PubMed Health⌕ Search

Biomedical subjects

I H Stevenson

Publications and source records attributed to I H Stevenson.

At least 19 recordsLinked to original sources
PubMed1992

Ethanol kinetics: extent of error in back extrapolation procedures.

1. Plasma ethanol concentrations were measured in 24 male volunteers for 9 h after a single oral dose of 710 mg kg-1. 2. The rate of decline of the plasma ethanol concentration (k0; mean +/- s.d.), was 186 +/- 26 mg l-1 h-1. 3. In each individual, three elimination rates were used to back-extrapolate plasma ethanol concentrations over 3 and 5 h periods from observed values at 4 h and 6 h post-dosing assuming zero-order kinetics. The extrapolated values were then compared with the observed concentrations. 4. Using the mean k0 values for the subjects the mean error in back extrapolation was small but highly variable. The variability in the error increased with the length of the extrapolation period. 5. When a k0 value of 150 mg l-1 h-1 (a value often cited as a population mean) was used for back extrapolation this resulted in significant under-estimation of actual values whereas the use of a k0 value of 238 mg l-1 h-1 (the highest value observed in the present study) resulted in significant over-estimation of actual values. 6. These results indicate that because the kinetics of ethanol are associated with substantial inter-subject variability the use of a single slope value to back calculate blood concentrations can give rise to considerable error.

Adult↗
PubMed1990

Modulation of the GABAA receptor by barbiturates and pregnane steroids: differential effects of the influence of assay temperature.

The effect of temperature on the modulation of the GABAA receptor by barbiturates and steroids has been investigated in-vitro using a radioreceptor binding assay. Displaceable [3H]muscimol binding to a crude membrane preparation from rat cerebral cortex was enhanced by the endogenous steroid metabolite, 5 beta-pregnan-3 alpha-ol-20-one, by the synthetic steroid, alphaxalone, and by pentobarbitone in a dose-dependent manner. Hydrocortisone and corticosterone had no significant effect on [3H]muscimol binding. Analysis of binding data using a curve-fitting program ('Ligand') showed that both pentobarbitone (1 mM) and 5 beta-pregnan-3 alpha-ol-20-one (10 microM) increased the apparent number of high affinity binding sites in the membrane but had no effect on the affinity of [3H]muscimol binding (Kd approx. 11 nM). Increasing the assay temperature from 0 degrees C to 35 degrees C decreased [3H]muscimol binding and decreased the enhancement of binding by pentobarbitone but had no effect on 5 beta-pregnan-3 alpha-ol-20-one enhancement of binding. 5 alpha-Pregnan-3 alpha-ol-20-one increased the apparent rate of association of [3H]muscimol binding to its receptor whereas pentobarbitone had no effect. These different effects on the apparent association rate and the different responses to temperature, suggest that the barbiturate and steroid may interact with the GABAA receptor through different binding sites.

Animals↗
PubMed1989

Kinetics of digoxin and anti-digoxin antibody fragments during treatment of digoxin toxicity.

Anti-digoxin antibody fragments (ADAF, 80 mg) were infused intravenously to successfully treat severe digoxin toxicity in an 82 year old woman. During treatment, total and free digoxin were determined using an Abbot TDX analyser and an ultrafiltration technique. ADAF were measured by an enzyme-linked immunosorbent assay. By 1 h after ADAF, total serum digoxin concentrations had risen 12-fold from a pretreatment level of 15.4 nmol l-1 but free digoxin fell from 10 to 0.1 nmol l-1, indicating greater than 99.9% digoxin binding to ADAF. However, the low free levels had rebounded to 7.7 nmol l-1 by 12 h, but despite this rise the patient's condition had improved. A serum ADAF/digoxin molar ratio of around five was associated with the low concentration of free digoxin at 1 h, while at later times with ratios roughly between 3 and 4, the free digoxin concentrations ranged between 2.0 and 7.7 nmol l-1. ADAF were mainly confined to the plasma during the first hour, but subsequently distributed into an apparent volume of 193 ml kg-1. The elimination half-lives of ADAF and total digoxin were 96 and 55 h, respectively. More than 50% of the estimated digoxin load had been excreted in the urine by 5 days; for ADAF the equivalent figure was only about 3%. Renal and/or bacterial degradation may have contributed to the low detection of urinary ADAF.

