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Biomedical subjects

K F Brown

Publications and source records attributed to K F Brown.

At least 37 records · Page 2Linked to original sources
PubMed1989

Bioavailability of hydroxychloroquine tablets in healthy volunteers.

1. Five healthy volunteers received, in a randomised crossover design study, a 155 mg oral tablet and an intravenous infusion of 155 mg racemic hydroxychloroquine (200 mg hydroxychloroquine sulphate) to assess the bioavailability of the commercially available tablet (Plaquenil, Winthrop Laboratories, Australia). 2. The terminal elimination half-life of hydroxychloroquine is more than 40 days, thus blood and urine samples were collected for 5 months following each dose to characterise adequately the terminal elimination phase and obtain accurate estimates of the areas under the concentration-time curves. 3. The mean (+/- s.d.) fraction of the oral dose absorbed, estimated from the blood and urine data, was 0.74 (+/- 0.13). A wide range of estimates of the fraction of the oral dose absorbed was calculated from the plasma data (0.41 - 1.53), reflecting the difficulties of accurate measurement of hydroxychloroquine in plasma. 4. A period of 6 months is required to achieve 96% of steady-state levels of hydroxychloroquine with the usual once daily, oral dosage regimen. Pharmacokinetic factors may thus be partly responsible for the delayed action of the drug in rheumatic conditions. 5. Haemodialysis will not aid in the case of oral overdose with hydroxychloroquine. Although the proportionate increase in clearance may be large, the increase in the fraction of the dose excreted will be negligible. The extensive sequestration of the drug by tissues limits effectiveness of haemodialysis.

Biological Availability↗
PubMed1988

A dose-ranging study of the pharmacokinetics of hydroxy-chloroquine following intravenous administration to healthy volunteers.

1. The pharmacokinetics of hydroxychloroquine were studied in five healthy volunteers following an intravenous infusion of 155 mg (2.47 +/- 0.25 mg kg-1) racemic hydroxychloroquine. Four of these volunteers also received a further 310 mg (4.92 +/- 0.45 mg kg-1) infusion of hydroxychloroquine and evidence of nonlinearities in the pharmacokinetics of hydroxychloroquine were sought. 2. No nonlinear elimination or distribution processes appeared to be operating at the doses of hydroxychloroquine used in this study, supporting the hypothesis that in the therapeutic dosing range the pharmacokinetics of hydroxychloroquine are linear. 3. Half-life and mean residence time were long (around 40 days) and large volumes of distribution were calculated (5,522 l from blood, 44,257 l from plasma). Sequestration into the tissues is an important feature of the disposition of hydroxychloroquine. The persistence of hydroxychloroquine in the body is due primarily to this extensive tissue distribution, rather than to low clearance (667 ml min-1 based on plasma data, 96 ml min-1 based on blood data). 4. Plasma data were more variable than blood data. Blood to plasma concentration ratios were not constant (mean +/- s.d.: 7.2 +/- 4.2). The data indicate that it is preferable to measure whole blood concentrations of hydroxychloroquine, rather than plasma concentrations, in pharmacokinetic studies. 5. The pharmacokinetics of hydroxychloroquine are similar to those of chloroquine.

Adult↗
PubMed1987

Alcuronium pharmacodynamics in dogs: effect-concentration relationships in the diaphragmatic and limb muscles.

Previous studies suggest that the muscles of the diaphragm are less sensitive to neuromuscular blocking agents than the limb muscles. However, this difference has not been characterized directly in terms of relaxant drug plasma concentrations. The pharmacodynamics of the non-depolarizing muscle relaxant alcuronium were therefore investigated in nine dogs using a constant-rate infusion regimen with simultaneous measurement of muscle paralysis in the limb and diaphragm. Maximum paralysis between 95 and 100% was achieved in both muscle groups, within approximately the same time interval. However, during onset of and offset of effect, the pharmacodynamic parameters ECp50 and ECp95 for the limb muscle were lower than in the diaphragm. From a pharmacodynamic effect model it was also predicted that Css(50) and Css(95) for the limb muscles are half those values for the diaphragm. Thus, the diaphragm is less sensitive to the action of alcuronium than are limb muscles. The half-time for equilibration of alcuronium between plasma and the effect site was two-fold lower for the diaphragm, and the rate of recovery from paralysis in diaphragmatic muscles was twice that observed in limb muscles. Collectively, these data suggest that there is a greater margin of safety in the diaphragmatic muscles and that the response of the peripheral limb muscles to nerve stimulation provides only a conservative index of recovery from competitive neuromuscular block in the diaphragmatic muscles.

