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Biomedical subjects

J W Black

Publications and source records attributed to J W Black.

At least 19 recordsLinked to original sources
PubMed1992

Inotropic polyazapentalene sulmazole analogues.

Aryl substituted 1H-imidazo[1,2-a]imidazole 8, imidazo[2,1-b]thiazole 9, 1,4-dihydroimidazo[4,5-d]imidazole 11, and 1(2),4-dihydroimidazo[4,5-c]pyrazoles 12-17 have been prepared. An X-ray crystallographic study confirmed the structure of 8 and showed this analogue to exist as the 1H-tautomer. These heterocycles were evaluated as inotropic agents and analogues 12, 15, and 17 found to display inotropic properties which were less potent in vitro, but more potent in vivo, than those of sulmazole. Structure-activity relationships are discussed.

Animals↗
PubMed1992

Combined dose-ratio analysis of cholecystokinin receptor antagonists, devazepide, lorglumide and loxiglumide in the guinea-pig gall bladder.

1. Interactions between cholecystokinin octapeptide (CCK-8) and CCKA-receptor antagonists derived from benzodiazepines (devazepide) and glutamic acid (lorglumide and loxiglumide) have been examined in an improved bioassay using the guinea-pig, isolated, gall bladder preparation. 2. The presence of CCKB-receptors in the assay was provisionally-ruled out on the basis of the low potency of pentagastrin in the assay. By applying analyses of both agonism and antagonism, pentagastrin was shown to behave as a partial agonist at the CCKA-receptor. 3. Devazepide, lorglumide and loxiglumide behaved as simple competitive antagonists of CCKA-receptors and pKB values of 9.98, 7.59 and 7.07 were estimated, respectively. 4. Application of a combined dose-ratio analysis to the interactions between CCK-8 and combinations of devazepide/lorglumide and devazepide/loxiglumide indicated that these molecules behave as syntopic, competitive, antagonists at the CCKA-receptor. 5. We conclude that the guinea-pig gall bladder assay contains a homogeneous population of CCKA-receptors and offer an explanation for the differences between our results and those obtained recently by Maubach et al. (1991) which were taken as preliminary evidence for CCKA-receptor heterogeneity.

Analysis of Variance↗
PubMed1992

Evidence that the apparent complexity of receptor antagonism by angiotensin II analogues is due to a reversible and syntopic action.

1. The interactions between angiotensin II (AII), two non-peptide antagonists DuP 753 and IMI, and eight peptide analogues of AII were investigated on the rabbit isolated aorta assay. DuP 753 and IMI behaved as simple competitive antagonists (pKB values 8.4 and 6.8, respectively). To different degrees, all the AII-peptide analogue interactions failed to meet the basic criteria for simple competition. In addition to rightward shift, the most significant feature was a concentration-dependent saturable depression of the upper asymptote of the AII concentration-effect curves. 2. 'Washout' and combined dose-ratio analysis experiments, in which DuP 753 was used as a reference antagonist, indicated that the profile of peptide antagonism was solely due to a reversible and syntopic action at the AII receptor. 3. By use of an operational model of agonism (Black & Leff, 1983) as a starting point, it was possible to account for the data with a new model which describes reversible receptor occupancy and occupied receptor-determined, saturable reduction in the efficacy of AII. Model-fitting gave estimates of pKB values for the peptide analogues and agonist affinity and efficacy parameters for AII. 4. The model was successfully tested by applying it to qualitatively similar results obtained in a cross-tissue analysis on guinea-pig aorta, ileum and stomach. 5. A 'molecular' interpretation of the efficacy changes, based on the concepts of receptor internalisation and expression, is offered.

Angiotensin II↗
PubMed1992

But ... is it really work? Social validity of employment training for persons with very severe disabilities.

The subjective judgments of "significant others" toward employment training for persons with very severe disabilities were investigated. Six respondent groups (n = 188) rated videotape samples of employment training of 4 students with mild to profound disabilities. Respondent ratings were analyzed for group by student disability level effects. Results indicated that all respondent groups had more positive evaluations of those students with mild versus severe to profound disabilities, although mean ratings at all levels of disability tended to be positive. A sizable percentage of the total sample expressed positive judgments of employment for even students with the most severe disabilities.

Activities of Daily Living↗
PubMed1991

Prevention of retrovirus infection after injury with contaminated instruments: an experimental study.

Owing to similarities between human immunodeficiency virus and feline retroviruses, the feline model was chosen for the study to investigate the efficacy of timely topical treatment of accidental human immunodeficiency virus infection in the operating room. Cats were subcutaneously inoculated with either feline leukemia virus or feline immunodeficiency virus. An effort was made to neutralize the virus in loco either by infiltration of the inoculation site with povidone-iodine or with monoclonal antibodies, or by cauterization and excision. The animals were periodically monitored for feline leukemia virus antigens or for feline immunodeficiency virus antibodies. The results indicated that in the feline model, the development of generalized virus infection may be prevented by local measures if applied immediately.

