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Biomedical subjects

D G Shand

Publications and source records attributed to D G Shand.

At least 73 records · Page 4Linked to original sources
PubMed1980

Increased alpha-1-acid glycoprotein and lidocaine disposition in myocardial infarction.

In 15 patients with confirmed myocardial infarction, alpha-1-acid glycoprotein rose significantly from 117 mg/dL at admission to 140 mg/dL at 36 hours (p less than 0.01), but not in 15 age- and sex-matched patients with chest pain only. Twelve patients were given prolonged infusions of lidocaine (2 mg/min). In patients with myocardial infarction, the rise in plasma alpha 1-acid glycoprotein concentration was associated with increased lidocaine binding and a rise in total lidocaine concentrations between 12 and 48 hours (p less than 0.05). Because of the binding changes, however, the rise in free drug concentration (31.2%) was significantly less than the 56.3% rise in total drug level (p less than 0.05). No changes in alpha 1-acid glycoprotein or lidocaine disposition were seen between 12 and 48 hours in the control subjects. Our results show that the rise in alpha 1-acid glycoprotein after myocardial infarction is associated with lidocaine accumulation, but increased plasma binding attenuates the rise in free drug. This suggests that the toxicologic implications of lidocaine accumulation may have been exaggerated and therapeutic monitoring of total plasma levels may be misleading.

Adolescent↗
PubMed1980

Active uptake of propranolol by isolated rabbit alveolar macrophages and its inhibition by other basic amines.

Propranolol and other basic amines are concentrated by the lung. To test the possibility that the alveolar macrophage might participate in this process, the uptake of dl-[3H]propranolol was studied in macrophages isolated from healthy male rabbits. Uptake was time, temperature, and pH dependent and was reduced in the presence of inhibitors of cellular energy metabolism, such as sodium azide, iodoacetate, sodium cyanide and 2,4-dinitrophenol. It was abolished by sonication of the cell suspension. Scatchard plots suggested at least three uptake processes, one of which appeared to be partition. Uptake of dl-[3H]propranolol was inhibited equally by increasing concentrations of both the dextro- and the levo-isomers, as well as the racemate. It was also markedly inhibited by the lysomotropic agents, ammonium chloride and chloroquine, and by a number of tertiary amines including imipramine, chlorpromazine and methadone. Endogenous amines, including noreprinephrine, epinephrine and histamine had no effect on uptake. These observations suggest that uptake processes in the lung for exogenous basic amines may differ from those for endogenous amines. Although uptake of endogenous amines has been localized to the vascular endothelium, the lysosome may be one intracellular site of accumulation for exogenous amines.

Amines↗
PubMed1979

Altered drug binding due to the use of indwelling heparinized cannulas (heparin lock) for sampling.

The effect of the use of the so-called heparin lock for blood sampling on the binding of propranolol has been studied and a cumulative dose-response curve to heparin constructed. The use of this method of blood sampling introduced considerable artifactual changes into the measurement of propranolol's plasma binding. The free fraction rose from 9.9% to 13.4% after only 50 U of heparin was used to flush the cannula. The increase in the free fraction of propranolol showed excellent correlation with the increase in free fatty acid levels (p less than 0.001, r = 0.996). The importance of ensuring that sampling techniques do not introduce artifactual changes in pharmacokinetic studies is emphasized.

Adult↗
PubMed1979

Effect of aging and cigarette smoking on antipyrine and indocyanine green elimination.

The plasma clearances of antipyrine (AP) and indocyanine green (ICG) have been measured after intravenous administration in each of 20 normal male subjects aged 22 to 72 yr. An additional 4 subjects aged 65 to 73 yr received only ICG. AP clearance fell with age in the group as a whole (r = 0.56; p less than 0.01), but when cigarette smoking habits were considered the relationship was apparent only in smokers (r = 0.68; p less than 0.02). In the under 40 yr group. AP clearance was higher in smokers than nonsmokers (p less than 0.02). There was no such difference in men over 40 yr of age. These observations suggest that the enzyme-inducing effect of smoking diminishes with advancing years. In contrast, and consistent with a reduction in liver blood flow, the clearance of the highly extracted ICG fell with age, irrespective of smoking habits (r = 0.57; p less than 0.004). These findings suggest that while hepatic drug clearance may be impaired in elderly people, the outcome depends not only on the effects of the aging process on the physiologic determinants of hepatic clearance (liver blood flow and the activity of the drug-metabolizing enzymes) but also on the effects of environmental factors, such as smoking.