Aged↗
PubMed1988

The effect of drug-specific active immunization on digoxin and benzylpenicillin disposition in the bile duct-cannulated rat.

Rats were immunized with a digoxin-human serum albumin conjugate i.m. This resulted in a several hundred-fold increase in plasma radioactivity and a 90% reduction in biliary drug elimination when [3H]digoxin (10 micrograms kg-1, i.v.) was subsequently injected into anaesthetized bile duct-cannulated rats. It was calculated that about 90% of the drug dose remained antibody-bound within the plasma compartment, with essentially no drug distributing into organs such as the heart and liver. Digoxin-specific antibody levels, determined by equilibrium dialysis, were high in the plasma but at least an order of magnitude lower in the bile. Immunization via Peyer's patches did not increase antibody levels in the bile. Immunization (i.m.) with a benzylpenicillin-human serum albumin conjugate gave specific antibody plasma titres with values less than 10% of those obtained after immunization with a digoxin-protein conjugate. However, although subsequent injection of the hapten (40 micrograms kg-1, [14C]benzylpenicillin, i.v.) was associated with much lower increases and decreases in plasma and biliary radioactivity, respectively, they were still statistically significant. It appears that endogenously-formed drug-specific antibodies, when present in the blood, will inhibit drug distribution and elimination. It is unlikely that their secretion in the bile plays a significant role in mediating biliary drug hapten elimination.

Animals↗
PubMed1988

The use of an enzyme-linked immunosorbent assay to study the disposition of sheep digoxin-specific immunoglobulin G and Fab fragments in the rat.

An enzyme-linked immunosorbent assay was developed for the measurement of sheep digoxin-specific immunoglobulin G and Fab fragments. With the latter, two preparations were examined, one available commercially (Digibind, Wellcome) and one prepared by ourselves (DSFab). The assay exhibited a greater sensitivity towards immunoglobulin G compared with Digibind and DSFab, presumably because the Fab preparations lacked some of the sheep-specific antigens present on the whole antibody molecule. The assay was used subsequently to examine the disposition of the antibody preparations after injection of 1 mg/kg i.v. into anaesthetised bile duct-cannulated rats. The plasma distribution half-lives (1.8-3.3 min) were similar for all three preparations, but while plasma elimination half-life values for Digibind and DSFab were much the same (110-115 min), that for immunoglobulin G was longer (425 min). The shorter half-life values for Fab fragments were linked to a rate of urinary elimination 10-20 fold faster. No antibody excretion in the bile was detected. The apparent volume of distribution of immunoglobulin G was 35 ml/kg, indicating that the whole antibody was largely confined to the plasma space. The volume of distribution for Digibind or DSFab (about 46 ml/kg) was not significantly larger than that for immunoglobulin G and much smaller than the extracellular fluid volume, which was measured as 305 ml/kg. Thus the distribution of sheep Fab fragments in the rat markedly differs from that in the baboon (Smith et al., 1979) where the apparent volume of distribution approximates to the extracellular fluid volume.

Animals↗
PubMed1987

The influence of digoxin-specific antibody fragments on digoxin disposition in the rat.

Pentobarbitone-anaesthetized bile duct-cannulated female rats were injected intravenously with an equimolar dose of digoxin-specific sheep antibody fragments (DS-Fab) at 2 or 60 min after a dose of [3H]digoxin. The plasma drug levels were promptly elevated by 7-fold or 12-30-fold when the DS-Fab were given at 2 or 60 min respectively. When tissue drug concentrations were measured 2 min after a dose of DS-Fab (given 60 min after digoxin) which caused a 30-fold increase in plasma concentration, reductions could be detected if corrections were made for the presence in the tissues of high plasma concentrations of DS-Fab-bound drug. For instance, reductions in the heart, liver and small intestine were 63, 58 and 48% respectively. However, by 120 min after digoxin injection the only detectable effects on tissue drug concentration were in the kidney, where concentrations had increased 14-fold or 7-fold when the DS-Fab were given at 2 or 60 min respectively. Over the 120 min period the urinary excretion of digoxin-derived radioactivity was enhanced, and in the case where DS-Fab were given at 2 min, a 3-fold increase in urinary excretion was seen, which resulted in a net increase in the overall drug elimination. This greater urinary elimination was accompanied by a marked increase in the amount of bound drug in the urine (control and experimental values were 4 and 36% respectively). The cumulative biliary excretion of radioactivity seemed to be slightly reduced by DS-Fab administration at 2 or 60 min, although this was not statistically significant. A lack of significant drug-specific binding in the bile suggested that the liver is not involved in the elimination of hapten-DS-Fab complexes. There was little effect on the intestinal secretion of the drug.

