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Biomedical subjects

R L Nation

Publications and source records attributed to R L Nation.

At least 73 records · Page 4Linked to original sources
PubMed1986

Pharmacokinetics of ranitidine in critically ill patients.

The plasma pharmacokinetics of ranitidine (50 mg i.v.) have been studied in 17 critically ill patients in an intensive care unit. Measurements of gastric aspirate pH were also made in 16 of these patients. Ranitidine therapy was part of the patients' normal drug regimen. Ranitidine plasma concentration was measured by high performance liquid chromatography and appropriate polyexponential equations were fitted to concentration-time data to enable calculation of relevant pharmacokinetic parameters. Values of the volume of the initial dilution space (median = 89 ml kg-1) and volume of distribution at steady state (median = 1.54 l kg-1) were about 60% of corresponding mean literature values for healthy controls. Plasma clearance (median = 4.22 ml min-1 kg-1) and terminal half-life (median = 4.7 h) were about 2-3 fold less and 2-3 fold greater, respectively, than values for healthy controls. There was wide interpatient variation in all the pharmacokinetic parameters. Renal impairment was considered to be largely responsible for the low plasma clearance. Gastric aspirate pH was measured at 0, 1 and 7 h after ranitidine administration and 58% of samples were found to be above pH 4. Four patients had gastric pH values which were consistently below pH 4 despite average trough plasma ranitidine concentrations equal to or greater than those required for a 50% suppression of gastric acid secretion in normal volunteers.

Adult↗
PubMed1984

Pharmacokinetics of cimetidine in critically ill patients.

Cimetidine disposition was studied after rapid (1 min) intravenous infusion in eight critically ill patients aged between 20 years and 77 years; one patient was studied on two occasions. Cimetidine dose was 300 mg in seven patients and 400 mg in the remaining patient. Arterial plasma cimetidine concentrations at the end of the infusion were very high and ranged from approximately 15-35 mg/l. Pharmacokinetic parameters displayed wide interpatient variability (coefficients of variation of 30-50%) and significant relationships emerged between some of these parameters and certain patient characteristics. Most notable, total systemic plasma clearance of cimetidine was directly related to estimated creatinine clearance (p less than 0.01). This relationship might prove to be a useful method of individualizing cimetidine dosage in critically ill patients.

Adult↗
PubMed1984

Disposition of betamethasone in parturient women after intramuscular administration.

When betamethasone phosphate equivalent to 8 mg betamethasone was administered intramuscularly in solution (Celestone Injection) to pregnant women, a large proportion of this ester was absorbed unchanged. Bioavailability of betamethasone from the phosphate ester was as high as after intravenous injection. When pregnant patients received the equivalent of either 6 or 12 mg betamethasone in a formulation containing 3.1 mg/ml betamethasone acetate suspended in a solution of 4 mg/ml betamethasone phosphate (Celestone Chronodose), much of the phosphate ester was absorbed intact but betamethasone acetate was not detected in plasma. Availability of betamethasone from Celestone Chronodose was much lower than from Celestone Injection. After administration of either formulation, maternal plasma cortisol concentrations fell towards a basal level but were rising again within 2 to 3 days of the last dose. We conclude that Celestone Chronodose does not provide prolonged release of betamethasone and offers no advantage over Celestone Injection.

Betamethasone↗
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

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

Pharmacokinetics of gentamicin in very low birth weight preterm infants.

Low birth weight preterm infants with suspected infection were administered gentamicin intramuscularly every 18 h (2.5 mg/kg) or 24 h (3.0 mg/kg). For both dosage regimens plasma gentamicin levels were monitored during a dosage interval on three separate occasions over a 10 day period. Both regimens gave satisfactory plasma concentrations and there was no important statistically significant difference between the two. The body clearance of gentamicin correlated with gestational age (r = 0.76, p less than 0.01). The results indicate either regimen may be useful in the clinical situation but from a practical standpoint administration every 24 h may be easier to comply with then every 18 h.

Drug Administration Schedule↗
PubMed1983

Pharmacokinetics of betamethasone in healthy adults after intravenous administration.

The pharmacokinetics of betamethasone and its phosphate ester are described in 8 healthy adults after i.v. bolus injection of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultraviolet detection using sample handling methods which prevented hydrolysis of the ester in vitro. Betamethasone phosphate disappeared rapidly from plasma (mean half-life = 4.7 min) as betamethasone levels rose. Betamethasone plasma levels reached a peak 10-36 min after administration of the phosphate before declining in a biexponential manner. The terminal slow disposition phase had a mean half-life of 6.5 h. Only about 5% of the dose was recovered from urine as betamethasone, indicating extensive extrarenal clearance of betamethasone. Protein binding and blood/plasma concentration ratio were also determined. In comparison with its stereoisomer, dexamethasone, betamethasone is also cleared mainly by metabolism but has a lower plasma clearance, is less plasma bound, has a higher blood/plasma concentration ratio, and a higher volume of distribution. Endogenous cortisol levels were measured in the subjects who received betamethasone phosphate and in a matched control group of 4 subjects who did not. Betamethasone abolished the normal episodic secretion of cortisol and rapidly reduced its plasma concentration to a basal level. Cortisol plasma levels were not restored at 24 h but had returned to normal by 48 h after dosing.

