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Biomedical subjects

R W Chapman

Publications and source records attributed to R W Chapman.

At least 109 records · Page 6Linked to original sources
PubMed1995

The pharmacology of SCH 50911: a novel, orally-active GABA-beta receptor antagonist.

Experiments were conducted to characterize the pharmacology of SCH 50911 ((+)-5,5-dimethyl-2-morpholineacetic acid hydrochloride), a structurally novel GABA-B receptor antagonist. Although more potent GABA-B antagonists have been reported, in this study SCH 50911 was compared with CGP 35348, a moderately potent and selective GABA-B antagonist with acceptable in vivo activity. SCH 50911 was more potent to inhibit the binding of GABA to the GABA-B receptor in rat brain (IC50 = 1.1 microM) than CGP 35348 (IC50 = 62 microM). SCH 50911 had no binding affinity for GABA-A, histamine H1, histamine H3, dopamine D1, dopamine D2, serotonin 5-HT2, or muscarinic m1, m2, or m4 receptors. However, SCH 50911 (IC50 = 2.2 microM) was active in a nonspecific muscarinic receptor binding assay, but was devoid of muscarinic agonist or antagonist activity in the isolated guinea pig ileum. SCH 50911 blocked inhibitory responses to baclofen of the guinea pig trachea in a competitive manner (pA2 = 5.8 +/- 0.004). CGP 35348 was 19-fold less potent in this assay (pA2 = 4.6 +/- 0.15). In vivo, SCH 50911 (ED50 = 2.9 mg kg-1, s.c.) and CGP 35348 (ED50 = 5.8 mg kg-1, s.c.) blocked the antitussive effects of baclofen in the guinea pig. In the cat, both SCH 50911 (10 mg kg-1, i.v.) and CGP 35348 (10 mg kg-1, i.v.) shifted the antitussive dose response relationship for baclofen to the right.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1995

Focal destructive cholangiopathy associated with amoxycillin/clavulanic acid (Augmentin).

Amoxycillin/clavulanic acid (Augmentin) has been widely used as a broad spectrum antibiotic since its introduction in 1981, since which time a number of reports of adverse hepatic reaction to the drug combination have been published. This paper describes five patients presenting with cholestatic illness within 8 weeks of a course of amoxycillin/clavulanic acid. The clinical picture indicated a direct link between the illness and the drug combination. Hepatic histology revealed a distinctive focal destructive cholangiopathy in all five patients, which has not previously been reported. Two also showed a granulomatous reaction, which has only previously been reported in one patient. Parallels are drawn with other diseases displaying bile duct destruction, and it is suggested that immunologically mediated drug-induced biliary damage may be involved. One of the five patients developed chronic liver disease with persistence of cholestatic liver biochemical tests, which has not previously been reported. The severity of the reaction and its prolonged course merit wider recognition of the possible adverse hepatic reaction to amoxycillin/clavulanic acid.

Adult↗
PubMed1995

Antibiotic prophylaxis for ERCP: a randomized clinical trial comparing ciprofloxacin and cefuroxime in 200 patients at high risk of cholangitis.

OBJECTIVE: To compare the efficacy and safety of oral ciprofloxacin and intravenous cefuroxime in patients at high risk of cholangitis after endoscopic retrograde cholangiopancreatography (ERCP). DESIGN: Prospective, randomized study. SETTING: A primary and tertiary referral centre. PATIENTS: A series of 232 consecutive patients who either had radiological evidence of biliary obstruction or were aged over 70 years were randomly assigned to receive either oral ciprofloxacin or intravenous cefuroxime before and after ERCP. Two-hundred and nine patients finished the study, with 23 being excluded because of withdrawal of consent or incomplete ERCP. INTERVENTIONS: Patients underwent ERCP: blood samples were taken for culture, full blood count and biochemistry before and after the procedure. Clinical follow-up was carried out 7 and 42 days after ERCP. MAIN OUTCOME MEASURES: Clinical, bacteriological or biochemical evidence of cholangitis, septicaemia or adverse drug reactions, and the cost of both protocols. RESULTS: Follow-up was recorded in all 209 patients who completed the study. By 42 days after ERCP, three patients had died (cholangiocancer, pancreatic cancer and renal failure). Cholangitis was diagnosed in one patient from each of the two trial groups. Blood cultures from the patient on ciprofloxacin gave negative results, but a post-ERCP blood sample from the patient on cefuroxime grew Pseudomonas aeruginosa, which was sensitive to ciprofloxacin. There were no serious side-effects in either study group, but two patients assigned to ciprofloxacin became too nauseous to take the medication. The cost of the cefuroxime protocol was l7.56 pounds per patient, compared with 4.76 pounds per patient for the ciprofloxacin protocol. CONCLUSION: A pre- and post-ERCP oral ciprofloxacin regime is safe and provides effective prophylaxis against ERCP-induced cholangitis and septicaemia in high-risk patients. It is also more economical than a regime of intravenous cefuroxime and does not require nursing staff with training in intravenous techniques.