Animals↗
PubMed1987

Disposition and hypoglycaemic action of glipizide in diabetic patients given a single dose of nifedipine.

Six well controlled Type 2 diabetics who had received glipizide therapy ranging from 5 mg to 30 mg daily for at least the previous 2 months were studied. On Days 1 and 15 nifedipine 20 mg or placebo respectively were given in a random crossover design after an overnight fast and with the morning dose of glipizide. Nifedipine did not influence the disposition of glipizide since there was no significant alteration in the maximum concentration, time to peak plasma concentration, elimination half-life or area under the curve. Neither did it have a major effect on plasma glucose or insulin although there was an early preprandial decrease in insulin level which reached significance at 1 h only (22.66 v 18.50 mIU/l).

Adult↗
PubMed1987

Comparative studies with the enantiomers of the glycol metabolite of propranolol and their effects on the cardiac beta-adrenoceptor.

The two enantiomers ((R)- and (S)-) of propranolol glycol, a metabolite of propranolol, have been synthesized, and their effects upon the beta-adrenoceptor studied by two methods. The ability of these compounds to antagonize the inotropic actions of isoprenaline was examined on spontaneously beating rat atrial preparations. Also, the effects of these enantiomers upon the binding of [3H]dihydroalprenolol to beta-receptors in rat cardiac ventricular membranes was studied. Experiments with the atria indicated that the (S)-glycol was a reversible competitive antagonist of isoprenaline with a potency approximately one thousand times lower than that of (+/-)-propranolol. In contrast, the (R)-glycol appeared to act as an irreversible antagonist, producing complex dose-response curves. The effects of these compounds to cause displacement of alprenolol binding were consistent with the organ bath data. The interaction of the (S)-glycol with the beta-receptor binding site was reversible (Ki of 27.6 +/- 4.2 microM) but less potent than that of (+/-)-propranolol (Ki of 0.99 +/- 0.07 nM). On the other hand, pretreatment of ventricular membranes with the (R)-glycol, followed by extensive washing techniques, resulted in alprenolol binding which did not regain control values, providing further evidence for an irreversible effect upon the beta-receptor. The possible significance of these pharmacological actions of the two enantiomers is discussed in terms of the in vivo metabolic pathways for propranolol.

Animals↗
PubMed1986

The effect of digoxin-specific active immunization on digoxin toxicity and distribution in the guinea-pig.

In guinea-pigs intravenously infused with digoxin, prior immunization using a digoxin-human serum albumin conjugate increased by 3- and 2.4-fold, respectively, the digoxin doses causing the first signs of cardiotoxicity and death. At death, serum digoxin concentration was four times higher in immunized than in control animals. In the immunized guinea-pigs 50% of the serum digoxin was protein bound, presumably mainly to digoxin-specific antibodies, since in the controls the bound fraction was only 1-2%. Generally, tissue digoxin concentrations were not increased to the same extent as the lethal dose, and in the heart and lungs the increase was not significant. With cardiac (ventricle) subcellular fractions, there was no difference between control and immunized animals in the digoxin concentration of the 'microsomal' pellet. This subfraction contains the plasma membrane and the associated sodium pumps which are considered to be the sites at which the pharmacologically active digoxin binds. It seems likely, therefore, that the greater digoxin resistance in the immunized animals can be explained on the basis of reduced drug access to the site of action within the heart.

Animals↗
PubMed1985

The serum pharmacokinetics of digoxin as an immunogen and hapten in the rabbit.

