LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK.

The respiratory system is directly exposed to low levels of lipopolysaccharide (LPS), present as a contaminant on airborne particles. In cystic fibrosis, the prevailing data identify structural changes of the airway epithelium, as well as tight junction dilatation. This study was aimed at determining the contribution of myosin light chain kinase to maintaining airway epithelium barrier integrity in the lung inflammatory response to LPS in rats. The effects of the selective myosin light chain kinase inhibitor, 5-iodonaphthalene-1-sulphonyl-homopiperazine (ML-7), were evaluated: 1) on pulmonary inflammation and airway epithelium barrier permeability alterations induced by intra-tracheal LPS from Pseudomonas aeruginosa; and 2) on levels of the phosphorylated form of the myosin light chain, which is increased in a human airway epithelial cell line (NCI-H292) and tracheal tissue after LPS exposure. The results show that LPS increased airway epithelium barrier paracellular permeability and lung inflammation, and that pre-treatment with ML-7 inhibited both effects. This effect of ML-7 was associated with the inhibition of phosphorylated myosin light chain in both NCI-H292 cells and tracheal tissue. The data, obtained using in vivo and in vitro approaches, demonstrate a key role for myosin light chain kinase in lung inflammation, and suggest that myosin light chain kinase could be a potential target for novel drugs intended for relief of lung injury.

Antidiarrhoeal properties of a novel sigma ligand (JO 2871) on toxigenic diarrhoea in mice: mechanisms of action.

BACKGROUND AND AIMS: Sigma ligands display antisecretory activity against various secretagogues, suggesting antidiarrhoeal properties. In this study, we evaluated: (i) the antidiarrhoeal effect of JO 2871, a high affinity sigma ligand, in three models of toxigenic diarrhoea in mice; and (ii) the site and mechanism of action of this compound. METHODS: Faeces were collected after toxin or vehicle administration in male DBA2 or NMRI mice. Diarrhoea was determined by cumulative stool weight (mg) over a 120 minute period. Diarrhoea was induced by intravenous administration of Salmonella enteriditis lipopolysaccharide (LPS), or oral administration of Escherichia coli heat stable (E coli-sta) or Clostridium difficile toxins. Two sigma ligands, igmesine and JO 2871, were administered either orally or intravenously, 60 and 30 minutes before the toxins, respectively. JO 2871 was also given orally 30 minutes after E coli-sta. In addition, JO 2871 was administered intracerebroventricularly five minutes before LPS and E coli-sta. BMY 14802 (1000 microg/kg orally), a sigma receptor antagonist, or cyclosomatostatin (CSS 1 microg/kg intravenously), a somatostatin antagonist, were given five minutes prior to JO 2871 in LPS, E coli-sta, and C difficile toxin treated mice. Gastric emptying and intestinal transit were evaluated after oral JO 2871 and BMY 14802 and intravenous CSS. RESULTS: Stool weight measured 120 minutes after administration of the toxins was significantly increased. Oral JO 2871 and igmesine dose dependently inhibited toxigenic diarrhoea in all models. ED(50) values obtained using JO 2871 (1-20 microg/kg) were more than 40 times lower than those obtained with igmesine. Oral JO 2871 given after E coli-sta also inhibited diarrhoea in a dose dependent manner (ED(50) 50 microg/kg). Both sigma ligands were active by the intravenous route on LPS and E coli-sta induced stool weight increases. JO 2871 administered intracerebroventricularly failed to block this effect at any dose tested. Both BMY 14802 and CSS reversed the antidiarrhoeal effect of oral JO 2871. JO 2871, BMY 14802, and CSS did not affect transit parameters. CONCLUSIONS: JO 2871 exerts a potent oral antidiarrhoeal effect, acting peripherally through sigma sites and somatostatin release.

Antinociceptive effect of pregabalin in septic shock-induced rectal hypersensitivity in rats.

Pregabalin [S-(+)-3-isobutylgaba] is a novel compound under development for its analgesic, anxiolytic, and anticonvulsant properties, and its interaction with the alpha(2)delta-subunit of voltage-dependent Ca(2+) channels. In this study, we investigate the antinociceptive activity of pregabalin in a rat model of delayed visceral hyperalgesia induced by i.p. lipopolysaccharide (LPS) administration. LPS (Escherichia coli, serotype O111:B4) leads to a delayed lowering threshold (9-12 h) of abdominal contractions in response to rectal distension (RD) in awake rats surgically prepared for electromyography of abdominal muscles. This allodynic effect of LPS was blocked by morphine (0.3 mg/kg s.c.), and the action of morphine was antagonized by naloxone (2.5 mg/kg s.c.). A single i.p. (10, 30 mg/kg) and oral (1, 3, 10 and 30 mg/kg) treatment of pregabalin dose dependently suppressed LPS-induced rectal hypersensitivity. When administered 2 h before RD (but preceded 12 h by LPS injection), the oral dose of 10 mg/kg was effective both in the allodynic response induced by LPS and in the intensity of the nociceptive response related to RD. Pretreatment by either naloxone or bicuculline (a GABA(A) antagonist, 0.5 mg/kg i.p.) did not affect the antiallodynic effect of pregabalin. We conclude that pregabalin is a therapeutic candidate in the treatment of gut hypersensitivity not acting through GABA(A) and opiate receptors.

