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Biomedical subjects

J W Paterson

Publications and source records attributed to J W Paterson.

At least 19 recordsLinked to original sources
PubMed1991

Disposition of dothiepin after overdose: effects of repeated-dose activated charcoal.

Although the tricyclic antidepressant dothiepin is often encountered in deliberate self-poisonings, there are no published studies of its disposition in overdose. In the present study, we have documented the plasma disposition of dothiepin and its major metabolites in eight overdose patients. All had high initial levels of dothiepin (819-3,851 micrograms/L), dothiepin-S-oxide (655-2,162 micrograms/L), nordothiepin (88-422 micrograms/L), and nordothiepin-S-oxide (176-530 micrograms/L) that were considerably above steady-state therapeutic concentrations. In three patients who received treatment with repeated-dose activated charcoal, dothiepin half-lives were 10.6, 12.5, and 13.1 h compared with the literature range of 18.5-24 h. All patients survived and none experienced any significant cardiovascular event despite exhibiting clinical signs of tricyclic antidepressant overdose. We suggest that repeated-dose activated charcoal treatment may decrease the dothiepin half-life after overdose.

Adult↗
PubMed1990

Epithelium-derived inhibitory factor in human bronchus.

The potencies of histamine and methacholine were significantly increased by approximately 2- and 5-fold respectively in human non-diseased isolated bronchi on removal of the epithelium. In contrast, no increases in spasmogen potency were observed following epithelium removal in bronchi obtained from a sample of asthmatic human lung. The failure of epithelium removal to increase asthmatic bronchial sensitivity to histamine may have been due to a reduction in the release of an epithelium-derived inhibitory factor (EpDIF) resulting from disease-induced epithelial damage. A co-axial bioassay system in which endothelium-denuded rat aorta was used as the assay tissue was used to detect the release of a vasorelaxant EpDIF from human bronchial tissue. Histamine (100 microM) and methacholine (25 microM), in the presence of indomethacin (5 microM), reduced phenylephrine-induced tone in endothelium-denuded rat aorta in co-axial assemblies by 75 +/- 11 and 67 +/- 9% respectively. Removal of the bronchial epithelium abolished these responses, indicating that they were mediated by an EpDIF. It is possible that human airway smooth muscle is sensitive to this vasorelaxant EpDIF and that the absence of the source of this factor following epithelium removal caused the increases in sensitivity to spasmogens. Alternatively, the human bronchial epithelium may also release an EpDIF selective for airway smooth muscle.

Animals↗
PubMed1990

Contractile effects and receptor distributions for endothelin-1 (ET-1) in human and animal airways.

ET-1 caused concentration-dependent, sustained contraction of all airway preparations tested and was most potent in mouse trachea, with rat trachea, human bronchus and guinea-pig trachea approximately 5, 10 and 70 fold less sensitive respectively. Human non-asthmatic and asthmatic bronchi were approximately equi-sensitive to ET-1. Quantitative light microscopic autoradiography demonstrated high levels of specific [125I]-ET-1 binding sites in airway smooth muscle of rat trachea greater than human asthmatic bronchus = human non-asthmatic bronchus greater than mouse trachea much greater than guinea-pig trachea. High levels of specific ET-1 binding were also revealed in peripheral airways and in alveolar wall tissue in human, rat and mouse lung. In a limited sample of asthmatic airway smooth muscle ET-1 receptor function and density was not elevated.

Animals↗
PubMed1990

PAF receptors in guinea-pig and human lung.

The autoradiographic distribution and density of specific binding sites for the PAF receptor antagonist [3H]-WEB 2086 was assessed in non-diseased and asthmatic human lung and in guinea-pig airway tissue. In general, only very low levels of specific binding were detected in these tissues with no evidence for PAF receptors in airway smooth muscle. Asthma does not appear to involve significantly increased airway PAF receptor expression.

Animals↗
PubMed1990

Adrenoceptors in airway smooth muscle.

