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Biomedical subjects

R W Chapman

Publications and source records attributed to R W Chapman.

At least 145 records · Page 8Linked to original sources
PubMed1991

Sch 37370: a new drug combining antagonism of platelet-activating factor (PAF) with antagonism of histamine.

Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are platelet-activating factor (PAF) and histamine. From a structural series with documented antihistamine activity, Sch 37370 has been identified as a dual antagonist of PAF and histamine. In vitro, Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 also blocks the binding of [3H]pyrilamine to histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered Sch 37370 is effective against bronchospasm to histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against bronchospasm due to leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced edema in the rat pleural cavity. In addition, Sch 37370 blocks bronchospasm induced by either antigen in sensitized guinea pigs or hyperventilation in nonsensitized guinea pigs. Sch 37370 also inhibits antigen-induced lung eosinophilia in sensitized guinea pigs and a reverse passive Arthus reaction in rats. Although Sch 37370 is not the most potent PAF antagonist or antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available antihistamine therapies.

Animals↗
PubMed1990

Selective inhibition of peripheral histamine responses by loratadine and terfenadine.

To determine the selectivity of the non-sedating antihistamines loratadine and terfenadine and the sedating antihistamine diphenhydramine for peripheral and central histamine H1-receptors, these compounds were examined against intravenous (i.v.) and intracerebroventricular (i.c.v.) histamine-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs. Animals were prepared with i.c.v. or i.v. cannulas and instrumented for the measurement of airway resistance (RAW) and dynamic lung compliance (CDyN). Loratadine, terfenadine or diphenhydramine were administered orally 2 h before either i.v. or i.c.v. injection of histamine. Each antihistamine blocked the i.v. histamine bronchospasm with the order of potency loratadine (ED40 = 0.08 mg/kg) greater than terfenadine (ED40 = 0.44 mg/kg) greater than diphenhydramine (ED40 = 5 mg/kg). These drugs also blocked i.c.v. histamine-induced bronchoconstrictions, but loratadine and terfenadine were approximately 10 times less potent against i.c.v. histamine bronchoconstriction than they were against i.v. histamine. In contrast, diphenhydramine was equipotent against i.c.v. and i.v. histamine bronchoconstriction. These results demonstrate that the non-sedating antihistamines loratadine and terfenadine, unlike diphenhydramine, are more effective against peripheral than central H1-receptors, probably because of poor penetration of the blood-brain barrier.

Animals↗
PubMed1990

Liver transplantation for acute hepatic failure?

In the absence of definitive medical treatment for severe fulminant hepatic failure, liver transplantation may be appropriate in selected patients. However, uniform and easily applicable criteria for diagnosis of severity and analysis of results are needed to prevent unnecessary transplantation and to ensure that patients who may benefit are appropriately treated. Previous regimens for treatment of fulminant hepatic failure were often advocated, on the basis of data from historical controls, for several years until controlled trials failed to show any benefit. To obtain reliable information more rapidly than achieved before, a controlled trial between specialist liver transplant units is needed to establish the role of emergency hepatic transplantation in patients with fulminant hepatic failure.

Acute Disease↗
PubMed1990

Endoscopic sphincterotomy for the palliation of ampullary carcinoma.

Palliative endoscopic sphincterotomy was performed on 17 patients with adenocarcinoma of the ampulla of Vater. An endoprosthesis was inserted immediately after the sphincterotomy in four of the patients. Fourteen patients made uncomplicated recoveries from the procedure and their jaundice resolved completely. Early complications developed in three patients. One patient died from haemorrhage. Two patients, both of whom had an endoprosthesis, developed cholangitis. The endoprosthesis was removed and another inserted in one patient and the other underwent surgery. Both thereafter made uncomplicated recoveries. Jaundice subsequently recurred in eight patients and further endoscopic treatment was successful in five of these patients. Eleven patients died between 4 days and 23 months after the sphincterotomy with a median survival of 12 months. Four patients remain alive between 3 and 17 months after treatment. The results indicate that reasonable palliation can be achieved safely by endoscopic sphincterotomy.

Adenocarcinoma↗
PubMed1990

Diclofenac associated hepatitis.