3H-digoxin was given intradermally 4 weeks before, and at 6 and 44 weeks after immunisation with a 3H-digoxin-human serum albumin conjugate. Before immunisation, the serum digoxin distribution and elimination half-life (t1/2) values were 4.2 h and 2.1 days respectively. The immunogen-associated radioactivity showed characteristic fluctuations during a prolonged distribution phase of about 5 days, but the t1/2 of 2.7 days was similar to that of digoxin, indicating that appreciable cleavage of digoxin from the albumin may have occurred during the distribution period. At 6 weeks after immunisation, following hapten injection there was again a prolonged distribution phase of about 5 days during which concentration of digoxin were some five-fold higher than corresponding pre-immunisation values. The serum elimination t1/2 was 4.1 days. At 44 weeks the differences were even more marked; the distribution phase was some 7 days, during which serum hapten concentrations were approximately ten-fold higher than pre-immunisation values. The serum elimination t1/2 was in this case about 25 days. Surprisingly digoxin-specific antibody titres at 6 and 44 weeks were not significantly different, indicating that measurement of titre, which is a function of both antibody concentration and affinity, is not in itself reliable in predicting changes in hapten pharmacokinetics.

Animals↗
PubMed1985

Responsiveness to oral diazepam in the elderly: relationship to total and free plasma concentrations.

The immediate and residual response to single doses of oral diazepam 10 mg was measured in 11 young and 12 elderly healthy volunteers using postural sway, digit symbol substitution scores and subjective ratings. The effect on postural sway was markedly accentuated in the older volunteers, but the difference between groups in the effect on the other measures used did not achieve significance. The corresponding plasma total diazepam concentrations were lower in the older subjects beyond 0.5 h post dose and the concentrations of plasma desmethyldiazepam did not differ between the groups. Diazepam plasma protein binding was significantly reduced in the elderly subjects, but the plasma free (unbound) diazepam concentrations did not exceed those in the young group. There was poor correlation between the responses measured and the concentrations of either total diazepam, desmethyldiazepam or free diazepam. The results suggest the occurrence of a non-uniform effect of age on different aspects of benzodiazepine response, and that where an accentuated effect occurs the mechanisms are substantially pharmacodynamic.

Adult↗
PubMed1985

The influence of digoxin antibodies on digoxin disposition and effect: studies in guinea-pigs and HeLa cells.

Pretreatment of guinea-pigs with digoxin-specific Fab (fragment antigen binding) fragments reduced the cardiotoxicity of intravenously infused digoxin (the lethal doses in Fab-treated and control animals were 1.0 and 0.6 mgkg-1, respectively). At death the serum digoxin concentration was elevated 2 fold in the Fab-treated animals, while the tissue concentrations were generally lower. The 30-40% lower cardiac digoxin concentration (seen in whole homogenate and throughout the subcellular fractions examined) was surprising; presumably this reflects a difference from the controls in the proportion of pharmacologically active/inactive digoxin in this organ. Adding digoxin-specific immunoglobulin G or the Fab fragments to HeLa cells before incubation with digoxin, reduced specific digoxin binding (Na pump-bound) slightly more than the non-specific binding. Adding specific antibody after digoxin, however, did not reduce digoxin binding or effect a recovery in Na pump activity. It seems that the protective effect of digoxin-specific antibodies seen in the guinea-pig can to some extent be simulated using HeLa cells. However, this is apparently not so regarding the widely-reported ability of these antibodies to reverse the action of digoxin.

Animals↗
PubMed1984

The effect of immunization with digoxin-specific antibodies on digoxin disposition in the mouse.