This review examines the roles and functional significance of alpha and beta-adrenoceptor subtypes in airway smooth muscle, with emphasis on human airway function and the influence of asthma. Specifically, we have examined the distribution of beta-adrenoceptors in lung and the influence of age, the epithelium, respiratory viruses and inflammation associated with asthma on airway smooth muscle beta-adrenoceptor function. Sites of action, beta 2-selectivity, efficacy and tolerance are also examined in relation to the use of beta 2-agonists in man. In addition, alpha-adrenoceptor function in airway smooth muscle has been reviewed, with some emphasis on comparing observations made in airway smooth muscle with those in animal models.

Adrenergic alpha-Agonists↗
PubMed1989

Co-axial bioassay of a smooth muscle relaxant factor released from guinea-pig tracheal epithelium.

1. The ability of guinea-pig trachea to release an epithelium-derived relaxant factor (EpDRF) was assessed in a co-axial bioassay system. 2. Histamine (100 microM) and methacholine (25 microM) caused endothelium-dependent relaxation of rat isolated aorta, presumably via the release of endothelium-derived relaxant factor (EDRF). In contrast, endothelium-denuded rat aorta did not relax in response to these agents. 3. EDRF release was detected in response to methacholine in a co-axial bioassay system, consisting of intact rabbit aorta tube (EDRF donor) and endothelium-denuded rat aorta strip (assay preparation). These results indicated the transfer of EDRF from a donor to an assay preparation, thereby validating the co-axial bioassay method. 4. Substitution of endothelium-intact rabbit aorta tube by epithelium-intact guinea-pig tracheal tube tissue in co-axial assemblies, still allowed the assay preparation to relax in response to histamine or methacholine. Removal of the intact tracheal tube from the system, or removal of the epithelium from the donor tracheal tube in co-axial preparations, abolished such relaxant responses. These observations are consistent with histamine- or methacholine-induced release of an epithelium-derived relaxant factor (EpDRF) from the trachea. 5. In the co-axial assembly comprising intact guinea-pig trachea and endothelium-denuded rat aorta, histamine and methacholine produced concentration-dependent, EpDRF-induced aortic relaxation. Mean concentrations of histamine and methacholine producing 50% of the maximum relaxation (EC50) were 39.8 microM and 2.7 microM respectively. Histamine-induced relaxation was inhibited in the presence of mepyramine (2 microM) and responses to methacholine were inhibited by atropine (0.1 microM). 6. Methylene blue (50 microM) had no effect on such relaxant responses, indicating that EpDRF does not activate guanylate cyclase. Furthermore, the cyclo-oxygenase inhibitor indomethacin (5 microM), the cyclo-oxygenase/lipoxygenase inhibitor BW 755C (150 microM) and the leukotriene receptor antagonist FPL 55712 (10 microM) each failed significantly to alter EpDRF-mediated relaxation of vascular smooth muscle suggesting that EpDRF is not a prostanoid. Platelet activating factor (Pat) failed to cause relaxation of endothelium-denuded rat aorta, indicating that this mediator was also not EpDRF. 7. EpDRF was also released from human bronchial segments. 8. This study provides direct evidence for the release of an EpDRF from non-diseased airway tissue and further suggests that healthy airway reactivity to spasmogens is modulated by the release of an endogenous protective, spasmolytic substance. The bronchial hyperreactivity of asthma may be partly caused by attenuated production of such an inhibitory signal.

Animals↗
PubMed1989

Alpha 1-adrenoceptor function and autoradiographic distribution in human asthmatic lung.

1. The autoradiographic distribution of alpha 1-adrenoceptors was investigated in non-diseased and asthmatic human lung by use of [3H]-prazosin (H-PZ). To validate binding and autoradiographic methods, H-PZ binding was also measured in rat heart. 2. Significant levels of specific H-PZ binding were detected in sections of rat heart. This binding was associated with a single class of non-interacting sites of high affinity (dissociation constant, Kd = 1.17 +/- 0.26 nM). The maximum binding capacity (Bmax) was 59.5 +/- 4.5 fmol mg-1 protein. 3. In sharp contrast, very low levels of specific H-PZ binding were found in both human nondiseased and asthmatic bronchus, although a high level of binding of [125I]-iodocyanopindolol (I-CYP, 50 pM) to beta-adrenoceptors was detected in these airways. Furthermore, very low levels of autoradiographic grains representing specific H-PZ binding were found in all airway structures in human non-diseased or asthmatic lung parenchyma. 4. Consistent with these data, the alpha-adrenoceptor agonist phenylephrine failed to induce significant increases in tone in bronchi isolated from either non-diseased or asthmatic human lung. Results indicate that asthma does not involve significant increases in airway alpha 1-adrenoceptor function.