Diclofenac is a widely used non-steroidal anti-inflammatory drug, being the most commonly prescribed of its kind in the world. This paper describes five cases of hepatitis with clinical features indicating a direct link with diclofenac. All the patients presented with an acute hepatitis, three being jaundiced. They gave a history of taking diclofenac up to the time of presentation, four of the five having started the drug within the previous 3 months. There were no other features in the histories to suggest alternative causes for the liver dysfunction. Liver function tests were grossly abnormal in all cases, showing a hepatitic picture. A liver biopsy was performed in 4 cases, and showed features of an acute hepatitis with inflammation and hepatocyte damage dominating. The liver dysfunction returned to normal on drug withdrawal in four of the five cases, with full recovery by 3 months. One patient developed steroid-responsive chronic active hepatitis. Hepatotoxicity associated with diclofenac is documented, but previously only a few isolated cases have been described. The occurrence of five cases in one gastroenterology unit over a 12-month period suggests that hepatitis associated with diclofenac may be commoner than previously supposed.

Aged↗
PubMed1990

Sch 37370: a potent, orally active, dual antagonist of platelet-activating factor and histamine.

Platelet-activating factor (PAF) and histamine are potent bronchospastic agents and possess additional properties such as induction of vasopermeability and activation of inflammatory cells that are consistent with their ability to mediate allergic and inflammatory responses. From a structural series with anticipated antihistamine activity, Sch 37370 (1-acetyl-4(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2- b]pyridine-11-ylidine)piperidine) has been identified as a dual antagonist of PAF and histamine in vitro and in vivo and has been compared with several selective antagonists of PAF and histamine. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 blocks the binding of [3H]pyrilamine to histamine-H1 receptors in rat brain membranes. Administered i.v. to guinea pigs, Sch 37370 is an equipotent antagonist of PAF and histamine-induced bronchospasm (ED50 = 0.6-0.7 mg/kg). Orally in guinea pigs, Sch 37370 is somewhat more effective against bronchospasms to histamine (ED50 = 2.4 mg/kg) than against PAF (ED50 = 4.1-6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). Sch 37370 only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is completely inactive at 50 mg/kg against leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced lethality in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1989

Two methods to detect DNA fragments produced by restriction enzymes.

This report summarizes two methods for detecting limited amounts of DNA from restriction endonuclease digests. The first is a photographic system for visualizing ethidium bromide-stained DNA fragments in agarose gels which can detect as little as 50-100 pg DNA per band. The second technique is direct sulfonation of DNA fragments bound to nylon membranes followed by visualization of the fragments by nonradioactive immunoblot methods. The immunohistochemical staining can detect 10 pg DNA per band. The direct sulfonation technique is not intended to identify specific DNA sequences; DNA-DNA hybridization with sulfonated probes has previously been described (P. Lebacq, D. Squalli, M. Duchenne, P. Poulety, and M. Johannes (1988) J. Biochem. Biophys. Methods 15, 255-266). Direct sulfonation can be used when samples are relatively free of contaminating nucleic acids and is a useful alternative to end-labeling. These highly sensitive techniques may be suitable when the DNA source is of limited quantity or in instances where radiolabeling is not permitted.

Animals↗
PubMed1989

Peripheral blood and portal tract lymphocyte populations in primary sclerosing cholangitis.

The relative distribution of lymphocyte subpopulations in the blood and liver of patients with primary sclerosing cholangitis (PSC) and related diseases has been studied using immunoenzyme techniques. The peripheral blood CD4/CD8 T lymphocyte ratio was significantly higher in active ulcerative colitis (UC) and in PSC with inactive UC than in inactive UC alone. In contrast, no relationship with disease activity was seen in Crohn's disease. The portal tract t lymphocyte count per high power field (mean +/- S.D.) was higher in pre-cirrhotic PSC (173 +/- 105) and primary biliary cirrhosis (PBC: 210 +/- 110) than in histologically normal liver (42 +/- 27). However, the overall portal tract CD4/CD8 ratio was similar in PSC (1.49), PBC (1.89) and normal controls (1.63). The results are consistent with immunological involvement in the pathogenesis of PSC, but argue against the hypothesis that changes in the peripheral blood T cell subsets are due to sequestration at the site of tissue inflammation.

Adolescent↗
PubMed1989

Mitochondrial and nuclear gene dynamics of introduced populations of Lepomis macrochirus.

A population of bluegill sunfish, Lepomis macrochirus, was introduced into three man-made ponds in 1966. Analyses of these ponds in 1984 and 1985 found significant mtDNA divergence without nuclear gene differentiation. The difference between nuclear gene and mtDNA measures of interpopulational divergence was very large and suggests that sexual asymmetries in life histories may be important considerations in mtDNA and nuclear gene rates of divergence. The rapid divergence of mtDNA haplotype frequencies suggests that sorting of previously existing variation may accelerate mtDNA divergence among recently isolated populations.

Alleles↗
PubMed1989

Endoscopic sphincterotomy for bile duct stones: an institutional review of 272 patients.

