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Biomedical subjects

R W Bury

Publications and source records attributed to R W Bury.

At least 19 recordsLinked to original sources
PubMed1992

The dissociation of GM-CSF efficacy from toxicity according to route of administration: a pharmacodynamic study.

The pharmacokinetics and pharmacodynamics of bacterially synthesized granulocyte-macrophage colony stimulating factor (GM-CSF) were studied in 33 patients. GM-CSF (0.3-30 micrograms/kg/d) was administered subcutaneously (s.c.) or intravenously (i.v.) by bolus or 2 h infusion for 10 d to three patients at each dose level, and serum levels measured by enzyme-linked immunosorbent assay (ELISA). Relationships between pharmacokinetic variables and GM-CSF efficacy and toxicity were investigated. GM-CSF appeared more effective s.c. than i.v. Correlations with response improved when patients with neutropenia or marrow infiltration by tumour were excluded. For the remaining patients, the correlation coefficients between the day 10 leucocyte count was highest with dose (R = 0.629, P less than 0.01), the duration GM-CSF concentrations exceeded 1 ng/ml (r = 0.524, P less than 0.05) and area under the concentration-time curve (R = 0.508, P less than 0.05). There was no correlation with peak serum GM-CSF (Cmax) (R = 0.188, P = NS). In contrast, the first dose reaction (characterized by hypoxaemia and hypotension) was associated with high Cmax (P less than 0.01) and i.v. administration. Fever, liver enzyme elevation and pericarditis occurred at 10-30 micrograms/kg and were not influenced by route. Since the variables correlating with response differed from those correlating with these toxicities, it appears that the therapeutic index for GM-CSF can be increased by modifying the method of administration.

Dose-Response Relationship, Drug↗
PubMed1991

Ponalrestat does not cause a protein binding interaction with warfarin in diabetic patients.

Ponalrestat (Statil, ICI; Prodiax, Merck Sharp and Dohme) is an aldose reductase inhibitor which is highly protein bound. Ponalrestat markedly displaced warfarin from its protein binding in vitro at a concentration of 500 micrograms ml-1, but not at a concentration of 50 or 100 micrograms ml-1. Twelve diabetic patients (six males), age range 38-65 years, in receipt of chronic stable warfarin therapy, were given ponalrestat (600 mg daily) for 2 weeks in an open trial. A matching placebo tablet was administered for 1 week before and after the active treatment period. Patients were seen ten times (four times during the ponalrestat phase), and during the ponalrestat phase, plasma samples were also taken before and at 3 h after the daily dose of ponalrestat. At none of the visits was there any significant change in prothrombin ratio (INR), plasma total or unbound warfarin concentrations, or percentage protein binding of warfarin. No clinical complications of combination treatment were detected. The maximum ponalrestat concentration observed in the patients was approximately 100 micrograms ml-1. We conclude that no significant interaction between these drugs occurs at the doses of ponalrestat studied.

Adult↗
PubMed1990

The effects of dose and route of administration on the pharmacokinetics of granulocyte-macrophage colony-stimulating factor.

The pharmacokinetics of granulocyte-macrophage colony stimulating factor (GM-CSF) (0.3-30 micrograms/kg) were studied after subcutaneous bolus (n = 16) or intravenous bolus (n = 5) injection or 2 h intravenous infusion (n = 12). Each method of administration gave a different GM-CSF concentration-time profile. Highest peak serum concentrations (Cmax) followed the intravenous bolus, and the time GM-CSF persisted at a concentration greater than 1 ng/ml (t greater than 1 ng/ml) was longer after a subcutaneous than after an intravenous injection. Area under the concentration-time curve (AUC), Cmax and t greater than 1 ng/ml all increased with dose for each method of administration. After intravenous administration, there was a two-phase decline in concentration. The half-life (t1/2) of the terminal phase following an intravenous bolus ranged from 0.24 to 1.18 h and, following intravenous infusion, from 0.62 to 9.07 h and appeared to increase with dose. The apparent clearance was greatest following subcutaneous injection at doses below 3 micrograms/kg, suggesting a saturable mechanism or different bioavailability. Only 0.001%-0.2% of the injected dose appeared in the urine as immunoreactive GM-CSF.