Alcuronium↗
PubMed1986

Health, vocational, and functional status in spinal cord injured athletes and nonathletes.

The relationship of sports involvement to medical complications, functional independence, and vocational status was studied in 67 individuals from 2 to 24 years after spinal cord injury (SCI). Sports participation ranged from none to 30 (means 7.6) hours/wk. No significant correlation was found between time spent in sports participation and number of medical complications, rehospitalizations, functional status, or employment. Subsequently, subgroups of SCI wheelchair basketball players (n = 19) and SCI nonathletes (n = 19) were compared in medical, functional, and vocational status. The athlete group showed significantly more average time per week of sports participation (p less than 0.03), as expected. Fewer physician visits (p less than 0.01) occurred in the athlete group. Trends toward fewer medical complications and fewer rehospitalizations were seen in the athletic group, but this did not reach statistical significance. Sports participation was not associated with increased risk of medical complications and did not limit available time for vocational pursuits. The positive benefits of sports involvement on the community reintegration process and the acquisition of functional skills for the newly disabled warrant further study. The long-term impact of sports involvement on prevention of cardiovascular disease, obesity, and other associated risks of a sedentary existence demands attention in our aging SCI population.

Activities of Daily Living↗
PubMed1985

High-performance liquid chromatographic assay for hydroxychloroquine and metabolites in blood and plasma, using a stationary phase of poly(styrene divinylbenzene) and a mobile phase at pH 11, with fluorimetric detection.

A sensitive rapid high-performance liquid chromatographic assay for hydroxychloroquine and three major metabolites, desethylhydroxychloroquine, desethylchloroquine and bisdesethylchloroquine, has been developed. An ion-suppression separation technique is used with a macroporous polymer, poly(styrene divinylbenzene), stationary phase and a mobile phase of methanol--water with triethylamine, pH 11. A single ether extraction from alkalinized plasma or whole blood, with chloroquine added as an internal standard, is used. Using fluorescence detection, with excitation at 337 nm, the limit of sensitivity is 1 ng/ml. Some anti-inflammatory drugs which may be used concurrently for rheumatoid disorders are shown not to interfere with the assay. Samples of whole blood and plasma obtained from rheumatoid patients contained hydroxychloroquine and all three metabolites.

Anti-Inflammatory Agents↗
PubMed1985

Plasma protein binding of ritodrine at parturition and in nonpregnant women.

The binding of ritodrine HCl in whole plasma from healthy nonpregnant women, parturients and matched umbilical venous plasma and in solutions of HSA and alpha 1-AGP has been studied by equilibrium dialysis. Binding to plasma from nonpregnant subjects and HSA was independent of ritodrine concentration over a wide range. The free fraction in plasma was high and significantly different between groups of nonpregnant (alpha = 0.64), parturient (alpha = 0.68) and matched umbilical venous plasma (alpha = 0.75). It would seem that variability in transplacental transfer of ritodrine, as a result of plasma binding fluctuations, will be minor.

Adolescent↗
PubMed1984

Naloxone protein binding in adult and foetal plasma.

Binding of naloxone hydrochloride was determined at 37 degrees C, by equilibrium dialysis against 0.067 M phosphate buffer, pH 7.4, in plasma obtained from 18 healthy adults, and 18 samples of umbilical cord venous (foetal) plasma. The percentage free fraction (% free) in plasma was independent of naloxone concentration (9 ng/ml to 2.5 micrograms/ml). Percent free naloxone in adult (means = 54.0) was lower (p less than 0.01) than in foetal (means = 61.5) plasma. In buffered solutions of purified HSA, %free naloxone (means = 68.7) was independent of HSA concentration over the range 3.0 g/dl to 5.5 g/dl. Adult plasma concentrations of alpha 1-acid glycoprotein (alpha 1-AGP) and beta-lipoprotein were higher (p less than 0.01) than foetal concentrations. Furthermore %free naloxone in foetal plasma decreased with the in-vitro addition of purified alpha 1-AGP. It is suggested that qualitative differences in adult and foetal albumin and quantitative differences in plasma levels of alpha 1-AGP and perhaps beta-lipoprotein are responsible for naloxone plasma binding differences between adults and the newborn.

