piperidines and octylonium

This review introduces the principles of visceral sensation and appraises the current approaches to management of visceral pain in functional GI diseases, principally IBS. These approaches include dietary measures including fibre supplementation, low fermentable oligosaccharides, disaccharides, monosaccharides and polyols diet, and pharmacological approaches such as antispasmodics, peppermint oil, antidepressants (tricyclic agents, selective serotonin reuptake inhibitors), 5-HT

Topics: Abdominal Pain; Anti-Infective Agents; Antidepressive Agents; Butyrophenones; Dipeptides; GABA Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Imidazoles; Irritable Bowel Syndrome; Mentha piperita; Parasympatholytics; Phenylalanine; Piperidines; Plant Oils; Probiotics; Quaternary Ammonium Compounds; Rifamycins; Rifaximin; Serotonin 5-HT3 Receptor Antagonists; Thiophenes; Visceral Pain

Lubeluzole, a neuroprotective anti-ischemic drug, was tested for its ability to act as both antibiotic chemosensitizing and antipropulsive agent for the treatment of infectious diarrhea.. In the present report, the effect of lubeluzole against antidiarrheal target was tested. The antimicrobial activity towards Gram-positive and Gram-negative bacteria was investigated together with its ability to affect ileum and colon contractility.. Concerning the antimicrobial activity, lubeluzole showed synergistic effects when used in combination with minocycline against four common Gram-positive and Gram-negative bacteria (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 29213, Pseudomonas aeruginosa ATCC 27853, and Escherichia coli ATCC 25922), although relatively high doses of lubeluzole were required. In ex vivo experiments on sections of gut smooth muscles, lubeluzole reduced the intestinal contractility in a dose-dependent manner, with greater effects observed on colon than on ileum, and being more potent than reference compounds otilonium bromide and loperamide.. All above results identify lubeluzole as a possible starting compound for the development of a novel class of antibacterial adjuvants endowed with spasmolytic activity.

Topics: Animals; Anti-Bacterial Agents; Antidiarrheals; Bacteria; Colon; Diarrhea; Dose-Response Relationship, Drug; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Guinea Pigs; Ileum; Loperamide; Male; Microbial Sensitivity Tests; Muscle Contraction; Neuroprotective Agents; Piperidines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Thiazoles

The pharmacological properties of otilonium bromide (OB) have been investigated using different experimental models, techniques, and conditions, and consequently, the results are not always easy to compare. The aim of the present work was to investigate the pharmacological properties of OB in human cultured colonic smooth muscle cells (HCSMCs), which is the main target of the drug 'in vivo'. Rat colonic strips were used to confirm the pharmacological properties.. Human cultured colonic smooth muscle cells were studied using the calcium imaging technique. Microelectrodes and muscle bath experiments were performed in rat colonic strips.. Otilonium bromide (OB) concentration dependently inhibited nifedipine-sensitive calcium transients induced by KCl (EC50  = 3.6 μM) and BayK8644 (EC50  = 4.0 μM). All the following experiments were performed in the presence of nifedipine. In HCSMC, carbachol-induced calcium transients were inhibited by OB (EC50  = 8.4 μM). Carbachol evoked 1-a smooth muscle depolarization (10 mV) that was antagonized by 100 μM OB; and 2-a contraction that was inhibited by OB (EC50  = 13.0 μM). 'Non-nitrergic (L-NNA 1 mM) non-purinergic (MRS2500 1 μM)' conditions were used to elicit endogenous excitatory responses. Electrical field stimulation caused 1-an atropine-sensitive excitatory junction potential that was inhibited by OB (EC50  = 8.9 μM) and 2-an atropine-sensitive contraction that was inhibited by OB (EC50  = 7.3 μM). In HCSMC, neurokinin A (NKA) and CaCl2 induced calcium transients that were inhibited by OB (NKA: EC50  = 11.7 μM; CaCl2 : EC50  = 17.5 μM).. Otilonium bromide causes inhibition of L-/T-type calcium channels, muscarinic, and tachykininergic responses that acting together explain the pharmacological properties of the compound.

Topics: Animals; Calcium Channel Blockers; Cells, Cultured; Colon; Humans; Indoles; Male; Muscarinic Antagonists; Myocytes, Smooth Muscle; Piperidines; Quaternary Ammonium Compounds; Rats; Rats, Sprague-Dawley; Receptors, Tachykinin

1. Otilonium bromide (OB) is a smooth muscle relaxant used in the treatment of irritable bowel syndrome. Otilonium bromide has been shown to interfere with the mobilization of calcium in intestinal smooth muscle, but the effects on other intestinal tissues have not been investigated. We identified the muscarinic receptor subtype coupled to calcium signals in colonic crypt derived from the human colonic epithelium and evaluated the inhibitory effects of OB. 2. Calcium signals were monitored by fluorescence imaging of isolated human colonic crypts and Chinese hamster ovary cells stably expressing the cloned human muscarinic M(3) receptor subtype (CHO-M(3)). Colonic crypt receptor expression was investigated by pharmacological and immunohistochemical techniques. 3. The secretagogue acetylcholine (ACh) stimulated calcium mobilization from intracellular calcium stores at the base of human colonic crypts with an EC(50) of 14 micro M. The muscarinic receptor antagonists 4-DAMP, AF-DX 384, pirenzepine and methroctamine inhibited the ACh-induced calcium signal with the following respective IC(50) (pK(b)) values: 0.78 nM (9.1), 69 nM (7.2), 128 nM (7.1), and 2510 nM (5.8). 4. Immunohistochemical analyses of muscarinic receptor expression demonstrated the presence of M(3) receptor subtype expression at the crypt-base. 5. Otilonium bromide inhibited the generation of ACh-induced calcium signals in a dose dependent manner (IC(50)=880 nM). 6. In CHO-M(3) cells, OB inhibited calcium signals induced by ACh, but not ATP. In addition, OB did not inhibit histamine-induced colonic crypt calcium signals. 7. The present studies have demonstrated that OB inhibited M(3) receptor-coupled calcium signals in human colonic crypts and CHO-M(3) cells, but not those induced by stimulation of other endogenous receptor types. We propose that the M(3) receptor-coupled calcium signalling pathway is directly targeted by OB at the level of the colonic epithelium, suggestive of an anti-secretory action in IBS patients suffering with diarrhoea.

Topics: Acetylcholine; Animals; Atropine; Calcium; Calcium Signaling; CHO Cells; Colon; Cricetinae; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Muscarinic Antagonists; Parasympatholytics; Piperidines; Pirenzepine; Quaternary Ammonium Compounds; Receptor, Muscarinic M3; Receptors, Muscarinic; Time Factors; Vasodilator Agents