Biomedical subjects

J Saunders

Publications and source records attributed to J Saunders.

At least 19 recordsLinked to original sources

PubMed1992

L-687,306: a functionally selective and potent muscarinic M1 receptor agonist.

The oxadiazole L-687,306 is a high affinity muscarinic agonist with a N-methylscopolamine/oxotremorine-M binding profile predictive of a partial agonist. L-687,306 showed marked selectivity in functional pharmacological assays. L-687,306 was a partial agonist at muscarinic M1 receptors in the rat ganglion but a high affinity competitive antagonist at guinea-pig cardiac M2 and ileal M3 muscarinic receptors. This compound gives an opportunity to study receptor reserve involved in muscarinic receptors in vitro and in vivo.

Animals↗

PubMed1992

Novel 5-HT3 antagonists: indol-3-ylspiro(azabicycloalkane-3,5'(4'H)-oxazoles).

The synthesis and biochemical evaluation of a series of spirofused indole oxazoline 5-HT3 antagonists is described in which the oxazoline ring acts as a bioisosteric replacement for esters and amides. The effect of substitution about the indole ring has shown the steric limitations of the aromatic binding site. Incorporation of a variety of azabicyclic systems within the rigid spirofused framework has allowed the definition of a binding model which incorporates a number of known antagonists and agonists. In this model steric constraints limit substitution around the indole ring although there is some bulk tolerance at the 1- and 2-positions. The importance of constraining the basic nitrogen within an azabicyclic system is underlined by comparison with the monocyclic piperidine. The highest affinity was observed for those compounds in which the basic nitrogen occupies a bridgehead position, the most potent analogue in this group being the azabicyclic [3.3.1] system (pIC50 = 8.95), suggesting lipophilic interactions may play a role in increasing affinity. A suggested model for agonist binding is included in which the basic nitrogens are superimposed and the 5-hydroxyl group of 5-HT is superimposed on the H-bond-accepting atom of the heterocyclic linking group.

Animals↗

PubMed1992

Synthesis and muscarinic activity of quinuclidinyl- and (1-azanorbornyl)pyrazine derivatives.

The synthesis and cortical muscarinic activity of a novel series of pyrazine-based agonists is described. Quinuclidine and azanorbornane derivatives were prepared either by reaction of lithiated pyrazines with azabicyclic ketones, followed by chlorination and reduction, or by reaction of the lithium enolate of the azabicyclic ester with 2-chloropyrazines followed by ester hydrolysis and decarboxylation. Substitution at all three positions of the heteroaromatic ring has been explored. Optimal muscarinic agonist activity was observed for unsubstituted pyrazines in the azanorbornane series. The exo-1-azanorbornane 18a is one of the most efficacious and potent centrally active muscarinic agonists known. Studies on the 3-substituted derivatives have provided evidence of the preferred conformation of these ligands for optimal muscarinic activity. Substitution at C6 gave ligands with increased affinity and reduced efficacy. Moving the position of the diazine ring nitrogens to give pyrimidine and pyridazine derivatives resulted in a significant loss of muscarinic activity.

Animals↗

PubMed1992

A nursing bioethics program.

In 1985 the Seattle Veterans' Administration Medical Center nursing service implemented a nursing program for bioethics with three goals: (1) to expand the nurse's knowledge of bioethical principles, (2) to develop the nurse's ability and confidence in analyzing bioethical dilemmas, and (3) to increase bioethical application at the bedside. Two psychosocial clinical nurse specialists (CNSs) led this highly successful nursing program that prepared nurses to more actively and responsibly participate in bioethical decision making within the medical center. The program offers an annual workshop for new members, holds a monthly discussion group, conducts a yearly enrichment program, and completes an annual evaluation report. This article describes nursing service bioethics program from planning through evaluation and the role of the CNS as program coordinator, facilitator, and educator in the expanding field of bioethics.

Education, Nursing, Continuing↗

PubMed1992

Clindamycin, erythromycin, and roxithromycin inhibit the proinflammatory interactions of Pseudomonas aeruginosa pigments with human neutrophils in vitro.