Animals↗
PubMed1991

Pharmacological analysis of agonist-antagonist interactions at acetylcholine muscarinic receptors in a new urinary bladder assay.

1. Agonist-antagonist interactions at acetylcholine (ACh) muscarinic receptors have been analysed by use of an improved urinary bladder assay, isolated and intact, from the mouse. With 5-methylfurmethide as agonist, validated cumulative concentration-effect curves were obtained in less than 7 min by re-dosing before the response plateaux began to fade. 2. The pKB value estimated for pirenzepine was 6.76. The pKB values estimated for atropine and N-methylatropine from data obtained at concentrations which produced dose-ratios greater than 20 and 60 were 8.90 and 9.58, respectively. 3. The deviation from simple competitive behaviour at low dose-ratios with atropine and N-methylatropine was consistent with the operation of saturable antagonist removal processes. The deviation observed with atropine was corrected by pre-incubation with methylbutyrate, an alternative substrate for 'atropine esterase'. 4. The simple competitive behaviour of N-methylatropine was restored following pre-incubation with the neuronal choline uptake blocker hemicholinium-3 (HC-3). However, the pKB estimated for N-methylatropine under these conditions was low. This latter result could be accounted for by the observed behaviour of HC-3 as a competitive antagonist of ACh muscarinic receptors (pKB = 4.01). 5. We conclude that the modified mouse urinary bladder assay is suitable for the quantitative analysis of muscarinic receptor interactions. In addition, we postulate the existence of a previously undescribed uptake mechanism for quaternary muscarinic receptor antagonists.

Animals↗
PubMed1990

Interpretation of agonist affinity estimations: the question of distributed receptor states.

In the receptor-transducer model of pharmacological agonism, rejection of the traditional assumption that receptor molecules are in vast excess of transducer molecules permits the receptors to become distributed among unbound, bound and complexed states. Under these conditions, agonist affinities are liable to be overestimated when the method of irreversible receptor antagonism is used. Graphical tests have been developed to detect distribution, and these were applied to experimental data from the interaction between 5-HT and phenoxybenzamine on aortic tissue. Significant receptor distribution was not detected by the method. However, in the model it was assumed that there was a linear relation between the concentration of ternary complex and pharmacological effect. If this relation was replaced with a saturable one the effect of receptor distribution would be masked. The implications for pharmacologists and medicinal chemists are discussed.

Adrenergic alpha-Antagonists↗
PubMed1990

Inotropic activities of imidazopyridines.

A series of 2-substituted 1H-imidazo[4,5-b]pyridines and the isomeric 1H-imidazo[4,5-c]pyridine derivatives has been prepared and evaluated as inotropic agents. The 1H-imidazo-[4,5-b] derivatives were found to be consistently more potent than their isomers in the [4,5-c] series in isolated guinea pig papillary muscle preparations. Structure-activity relationships and the species-dependence of inotropic potencies are discussed.

Anesthesia↗
PubMed1990

Cardiotonic 'C' ring modified isomazole analogues.

Isomazole analogues which have achiral electron withdrawing substituents at the 4'-position and analogues with heterocyclic 'C' rings have been synthesized and evaluated as inotropic agents. It was found that pyridyl could replace phenyl in the 'C' ring without loss of activity. The 4'-methylsulphonyl, -cyano, -carboxamido, and acetyl analogues had similar inotropic potencies to Isomazole whilst displaying superior cardiovascular profiles in in vivo studies.

Animals↗
PubMed1990

Inotropic "A" ring substituted sulmazole and isomazole analogues.

A series of "A" ring substituted sulmazole and isomazole analogues have been prepared and evaluated as inotropic agents. pKA's, protonation sites, and log P values were measured for selected compounds and their electronic properties were calculated. No simple correlation between inotropic activity and pKA, protonation site, or log P value was observed. However, in vitro inotropism did correlate with the calculated charge density of the "B" ring imidazo nitrogen atom. The 6-position of sulmazole appeared to be the most tolerant toward substituents, the 6-amino derivative 7 being a more potent inotrope than sulmazole itself. 4-Methoxyisomazole 13 had comparable in vivo inotropic properties to those of isomazole.

Animals↗
PubMed1990

Humoral immune response to the bovine immunodeficiency-like virus in experimentally and naturally infected cattle.

Calves inoculated with bovine immunodeficiency-like virus (BIV) produced virus-specific antibodies that could be detected from 2 weeks to 2.5 years postinoculation by using both indirect fluorescent-antibody and Western immunoblot assays. Antibodies were primarily to p26. Virus and BIV-specific antibodies were isolated from calves given BIV-infected blood. Antibodies to BIV proteins were found in sera from naturally infected cattle.

Animals↗
PubMed1988

Correlation between log POCT/H2O and pKB estimates for a series of muscarinic and histamine H2-receptor antagonists.

