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Discussion Starter · #1 · EPHAR '99 - Second European Congress of Pharmacology(Part III)3-7 July 1999, Budapest, HungaryReported by Charlotte Worker, Current Drugs Ltd, London, UKAmongst other topics covered on the third day of the EPHAR meeting, a symposium was dedicated to the discussion of new trends in gastrointestinal pharmacology. This included a detailed review in the use of COX-2 inhibitors and growth factors as GI-safer therapeutics for the treatment of ulceration and other GI complications. In another session, the pharmacology and biology of serotonin receptors was discussed, highlighting the advances made in the discovery of receptor subtypes and their putative function. A particularly interesting and well-presented symposia was scheduled in the afternoon program, detailing the use of amiodarone-like agents in the treatment of cardiac arrhythmias; this session was sponsored by Sanofi-Synthelabo, with many presentations in this session given by representatives from the company. Serotonin receptors in neuropsychopharmacologySerotonergic CNS drugs, which act on serotonin (5-HT) and dopamine receptors, have been of great interest recently. Many publications point to the potential for 5-HT receptor antagonists in the treatment of migraine, depression and anxiety, amongst other indications. D Hoyer (Novartis Pharma AG, Basel, Switzerland) outlined the molecular pharmacology and biology of 5-HT receptors. There are seven classes of receptor characterized to date, with most classes having subtypes (1A, 1B, 1D, 1e, 1f, 2A, 2B, 2C, 3, 4, 5A, 5B, 6 and 7). The characterization of 5-HT receptors is based on: the structure of the protein; operational information (ie the ligand affinity); and, transductional function. All 5-HT receptors are G-protein coupled receptors, except 5-HT3 receptors, which form ligand-gated ion channels. 5-HT1 inhibits adenylyl cyclase, whilst 5-HT4, 6 and 7 are all known to stimulate adenylyl cyclase. 5-HT2 receptors activate phospholipase C and the transductional features of 5-HT5 receptors have yet to be established. Various compounds are selective for different receptors; SB-203186 (SmithKline Beecham plc) and SDZ-216-454 (Novartis AG) are 5HT4 antagonists and agonists, respectively, whilst WAY-100635 (Wyeth-Ayerst Pharmaceuticals Inc) antagonizes the 5-HT1a receptor. The distribution of receptor subtypes and splice variants was also discussed.Gastrointestinal (GI) pharmacologyS Szabo (University of California Irvine, CA, USA) gave a presentation on angiogenesis and growth factors as new targets in GI pharmacology. Ulceration in the GI tract can be caused by etiologic agents, the bacterium H Pylori, ethanol, stress and through the use of NSAIDs. The formation of ulcers can occur quite easily, it is the poor healing of ulcers that is often the premise for therapeutic intervention. Angiogenesis and vasculogenesis play an important regenerative role in ulcerated tissue or after smooth muscle damage. VEGF and other growth factors (bFGF, PDGF and EGF) stimulate ulcer healing through their angiogenic effects; one single dose of VEGF is enough to instigate ulcer healing in animals through gastric specific generation of vascular permeability. In light of this, and the fact that VEGF, bFGF and PDGF are now all implicated in inflammatory bowel disease, these growth factors have become a target in gastroprotection.K Rainsford (Sheffield Hallam University, Sheffield, UK) outlined the recent developments in the search for GI-safer drugs. Selective COX-2 inhibitors have been a focus of drug development, with the drug celecoxib (GD Searle & Co) reaching the market at the beginning of 1999. Some safety issues have been raised about this drug and COX-2 inhibitors in general, after reports of GI bleeding in some patients taking celecoxib. However, COX-2 inhibitors showing no cross-reactivity with COX-1 (which is involved in prostaglandin formation and mucosal protection), have proved efficacious in ulcer healing. Combined COX-1/2 inhibitors, such as ibuprofen, have generated interest through their low GI toxicity. A study, using a porcine mucosal culture system to demonstrate competition between ibuprofen enantiomers, showed that the R(-)- form of the drug was able to prevent the S(+)- form from inhibiting prostaglandin production in the stomach; this competition could be important in other enantomeric NSAIDs.Other developments with GI-safer drugs have included the less ulcerogenic NO-donating NSAIDs and the 'masked' NSAIDs, which are encapsulated to avoid direct interaction with mucosal cells. All of these advances, along with the COX inhibitors, have furthered the understanding concerning the precise mode of action of the NSAIDs.F Halter (West Los Angeles Veterans Affairs Medical Center, Los Angeles, CA, USA) presented data, generated in his group, using an in vitro ulcer model to investigate whether hepatocyte growth factor (HGF)-enhanced cell migration is associated with COX-2 activation. In experimental models of ulcer healing, HGF has been shown to increase the rate of healing through an upregulation of epithelial cell proliferation and cell migration. Cross-talk between HGF and COX-1/2 has previously been established; these studies confirmed that COX-2 inhibitors and, to a greater extent combined COX-1/2 inhibitors, interfered with the HGF-promoted increase in wound healing.Amiodarone-like agents in cardiac arrhythmiasThree amiodarone-like drugs, at different stages of development, were discussed in this session. P Gautier (Sanofi Recherche SA, Gentilly, France) talked of the pharmacology of dronedarone (Sanofi-Synthelabo), a non-iodinated benzofuran derivative, showing