The Pseudomonas aeruginosa-derived phenazine pigments pyocyanin and 1-hydroxyphenazine (1-hp) prime human neutrophils for enhanced, stimulus-activated release of superoxide and myeloperoxidase (MPO), respectively. In the present study, the modulatory potentials of the antimicrobial agents clindamycin, erythromycin, and roxithromycin (10 and 20 micrograms/ml) on the prooxidative interactions of pyocyanin and 1-hp (12.5 microM) with human neutrophils have been investigated. Clindamycin, erythromycin, and especially roxithromycin caused dose-related inhibition of the generation of superoxide by both untreated and pyocyanin-treated neutrophils during activation with either the synthetic chemotactic tripeptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) or the calcium ionophore A23187. The antimicrobial agents also inhibited the generation of reactive oxidants by the MPO-H2O2-halide system during activation of both untreated and 1-hp-treated neutrophils by FMLP. These effects appeared to be due to drug-related interference with membrane-associated oxidative metabolism, since none of the antimicrobial agents inhibited the release of MPO by activated neutrophils, nor did they possess oxidant-scavenging properties. These data demonstrate that clindamycin, erythromycin, and especially roxithromycin antagonize the proinflammatory interactions of pyocyanin and 1-hp with neutrophils and indicate a possible therapeutic role for these antimicrobial agents in the prevention of tissue damage in diseases characterized by P. aeruginosa infection.

Clindamycin↗

PubMed1992

Non-nucleoside inhibitors of HIV reverse transcriptase: screening successes--clinical failures.

A little less than two years ago, the first report describing non-nucleoside inhibitors of HIV reverse transcriptase (RT) led to the high anticipation that a range of new drugs could soon be available for the treatment of AIDS. The intervening period has given rise to several such agents but recent clinical trial data has indicated this optimism to be premature. This short review seeks to trace the brief history of the drug discovery process and to assess whether there are lessons to be learnt from the episode.

Antiviral Agents↗

PubMed1992

Who's for CPR?

Explore the source record for details and available documents.

Cardiopulmonary Resuscitation↗

PubMed1992

Can consultants resuscitate?

Twenty-four of 53 hospital consultants responded to an offer to attend a resuscitation training course. Fourteen of them had never had resuscitation training. Their performance of basic life-support was assessed before and after training according to the Resuscitation Council UK recommendations. Their initial performance of basic life-support on a manikin was extremely poor. One hour of training and practice resulted in statistically significant improvements.

Cardiopulmonary Resuscitation↗

PubMed1991

A comparison of serum neutralisation, immunofluorescence and immunoperoxidase tests for the detection of antibodies to chicken anaemia agent.

A comparison was made of the serum neutralisation, immunofluorescent antibody and immunoperoxidase tests for the detection of antibodies to chicken anaemia agent. Serum samples from groups of chicks with and without maternally derived antibody to the agent were tested and the response of chicks after inoculation with the agent was also measured. The serum neutralisation test was reliable and sensitive, but expensive and could take up to three weeks to obtain a result. The immunofluorescent antibody test was cheaper and required only one day to obtain a result, but it was not as sensitive in detecting low levels of antibody to the chicken anaemia agent. The immunoperoxidase test was also cheaper but took two days to obtain a result and required one more manipulation than the immunofluorescence test. It was comparable to the serum neutralisation test in its ability to detect low levels of antibody.

Anemia↗

PubMed1991

Return of ATP/PCr and EEG after 75 min of global brain ischemia.

Acute, progressive global brain ischemia was induced in awake or anesthetized rats for 5-75 min. Ischemia was achieved with a subclavian-carotid artery occlusion technique (SCOT). After thoracotomy, both subclavian arteries (proximal to their vertebral branches) were tied-off and carotid artery catheter-snares installed. Results show progressive morphological, physiological and neurochemical damage when CBF was reduced from preischemic levels of 115 ml to 0 blood flow. 31P magnetic resonance spectroscopy of high energy phosphate metabolites in vivo showed loss of PCr and beta-ATP signals after 6 min brain ischemia. Energy metabolite levels, EEG and CBF normalized within hours after reperfusion. Degree of neuropathologic damage to hippocampal region appeared linearly related to the ischemic duration of ischemia. Thus, acute global brain ischemia resulted in loss of high energy phosphate metabolites, EEG and neuronal integrity in the hippocampal subfields. Reperfusion following short (5 min) or long (75 min) periods of global brain ischemia induced return of 31P-spectra, EEG and CBF to normal but was unable to reverse all of the neuronal damage at the end of the 72-h observation period.

Adenosine Triphosphate↗

PubMed1991

Novel 5-HT3 antagonists. Indole oxadiazoles.