1. With histamine used as agonist, pKB values were estimated for seventeen histamine H2-receptor antagonists on assays involving acid secretion by the mouse isolated stomach and contraction frequency of the guinea-pig right atrium. 2. With the exception of oxmetidine, SK&F 94,826 and SK&F 94,206 on the right atrium assay, the compounds behaved as simple competitive antagonists on both assays. Although the former three compounds produced concentration-dependent, parallel, displacement of the histamine concentration-effect curves, subsequent analysis indicated Schild plot slope parameters significantly less than unity. However, the application of a combined dose-ratio analysis indicated that their antagonistic behaviour did not differ from expectations for simple competition at dose-ratios of approximately 20, and pKB values were estimated on this basis. 3. In accordance with previously reported data, pKB values were found to be consistently lower on the stomach than atrial assays. The pKB value for tiotidine was underestimated to the same extent on the stomach assay when impromidine was used as agonist. 4. The removal of the serosal muscle from the mouse stomach, achieved by using an isolated, perfused, mucosal sheet preparation, did not significantly affect the underestimation of the pKB value for metiamide. 5. Linear regressional analysis indicated a significant, positive, correlation between lipophilicity (log POCT/H2O) of the antagonists and the degree of antagonist pKB value underestimation on the gastric secretion assay.

Animals↗
PubMed1988

A hazard of pressure support ventilation.

Many of the newer models of mechanical ventilators include the pressure support (PS) mode of ventilation as a standard feature. The mechanism for the termination of a pressure support breath varies considerably among the various ventilators. The potential for the sudden inadvertent application of a high, unremitting pressure support breath or continuous positive airway pressure (CPAP) clearly exists with some ventilators and is illustrated in two cases. The potentially adverse consequences of high levels of CPAP are predictable and have been well described. Standard ventilator monitoring systems which do not include mean airway pressure monitoring may not detect this problem before significant adverse consequences have occurred. Even when detected, this unfamiliar complication may be difficult to recognize by the uninitiated. Physicians utilizing this mode of ventilation must be familiar with the terminating mechanism of their particular ventilator and choose appropriate monitoring.

Equipment Failure↗
PubMed1987

The libidinal cocoon: a nurturing retreat for the families of plane crash victims.

In 1985 the families of 137 passengers killed when a Delta Airlines jet crashed at Dallas-Fort Worth International Airport stayed in a secluded hotel while waiting for the victims' bodies to be retrieved and identified. In this protected environment, which the author calls the "libidinal cocoon," the families received intensive nurturing from the author, a Dallas psychiatrist; a team of Red Cross nurses; hotel staff; airline representatives; clergy; and each other. The supportive environment allowed the families to regress safely and to satisfy the basic yearning, intensified in times of personal loss, for an idealized caretaker who will meet all one's needs. The author believes this kind of intervention may be useful in future disasters with massive casualties.

Aircraft↗
PubMed1986

Pharmacological analysis of the inhibition by pirenzepine and atropine of vagal-stimulated acid secretion in the isolated stomach of the mouse.

The muscarinic receptors involved in the vagal stimulation of gastric acid secretion in the mouse isolated stomach assay have been examined by analysing the effects of pirenzepine and atropine on fully-defined frequency-effect curves. Both atropine and pirenzepine produced concentration-dependent inhibition of vagal-stimulated acid secretion in a manner consistent with a model describing competitive antagonism of endogenous acetylcholine, which was assumed to be released by vagal stimulation. The results obtained are quite compatible with the hypothesis that vagal stimulation involves muscarinic receptors which are homogeneous with those previously found on histamine and oxyntic cells in the mouse stomach assay. These results find no evidence for muscarinic receptor heterogeneity and reinforce the hypothesis that the selectivity of pirenzepine in vivo relative to atropine is due to the loss of atropine into the gastric secretion.

Acetylcholine↗
PubMed1986

Analysis of competitive antagonism when this property occurs as part of a pharmacological resultant.

In this paper, pharmacological resultant is defined as the net effect of a single compound resulting from the simultaneous expression of two or more specific actions. The principles of concentration-ratio analysis are extended to develop a method for detecting and quantifying competitive antagonism when this property is a component of a pharmacological resultant. The method is general to the extent that it allows analysis of competitive antagonism in combination with all types of post-receptor intervention. Essentially it depends on the altered expression of competition by a reference antagonist. It incorporates tests for validating its application and it is independent of agonist concentration-effect curve shape: in these respects the method is analogous to Schild plot-analysis of simple competition. The methodology for the practical application of the analysis is exemplified by studying the net effect of a combination of a phosphodiesterase inhibitor (isobutylmethylxanthine) and histamine H2-receptor antagonist (metiamide) on histamine-stimulated tachycardia in guinea-pig, isolated, right atrium. Cimetidine was used as the reference antagonist. The equation used in this analysis is similar in form to one recently described by Hughes & Mackay (1985) to elucidate the situation when competitive antagonism occurs in combination with functional interactions. The relation between their method and the present analysis is discussed.

1-Methyl-3-isobutylxanthine↗