particular promise in clinical studies. This multichannel blocker, currently in phase II trials for the treatment of heart arrhythmia, displayed a similar antiarrhythmic efficacy to amiodarone. However, dronedarone, administered at 1 to 10 mg/kg doses in a canine model, was shown to have different pharmacokinetics to amiodarone, conferring an improved side-effect profile.E-047/1 (Ebewe Arzneimittel Ges mbH) was discussed by M Maryleitner (Ebewe Arzneimittel Ges mbH, Unterach, Austria). Like dronedarone, E-047/1 also displays a more favorable pharmacokinetic profile than amiodarone. In a guinea pig model of ventricular fibrillation, it is able to block the delayed rectifier potassium current, and rapidly blocks the sodium channel and, to a lesser extent, the calcium channel. In dogs, E-047/1 is also able to dose-dependently terminate, and prevent the reinduction of, atrial fibrillation. The drug has been tested in a phase II trial in patients after cardiac surgery, to evaluate the efficacy of the drug, its safety and tolerability and also to determine the incidence of primary ventricular arrhythmias in patients. After administration of a 2 mg/kg bolus dose of the drug, E-047/1 was shown to have a 55% efficacy 15 minutes after administration. No side effects were observed and the drug was shown to have no proarrhythmogenic potential. The half-life of E-047/1 was 6 to 8 hours, increasing its potential as an antiarrhythmic therapeutic. Dr Maryleitner also commented that this drug is available for licensing.A description of the pharmacology of GYKI-16638 (Egis Gyogyszergyar RT), another amiodarone-like compound with therapeutical potential, was presented by P M�tyus (Albert Szent-Gy�rgyi Medical University, Szeged, Hungary). GYKI-16638 was generated from a series of compounds with both class Ib and class III antiarrythmic structural features, using the DISCO technique, which matches the distance between chemical groups. The series of compounds was synthesized with the intention of avoiding the non-cardiac side effects of amiodarone. GYKI-16638 has been shown to lessen the action potential duration in dog ventricular muscle and to abolish early afterdepolarization in dog cardiac purkinje tissue. It has no effect on slow delayed rectifier potassium current and has shown high in vivo antiarrythmic activity in rabbits. In human ventricular muscle, GYKI-16638 displays class III antiarrythmic characteristics, lengthens the action potential duration, has good bioavailability and has shown no significant side effects on blood pressure or cardiovascular parameters. Along with the fact that the drug has given favorable results in an acute toxicity study, it has become an attractive antiarrythmic drug candidate. During the 'question and answer' session, GYKI-16638 was also described as having an indirect but insignificant calcium channel blocking activity as well as on significant b -blocking action.Peptide receptor agonists and antagonistsG Varga (Semmelweis University, Budapest, Hungary) opened this session with an overview of peptide receptor agonists and antagonists. He outlined the history of the discovery of the regulatory peptides, originally in the gastrointestinal tract, and went on to describe the changes in their application, from research tools to established drugs.Regulatory peptides, a particularly 'hot topic' in pharmaceutical research today, were originally thought to be hormones produced by specialized epithelial endocrine cells. However, four additional types of cells have been shown to release regulatory peptides: neurons, releasing neurotransmitters, such as substance P; autocrine cells, releasing agents with autocrine function; paracrine agent-releasing paracrine cells; and, factors released by spermocrine cells. Hence, regulatory peptides have been shown to be involved in the coordination of a wide range of regulatory processes, including digestion, food intake and acute systemic effects to local control of growth and differentiation. This understanding has led to a drive for the development of peptide agonists and antagonists.Compounds originally used in laboratory research were needed, in large quantities and in a pure form, to induce the physiological and pharmacological effects of the regulatory peptides, in vitro and in vivo. It was discovered that most of the regulatory peptides have more than one receptor subtype, therefore highly selective compounds needed to be developed which would act specifically on a receptor subtype or state. In addition, the biological half-life of the compounds, already used as research tools, needed to be extended in order to potentiate sustained drug action.Many regulatory peptides fall under the category of cholecystokinin (CCK) and CCK-like peptides. The identification of a high and low affinity CCK-A receptor in rat, led to the observation that antagonism and agonism of the receptor caused effects in many different target tisues. A selective CCK-A antagonist, devazepide (Merck & Co Inc) and a monoclonal antibody against CCK-A were used to examine the mechanism of this receptor and the regulation of enzyme secretion and food intake in rats. It was found that the amylase response was decreased on food intake when the antagonist/antibody were introduced, suggesting that endogenous CCK stimulates enzyme secretion by an endocrine mechanism. Other peptides have diverse roles in various tissues: bombesin-like regulatory peptides have been implicated in human cancers and gastrin-releasing peptide (GRP) receptors have been characterised in a pancreatic adenocarcinoma cell line. In addition, data suggests that HPAF cells highly express GRP-preferring bombesin receptors and that occupation of the receptor leads to