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Biomedical subjects

D P Venter

Publications and source records attributed to D P Venter.

10 recordsLinked to original sources
PubMed2006

The pharmacological effects of ozone on isolated guinea pig tracheal preparations.

Ozone is a potent oxidizing agent with a variety of potential uses, including its antimicrobial and deodorising properties. The recent increased use of ozone led to questions regarding its safety in humans. This study specifically focussed on the in vitro effect of ozone on isolated guinea pig tracheal tissue as well as its effect on the isolated trachea in the presence of various drugs with well-known effects, including methacholine and isoproterenol. The results found in this study identified two direct effects on the isolated trachea due to ozone exposure: (1) a definite contraction of the isolated trachea immediately after exposure to ozone, and (2) a clearly visible and significant hyper responsiveness of the isolated trachea to irritants, e.g. methacholine. Although ozone has a negative effect on the trachea, it was concluded that ozone has no adverse effect on muscarinic receptors. We found that ozone has a significant desensitizing effect on the pharmacological response of beta sympathomimetics (isoproterenol), while isoproterenol itself has a relaxing effect on the ozone-induced contraction of the isolated trachea. Observations in this in vitro study further emphasised that ozone does have a negative effect on respiratory health. It is underlined that the inhalation of ozone should be avoided by workers who are often in contact with the gas, and especially by those with existing airway diseases. An apparent EC(50) value of ozone on the trachea was established by two different methods as 5.71 and 9.78 x 10(-3 )M, respectively.

Animals↗
PubMed2004

Recent advances in drug action and therapeutics: relevance of novel concepts in G-protein-coupled receptor and signal transduction pharmacology.

PROBLEM STATEMENT: During especially the past two decades many discoveries in biological sciences, and in particular at the molecular and genetic level, have greatly impacted on our knowledge and understanding of drug action and have helped to develop new drugs and therapeutic strategies. Furthermore, many exciting new drugs acting via novel pharmacological mechanisms are expected to be in clinical use in the not too distant future. SCOPE AND CONTENTS OF REVIEW: In this educational review, these concepts are explained and their relevance illustrated by examples of drugs used commonly in the clinical setting, with special reference to the pharmacology of G-protein-coupled receptors. The review also addresses the basic theoretical concepts of full and partial agonism, neutral antagonism, inverse agonism and protean and ligand-selective agonism, and the relevance of these concepts in current rational drug therapy. Moreover, the mechanisms whereby receptor signalling (and eventually response to drugs) is fine-tuned, such as receptor promiscuity, agonist-directed trafficking of receptor signalling, receptor trafficking, receptor 'cross-talk' and regulators of G-protein signalling (RGSs) are discussed, from theory to proposed therapeutic implications. CONCLUSIONS: It is concluded that the understanding of molecular receptor and signal transduction pharmacology enables clinicians to improve their effective implementation of current and future pharmacotherapy, ultimately enhancing the quality of life of their patients.

Cell Communication↗
PubMed1998

A new method for determining affinity constants on isolated organs when a threshold value and spare receptors are present.

It was shown in previous studies that fixed ratio combinations of agonists with competitive antagonists emulate partial agonists and, therefore, mediate submaximal concentration-effect (E/[A]) curves. A linear plot was obtained by plotting the relative height (H) of these submaximal curves against phiH, where phi=[antagonist]/[agonist]. In this study, it was shown that in an agonist-effector system comprising a possible threshold value, the use of fixed ratio agonist-competitive antagonist concentrations (artificial partial agonists) induces E/[A] curves of different heights which allows one to quantify the threshold value. A nonlinear parabolic-like plot may be obtained when a threshold value is present in an agonist-effector system. By quantifying the threshold value, the nonlinear plot was converted to a linear plot from which the apparent affinity (KA) and an efficacy related parameter (eES) of an agonist could be estimated. The practical applicability of the method was shown by applying the method to E/[A] curves obtained for agonists (noradrenaline and acetylcholine) obtained in the presence and absence of increasing concentrations of their respective competitive antagonists on different effectors.

Binding, Competitive↗
PubMed1997

Efficacy. I: A new method for estimating relative efficacy of full agonists via a newly defined efficacy related parameter.