Adult↗
PubMed1989

Autoradiographic localization of beta-adrenoceptors in asthmatic human lung.

The autoradiographic distribution and density of beta-adrenoceptors in human non-diseased and asthmatic bronchi were investigated using [125I]iodocyanopindolol (I-CYP). Analysis of the effects of the beta-adrenoceptor antagonists on I-CYP binding demonstrated that betaxolol (20 nM, beta 1-selective) had no significant effect on specific grain density in either nonasthmatic or asthmatic human bronchus, whereas ICI-118551 (20 nM, beta 2-selective) inhibited I-CYP binding by 85 +/- 9% and 89 +/- 3%, respectively. Thus, homogeneous populations of beta 2-adrenoceptors existed in bronchi from both sources. Large populations of beta-adrenoceptors were localized to the bronchial epithelium, submucosal glands, and airway smooth muscle. Asthmatic bronchial tissue featured epithelial damage with exfoliated cells associated with luminal mucus plugs. A thickened basement membrane and airway smooth muscle hyperplasia were also evident. High levels of specific I-CYP binding were also detected over asthmatic bronchial smooth muscle, as assessed by autoradiography and quantitation of specific grain densities. Isoproterenol and fenoterol were 10- and 13-fold less potent, respectively, in bronchi from asthmatic lung than in those from nonasthmatic lung. However, this attenuated responsiveness to beta-adrenoceptor agonists was not caused by reduced beta-adrenoceptor density in asthmatic airways. A defect may exist in the coupling between beta-adrenoceptors and postreceptor mechanisms in severely asthmatic lung.

Asthma↗
PubMed1988

Beta-adrenoceptor desensitization in guinea-pig isolated trachea.

Exposure to (-)-isoprenaline (25 microM, 1 h) caused a stereoselective, time and concentration-related decrease in smooth muscle beta 2-adrenoceptor function in guinea-pig trachea. Furthermore, tracheal relaxant responsiveness to the beta-adrenoceptor agonists (+/-)-fenoterol and (-)-noradrenaline was reduced, while that to theophylline and nitroprusside was unaffected. Responsiveness to forskolin was marginally but significantly reduced. Indomethacin, a cyclooxygenase inhibitor and mepacrine, an inhibitor of phospholipid turnover, had no significant effect on the extent of isoprenaline-induced desensitization. Conversely, cortisol (25 microM) significantly reduced desensitization and enhanced the rate of spontaneous recovery of responsiveness to isoprenaline. Desensitization was not accompanied by a reduction in the density of beta-adrenoceptors in the trachea, as assessed by binding and light microscopic autoradiography using [125I]iodocyanopindolol [( 125I]CYP). Thus, desensitization was probably caused primarily by beta-adrenoceptor/adenyl cyclase uncoupling. This model may be useful in investigations of the effect of glucocorticoids on the beta-adrenoceptor dysfunction recognized in severe asthma.

Animals↗
PubMed1988

An overview of the current status of the drug therapy of asthma.

The importance of inflammation as the central lesion in asthma is being increasingly recognised and it is proposed that the emphasis of therapy should be altered from simply treating symptoms, to trying to control inflammation at an early stage of the disease. A "tight control" treatment program to achieve this is outlined. Treatment regimes for asthma may therefore need to be re-assessed, although the most commonly used drugs (beta 2-adrenoceptor agonists, theophylline, corticosteroids and cromoglycate) are effective if used properly. For the majority of patients management is grossly inadequate in terms of diagnosis, assessment of disease severity and treatment. The death rate from asthma still remains unacceptably high and some strategies are outlined for the identification of patients at risk and the improvement of their management. This overview considers four central issues: (1) the lesions that should be the target for drug treatment; (2) an outline of the available drug treatment; (3) the aims of treatment and (4) the success of drug treatment in terms of morbidity and mortality.