The synthesis and biochemical evaluation of a series of indole oxadiazole 5-HT3 antagonists are described. The key pharmacophoric elements have been defined as a basic nitrogen, a linking group capable of H-bonding interactions, and an aromatic moiety. The steric limitations of the aromatic binding site have been determined by substitution about the indole ring. Variation of the heterocyclic linking group has shown that while two hydrogen-bonding interactions are possible, only one is essential for high affinity. The environment of the basic nitrogen has been investigated and shown to be optimal when constrained within an azabicyclic system. These results have been incorporated into a proposed binding model for the 5-HT3 antagonist binding site, in which the optimum distance between the aromatic binding site and the basic amine is 8.4-8.9 A and the steric limitations are defined by van der Waals difference mapping.

Animals↗

PubMed1991

Tetrahydropyridyloxadiazoles: semirigid muscarinic ligands.

Recent studies have described novel azabicycle-based muscarinic agonists which readily penetrate into the central nervous system and are capable of displaying high efficacy at cortical sites. The current paper describes the synthesis and biochemical assessment of semirigid muscarinic ligands which were used to map the requirements of the cortical muscarinic receptor and to study the degree of conformational flexibility required to cause receptor activation. Analogues 6 and 9 provide high-efficacy muscarinic agonists at cortical sites; however, C-alkylation on the tetrahydropyridine ring resulted in more rigid analogues and showed lower predicted efficacy. Molecular mechanics calculations indicated a preference for the E rotameric form. This conformation was also observed in the X-ray crystal structure of ethenyloxadiazole 12. The new compounds were tested in a biochemical assay designed to measure receptor affinity and to predict cortical efficacy.

Animals↗

PubMed1991

Comparison of platelet-rich plasma collection using the Haemonetics PCS and Baxter Autopheresis C.

We have compared 118 platelet-rich plasma donations collected using the Autopheresis-C Platelet cell (Auto C) with 166 donations using the Haemonetics PCS. The median platelet yield from the Auto C was superior (2.51 vs. 1.54 x 10(11] although collection times differed (60 vs./40 min). There was greater variability in the platelet yield from the Auto C (0.45-5.6 vs./0.26-2.8 x 10(11], but leucocyte contamination was not significantly different. After secondary processing, there was significantly less residual platelet-poor plasma (272 vs. 369 ml). Platelet function assessed during 5 days of storage was satisfactory for both, although platelet aggregation responses to collagen and adenosine diphosphate were superior in the Auto C platelets.

Humans↗

PubMed1991

Effect of U74006F on forebrain ischemia in rats.

We examined the effect of a putative lipid peroxidation inhibitor, the 21-aminosteroid U74006F, on transient forebrain ischemia in rats. Acute-treatment rats received either 3 mg/kg U74006F (n = 7) or carrier vehicle (n = 5) intravenously 30 minutes before ischemia, sustained-treatment rats received the same treatment before ischemia followed by 3 mg/kg U74006F (n = 6) or carrier vehicle (n = 5) intraperitoneally every 6 hours for 48 hours, and control rats (n = 7) received no injection. Coronal magnetic resonance images were obtained daily for 3 days, followed by the histological examination of perfusion-fixed brains. Control rats demonstrated magnetic resonance image changes indicative of neuronal damage in the striatum at 24 hours postischemia, followed by changes in the hippocampus and neocortex at 48 hours. No significant effect of U74006F treatment on striatal or hippocampal injury was demonstrated. However, both the acute and sustained U74006F treatments produced a significant reduction in the severity of neuronal damage in the neocortex (p less than 0.05). Our results suggest that U74006F is of benefit in ameliorating ischemic neuronal injury, particularly in the neocortex, and raise the possibility of regional variability in lipid peroxidation following an ischemic insult.

Animals↗

PubMed1990

Comparative in vitro activity of several antimicrobial agents against selected clinical isolates.

A comparison between the in vitro activities of ceftazidime, cefotaxime, ceftriaxone, ampicillin, piperacillin, gentamicin, tobramycin and netilmicin was performed on selected clinical isolates. The activity of the agents was assessed by means of minimum inhibitory concentration determinations, and time-kill studies. The third generation cephalosporins were active against all members of the Enterobacteriaceae excluding some Enterobacter species. Their activity against these bacteria was generally comparable and greater than that of piperacillin. Netilmicin was the most active of the aminoglycosides tested against members of the Enterobacteriaceae; however, aminoglycoside-resistant strains were encountered. Ceftazidime was the most active of the third generation cephalosporins against the non-fermenters (e.g. Pseudomonas and Acinetobacter spp), its inhibitory activity also being greater than that of piperacillin. Using a time-kill study, ceftazidime also demonstrated greater bactericidal activity than piperacillin against an isolate of Pseudomonas aeruginosa. The aminoglycoside demonstrating the greatest activity against the non-fermenters was tobramycin.