Adult↗
PubMed1994

Histamine H3 receptors inhibit sympathetic modulation of airway microvascular leakage in allergic guinea pigs.

Histamine H3 receptor modulation of antigen-induced airway microvascular leakage (AML) during sympathetic nerve stimulation was studied in guinea pigs. Intravenous administration of ovalbumin (100 micrograms) to sensitized guinea pigs produced AML that was reduced by electrical stimulation of sympathetic sites in the dorsal medulla. The sympatho-inhibition of this AML was attenuated by the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 100 micrograms/kg). The effect of (R)-alpha-methylhistamine was blocked by i.v. administration of the histamine H3 antagonists, thioperamide (1 and 3 mg/kg), burimamide (1-10 mg/kg) and impromidine (1 and 3 mg/kg). Thioperamide (3 mg/kg) and impromidine (3 mg/kg), but not burimamide (10 mg/kg) blocked the reduction in blood pressure due to (R)-alpha-methylhistamine. These results show that histamine H3 receptors inhibit sympathetic nerves that control the airway vasculature.

Animals↗
PubMed1994

Superficial thrombophlebitis, dysplasia, and cholangiocarcinoma in primary sclerosing cholangitis.

Cholangiocarcinoma occurs in approximately 10% of patients with primary sclerosing cholangitis. Usually, liver failure, rapidly progressing jaundice, and an increase in alkaline phosphatase levels are suggestive diagnostic features. We report two cases of patients with primary sclerosing cholangitis who developed cholangiocarcinoma without jaundice and with no changes in their serum biochemistry. Both patients were taking ursodeoxycholic acid at the time of tumor diagnosis. Initial suspicion of malignancy was based on the development of superficial thrombophlebitis. Liver histology showed evidence of bile duct epithelial dysplasia in areas free from tumor in one patient, and in the other, bile duct epithelial dysplasia preceded the appearance of cholangiocarcinoma by at least 18 months. In one of the cases, the dysplastic epithelium stained positively for carcinoembryonic antigen. The histological finding of bile duct epithelial dysplasia in patients with primary sclerosing cholangitis may suggest either imminent or actual development of cholangiocarcinoma and may thus affect consideration of orthotopic liver transplantation. In addition, the development of superficial thrombophlebitis in patients with primary sclerosing cholangitis should arouse suspicion of the presence of cholangiocarcinoma even if there is no evidence of deterioration of the liver function or a dominant stricture on endoscopic retrograde cholangiography.

Adult↗
PubMed1994

HLA DR4 is a marker for rapid disease progression in primary sclerosing cholangitis.

BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree associated with an increase in the HLA alleles DR3, DR52a, DR2, Dw2, and a decrease in DR4. However, it is not certain which of these alleles provides the primary associations. Our aim was to establish the primary HLA associations with PSC and to assess the ability of HLA alleles to mark for disease progression. METHODS: By applying molecular techniques to archival tissue, we have genotyped 83 PSC patients from two populations and 131 controls for the alleles HLA DR2, DR3, DR4, DRw12, DR52a, and Dw2. RESULTS: HLA DR3, DR52a, DR2, and Dw2 were all significantly increased in PSC, with the relative risk for DR52a and Dw2 being greater than for DR3 and DR2, respectively. HLA DR4 was significantly decreased, but this may be artifactual to the DR3, DR2 increase. HLA DR4 and not DR52a marks for rapid disease progression in both our PSC populations. CONCLUSIONS: HLA DR52a and Dw2 are the best candidate alleles for providing the known HLA association with PSC. HLA DR4 and not DR52a marks for rapid disease progression in our two PSC populations.