Adrenergic beta-Agonists↗
PubMed1988

Epithelial dysfunction and airway hyperreactivity in asthma.

It is clear that the central airway epithelium plays an important role in restricting access of inhaled solutes to sub-epithelial airway wall structures. Non-specific airway hyperreactivity to spasmogens in asthma may result partly as a consequence of the compromise of the epithelium as a barrier to solute diffusion. However, impaired epithelial production and release of smooth muscle relaxant factor(s) may also contribute to airway hyperresponsiveness. Virally precipitated asthma also involves inflammation-induced epithelial damage. Beta-adrenoceptor hypofunction induced by respiratory viruses may also contribute to bronchial obstruction.

Adrenergic beta-Antagonists↗
PubMed1986

Autoradiographic localisation of ascorbic acid-dependent binding sites for [125I]iodocyanopindolol in guinea-pig trachea.

Light microscopic autoradiography showed that the supposedly beta-adrenoceptor-selective radioligand [125I]iodocyanopindolol (I-CYP) bound to sites in both the guinea-pig tracheal epithelium and smooth muscle that were sensitive to propranolol and isoprenaline. Low levels of binding were associated with sub-epithelial mucosal cells. Ascorbic acid caused a concentration-related increase in total I-CYP binding which was predominantly associated with the sub-epithelial mucosa, was not inhibited by propranolol, and was thus not associated with beta-adrenoceptors.

Animals↗
PubMed1986

An ultrastructural study of mast cells in the alveolar wall of normal and asthmatic lung.

Specimens of normal and asthmatic lungs were studied at the electron microscopic level and the frequency and ultrastructural features of mast cells and their granules within the alveolar wall were assessed with morphometric techniques. The numerical density of mast cells per square millimetre of alveolar wall was 299 (SD = 258) in normal and 366 (SD = 260) in asthmatic lung. The mean area of the mast cell nucleated profile was 25.7 microns2 (SD = 6.3) in normal lung and 29.8 (SD = 6.2) in asthmatic. The average number of secretory granules per single mast cell nucleated profile was 55 (SD = 13) in normal lung and 60 (SD = 12) in asthmatic lung. The diameter of the individual secretory granule was 338.9 nm (SD = 42.6) in normal and 345.6 (SD = 47.7) in asthmatic lung. The volume density of secretory granules in normal and asthmatic lung was 6.31 microns3 and 5.81 microns3, respectively. The mean diameter of the individual subunit ('scroll') inside the secretory granule was 88.8 nm for both normal and asthmatic lung. In normal lung 64.2% of granules were of 'scroll' and 'combined' type, and 35.8% of granules were 'particulate' or 'empty'. In specimens from asthmatic patients 40.3% of granules had 'scroll' or 'combined' structures and 59.7% were 'particulate' or 'empty'. Our data suggest that there is no difference between the number of mast cells in normal and asthmatic lung. However, in pulmonary mast cells from asthmatic lung, degranulation is more common than in normal lung.

Adolescent↗
PubMed1986

In vitro responsiveness of human asthmatic bronchus to carbachol, histamine, beta-adrenoceptor agonists and theophylline.

Responses of human bronchial strip preparations to contractile and relaxant agonists were measured in preparations from non-diseased and from asthmatic lung obtained 3-15 h post-mortem. The potencies of carbachol and histamine were approximately two times less in asthmatic than in non-diseased bronchi. This was statistically significant for carbachol (P less than 0.05), but not for histamine (P greater than 0.05). These results clearly indicate that the bronchial hyperreactivity to airway spasmogens observed in asthma is exclusively an in vivo phenomenon not involving increasing sensitivity of bronchial smooth muscle. The potencies of the beta-adrenoceptor agonists isoprenaline, fenoterol and terbutaline were significantly reduced by 4-5 fold in asthmatic bronchi compared with non-diseased airways. In contrast, theophylline was equipotent in the two populations of airway preparations. Thus, it appears that severe asthma is associated with decreased bronchial smooth muscle beta 2-adrenoceptor function.

Adolescent↗