Adult↗
PubMed1984

Pharmacokinetic and pharmacodynamic modelling with pancuronium.

The pharmacokinetics and pharmacodynamics of pancuronium were studied following intravenous infusion in eleven patients undergoing surgical anaesthesia. Measurement of the plasma concentrations (Cp) of the neuromuscular blocking agent ( NMBA ) and the concomitant intensities of paralysis allowed their simultaneous modelling. The pharmacokinetic parameters derived for pancuronium were in the range of previously reported values, except that the mean total systemic plasma clearance (0.79 +/- 0.28 ml X min-1 X kg-1) was reduced and the mean terminal phase half-life (169 min) was longer in these patients. Plasma concentration and % paralysis data were successfully fitted to a previously proposed pharmacodynamic model. This model assumes a separate effect compartment which exchanges drug directly with the central kinetic compartment (integrated effect model). The 'steady-state' Cp necessary to produce 50% paralysis ( ECpss (50] was estimated to be 0.21 +/- 0.08 micrograms X ml-1 (mechanical response) and 0.18 +/- 0.05 micrograms X ml-1 (EMG response). An analysis using the Hill equation of the Cp-response relationship, during and after the constant-rate infusion of pancuronium bromide, resulted in effective plasma concentrations for 50% paralysis ( ECp50 ) of 0.35 +/- 0.06 micrograms X ml-1 and 0.20 +/- 0.09 micrograms X ml-1, respectively, for mechanical twitch response. The corresponding values for EMG response were 0.32 +/- 0.06 micrograms X ml-1 and 0.17 +/- 0.06 micrograms X ml-1. Using this latter approach, the ECp50 estimated during onset of paralysis was significantly higher than that estimated during offset of paralysis (p less than 0.05); no such difference was apparent between this latter parameter and the ECpss (50) of the integrated effect model (p greater than 0.05). No significant differences were observed between any of the pharmacodynamic parameter estimates generated from the data obtained from the two methods of assessment of neuromuscular function (mechanical vs. EMG response) (p greater than 0.05).

Adult↗
PubMed1984

Altered d-tubocurarine disposition during cardiopulmonary bypass surgery.

Kinetics of the neuromuscular blocker d-tubocurarine (dTc) were investigated in 13 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 1 hr before CPB surgery, each received dTc as an intravenous bolus of 0.6 mg/kg and a maintenance infusion of 3 micrograms/kg/min. dTc plasma concentration-time data before CPB did not differ from those reported in normal surgical patients. There was an abrupt discontinuity in the plasma concentration-time profile with the onset of CPB, and both total and free plasma concentrations increased 400% during the period of CPB. Although computer simulations suggest that these rises in dTc plasma concentrations can be attributed to contraction in central compartment volume, there also was decreased renal and total plasma clearance of dTc together with a prolonged elimination 1 1/2, which suggests that clearance processes of dTc are also altered as a result of CPB. A 27% rise in dTc free fraction in plasma during CPB could be attributed to hemodilution associated with the CPB procedure itself. Lower doses of dTc will need to be used in patients undergoing surgery that involves CPB unless the concentration-effect relationship for dTc is so altered that higher concentrations are needed to elicit the same response as in normal patients.

Adult↗
PubMed1983

Determination of naloxone in blood by high-performance liquid chromatography.

A rapid, sensitive, selective and reproducible reversed-phase high-performance liquid chromatographic method is described for the quantification of naloxone in small blood samples of premature infants. Naloxone and the internal standard, naltrexone, are extracted from alkalinized blood into diethyl ether and subsequently back extracted into 0.05% (v/v) phosphoric acid before chromatographing on a reversed-phase system. The mobile phase comprises 85 parts of acetonitrile and 15 parts of 0.06% (v/v) triethylamine in an aqueous phosphoric acid solution at pH 5 and is pumped at 1.5 ml/min. The retention times of naloxone and naltrexone were observed to be 5.4 and 7.5 min respectively. Ultraviolet detection at 214 nm enabled a limit of detection of 1 ng to be achieved. The reproducibility of the method was good at both 100 ng (C.V. = 3.4%; n = 9) and 10 ng (C.V. = 5.1%; n = 6). The high sensitivity and speed with which this assay can be performed makes it especially useful for the estimation of naloxone in small volumes (0.3-0.6 ml) of blood. It is thus particularly valuable for the determination of naloxone blood concentration-time profiles in premature infants where the minimization of the volume of blood collected is of paramount importance.