Amino Acid Sequence↗
PubMed1994

A 2-year follow-up study of anti-neutrophil antibody in primary sclerosing cholangitis: relationship to clinical activity, liver biochemistry and ursodeoxycholic acid treatment.

A specific anti-neutrophil antibody was recently described in primary sclerosing cholangitis and was detected using an indirect immunoalkaline phosphatase method. The present study examined the relationship of this antibody with respect to time, clinical activity, liver biochemistry, histology and ursodeoxycholic acid treatment. Fourteen patients with primary sclerosing cholangitis were followed up at regular intervals for 2 years. Clinical activity, liver biochemistry, histology and anti-neutrophil antibody titre were determined during the study period. A fluctuating course of the anti-neutrophil antibody was noted in both untreated patients and in those who were on ursodeoxycholic acid. This finding will have clinical implications if anti-neutrophil antibody is used to screen for potential primary sclerosing cholangitis in the future. The results suggest that several determinations of the antibody would need to be carried out over a period of time. No correlation was found between the antibody titre, clinical activity, liver biochemistry or histology. Anti-neutrophil antibody in primary sclerosing cholangitis probably has no pathogenic significance and is an epiphenomenon.

Adult↗
PubMed1994

Peripheral and central sites of action of GABA-B agonists to inhibit the cough reflex in the cat and guinea pig.

1. The GABA-B receptor agonists baclofen and 3-aminopropylphosphinic acid (3-APPi) have antitussive activity in the cat and guinea pig. The purpose of this study was to investigate the sites of action of these GABA-B receptor agonists to inhibit the cough reflex. 2. Single intracerebroventricular (i.c.v.) cannulas were placed in the lateral ventricles of anaesthetized guinea pigs. Approximately 1 week later, the animals were exposed to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted. 3. Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. Cannulas were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of baclofen, 3-APPi, the centrally active antitussive drug codeine or the peripherally active antitussive drug BW443c. Dose-response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally acting drug. 4. In the guinea pig, baclofen (3 mg kg-1, s.c.) and 3-APPi (10 mg kg-1, s.c.) inhibited capsaicin-induced cough by 50% and 35% respectively. The antitussive activity of baclofen was completely blocked by i.c.v. administration of the GABA-B receptor antagonist CGP 35348 (10 micrograms). Conversely, the antitussive effect of 3-APPi was unaffected by i.c.v. CGP 35348. However, systemic administration of CGP 35348 (30 mg kg-1, s.c.) completely blocked the antitussive activity of 3-APPi (10 mg kg-1, s.c.). In separate experiments baclofen alone (1 microg, i.c.v.) inhibited capsaicin-induced cough by 78%. 3-APPi (10 and 100 microg, i.c.v.) had no effect on capsaicin-induced cough in the guinea pig.5. In the cat, potencies (ED50) of the standards and GABA-B agonists by the i.v. route were: codeine(0.34 mg kg-1), BW443C (0.17 mg kg-1), baclofen (0.63 mg kg-1) and 3-APPi (2.3 mg kg-1). Potencies of these drugs by the i.a. route were: codeine, 0.013 mg kg-1; BW443C, 0.06mg kg-1; baclofen,0.016mg kg-1; and 3-APPi, 0.87 mg kg-1. The EDRs for each drug were: codeine, 26; BW443C, 3;baclofen, 39; and 3-APPi, 3.6 We conclude that in both the cat and guinea pig baclofen inhibits cough by a central site of action,while 3-APPi inhibits cough by a peripheral site of action.

Animals↗
PubMed1994

Characterization of a murine model of allergic pulmonary inflammation.