Adult↗
PubMed1983

Disposition of betamethasone in parturient women after intravenous administration.

The pharmacokinetics of betamethasone and its phosphate ester are described in nine women in late pregnancy who each received a bolus intravenous dose of 10.6 mg betamethasone phosphate. Both compounds were measured by high-performance liquid chromatography with ultra-violet detection using sample handling methods which prevent in vitro hydrolysis of the ester. The plasma clearance of betamethasone phosphate (mean = 980 ml/min) and its apparent distribution volume (mean = 5.61) were both higher than previously found for nonpregnant subjects, but its half-life (mean = 4.6 min) was unchanged. Plasma concentrations of betamethasone reached a peak 5-37 min after dosing with betamethasone phosphate, then declined biexponentially with a mean terminal half-life of 262 min. Plasma clearance in pregnant patients (mean = 287 ml/min) was higher than previously reported for nonpregnant subjects. Evidence from urinary excretion and plasma binding measurements and the previously reported transplacental plasma concentration gradient indicated that the increase in clearance was due to increased metabolism possibly by the placental/fetal unit. Plasma binding of beta-methasone was higher in maternal than fetal plasma; binding to alpha 1-acid glycoprotein was more important than binding to albumin as a determinant of this difference. In pregnant patients the decline of endogenous cortisol concentrations in maternal venous plasma was less marked and slower than in nonpregnant subjects. The data now available allows comparison of pharmacokinetic properties between betamethasone and its stereoisomer dexamethasone with respect to their use in preventing neonatal respiratory distress syndrome.

Adult↗
PubMed1983

Pharmacokinetic optimisation of aminophylline infusions in critically ill patients.

The method of Chiou et al. was used to predict theophylline kinetics in eleven critically ill patients with either acute severe asthma or bronchoconstriction. Following the commencement of an accurately metered infusion of aminophylline, venous blood samples were taken at approximately 1, 5 hours and 7-12 hours for measurement of plasma theophylline concentration. The 1- and 5-hour levels were used to estimate total body clearance and plasma concentration of theophylline at the 7-12 hour sampling time. Using these values, the infusion rate was adjusted if necessary and the protocol repeated. Initial predictions were unreliable in two patients because of continued absorption of theophylline from pre-infusion therapy with aminophylline suppositories or slow-release theophylline tablets. In the remaining studies there was a significant correlation (y = 0.9x + 0.55, r2 = 0.93, p less than 0.01, n = 19) between predicted and actual plasma concentrations at the 7-12-hour sampling time. In three patients, sequential estimates of theophylline clearance showed an approximate twofold variation and in another two patients, there was evidence of concentration-and/or time-dependent theophylline kinetics.

Acute Disease↗
PubMed1982

Diazepam plasma binding in the perinatal period: influence of nonesterified fatty acids.

The plasma binding of diazepam was determined serially in 24 women undergoing either elective induction of labour (vaginal or emergency caesarean delivery) or elective caesarean section at term and in 5 nonpregnant women requiring abdominal surgery. In the majority of pregnant patients, a marked increase in diazepam percentage free was observed during labour or prior to caesarean section, reaching a maximum, 1.6 to 3.2 fold increase at delivery or within 4 h postpartum; by the fifth day postpartum, diazepam percentage free was lower than on admission to hospital. In contrast, little change in diazepam percentage free was observed during the perisurgical period in nonpregnant patients. In parturient and surgical patients, the time courses of diazepam percentage free and plasma nonesterified fatty acid (NEFA) concentration were parallel. Bivariate regression analyses of pooled data demonstrated a strong correlation (r = 0.642, p = less than 0.010 between diazepam percentage free and corresponding NEFA concentration and a weaker correlation between diazepam percentage free and both albumin (r = 0.319, p less than 0.02) or total protein (r = 0.438, p less than 0.01). From multiple linear regression it was demonstrated that 54% of the variability in diazepam percentage free could be attributed to plasma NEFA and albumin concentrations. NEFA displacement of plasma bound diazepam was substantiated using crystalline human serum albumin. An approximate 65% increase in plasma alpha 1 acid glycoprotein levels was observed posttrauma in both parturient and surgical patients but was unrelated to diazepam binding events. A relationship between diazepam plasma binding changes and concurrently altered disposition of diazepam during parturition is postulated.

Adult↗
PubMed1982

Absorption of oral neomycin in premature infants with suspected necrotizing enterocolitis.