Gastrointestinal functional bowel disorders: new therapies.

Present therapies for functional gastrointestinal disorders are symptomatic and mainly treat altered bowel habits. New therapies are focused on nerve-gut communication dysfunction: 5-HT3 antagonists and 5-HT4 agonists have demonstrated activity in clinical trials. Promising targets for upper gut dysmotility drugs are motilin and cholecystokinin A receptors. Tachykinins, calcitonin gene-related peptide or glutamate antagonists are the most relevant candidates for visceral pain.

[Mass treatment of onchocerciasis in 1996]. / Le traitement de masse de l'onchocercose en 1996.

Mass treatment of onchocerciasis has changed radically in the last 20 years. With implementation of the Onchocerciasis Control Programme (OCP), use of insecticides to control vector larvae has been effective but has not been extended to all infected areas due to the cost. The consequences of this problem have been lessened thanks to ivermectin, an effective drug that can be administered in a single yearly dose. Although ivermectin does not appear to induce major side-effects, surveillance is necessary after administration in polyparasitized subjects living in zones where loaiasis is present and in hypermicrofilaremic subjects. To assist in the fight against onchocerciasis, ivermectin is distributed free of charge through the Mectizan Foundation by Merck Laboratories. Inexpensive community distribution programs with active participation of the populations at risk have demonstrated their usefulness. The results of mass treatment through the Mectizan Foundation have been excellent. Non-governmental organizations and in particular the Organization for the Prevention of Blindness (OPB) have become increasingly involved in the fight against onchocerciasis. The campaign conducted by the OPB in Mali, Senegal and Guinea illustrate this involvement. The role of non-governmental organizations expanded greatly with the implementation of the APOC programme supported by the World Bank.

Neuropeptide Y and sigma receptor agonists act through a common pathway to stimulate duodenal alkaline secretion in rats.

Neuropeptide Y (NPY) has been shown to mimic the effects of some sigma receptor agonists in the brain and to possess the same proabsorptive effect as these agonists in the isolated mouse jejunum. The aim of present study was to investigate the effect of NPY on duodenal alkaline secretion in the rat and to define its mode of action. NPY (0.01 to 3 micrograms/kg i.v.) induced a dose-related increase in duodenal bicarbonate secretion, the maximal effect being obtained at 1 micrograms/kg. This response was significantly inhibited by the i.v. administration of haloperidol, BMY 14802, devazepide, hexamethonium, tetrodotoxin and by bilateral truncal vagotomy, but not by SCH 23390, sulpiride, prazosin or atropine, whereas i.c.v. devazepide had no effect. This pharmacological profile is identical to that reported for sigma receptor agonists. The results suggest that NPY and sigma ligands act through a common pathway to stimulate duodenal alkaline secretion in the rat.

Effects of a new sigma ligand, JO 1784, on cysteamine ulcers and duodenal alkaline secretion in rats.

BACKGROUND: The ulceroprotective effects of JO 1784 [(+)-N-cyclopropyl-methyl-N-methyl-1,4-diphenyl-1-ethyl-but-3-en-1-yl amine, hydrochloride], a new specific and highly selective sigma ligand, were examined in rats. METHODS: Different models of gastric ulcers (4-hour restraint stress, aspirin, ethanol, and taurocholate) and cysteamine-induced duodenal ulcers were used. The gastric acid secretion (4-hour Shay rat preparation) and the duodenal bicarbonate secretion were also studied. RESULTS: JO 1784 elicited a potent protection against duodenal ulcers but had a weaker protective effect on any of the gastric ulceration models tested. It displayed no gastric antisecretory activity but induced a dose-dependent stimulation of duodenal bicarbonate secretion. Haloperidol, hexamethonium, tetrodotoxin, bivagotomy (but not atropine), and the intravenous but not intracerebroventricular administration of devazepide, a cholecystokinin A antagonist, inhibited the stimulatory effect of JO 1784. CONCLUSION: These results show that JO 1784, a selective sigma ligand, is a potent protector of the duodenal mucosa. This activity may be related to its stimulating effect on bicarbonate secretion, which is driven through a complex nervous mechanism involving muscarinic synapses, vagal afferent fibers, and peripheral cholecystokinin receptors. This drug might open a new specific way in the treatment of duodenal ulcers.