Pulmonary inflammation with eosinophil (EOs) infiltration is a prominent feature of allergic respiratory diseases such as asthma. In order to study the cellular response during the disease development, an animal model of IgE-mediated pulmonary inflammation with characteristic eosinophilia is needed. We developed a method for inducing severe pulmonary eosinophilia in the mouse and also studied the numbers of EOs in blood and bone marrow and the response to corticosteroid treatment. Animals were sensitized with alum-precipitated ovalbumin (OVA) and challenged with aerosolized OVA 12 days later when serum IgE levels were significantly elevated. Four to eight hours after challenge there were moderate increases in the number of EOs in the bone marrow and peripheral blood, but only a few EOs were observed in the lung tissue and in bronchoalveolar lavage (BAL) fluid. Twenty-four hours after challenge, there was a marked reduction of EOs in bone marrow, while the number of EOs peaked in the perivascular and peribronchial regions of the lung. Forty-eight hours after challenge, the highest number of EOs was found in the BAL fluid, making up > 80% of all cells in that compartment. The high levels of EOs in the lung tissue and BAL fluid lasted for 2-3 days and was followed by a more moderate but persistent eosinophilia for another 10 days. Nonsensitized animals showed no significant changes in the number of EOs in BAL fluid, lungs, blood or bone marrow. Histopathological evaluation also revealed epithelial damage, excessive mucus in the lumen and edema in the submucosa of the airways.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1994

Defining the immunogenetic susceptibility to primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p < 0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.

Alleles↗
PubMed1993

5-HT3 receptors augment neuronal, cholinergic contractions in guinea pig trachea.

Serotonin (5-HT) and the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine enhanced electrical field stimulated contractions of the isolated guinea pig trachea. 5-HT (EC50 = 3.5 microM) was twice as potent as 2-methyl-5-hydroxytryptamine (EC50 = 7.4 microM). The effects of 5-HT and 2-methyl-5-hydroxytryptamine were antagonized by the selective 5-HT3 receptor antagonist; zacopride (apparent pA2 = 7.60 against 2-methyl-5-hydroxytryptamine). 2-Methyl-5-hydroxytryptamine (10 microM) had no effect on contractile responses to exogenous acetylcholine. Furthermore, the increase in electrical field stimulated contraction by 2-methyl-5-hydroxytryptamine was unchanged by hexamethonium (100 microM) but contractions were blocked by atropine (1 microM). These results suggest that excitatory 5-HT3 receptors exist on postganglionic cholinergic nerves in the isolated guinea pig trachea.

Animals↗
PubMed1993

A magnetic resonance imaging evaluation of histamine-mediated allergic response in the guinea pig nasopharynx.

BACKGROUND: Magnetic resonance imaging (MRI) is a powerful technique for visualizing tissues with a high water content. In this study we used MRI to evaluate the effect of antigen and mediators of allergic responses on the nasopharyngeal airway of guinea pigs. METHODS AND RESULTS: Longitudinal relaxation time-weighted transverse images of the nasopharyngeal airway revealed a clearly defined airway lumen and mucosa. Topical administration of ovalbumin (0.00006% to 0.06%) to the nasopharyngeal airway of sensitized guinea pigs caused a concentration-dependent reduction (34% +/- 1%, maximum) in airway luminal volume and a corresponding increase (28% +/- 3%, maximum) in the volume of the airway mucosa. These effects were duplicated by histamine (10(-5) to 10(-3) mol/L), but not by methacholine (10(-3) mol/L). The antigen-induced changes in airway and mucosal volumes were dose-dependently inhibited by the H1-antagonist loratadine (0.3 to 3 mg/kg, administered orally). On the other hand, topical administration of a decongestant drug, oxymetazoline (250 micrograms per guinea pig), had no effect on the response to antigen. CONCLUSIONS: These results indicate that MRI is a useful technique to measure allergic responses in the airways and identify that histamine is an important mediator of the obstruction that occurs in the nasopharyngeal airway of guinea pigs after antigen challenge.

Animals↗
PubMed1993

GABAB receptors in the lung.

gamma-Aminobutyric acid (GABA), an important inhibitory neurotransmitter in the mammalian CNS, is also found in peripheral tissues, including the lung. Recent pharmacological studies using selective ligands for GABAA and GABAB receptors demonstrate that of these two, the GABAB receptor is the important receptor subtype controlling lung functions. GABAB agonists inhibit a variety of responses in the airways, including neuronally induced cholinergic- and tachykinin-mediated smooth muscle contraction, microvascular leakage, anaphylactic bronchospasm and cough. Because these conditions are seen in certain respiratory diseases, such as asthma, a selective GABAB agonist may have therapeutic potential for the treatment of this respiratory disorder.