Adult↗
PubMed1989

Prolapsed thoracic intervertebral disc: the importance of CT assisted myelography.

We present six new cases of prolapsed thoracic intervertebral disc (PTIVD), and review the clinical and radiological features, particularly with regard to the role of computed tomography (CT) examination in the diagnosis and management. In patients with atypical lower limb pain, particularly when associated with sphincter disturbances, lumbar myelography is incomplete unless supplemented by an examination of the conus region and lower thoracic cord. The supplementary use of CT in suspected PTIVD is of considerable value to the surgeon in determining the size, position, and volume of the sequestration, and the extent of excavation of the spinal cord by prolapsed disc material.

Aged↗
PubMed1989

Unbound phenytoin plasma concentrations in patients comedicated with sodium valproate--the predictive value of plasma albumin concentration.

1. Phenytoin protein binding in epileptic patients on phenytoin as monotherapy has been compared with protein binding in patients treated with both phenytoin and sodium valproate. In addition the relative value of assayed total phenytoin plasma concentrations and assayed unbound phenytoin plasma concentrations and the value of predicted unbound phenytoin plasma concentrations in predicting phenytoin toxicity has been assessed. 2. The mean phenytoin unbound fraction for patients taking sodium valproate (0.122) was significantly greater than for those on monotherapy (0.082). 3. There were six episodes of clinical toxicity. In five toxic episodes the assayed unbound phenytoin plasma concentration was a better reflection of toxicity than the assayed total phenytoin plasma concentration, and four of these occurred in patients on sodium valproate. 4. Unbound phenytoin plasma concentrations were predicted from a single regression equation correlating all assayed total phenytoin plasma concentrations with assayed unbound phenytoin plasma concentrations, from two separate regression equations for each group of patients, and from the correlation between phenytoin protein binding and plasma albumin concentration. 5. The unbound phenytoin plasma concentrations predicted from the two regression equations were statistically no less effective than the assayed unbound phenytoin plasma concentrations in assessing toxicity. 6. Despite a correlation between plasma albumin concentrations and phenytoin protein binding, the use of albumin concentrations in predicting unbound phenytoin plasma concentrations appeared to be of little additional benefit.

Adult↗
PubMed1988

Screening procedure for stimulant laxatives in urine using high-performance liquid chromatography with diode array detection.

We describe a liquid chromatographic screening procedure for the detection of stimulant laxatives in urine. A 2-ml urine sample was incubated with 500 U of beta-glucuronidase for 2 h at 60 degrees C. The sample was acidified with sodium acetate (pH 5.0) and extracted with 5 ml of an isopropanol-chloroform (1:9) mixture. The organic layer was cleaned up further by washing with 5 ml disodium hydrogen-phosphate (pH 7.5) before being transferred to a conical tube and evaporated to dryness. The residue was reconstituted in 100 microliters mobile phase and 3 microliters were injected onto a Hewlett-Packard Hypersil ODS (5 microns) column. The ultraviolet absorbance of the eluent was monitored at 225 nm. Rhein, bisacodyl diphenol, bisoxatin diphenol, phenolphthalein, bisacodyl, bisoxatin and danthron all eluted within 6 min. The screen was evaluated using urine specimens obtained from 19 patients who claimed they had taken one or more of the laxatives under consideration within the past 48 h. Only two patients who claimed to have taken Coloxyl and Danthron showed negative results. Eighteen of twenty laxatives (90%) taken by the patients were detected and their identity verified by plotting post-run ultraviolet spectra. We therefore conclude that the screen is sufficiently reliable to be of help in the early detection of surreptitious abusers of stimulant laxatives.

Adult↗
PubMed1987

Liquid chromatographic screening of diuretics in urine.