Central and peripheral effects of prostaglandin E2 and enprostil on gastric acid secretion in the rat.

The intracerebroventricular (i.c.v.) administration of prostaglandin E2 (PGE2) inhibits gastric secretion at doses that are inactive by i.v. administration in the rat. The present study was undertaken to examine the central and peripheral effects of enprostil, a potent synthetic PGE2 analogue, on gastric acid secretion as compared to those of PGE2. We used conscious rats equipped with a chronic gastric fistula and a cannula to allow injection into the third ventricle of the brain. Gastric acid output was measured under basal interdigestive conditions and during stimulation with submaximal doses of pentagastrin and histamine. Total inhibition of basal and stimulated gastric acid output was obtained after i.c.v. PGE2 and after i.c.v. or i.v. enprostil administration. After i.v. PGE2, the maximal observed inhibition was not greater than 50%. The ratio of ED50 values for i.v. administered to i.c.v. administered PGE2 was 64 or more, whereas the ratio of ED50 values for i.v. enprostil to i.c.v. enprostil was 9 to 13. Under all conditions studied, enprostil was more potent than PGE2 and this greater potency was more prominent after i.v. administration (ratio 250 to 2500) than after i.c.v. administration (ratio 10 to 400). The blockade of alpha 2-adrenoceptors by idazoxan did not suppress the inhibition of gastric secretion produced by i.c.v. PGE2 or enprostil. It is concluded that low doses of PGE2 inhibit gastric acid output mainly through a central mechanism, whereas low doses of enprostil potently inhibit gastric acid output through both a central and a peripheral mechanism. alpha 2-Adrenoceptors are not essential for the effect of i.c.v. prostanoids on gastric acid secretion.

[Ambulatory surgery of cataracts in Eastern Senegal]. / La chirurgie ambulatoire de la cataracte au Sénégal Oriental.

The epidemiologic data and surgical results of 253 cataract extractions performed in a new department of Ophthalmology in Eastern Senegal were reviewed. 87 per cent have been operated without hospitalization, with restricted follow up. The complication rate was low, showing that this kind of surgery was suitable to local socio-economical conditions.

[Substance P: a peripheral inhibitor of gastric acid secretion in the rat]. / La substance P: un inhibiteur periphérique de la sécrétion gastrique acide chez le rat.

The inhibition of some peptidases in the central nervous system induces a decrease in gastric acid secretion. The present experiments indicate that substance P is not likely a candidate to mediate this effect in rats. Substance P, indeed, potently inhibits gastric acid secretion, but this effect appears mainly peripheral.

Central and peripheral effects of prostaglandin E2 and enprostil on exocrine pancreatic secretion in rats.

Prostaglandin E2 (PGE2) has been reported to exert some centrally mediated effects on intestinal motility and secretion and on gastric secretion, but it is not known whether such central effects exist on pancreatic secretion. The central and peripheral effects of PGE2 and enprostil, a long-acting, potent PGE2 analogue, were studied in conscious and anesthetized rats fitted with pancreatic fistulae. In chronically implanted, conscious rats, PGE2 inhibited the secretion of fluid, bicarbonate, and total protein in the pancreatic juice, both after i.v. or intracerebroventricular (icv) injections. The maximal inhibition was similar after both injection procedures (about 45% for fluid and bicarbonate and 60% for protein), but the potency of PGE2 was three to 10 times greater by the icv than the i.v. route. Enprostil also inhibited pancreatic secretion in a dose-related way. The maximal inhibition was larger than after PGE2 injection (about 70% for fluid and bicarbonate and 90% for protein). The potency of enprostil was five to 10 times lower by the icv than by the i.v. route. The diversion of gastric secretion suppressed the effect of icv PGE2 on fluid and bicarbonate output but not on protein and did not change the effect of enprostil on all the variables of pancreatic secretion. Adrenergic antagonists did not suppress the effect of icv PGE2 or enprostil on pancreatic secretion. In anesthetized rats, i.v. PGE2 inhibited hormone-stimulated protein secretion but did not change fluid and bicarbonate output, while i.v. enprostil inhibited cholecystokinin-stimulated fluid, bicarbonate, and protein output in the pancreatic juice.(ABSTRACT TRUNCATED AT 250 WORDS)

Thiorphan and acetorphan inhibit gastric secretion by a central, non-opioid mechanism in the rat.

