Cyclic AMP-mediated chloride secretion is induced by prostaglandin F2α in human isolated colon

Background and purpose:

Prostaglandin F_2α (PGF_2α) is implicated in the pathogenesis of inflammatory bowel disease and colorectal cancer. This study investigates the effects of PGF_2α on electrophysiological parameters in isolated human colonic mucosa.

Experimental approach:

Ion transport was measured as changes in short-circuit current across human colonic epithelia mounted in Ussing chambers. Colonic crypts were isolated by calcium chelation and cyclic adenosine monophosphate (cAMP) was measured by ELISA.

Key Results:

PGF_2α stimulated chloride secretion in a concentration-dependent manner with an EC₅₀ of 130 nM. The PGF_2α induced increase in chloride secretion was inhibited by AL8810 (10 µM), a specific PGF_2α receptor antagonist. In addition, PGF_2α (1 µM) significantly increased levels of cAMP in isolated colonic crypts.

Conclusions and implications:

PGF_2α stimulated chloride secretion in samples of human colon in vitro through a previously unrecognizd cAMP-mediated mechanism. These findings have implications for inflammatory states.     

BGC20-1531, a novel,potent and selective prostanoid EP4 receptor antagonist: a putative new treatment for migraine headache

Background and purpose:

Prostanoid EP₄ receptor antagonists may have therapeutic utility in the treatment of migraine since EP₄ receptors have been shown to be involved in prostaglandin (PG)E₂-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP₄ receptor antagonist.

Experimental approach:

BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP₄ receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo.

Key results:

BGC20-1531 exhibited high affinity at recombinant human EP₄ receptors expressed in cell lines (pK_B 7.6) and native EP₄ receptors in human cerebral and meningeal artery (pK_B 7.6–7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE₂-induced vasodilatation of human middle cerebral (pK_B 7.8) and meningeal (pK_B 7.6) arteries in vitro, but had no effect on responses induced by PGE₂ on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1–10 mg·kg⁻¹ i.v.) caused a dose-dependent antagonism of the PGE₂-induced increase in canine carotid blood flow in vivo.

Conclusions and implications:

BGC20-1531 is a potent and selective antagonist at EP₄ receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.     

COMBINATION ANTI-PARATUBERCULOSIS THERAPY WITH CLARITHROMYCIN, RIFABUTIN and CLOFAZIMINE IN THE TREATMENT OF CROHN'S DISEASE. A PRELIMINARY REPORT ON THE AUSTRALIAN MULTICENTRE TRIAL

Mycobacterium paratuberculosis has been proposed as the cause of Crohn's disease, although this remains controversial. Observational studies of antibiotics with activity against this organism have led to the establishment of an Australian multicentre placebo-controlled trial of clarithromycin, rifabutin and clofazimine in patients with active Crohn's disease. All subjects receive treatment with a tapering regimen of prednisolone for the initial 16 weeks, combined with either antibiotics or matching placebos. If remission is achieved at the end of this period and prednisolone has been ceased they continue the trial medications for 2 years. The primary outcomes – remission rates at 1, 2 and 3 years – aim to determine whether these antibiotics are of long-term benefit in Crohn's disease. Secondary outcomes include rate of remission at 4 months, safety and quality of life.
As of May 2001, 171 of the required 212 subjects have been enrolled. Eighty-seven of 146 potential subjects have reached 16 weeks in remission (60%). Eighty of these are ongoing (92%). Only five withdrawals from the trial have occurred for adverse events thought probably related to trial medications – four subjects with raised LFTs and one who developed a rash. Other withdrawals have been mainly due to lack of response or worsening of Crohn's disease (37), hypomania from steroids (one patient) and pregnancy (one patient on placebo). There have been 11 withdrawals for protocol violations. An Independent Data Monitoring Committee has analysed progress of the trial and unanimously recommended that it continue.
This study is the largest and longest suitably powered randomised controlled trial of antibiotics undertaken in Crohn's disease. It will determine whether this antibiotic combination alters the natural history of this disorder.
This study is being supported by Pharmacia Australia Pty Limited.     

A supervised land cover classification of a western Kenya lowland endemic for human malaria: associations of land cover with larval Anopheles habitats

Background  

A supervised land cover classification was developed from very high resolution IKONOS satellite data and extensive ground truth sampling of a ca. 10 sq km malaria-endemic lowland in western Kenya. The classification was then applied to an investigation of distribution of larval Anopheles habitats. The hypothesis was that the distribution and abundance of aquatic habitats of larvae of various species of mosquitoes in the genus Anopheles is associated with identifiable landscape features.     

Presentation, acute illness, and learning difficulties in salt wasting 21-hydroxylase deficiency

The presentation, pattern of acute illness, and incidence of learning difficulties are described in 63 (33 boys, 30 girls) children with salt wasting 21-hydroxylase deficiency, drawn from a cohort study of congenital adrenal hyperplasia in the South West Region of England between 1968 and 1988. Thirty boys presented with a salt losing crisis from birth whereas the other three boys presented between 2 and 14 months of age with failure to thrive and hyponatraemia. Diagnostic uncertainty led to 13 (43%) of 30 girls developing a salt losing crisis. Five girls were misassigned as boys at birth. There were four deaths in the group, two due to salt losing crisis, one to complications of prematurity possibly compounded by 21-hydroxylase deficiency, and one from heart failure probably related to an excess of steroids. Acute admissions were common, especially during the first year of life, with convulsions in 7% of admissions. The 9% incidence of hypoglycaemia was considered to be an underestimate as blood glucose was measured in only 56 (22%) of 254 admissions. No convulsions occurred in the 38 (15%) admissions where the parents had given intramuscular hydrocortisone before bringing the child to hospital. A high incidence of learning difficulties was found among the 59 surviving children (9/30 (30%) boys and 6/29 (21%) girls), and in only two children could any factor other than 21-hydroxylase deficiency be invoked. Analysis of the subgroup with learning difficulties indicated that they were more ill at presentation with a significantly higher incidence of hypoglycaemia, and that growth in the first year was significantly worse. It is concluded that congenital adrenal hyperplasia remains a formidable disorder with an appreciable mortality and morbidity. The high incidence of learning difficulties seen in salt wasting 21-hydroxylase deficiency needs further attention. A prospective study is indicated to examine the effect of neonatal screening on morbidity from congenital adrenal hyperplasia, particularly the intellectual impairment seen in this study.     

Travel and changes in routine do not increase the risk of sudden infant death syndrome

We investigated the relationship between travel and changes in routine and the sudden infant death syndrome (SIDS) among 485 SIDS cases compared with 1800 randomly selected control infants. There was no increased risk of SIDS with travel. Special events, such as christenings, were not associated with an increased risk of SIDS. However, visits to and by friends or relatives were associated with a significantly reduced risk of SIDS after controlling for potential confounders (odds ratios = 0.70; 95% confidence interval = 0.52, 0.96). These findings may indicate less social support in SIDS cases.