Anaphylaxis↗
PubMed1993

Dextropropoxyphene induced hepatotoxicity: a report of nine cases.

Nine patients are described with jaundice, upper abdominal pain and malaise attributable to dextropropoxyphene hepatotoxicity. In each case the history was suggestive of large bile duct obstruction. All patients underwent ultrasound examination and percutaneous liver biopsy. Three patients also underwent endoscopic retrograde cholangio pancreatography. The histological features of the biopsies concur with previously reported cases of dextropropoxyphene hepatotoxicity. The histological changes seen on biopsy were remarkably constant, consisting of centrilobular cholestasis, portal tract inflammation and bile duct abnormalities, in all cases mimicking large bile duct obstruction. Fifteen previous patients with probable dextropropoxyphene hepatotoxicity have been described. The occurrence of 9 further cases at one centre, 6 presenting within 12 months, suggests that it is much more common than previously assumed and may be misdiagnosed as large bile duct obstruction.

Adult↗
PubMed1993

Antitussive effects of GABAB agonists in the cat and guinea-pig.

1. GABAB agonists inhibit neuronal processes which are important in the pathogenesis of airway disease, such as bronchospasm. Cough is a prominent symptom of pulmonary disease, but the effects of GABAB agonists on this airway reflex are unknown. Experiments were conducted to determine the antitussive effect of GABAB receptor agonists in comparison to the known antitussive agents, codeine and dextromethorphan. 2. Unanaesthetized guinea-pigs were exposed to aerosols of 0.3 mM capsaicin to elicit coughing, which was detected with a microphone and counted. Cough also was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was recorded from electromyograms of respiratory muscle activity. 3. In guinea-pigs, the GABAB agonists baclofen and 3-aminopropyl-phosphinic acid (3-APPi) produced dose-dependent inhibition of capsaicin-induced cough when administered by subcutaneous or inhaled routes. The potencies of baclofen and 3-APPi compared favourably with codeine and dextromethorphan. 4. The GABAB antagonist, CGP 35348 (0.3- 30 mg kg-1, s.c.) inhibited the antitussive effect of baclofen (3.0 mg kg-1, s.c.). However, CGP 35348 (10 mg kg-1, s.c.) had no effect on the antitussive activity of codeine (30 mg kg-1, s.c.). The antitussive effect of baclofen was not influenced by the GABAA antagonist, bicuculline (3 mg kg-1, s.c.) or naloxone (0.3 mg kg-1, s.c.). 5. In the cat, baclofen (0.3-3.0 mg kg-1, i.v.) decreased mechanically-induced cough in a dose-dependent manner. In this model, baclofen (ED50 = 0.63 mg kg-1) was less potent than either codeine or dextromethorphan. The antitussive effect of baclofen in the cat was antagonized by the GABAB antagonists, CGP 35348 (10 mg kg-1, i.v.) and 3-aminopropylphosphonic acid (3 mg kg-1, i.v.).6. We show that baclofen and 3-APPi have antitussive effects in the guinea-pig and cat and these effects are mediated by GABAB receptors.

Animals↗
PubMed1993

Antineutrophil antibody: a test for autoimmune primary sclerosing cholangitis in childhood?

The detection of an antineutrophil antibody which is highly sensitive and specific for adult primary sclerosing cholangitis using indirect immunoalkaline phosphatase has been previously described. In this study, the diagnostic potential of this method in childhood primary sclerosing cholangitis is described. A range of 72 blinded children's sera (36 boys), aged six months to 21 years (10 primary sclerosing cholangitis, eight autoimmune chronic active hepatitis, 10 alpha-1 antitrypsin deficiency, 12 extrahepatic bile duct atresia, 11 ulcerative colitis and 21 normal subjects) was assayed. Eight of the 10 primary sclerosing cholangitis patients were correctly identified. Three patients with chronic active hepatitis also showed the characteristic primary sclerosing cholangitis pattern of staining. No ulcerative colitis patients or any other patients showed this pattern of staining. All normal subjects were negative. As in adult primary sclerosing cholangitis, there is a specific antineutrophil antibody in childhood primary sclerosing cholangitis and this provides further evidence towards an autoimmune aetiology of this condition. The test may have diagnostic potential.

Adolescent↗