The results of the first 283 endoscopic sphincterotomies (ES) attempted in Oxford for bile duct stones are described. Endoscopic sphincterotomy was achieved in 272 patients (96%) and complete duct clearance was achieved in 88% of these patients; an overall success rate of 85%. Complications occurred in 26 patients (10%), five of whom required an emergency laparotomy. Eight patients died within 30 days of ES but only two deaths were attributed directly to the procedure. Although the sphincterotomies were performed by several endoscopists in varying stages of training, the results are similar to those from other large reports. In the last year of the study (1987), 58 patients were referred from within the Oxfordshire District which suggests an annual demand for ES for bile duct stones of 11 patients per 100,000 of population.

Adult↗
PubMed1989

Anti-neutrophil nuclear antibody in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis.

We have previously described circulating autoantibodies to a portal tract antigen in patients with primary sclerosing cholangitis. In this study the antigen has been shown by double-labelling studies to be specifically located in the nuclei of tissue neutrophils. Using isolated peripheral blood neutrophils and an immunoperoxidase technique, anti-neutrophil nuclear antibody (ANNA) was found in the serum of 84% of patients with primary sclerosing cholangitis (PSC: n = 32) with a median titre of 1/1000 and a peak titre of 1/500,000. ANNA was also detected in 86% of patients with inflammatory bowel disease alone (IBD: n = 76) with a median titre of 1/10 and a peak titre of 1/10,000. In contrast, only 12% of controls had ANNA, and in none was the titre greater than 1/10. In PSC the ANNA titre correlated with the serum aspartate transaminase concentration, suggesting that it is related to disease activity. In IBD the titre of ANNA was significantly higher in patients with recently active disease. There was no significant difference between the titres seen in ulcerative colitis and Crohn's disease. ANNA was not associated with neutropaenia. The results provide further evidence of involvement of autoimmune mechanisms in inflammatory bowel disease and primary sclerosing cholangitis.

Adolescent↗
PubMed1988

Simple, noninvasive method to measure the antibronchoconstrictor activity of drugs in conscious guinea pigs.

A simple, noninvasive method is described for measurement of the oral antibronchoconstrictor activity of drugs in conscious guinea pigs. The guinea pigs were placed in a head-out plethysmograph for measurement of tidal volume (VT), and a head chamber was used to deliver a hypercapnic gas mixture (10% CO2, 69% N2, 21% O2) and histamine aerosol (0.05% for 30 s). Inhalation of CO2 caused an increase in VT that was reduced (61 +/- 3%) by exposure to histamine. The histamine-induced reduction of VT was significantly (p less than 0.05) reduced 1 hr after oral administration with the bronchodilators albuterol (1 and 10 mg/kg) and aminophylline (100 mg/kg), the calcium antagonist nifedipine (30 mg/kg), and the antihistamine chlorpheniramine (0.5 mg/kg). These results demonstrate the oral antibronchoconstrictor activity of drugs in this model. The major advantages of this technique are that it is simple to operate, is noninvasive, and does not require anesthesia.

Aerosols↗
PubMed1988

Effect of the PAF antagonists, CV-3988 and L-652,731 on the pulmonary and hematological responses to guinea pig anaphylaxis.

To define the role of PAF in the acute phase of guinea pig anaphylaxis, we have measured the pulmonary (bronchoconstrictor) and hematological (thrombocytopenia, leukopenia, hemoconcentration, plasma TxB2 increase) responses to PAF infusion and compared these responses to the effect of antigen exposure in actively and passively sensitized guinea pigs. We have also determined the effect of the structurally unrelated PAF antagonists, CV-3988 and L-652,731 on these responses. Intravenous administration of PAF (50-400 ng/kg) caused a dose-related bronchoconstriction, thrombocytopenia, leukopenia, hemoconcentration and increase in plasma TxB2. These PAF-induced responses were inhibited, to a variable degree, by pretreatment with CV-3988 (3 and 10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). Intravenous administration of ovalbumin to actively or passively sensitized guinea pigs caused bronchoconstriction, thrombocytopenia, leukopenia and hemoconcentration, but there was no increase in TxB2. Moreover, the anaphylactic bronchoconstriction, thrombocytopenia, leukopenia (actively sensitized) and hemoconcentration were not inhibited by CV-3988 (10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). The different profile of changes produced by PAF and allergic anaphylaxis and the failure to alter the responses to allergic anaphylaxis with PAF antagonists suggest that PAF is not an important mediator of the acute phase of guinea pig anaphylaxis.

Anaphylaxis↗