Adult↗
PubMed1979

Reduced beta-adrenoceptor sensitivity in the elderly.

The effect of age on sensitivity to both isoproterenol and propranolol has been investigated in 27 male volunteers aged 21 to 73 yr. The dose of isoproterenol (given as a rapid intravenous injection) required to increase the resting heart rate by 25 bpm (I25) increased with age. The I25 was repeated during an intravenous infusion of propranolol and the dose ratio (I25 after propranolol divided by the control I25) determined. This was related to the concentration of free propranolol in plasma. It was found that the effectiveness of any given free concentration diminished progressively with age. These data are consistent with a diminished responsiveness of the beta-adrenoceptor to both agonist and antagonist drugs with advancing years.

Adrenergic beta-Agonists↗
PubMed1979

Estimation of kinetic parameters from a two-point determination of the drug cumulation factor.

A method is described which allows the calculation of kinetic parameters of drugs from two data points, involving a set of simple algebraic equations. This method is based on cumulation characteristics of drugs during multiple dosing. The necessary two blood samples are collected at the end of the first dosing interval and before a succeeding dose after steady state has been reached. The method is applicable for drugs which exhibit linear kinetic characteristics not subject to concentration or time-dependent phenomena. The estimates of the kinetic parameters are associated with different ranges of possible errors, with total clearance being the most reliable estimate. The potential clinical utility of this method is discussed.

Humans↗
PubMed1979

Interaction of topical and oral timolol in glaucoma.

The interaction of oral and topical timolol maleate was studied in patients with open-angle glaucoma. The oral and topical preparations given separately produced a significant and comparable reduction of the intraocular pressure, but no additive effect was observed when both preparations were given together. Pulse- and blood pressure-lowering effects of oral timolol were not enhanced by the application of topical timolol. These systemic effects were not found in those patients using topical timolol alone.

Administration, Oral↗
PubMed1979

Propranolol binding in plasma during cardiopulmonary bypass.

The effect of cardiopulmonary bypass on the plasma binding of propranolol was examined in seven patients. The fraction of propranolol free in plasma doubled, increasing from 6.6 to 13.5 per cent (P less than 0.001) following the administration of heparin, 400 IU/kg. Once cardiopulmonary bypass was concluded and protamine, 8 mg/kg, given, the free fraction decreased from 13.4 to 8.7 per cent (P less than 0.005). There was a further significant decrease to 6.5 per cent over the next 3.1 hours (SE +/- 0.3). Those alterations in the free fraction, which would result in more drug being available for binding to receptor sites and for exerting its pharmacologic effect, were due principally to the changes in free fatty acid levels produced by heparin and protamine, but also to the hemodilution produced by the pump prime.

Cardiopulmonary Bypass↗
PubMed1979

Presystemic drug elimination.

The presystemic elimination of a large number of compounds is clearly established and represents a common and unavoidable cause of reduced bioavailability. The liver, intestine, and lungs have been identified as potential organs contributing to this effect but only in the case of the liver are sufficient data available for comprehensive analysis. More information on intestinal and pulmonary metabolism is clearly needed. Simple methods of kinetic analysis already exist, however, to assess the relative importance of these organs in presystemic elimination, especially in relation to the pre- and postabsorptive types of elimination that may occur.

Animals↗
PubMed1979

Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man.

We assessed the release of neuronal and adrenomedullary catecholamines in response to various stimuli of the sympathetic nervous system in normal subjects. Plasma catecholamines and their urinary metabolites, normetanephrine and metanephrine, were measured. Sodium restriction increased supine plasma norepinephrine by 37% and ambulatory plasma norepinephrine by 22%, with urinary normetanephrine excretion increased 29%. The sodium restriction did not elevate plasma epinephrine or urinary metanephrine. The most potent stimuli of norepinephrine were treadmill exercise, orthostasis, caffeine, the cold pressor test, sodium restriction and handgrip exercise, in descending order. Plasma epinephrine was increased by caffeine, treadmill exercise, the cold pressor test, handgrip exercise and the Valsalva maneuver, in that order. Syncope resulted in profound changes in plasma epinephrine but only modest changes in plasma norepinephrine. We conclude that in man, there is frequent dissociation between the effects of different stimuli on neuronal and adrenomedullary catecholamine release.

