relatively unaffected by transient high concentrations of antibiotic in the blood plasma.

Adult↗
PubMed1976

Can digoxin dose requirements be predicted?

A search for patient variables relevant to digoxin dose requirements was made in fourty-three patients with a wide range of renal and hepatic function. The daily dose of digoxin to achieve a mean serum concentration of 1.5 ng/ml, the standardized dose, was calculated for each patient. The standardized dose correlated significantly with the following variables, in descending order of correlation coefficient; creatinine clearance, serum creatinine concentration, body weight and serum albumin concentration. An equation containing the two independent variables, creatinine clearance and serum albumin concentration, had a significantly stronger correlation with standardized dose than creatinine clearance alone. Attempts were made in each patient to predict the standardized dose using both empirical prescribing methods and the published nomograms. Although a maximum of 70% of the variance of the standardized dose was explained, this corresponded approximately to one patient in three having a predicted dose outside the 95% confidnece limits for the standardized dose. There remain important sources of individual variation in digoxin dose requirements yet to be identified. Future application of empirical prescribing methods, such as multiple linear regression and Bayes' theorem, to prescription for large, defined patient groups may improve dose prediction for individual patients.

Digoxin↗
PubMed1976

Computer assisted prescribing of drugs.

Computer programs for drug dosage adjustment may be fixed, adaptive or empirical. The aminoglycoside antibiotic dosage requirements of individual patients are relatively predictable, and it seems to be adequate to assume that volume of distribution is a fixed proportion of body weight and that renal clearance is a fixed proportion of creatinine clearance. This approach has been less successful with digoxin because patient compliance, the proportion absorbed and liver clearance are not yet predictable. Accordingly, adaptive programs have been developed which use feedback from drug concentration measurements to predict the future dosage needs of the patient. When individual needs are known for a large patient group it becomes possible to predict the dosage requirements of a new patient from the same population by empirical methods. Computer programs for dosage adjustment will not be widely used until their scope is increased and objective evidence of clinical benefit is obtained.

Bayes Theorem↗