Anti-Bacterial Agents↗

PubMed1990

Selective, delayed increase in transfer constants for cerebrovascular permeation of blood-borne 3H-sucrose following forebrain ischaemia in the rat.

Experiments were conducted to explore the time course of changes in blood-brain barrier (BBB) permeability that may occur in the 2-vessel occlusion model of stroke in the rat. Anaesthetized Sprague-Dawley rats underwent 10 min of cerebral ischaemia produced by bilateral carotid occlusion plus haemorrhagic hypotension. After 6 min, or 3, 6, 18, 24, 48 h recovery and re-anaesthetization, an i.v. injection of 3H-sucrose was permitted to circulate for 30 min. Regional transfer constants (Ki) for BBB permeation of sucrose were calculated from the ratio of sucrose concentration in parenchyma relative to the time-integrated plasma concentration. In the 6-min group, all cerebral regions showed evidence of early BBB leakiness (increase in Ki above non-stroke baseline) which was maximal in forebrain cortex. This effect was diminished at subsequent time points, except in striatum and hippocampus which exhibited delayed intensification of opening, maximal in the 6 h group. Ki values had largely normalized by 24 h. Ki values were also determined 6 min, 6 h and 24 h after a 20-min stroke procedure. Early and regionally selective, delayed BBB openings were also seen, but recovery was not evident in cerebral regions at 24 h. Cortex exhibited a large increase in Ki indicating that a delayed, marked deterioration of BBB integrity had developed between the 6 h and 24 h time points. It is concluded that the combination of transfer constant measurements and the 2-vessel occlusion model could provide a sensitive means for investigating the cerebrovascular consequences and therapy of stroke.

Animals↗

PubMed1990

Spread of non-typable multiply resistant Haemophilus influenzae in a South African hospital.

In July 1987 non-typable Haemophilus influenzae strains resistant to both ampicillin and chloramphenicol were isolated from the endotracheal aspirate of two children with pneumonia at Baragwanath Hospital, Johannesburg, South Africa. A study was therefore undertaken to determine the carriage rates of Haemophilus influenzae strains in the nasopharynx of children and staff in the index ward and in three control wards. Using a disc diffusion and an agar dilution method the susceptibility was determined of 100 isolates to ampicillin, chloramphenicol, erythromycin, rifampicin, amoxicillin/clavulanic acid, gentamicin, cefaclor, cefotaxime, tetracycline, sulphamethoxazole, trimethoprim and trimethoprim/sulphamethoxazole (1:19). The overall carriage rate of Haemophilus influenzae on admission was 76%. In the index ward, children carrying multiply resistant strains differed from the other children in that there was a longer mean duration of hospitalization, a lower proportion of males, and a higher proportion who had previously received antibiotics. All ampicillin resistant strains were shown to produce beta-lactamase. Only four isolates belonged to serotype b, of which three were ampicillin resistant and chloramphenicol sensitive while one was resistant to both drugs. Nasopharyngeal spread of resistant non-typable strains of Haemophilus influenzae was demonstrated to affect the management of paediatric patients in the hospital.

Ampicillin Resistance↗

PubMed1990

Novel quinuclidine-based ligands for the muscarinic cholinergic receptor.

Recent clinical studies on Alzheimer's patients have implied that only agents displaying high efficacy at the cortical muscarinic receptor have yielded encouraging results. This paper describes the design, synthesis, and biochemical characterization of novel quinuclidine-based muscarinic agonists which can readily penetrate into the central nervous system and which are capable of displaying high efficacy at cortical sites. With use of a biochemical assay capable of measuring receptor affinity and predicting cortical efficacy, it has been discovered that an oxadiazole ring and related heterocycles can function as bioisosteric replacements for the ester moiety found in several known muscarinic ligands. Within this series there exist compounds which span the efficacy range from high-efficacy agonist through partial agonists to antagonists with affinity comparable or superior to that of classical quaternary ammonium ligands. Consistent with recent molecular biology studies, structure-activity trends are interpreted in terms of separate binding sites for agonists and antagonists with H-bonding interactions characterizing agonist behavior and lipophilic binding characterizing antagonist behavior. Thus the aminooxadiazole moiety has structural features which are optimized for an agonist profile.

Animals↗