Chromatography, High Pressure Liquid↗
PubMed1983

Heat inhibition of in vitro lipolysis and 14C ibuprofen protein binding in plasma from heparinized uraemic subjects.

Protein binding determination in post heparin plasma samples is complicated by the continued post heparin lipase activity, in vitro, during the binding analysis. The decomposition of lipoproteins and accumulation of nonesterified fatty acids (NEFA) results in artifically elevated free fractions of many drugs. This artefact is particularly accentuated in haemodialysis patients who are frequently hypertriglyceridaemic and receive large doses of heparin. Rapid heat treatment (60 degrees for 15 min) of plasma from heparinized uraemic subjects is shown to inhibit the in vitro lipolysis occurring during 2 hours of equilibrium dialysis at 37 degrees (ED). Mean NEFA concentrations in heat treated plasma after ED (means = 400 +/- 141 mumol/L) were not different (p greater than 0.05, n = 9) from the baseline values in fresh plasma (means 351 +/- 117 mumol/L) but were considerably less (p less than 0.005) than NEFA levels in untreated plasma after ED (means = 1025 +/- 523 mumol/L). The degree of in vitro lipolysis inhibition (92 +/- 6.6%) was very much greater than using the chemical inhibitors phenyl methyl sulphonyl fluoride, EDTA, Triton X100 or protamine sulphate. Heat treatment at 60 degrees for 15 min increased the percentage of free 14C ibuprofen in 3.5% isolated human serum albumin from 0.34% to 0.62%. Reduced binding as a result of heat treatment was not observed however in whole plasma. The percentage free ibuprofen in heat treated, whole plasma from both heparinized and non heparinized subjects (means = 1.22 +/- 0.19; n = 29) was not different (p greater than 0.05) from the percentage free determined in plasma from a non heparinized group (means = 1.16 +/- 0.23; n = 15). In contrast the % free ibuprofen in untreated plasma from heparinized subjects was markedly higher (means = 1.56 +/- 0.41; n = 24; p less than 0.05). There was a strong correlation between % free ibuprofen and plasma NEFA concentration (r = 0.8; p less than 0.005; n = 68). The heat treatment of plasma for 15 min at 60 degrees is proposed as an effective means of controlling heparin induced lipolysis in vitro and may be valuable in overcoming the post heparin binding artefact.

Adolescent↗
PubMed1983

Differential transplacental binding of diazepam: causes and implications.

Diazepam plasma binding was determined in 17 matched pairs of maternal and foetal plasma, collected at delivery. Diazepam % free was higher (p less than 0.001) in maternal (mean 3.24%) than in either umbilical venous (mean 1.50%) or umbilical arterial (mean 1.24%) plasma. The data from in vitro dialysis studies were consistent with the reported higher diazepam concentrations in infants than in mothers at delivery. Plasma nonesterified fatty acids (NEFA) concentrations were higher (p less than 0.001) in maternal (mean = 643 microM) than in matched umbilical venous plasma (means = 211 microM) and there was a significant correlation (p less than 0.01) between diazepam % free and corresponding plasma NEFA concentration for pooled data (r = 0.871, n = 34). Multiple and partial regression analysis indicates that transplacental differences in albumin, bilirubin and total protein concentrations made a minimal contribution to diazepam binding differences between mother and foetus and that approximately 76% of the variability in diazepam % free was accounted for by plasma NEFA concentration. The binding of diazepam to human serum albumin (HSA) was markedly perturbed by the presence of NEFA but not by bilirubin and there was no apparent cooperativity between bilirubin and NEFA on diazepam-HSA binding. Moreover, our findings provide further evidence that substantial differences in binding affinities exist between foetal and maternal plasma albumins.