The oral absorption of neomycin was studied in 2 premature infants (32 weeks of gestation) with suspected necrotizing enterocolitis. 1 infant received 50 mg and the other 100 mg of neomycin sulfate/kg/day in 4 divided doses for approximately 7 days. Plasma neomycin levels were determined by a micro, sensitive and specific high-performance liquid chromatographic assay developed in our laboratory. Plasma levels as high as 2.9 and 4.5 micrograms/ml were observed in these 2 infants. A urinary recovery study for 1 infant revealed that at least 3.7% of the oral dose was absorbed. The significant and persistent plasma levels of neomycin in these patients suggest the need for extreme caution in using this potentially toxic antibiotic for prolonged treatment in neonates.

Chromatography, High Pressure Liquid↗
PubMed1981

Leaching of 2-(2-hydroxyethylmercapto) benzothiazole into contents of disposable syringes.

A contaminant was found to leach into the contents of two brands of disposable syringes. It was identified as 2-(2-hydroxyethylmercapto) benzothiazole and is believed to be formed during manufacture of the syringes as a result of a reaction between 2-mercaptobenzothiazole, a rubber vulcanization accelerator, and ethylene oxide, used for sterilization. The contaminant was isolated form the rubber plunger-seal and identified using mass, NMR, and UV spectroscopic methods. The amount of contaminant appearing in the contents of syringes was measured; up to 140 micro g was found under clinically relevant conditions. This finding has important implications with respect to the use of these syringes for drug administration and for the collection of blood for drug analyses.

Adsorption↗
PubMed1981

Meperidine binding in maternal and fetal plasma.

Meperidine protein binding was measured in nine pairs of maternal and fetal plasma samples obtained at delivery. For the maternal samples, percent bound and binding ratio (bound/free, B/F) were 63.3 +/- 6.18% (SD) and 1.79 +/- 0.45, and for the fetal samples the corresponding values were 51.7 +/- 4.53% and 1.09 +/- 0.21. In each case the binding was higher in the mother than in the fetus (p less than 0.01). Plasma alpha 1-acid glycoprotein (alpha 1-AGP) concentrations were higher (p less than 0.01) in maternal than in fetal samples, and there was a correlation between meperidine B/F and plasma alpha 1-AGP concentration for the maternal and fetal samples (r = 0.752, p less than 0.01). Binding studies with purified alpha 1-AGP showed that this was a cause-effect relationship. The transplacental binding differential was attributable partially to the maternal-fetal difference of plasma alpha 1-AGP concentrations. Meperidine was 17.5 +/- 0.35% bound in a 3.5 gm/100 ml solution of human serum albumin; however, there was an inverse correlation (r = -0.798, p less than 0.01) between B/F and plasma albumin concentration for the maternal and fetal samples. A relatively large proportion (75%) of the overall variability in B/F was accounted for by plasma alpha 1-AGP and albumin. Plasma binding of this basic drug was not greatly influenced by the perinatal levels of bilirubin and nonesterified fatty acids. The common clinical observation of greater fetal than maternal plasma total meperidine concentrations at delivery is not the result of more extensive protein binding in fetal than in maternal plasma.

Adolescent↗
PubMed1981

Relationship between the transplacental gradients of bupivacaine and alpha 1-acid glycoprotein.

1 The binding of bupivacaine (400 ng/ml) to isolated alpha 1-acid glycoprotein was studied at two protein concentrations. At 20 mg/100 ml the extent of bupivacaine binding was 31.0 +/- 1.8% (mean +/- s.d., n = 4), and at a protein concentration of 60 mg/100 ml binding of bupivacaine was 85.8 +/- 1.5% (n = 4). 2 Bupivacaine and alpha 1-acid glycoprotein concentrations were measured in plasma samples collected from a maternal peripheral vein and the umbilical vein at delivery (n = 23). The ratio of the foetal:maternal bupivacaine concentrations ranged from 0.17 to 0.52, while the foetal:maternal ration for alpha 1-acid glycoprotein concentrations ranged from 0.20 to 0.96. A positive relationship emerged between the two ratios (P less than 0.01). 3 The alpha 1-acid glycoprotein concentration gradient across the placenta, and interindividual variability in the gradient appear to contribute to the low and variable transplacental bupivacaine concentration ratio observed.

Bupivacaine↗
PubMed1981

Effects of epidural anesthesia on newborns and their mothers.

The effects of epidural anesthesia on newborns were studied using a sample of babies from mothers having (a) little or no medication during childbirth (N = 15), (b) epidurals with bupivacaine (N = 20), and (c) epidurals in combination with oxytocin to stimulate labor (N = 20). Outcome measures included assessments of neonatal behavior (Brazelton Scale), mother-baby interaction during feeding, and mothers' perceptions of their babies' behavior during the first month after delivery. Effects of drugs on the neonatal behavior were strongest on the first day. By the fifth day, there was evidence of behavioral recovery, but the medicated babies continued to exhibit poor state organization. At 1 month, examiners observed few differences between groups, but unmedicated mothers reported their babies to be more sociable, rewarding, and easy to care for, and these mothers were more responsive to their babies' cries. The importance of the first encounters with a disorganized baby in shaping maternal expectations and interactive styles was discussed.

Anesthesia, Epidural↗