After intravenous dosing, digoxin was rapidly distributed to tissues, with a distribution half-life of 3.0 min. The highest digoxin concentrations at 1 hr post dosing were found in lymph nodes, adrenals, gallbladder (including contents), liver and kidney respectively. Digoxin concentrations in the heart, spleen, brain, lung, skeletal muscle and fat were similar to, or lower than, those in the plasma. The apparent volume of distribution (AVd) was 1 l/kg, and the plasma elimination half-life and clearance (Cl) 2.8 hr and 0.25 l/kg per hr respectively. When digoxin was given one day after passive immunization with digoxin-specific immunoglobulin G (IgG) or Fab fragments the respective plasma digoxin concentrations were elevated some 26- and 5-fold respectively compared with control values. Consequently there were reductions in AVd (93 and 32%) and Cl (94 and 50%). The effect of IgG treatment on clearance was still apparent when the hapten was given up to 14 days after immunization, while the weaker effect of Fab-treatment was less persistent. Although tissue digoxin concentrations were slightly lower in the immunised mice, it was only in the lymph nodes at 10 and 14 days after IgG treatment that the reduction in hapten concentration was statistically significant.

Animals↗
PubMed1984

Side-effect 'tolerance' in elderly long-term recipients of benzodiazepine hypnotics.

The outcome of long-term benzodiazepine hypnotic therapy has been investigated in a group of elderly patients in the community; 220 receiving nitrazepam and 33 flurazepam. The estimated duration of therapy was as long as 15 years in some cases. More than half were taking doses greater than 5 mg and 15 mg, respectively, the majority on a regular nightly basis in accordance with the instructions on containers. The plasma concentrations of nitrazepam and the active desalkyl metabolite of flurazepam correlated positively with weight-related dose. In the case of desalkyl-flurazepam, but not nitrazepam, the levels were substantially higher than those previously reported in young individuals. There was sustained patient satisfaction with the effectiveness of the hypnotics and, despite the high plasma levels, little subjective or objective evidence of unwanted sedation, confusion or unsteadiness. The findings of the survey suggest the development of both pharmacodynamic tolerance to the unwanted sedative effects of these drugs and a degree of dependence in long-term recipients.

Aged↗
PubMed1983

Antithyroid effect of chlorpropamide?

1 The relationship between plasma chlorpropamide concentration and thyroid function was examined in 87 maturity onset diabetic patients receiving chronic therapy. 2 Although plasma chlorpropamide concentration was weakly negatively correlated with serum thyroxine (r = 0.33, P less than 0.01) the mean serum thyroxine and thyrotrophin (TSH) were not different from that of a matched control group of diabetics treated with diet alone. 3 Serum thyroxine was negatively correlated with the duration of diabetes in both groups. 4 These results suggest that chlorpropamide does not have a clinically significant antithyroid effect.

Adult↗
PubMed1982

Nadolol in thyrotoxicosis.

1 Twenty outpatients with thyrotoxicosis received the non-selective beta-adrenoceptor antagonist nadolol as sole treatment for 3 weeks. 2 Clinical improvement as measured by reduction in thyrotoxicosis therapeutic index occurred during the first week of treatment and was continued thereafter, and was accompanied by a significant reduction in serum T3 and elevation of serum reverse T3. 3 As measured by reduction in exercise heart rate, during chronic dosing nadolol 160 mg once daily produced blockade of beta-adrenoceptors for 12 h in all patients and 24 h in all but 2. 4 Wide interindividual variability was noted in steady state plasma nadolol concentrations, in part related to age and renal function. 5 Steady state plasma nadolol concentrations were related to reduction in heart rate.

Adrenergic beta-Antagonists↗
PubMed1981

Plasma propranolol steady state concentrations in thyroid disorders.

Plasma propranolol steady-state concentrations (Css) were measured in 24 hyperthyroid and 6 hypothyroid patients before and after correction of the thyroid disorder. Following treatment of hyperthyroidism by surgery, antithyroid drugs or radioiodine, there was a significant rise in the plasma propranolol Css in patients receiving propranolol either 160 mg/day, 240 mg/day, or 480 mg/day. In addition, in five patients the area under the plasma propranolol concentration versus time curve during a dosing interval increased significantly from 405 ng/ml/h when hyperthyroid to 778 ng/ml/h when euthyroid. In the hypothyroid patients given propranolol 160 mg/day concomitantly with 1-thyroxine therapy the plasma propranolol Css fell significantly when euthyroid. There was a small but significant increase in the degree of plasma protein binding of propranolol, following treatment of hyperthyroidism and a significant decrease following correction of hypothyroidism. It is concluded that thyroid disorders markedly influence propranolol handling.

Adolescent↗