Adult↗
PubMed1983

Gallamine disposition in open-heart surgery involving cardiopulmonary bypass.

Kinetics of gallamine, a neuromuscular blocker, were investigated in 22 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 60 min before CPB, 11 patients received 480 mg gallamine IV; the other 11 patients received an initial dose of 240 mg IV, followed by another 240 mg through the pump priming fluid at the start of CPB. In 14 of our patients, the time course of gallamine concentrations in the plasma before, during, and after CPB was similar to that in normal surgical patients, indicating little or no effect of cardiac disease or CPB. In the remaining patients, perturbations were not observed before CPB, but with its onset there were varying changes, typically, rises in gallamine concentration ranging from an alteration during the period of CPB only or during the elimination phase, to an alteration at all times after starting CPB. Although the mechanism for this rise in gallamine plasma concentrations during and after CPB is not known, computer simulations suggest that it is due to a contraction in blood volume or decreased tissue perfusion during the period of extracorporeal circulation. Gallamine disposition differed only moderately in our patients from that in control patients. Therefore, from a kinetic viewpoint, provided that renal function is not impaired, gallamine is not contraindicated in CPB surgery.

Adult↗
PubMed1983

Alcuronium kinetics and plasma concentration-effect relationship.

The kinetics and dynamics of the neuromuscular blocker alcuronium were investigated in 12 surgical patients who received bolus and infusion regimens. In six patients the duration of the infusion was sufficiently long so that a steady-state alcuronium plasma concentration was reached (mean SD, 0.80 +/- 0.23 micrograms/ml). In the remaining six patients a steady state was not reached but the alcuronium concentration at the end of the infusion was 0.91 +/- 0.39 micrograms/ml. Alcuronium kinetic parameters did not differ between the two groups or from those obtained previously after bolus doses. In six patients for whom sufficient alcuronium concentration-time response data were available over the 0 to 100% response range, various mathematic models were used to characterize the concentration-effect relationship. A dynamic model incorporating a separate effect compartment connected to the central compartment was found to be the most appropriate. The (mean +/- SD) rate constant for equilibration of alcuronium concentration and effect was found to be 0.24 +/- 0.11 min-1, whereas the steady-state concentration required to induce 95% paralysis was 0.91 +/- 0.35 micrograms/ml (mean +/- SD).

Adolescent↗
PubMed1983

Alcuronium kinetics in patients undergoing cardiopulmonary bypass surgery.

1 The disposition of alcuronium was investigated in 10 patients undergoing surgery involving cardiopulmonary bypass (CPB) and compared with results from a group of non-cardiac patients studied previously. 2 After intravenous administration of a combined bolus and infusion dosage regimen, plasma concentrations fell in a bi-exponential fashion to a mean value of 0.55 micrograms/ml immediately before the start of extracorporeal circulation. 3 During CPB an apparent steady-state of alcuronium was reached immediately after commencement of CPB, however plasma concentrations were some 50% higher than those noted prior to commencement of CPB and those predicted using previous pharmacokinetic data from normal surgical patients. 4 Once CPB was completed and the alcuronium infusion terminated, post-infusion alcuronium plasma concentrations again appeared to decline bi-exponentially with time. 5 Of the pharmacokinetic parameters which were calculated model-independently, the apparent volume of distribution (Vss) was unchanged (329 vs 313 ml/kg) and the elimination half-life (t1/2,z) (532 vs 199 min) was prolonged and the plasma clearance (CL) (0.8 vs 1.34 ml min-1kg-1) markedly reduced in these patients compared to non-cardiac surgical patients. 6 As a result of these changes in alcuronium concentration during CPB and the diminished elimination of alcuronium following CPB, a closer monitoring of neuromuscular function may be necessary in cardiac patients undergoing CPB.

Adult↗
PubMed1983

Stimulatory protein kinase modulator, the cation-binding protein and megamodulin. 3. Isolation from baker's yeast.

Three peak-activity fractions of megamodulin were noted in Sephadex G-100 filtration of its crude preparation from baker's yeast (Saccharomyces cerevisiae). Megamodulin thus prepared and its Mg2+-binding complex were shown not only to augment the activity of rabbit brain megamodulin-dependent protein kinase I (M-PK1) but also to interact with arginine-rich histone.

Animals↗