A new method for estimating relative efficacies and relative intrinsic efficacies of agonists is described. Relative efficacy is estimated by employing a newly defined efficacy related parameter (eES) and it may be estimated without prior knowledge of efficacy values or the value of the equilibrium dissociation constants, KA, of agonist-receptor complexes. The parameter eES is directly related to efficacy (e) and is defined as the ratio of maximal stimulus to maximal effect of an agonist. The value of eES indicates whether or not spare receptors are present for a particular agonist-effector system. The eES values of agonists are estimated by utilizing submaximal concentration-effect curves determined with fixed agonist-competitive antagonist concentration combinations and choosing a suitable reference (height of an agonistic concentration-effect curve) to which the height of the stimulus concentration-effect curves of the agonist may be compared. In addition to eES, other new agonist-effector parameters, namely SEm/Sm and phi min, were also defined.

Binding, Competitive↗
PubMed1997

Efficacy. II. Estimation of a newly defined efficacy related parameter.

A new method for estimation of agonist-affinity (KA) and relative efficacy was introduced. This method afforded a procedure by which relative efficacy may be estimated while the actual KA values of agonist-receptor complexes are unknown. The relative efficacy may be estimated by employing a newly defined drug parameter, namely the eES value. The eES value is related to drug efficacy and is defined in such a manner that an isolated eES is a meaningful quantity which may indicate whether or not spare receptors are present in an agonist-effector system. The estimation of eES was based on the fact that fixed agonist-competitive antagonist combinations mimic partial agonists and mediate submaximal concentration-effect curves. However, for the practical estimation of eES one may employ data acquired from agonistic concentration-effect curves determined in the absence and presence of increasing concentrations of a competitive antagonist. This procedure was illustrated by utilizing theoretical concentration-effect curves and applied practically by estimating eES and KA values acquired from sets of carbachol and salbutamol curves. The sets of carbachol and salbutamol concentration-effect curves were determined in the absence and presence of their respective competitive antagonists, namely tripitramine and pindolol.

Adrenergic beta-Agonists↗
PubMed1996

New methods for determining dissociation constants of agonist-receptor complexes.

Methods are presented which enables the dissociation constant of agonist-receptor complexes (KA) to be estimated without knowledge of the relative intrinsic efficacies. The dissociation constants are estimated from fixed agonist-competitive antagonist concentration combinations which simulate partial agonists. In general, estimating of KA by employing these methods require phi and KB to be known; where phi = [antagonist]/[agonist] and KB is the dissociation constant of the competitive antagonist-receptor complex. Some of these methods require only knowledge of phi, while KB may be unknown. A method is also described to estimate KA without knowing the value of KB and the competitive antagonist concentration. In addition to the estimation of KA values, a new method for estimation of the dissociation constants of competitive antagonist-receptor complexes (KB) is reported. One of the new methods was exemplified practically by using sets of experimental agonist concentration-effect curves determined in the absence and presence of increasing concentrations of competitive antagonists. From this pharmacological data the apparent KA value for carbachol (in muscarinic M3 receptors of the guinea-pig ileum) was determined. This action illustrated that the apparent affinity values (KA) and height of the stimulus curve of an agonist may be determined from published pharmacological data. This procedure affords a possibility to establish whether or not spare receptors are present in a particular system. It was also shown that relative affinity values provide more reliable information than does isolated KA values.

Animals↗
PubMed1994

Indirectly acting agonists. A model for the functional interaction of released endogenous double agonists.

A theoretical model is presented to describe the functional interaction of an endogenous double agonist released by an indirectly acting agonist. The model takes into account the functional interaction of a released double (dualistic) agonist and describes both functional synergism and antagonism. It was shown that receptor density plays an important role in determining the profiles of concentration-effect curves and that it is necessary that the model should incorporate a parameter which describes receptor density. The model predicted that the shape of the concentration-effect curves may be sigmoid or bell-shaped. The theoretical predictions are comparable with experimental results.

Animals↗
PubMed1987

A model for agonists acting directly as well as indirectly.

A theoretical model is presented to describe the receptor interaction of a drug which possesses indirect as well as direct pharmacological action. Sets of theoretical log concentration-effect curves predicted by this model are presented. The model predicts that the shape of the log concentration-effect curves may be sigmoid (S-shaped), biphasic (bell-shaped) or composed of a combination of two sigmoid curves, joined together by a plateau. The theoretical predictions are comparable with the results obtained from an experimental study.

Animals↗