a sequence of intracellular events.The peptide agonists and antagonists have proved useful as diagnostic and now therapeutic tools. Their applications in radioimmune assays has led to the facilitation in the diagnosis of gut disorders and some cancers. As therapeutics: motilin and tachykinins have proved useful; CCK antagonists are efficacious in the treatment of intestinal motility and gall bladder function; and, somatostatin agonists have been used to treat various different syndromes. However, the therapeutic value of these compounds is limited by the fact that knowledge is still limited on the function of peptides and that most peptides need to act in synergy with each other. In addition, many of the regulatory peptides have a fine-tuning role on the effect of other nonpeptide mediators, which could mean that undesirable knock-on effects with agonists/antagonists may outweigh the therapeutic advantages.D Hoyer (Novartis Pharma AG, Basel, Switzerland) spoke about the somatostatin (SRIF/somatropin release inhibiting factor) analogs and the pharmacological basis for their clinical use. SRIF is widely distributed and may have effects in many disease indications. Cortistatin, the product of a different gene, is very similar to SRIF in that they appear to share the same receptor, are both able to inhibit forskolin-stimulated adenylate cyclase and they can both moduate GTPg S binding by SRIF receptors. Simulation of the SRIF receptor appears to affect many pathways, but the main clinical effect of SRIF agonists, such as octreotide (Novartis AG), is as an antiproliferative. This is supported by the observation that SRIF can have growth inhibiting effects on a number of tumors expressing high levels of SRIF receptor. Labelled SRIF agonists have also been developed as imaging agents eg OctreoScan (NeXstar Pharmaceuticals Inc), which is used to detect tumors. It is hoped that SRIF agonists may prove useful as radiotherapeutic ligands in cancer therapy, although they are also showing promise as therapeutics for agromegaly, GI disorders, and neuroendocrine and gastroenteropancreatic tumors.C Scarpignato (University of Parma, Italy) presented an overview of the CCK antagonists. CCK and gastrin belong to the same family of regulatory peptides. Their distribution is similar and there is significant crossover between the CCK-B receptor and the gastrin receptor. However, these mediators are rleased by different cells and their physiological actions are very different. CCK binds to at least two different receptors: CCK-A and CCK-B. CCK-A is confined to discreet regions of the brain and probably modulates the actions of CCK in the CNS. CCK-B is also found in the brain, but is also abundant in the GI system. Ten classes of CCK antagonists, and hundreds of compounds, have been described. These include the CCK-A antagonists PD-140548 (Parke-Davis & Co) and SR-27897 (lintitript; Sanofi-Synthelabo), and CCK-B antagonists, LY-262691 (Eli Lilly & Co), L-365260 (Merck & Co Inc) and YM-022 (Yamanouchi Pharmaceutical Co Ltd). CCK-A antagonists include loxiglumide, dexloxiglumide and CR-2194 (all Rotta Research Lab SpA), and devazepide (Merck & Co Inc).CCK has a broad spectrum of mainly inhibitory physiological activities on the digestive system, including pancreatic and gastric secretion, GI motility, hormone release and food intake. Following animal studies showing that CCK-A antagonists could inhibit the effect of the endogenous peptide, these antagonists entered development as prokinetics for the treatment of GERD, bowel disorders (eg IBS) and gastroparesis. Loxiglumide has proved effective for all these indications, as well as, a treatment for biliary colic, chronic pancreatitis and pancreatic cancer (where it is showing particular promise); an NDA has been filed for the drug to be used in GI motility disorder and GI disease. Dexloxglumide is also showing promise in phase III trials. However, devazepide was halted in phase III trials due to complications in the gall bladder. CCK-A receptor antagonists have also been used to treat problems associated with food intake (eg CR-2194, which is able to reduce basal and gastrin stimulated acid secretion). However, it is probable that this class of drugs may not prove to be an effective therapy for this indication.CCK-B antagonists are being studied for a variety potential indications such as, antisecretory and antiproliferative drugs for GI cancers, treatment of acid-related disorders (such as peptic ulcers), treatment of benzodiazepine dependence and as anxiolytics; L-365260 (Merck & Co Inc), a CCK-B antagonist, is in phase II trials for the treatment of anxiety disorders. Dr Scarpignato commented that CCK-B antagonists have generally been disappointing as anti-panic agents in clinical trials, but they may have considerable promise as therapeutics in colonic cancer. He added that, future directions in CCK research may be in the development of CCK-B binders to elicit the therapeutic effects.In the questions that followed this presentation, it was asked whether loxiglumide treatment had caused stone growth in the gall bladder during clinical trials. Dr Scarpignato commented that many of the CCK-A antagonists were halted in development because of this side effect, although loxiglumide does not appear to have this effect in trials so far. It was also asked whether it would be accurate to say that CCK antagonists can only be effective, in GI disorders, after intake of food types that will stimulate the release of the CCK protein, such as proteins and fat. Dr Scarpignato agreed, adding that such an dramatic GI effect may not be seen with glucose intake, for instance [333128].
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