We describe a liquid chromatographic screening procedure for the detection, in urine, of twelve of the fifteen potassium-depleting diuretics available in Australia. A 2-ml urine sample was acidified with NaH2PO4 (pH 4.1) and extracted with 4 ml ethyl acetate. The sample was cleaned up further by washing with 5 ml Na2HPO4 (pH 7.5). The ethyl acetate was then evaporated to dryness, the residue reconstituted in 100 microliters mobile phase and 5 microliter were injected onto a Merck LiChrosorb RP-18 (5 microns) column. The ultraviolet absorbance of the eluent was monitored at 271 nm for 10 min. The screen was evaluated by giving each of thirty volunteers the lowest recommended dose of one of the diuretics in the study and obtaining urine samples 4, 8 and 24 h after having taken the dose. Twelve diuretics, chlorothiazide, hydrochlorothiazide, quinethazone, chlorthalidone, methyclothiazide, clopamide, frusemide, metolazone, mefruside, bendrofluazide, cyclopenthiazide and bumetanide, were all detectable up to 24 h after a dose. We therefore conclude that the screen would be reliable for the detection of these diuretics in urine.

Chromatography, High Pressure Liquid↗
PubMed1987

Elimination of enoxacin in renal disease.

The elimination of enoxacin was investigated in 15 subjects, 10 of whom were hospital outpatients with renal disease and varying degrees of renal impairment. Each was given enoxacin orally (200 mg b.i.d.) for 7 days. Blood specimens collected over 24 hours after the final dose of enoxacin and urine collected during the 12-hour dose interval after the final dose were assayed for enoxacin by HPLC. The elimination half-life of enoxacin increased with worsening renal function. In general, patients with diminished renal function had lower plasma enoxacin clearance values than had normal subjects, and a statistically significant correlation between apparent oral clearance and creatinine clearance was observed. Excretion of enoxacin by the kidney accounted for 26% to 72% of the apparent plasma clearance in normal subjects. This was markedly reduced in patients with severe renal failure.

Administration, Oral↗
PubMed1987

Plasma concentrations of unbound valproate and the management of epilepsy.

The range of protein binding of valproate and the use of unbound and total plasma concentrations of the drug were studied in an outpatient population of 70 epileptics. The unbound fraction of plasma valproate ranged from 4.2% to 11.7% with a median of 7.1%. A non-linear relationship was found between unbound and total plasma valproate concentrations and was best described by a cubic regression (r2 = 0.88). This concentration dependent protein binding was also demonstrated by a linear relationship between total plasma valproate concentration and unbound fraction (r = 0.46). As expected, there was no correlation across the patient population between plasma concentrations of valproate and seizure frequency. In an individual patient, however, plasma valproate levels usually correlated with change in clinical status, although this correlation was no better for unbound levels than total levels. There were only three patients in whom unbound valproate levels correlated better with clinical effect than total levels, whereas there were six patients in whom total levels correlated better than unbound levels. It is therefore concluded that monitoring sodium valproate therapy with unbound concentrations is rarely helpful and the routine use of unbound valproate levels cannot be advocated.

Adolescent↗
PubMed1987

A kinetic study of sulindac in the elderly.

To study the disposition of the anti-inflammatory drug sulindac, its active sulphide metabolite, and the inactive sulphone metabolite, sulindac (200 mg twice daily) was given to eight elderly subjects for at least 14 consecutive days. The drug was then ceased for 72 hours, and suitable samples were collected to study its elimination. The mean steady-state concentration for sulindac was 5.0 micrograms/ml, for sulindac sulphide was 6.5 micrograms/ml, and for sulindac sulphone was 13.2 micrograms/ml. These are approximately twice the reported steady-state levels for the respective redox forms in healthy young adults. The mean half-lives of sulindac, sulindac sulphide, and sulindac sulphone were 18.3 hours, 22.3 hours, and 54.6 hours, respectively. One patient who had mildly abnormal liver function tests developed more severe abnormalities whilst receiving sulindac. These returned towards normal after cessation of treatment. This patient had the highest steady-state plasma concentration of sulindac sulphone. It is concluded that care should be taken with the use of sulindac in the elderly, and control of patients' symptoms should be attempted with lower doses of the drug before the standard dose of 200 mg twice daily is administered.

Age Factors↗