Thiorphan and its prodrug, acetorphan, are two inhibitors of enkephalinase (EC 3.4.24.11), a membrane-bound peptidase which plays an important role in the metabolic degradation of enkephalins. Since exogenous opioids have been reported to both stimulate and inhibit gastric secretion, the effects of thiorphan and acetorphan were studied in conscious rats equipped with chronic gastric fistulas. While i.v. thiorphan had no effect, both i.c.v. thiorphan and i.v. acetorphan potently inhibited the basal gastric acid output and the acid output stimulated by pentagastrin. Conversely, neither drug affected the histamine- or methacholine-induced stimulation of acid secretion. Neither thiorphan or acetorphan had any effect on the acid secretion stimulated by a combination of pentagastrin and acetylcholine in vagotomized rats. The results strongly suggest that both drugs inhibit gastric secretion through an effect at the level of the central nervous system, which decreases the vagal drive to the stomach. However, the effects of thiorphan and acetorphan were not prevented by naloxone. This is at variance with most of the effects of these drugs reported to date, including the inhibition of gastric secretion in cats. Furthermore, these effects were observed at doses which could inhibit other enzymes apart from enkephalinase. This suggests that the antisecretory action in rats is related to the protection of some non-opioid peptide(s) from degradation. In conclusion, both peptidase inhibitors inhibit gastric secretion of the rat through a central mechanism involving unknown, non-opioid peptide(s).

Acetorphan, an enkephalinase inhibitor, decreases gastric secretion in cats.

Acetorphan is an inhibitor of "enkephalinase" (EC 3.4.24.11) which has been shown to reduce in vivo and in vitro the degradation of enkephalins and other peptides. The effects of acetorphan on gastric secretion were studied in cats fitted with gastric fistulae and Heidenhain pouches. Acetorphan inhibited by 40-60% the acid secretion from the gastric fistulae after stimulation by submaximal doses of pentagastrin, histamine and 2 deoxy-D-glucose. These inhibitions were reduced or suppressed by naloxone. The meal-stimulated secretion from the fistulae was not changed after acetorphan. Acetorphan slightly and progressively reduced the pentagastrin-stimulated acid output from the Heidenhain pouches, and this effect was naloxone resistant. No change was found in the secretion from Heidenhain pouches under histamine stimulation, while meal-induced secretion of the pouches was increased by acetorphan, and this increase was not prevented by naloxone. Endogenous opioids probably exert an inhibitory regulatory control upon the gastric secretion of cats. In addition, non-opioid factors may be involved in the effect of acetorphan on meal-stimulated secretion.

[Orbital and ocular tumors in the Republic of Mali]. / Les tumeurs orbito-oculaires en République du Mali.

Analysing 82 cases of oculo-orbital tumours in Malian patients, the authors find the classical features characterizing ocular carcinoma in Africa, i.e. early arising, development, late request for treatment. They stress on the age of the patients at the occasion of the first request for treatment in case of retinoblastoma, and notice the special frequency of squamous cell carcinoma with conjunctival or limbic localization.

Growth-hormone releasing factor does not antagonize somatostatin effects on pancreatic and gastric secretions.

The effect of human GRF 44 upon somatostatin-inhibited pancreatic and gastric secretions was studied in rats with chronic fistulas. GRF did not show any antagonist action of somatostatin on these gastro-intestinal organs. GRF alone had a small inhibitory effect on gastric acid output.

[Central inhibition of external pancreatic secretion by D-ala-2-metenkephalinamide in rats]. / Inhibition centrale de la sécrétion pancréatique externe par le D-ala-2-metenképhalinamide chez le rat.

Intracerebroventricular injections of D-Ala-2-Metenkephalinamide (D Alamide), a slowly metabolized Metenkephalin analogue, were made to conscious rats equipped with a chronic pancreatic fistula allowing the collection of pure pancreatic juice in its entirety. D Alamide induced a dose-related decrease in the volume of basal pancreatic secretion, as well as of bicarbonate and protein outputs. The effective doses of D Alamide were of the same order of magnitude as those necessary to induce analgesia or to decrease intestinal transit time in rats, as reported by others. The effect of D Alamide was totally blocked by naloxone, an opiate antagonist known to easily traverse the blood-brain barrier, while no blockade was found with naloxone methyl-bromide, an opiate antagonist which traverses the blood-brain barrier poorly and thus acts only peripherally. These results strongly suggest that the inhibition of pancreatic secretion induced by D Alamide is a central effect.