Adolescent↗
PubMed1979

Suppression of chronic ventricular arrhythmias with propranolol.

The antiarrhythmic efficacy of propranolol was evaluated in 32 patients with chronic high frequency ventricular arrhythmias in a placebo-controlled protocol. After a placebo control period, propranolol was begun and the dosage increased sequentially until arrhythmia suppression was achieved, side effects appeared, or a maximum dosage of 960 mg/day was reached. Computerized analysis of ambulatory recordings was used to quantify the arrhythmias. Twenty-four patients had 70--100% arrhythmia suppression at plasma levels ranging from 12--1100 ng/ml (end of dosing interval). Eight patients in this group had frequent episodes of ventricular tachycardia that were totally suppressed at or below the dosage that produced greater than or equal to 70% suppression of ventricular ectopic depolarizations (VEDs). A biphasic dose-response curve was seen in five patients who responded with a decrease in arrhythmia frequency in the lower ranges of dosages but had increased frequency of ectopic rhythms as the dosage was increased above the optimal level. Only one-third of patients responded at doses less than or equal to 160 mg/day. However, with dosages of 200--640 mg/day, an additional 40% responded. Propranolol appears to control ventricular arrhythmias safely and effectively in many patients. The finding that the antiarrhythmic effect in many patients required plasma concentrations greater than those that produce substantial beta-adrenergic blockage raises a question whether blockade of cardiac beta receptors can directly account for all of the antiarrhythmic actions of propranolol.

Adult↗
PubMed1979

Reduction of plasma renin activity by inhibition of the fatty acid cyclooxygenase in human subjects: independence of sodium retention.

We carried out the present studies to determine whether the suppression of plasma renin activity (PRA) that follows inhibition of prostaglandin (PG) synthesis can be dissociated from the sodium-retaining effects of these drugs. In an initial investigation we studied the effect of indomethacin on PRA in normal subjects in balance on a 10 mM Na+ diet to prevent Na+ retention. Under these experimental conditions indomethacin did not lower PRA even though the fatty acid cyclooxygenase was inhibited, as indicated by a greater than 70% reduction in the major urinary metabolite of prostaglandin E (PGE-M). Sodium depletion leads to enhanced sympathetic activity. We therefore studied the effect of indomethacin on a group of subjects in 10 mM Na+ balance in whom the effect of increased beta-sympathetic activity was blocked by the administration of propranolol. In this group, indomethacin caused 65% suppression of PGE-M and had no effect on Na+ balance, but reversibly reduced PRA in the supine and upright positions by 84% and 70%, respectively. In normal subjects in 10 mM Na+ balance, the isoproterenol-induced increase in PRA also was unaffected by indomethacin. These data establish that inhibition of the cyclooxygenase can result in a reduction of PRA that is independent of changes in Na+ balance or beta-sympathetic tone.

Adult↗
PubMed1979

Importance of blood-collection tubes in plasma lidocaine determinations.

In 25 clinical samples serum lidocaine concentrations fell from a mean of 6.5 +/- 2.1 mg/L (mean +/- SD) to 4.9 +/- 1.8 mg/L (p less than 0.001) when the blood sample was allowed to make contact with the stopper of the Vacutainer collection tube. In vitro experiments showed that this effect of the stopper occurred only with whole blood and was dependent on sample concentration. The plasma binding of lidocaine decreased from a normal value of 56% +/- 2.2 (mean +/- SD) to 28% +/- 2.2 (p less than 0.001) when exposed to the Vacutainer stopper. We conclude that a chemical leached from such stoppers displaces lidocaine from its plasma-binding sites and that the drug is then redistributed into the erythrocytes, producing spuriously low lidocaine concentrations in plasma or serum. Such artifacts are important in therapeutic drug monitoring and can lead to erroneous clinical decisions.

Disposable Equipment↗