Current Pharmaceutical Design - Volume 16, Issue 10, 2010

Many people of the total inhabitans suffers from the primary gastrointestinal (GI) damage with unknown etiology and secondary GI damage of which clinical feature appears in association with the presence of different physical, chemical, viral or bacterial and other noxious agents, including big numbers of drugs. In our days, a great attention has been paid to patients infected with Helicobacter pylori (H. pylori), and also to an extremely big number of patients who receive nonsteroidal anti-inflammatory drugs (NSAIDs) for treatment of thrombophylia, arteriosclerosis, stroke, myocardial heart attack or degenerative joint diseases. H. pylori produces dominantly duodenal ulcer, atrophic gastritis, dysplasia and malignancy in the stomach, meanwhile NSAIDs induce GI side effects (bleeding, ulceration, inhibition of bicarbonate secretion, changes in motility, etc). Especially, the medical indication of NSAIDs is a relatively low when considered from evidence based medicine (EBM), because their application in patients with above mentioned diseases is absolutely indicated, while this is contraindicated in patients with GI diseases. Consequently, the research is necessary in the basic and clinical fields. We have decided to publish a special issue in Current Pharmaceutical Design under the title of “Recent Advances in Gastrointestinal Pharmacology: From Basic Science to Clinical Practice”. This issue provides a collection of articles based on the presentations at a symposiums during 13th International Conference on GI Research at Split, Croatia in 2009. This issue contains 8 articles, each dealing with the topic on ”peptides as potential drugs for cancer therapy“, ”role of Hsp 70 in various GI diseases”, “roles of orexigenic peptides in gastric cytoprotection and ulcer healing”, “capsaicin; from plant cultivation to drug production”, “gastric cytoprotection by pentadecapeptide BPC157”, “complexity of gastric acid secretion revealed by targeted gene disruption”, “soluble dietary fiber against NSAID-induced small intestinal damage” and “prostaglandin EP receptor subtypes in gastroduodenal HCO3 - secretion”. We wish to thank all of the authors for their scholarly contributions to this issue. It is satisfying to see their efforts in this issue that, it is hoped, will provide those who read it with a better appreciation and greater insight into the exciting challenges we still face in the treatment of GI diseases. Finally, we hope that this special issue will stimulate both the experimental and clinical researches in future and contribute to the development of novel therapeutic strategies for GI diseases.

The development of more selective agents focused on targeted delivery of imaging probes and drugs to different tumor sites is the current trend in cancer diagnosis and therapies. Peptides are small amino acid sequences that can be isolated to bind to a predetermined target and are potentially capable of interfering with its function. These specific peptides isolated can inhibit individual signaling components, which are essential in cancer development and progression. Phage display is a powerful technology for selecting and cloning peptides displayed on the surface of bacteriophage. Billionclone-peptide libraries can be rapidly and simultaneously selected by phage biopanning, leading to large numbers of hits. Although peptides account for only a small part of current therapeutic agents, their potential is being improved by new technologies affecting their modification, delivery, stability and their application in preclinical settings. This review will highlight how to isolate peptides that target pivotal molecules in cancer development and progression through phage library biopanning and how to modify these peptides to enhance their anticancer efficacy.

It is well known that heat shock proteins (HSPs) are induced by various stressors in order to confer protection against such stressors. Since stressor-induced tissue damage is involved in various diseases, especially gastrointestinal diseases, such as gastric ulcer, it has been thought that HSPs are protective against these diseases. Indirect lines of evidence, such as identification of geranylgeranylacetone (GGA, a leading anti-ulcer drug in Japanese market) as non-toxic HSP-inducer, suggest that HSPs provide a major protective mechanism against irritant-induced gastric lesions. However, no direct evidences that support this notion exits. Furthermore, because GGA has other gastroprotective effects, it was not clear whether HSP-induction by GGA is the main mechanism for its anti-ulcer effect. In this article, I review our recent work on protective roles of HSPs against gastrointestinal diseases, using transgenic mice. We obtained genetic evidence showing not only that HSPs are protective against irritant-induced gastric lesions but also that GGA achieves its anti-ulcer effect through induction of HSPs. We also obtained genetic evidence that HSPs are protective against inflammatory bowel disease (IBD)-related colitis and lesions of small intestine. Furthermore, we found that GGA is effective against these diseases. Based on these observations, we propose that non-toxic HSP-inducers, such as GGA are therapeutically beneficial for these diseases.

It is well known that the capsaicin stimulates (in small doses) or impairs (in high doses) the capsaicin-sensitive afferent nerves and the final effects of capsaicin depend on its applied doses. The effects of capsaicin were analyzed on the gastrointestinal mucosal protection and injury in animal experiments and in human beings (from 1980 up to now). From 2005 to 2008 an interdisciplinary group (21 researchers) participated in the production of orally applicable drug or drug combinations from capsaicin for human medical therapy of patients suffering from cardiovascular, degenerative joint and locomotor diseases, who received in their treatments non-steroidal antiinflammatory compounds (NSAIDs). Our studies were based on the results of the NSAIDs-induced gastrointestinal side effects could be detected by application of small doses of capsaicin. Because natural (plant origin) capsaicin is chemically does not represent a uniform entity and used in the international research, consequently the authors met a lot of unpredictable scientific problems during the time of production of new capsaicin containing (alone or in combinations) drug before receiving official permissions from the different national and international authorities to start the classical human clinical pharmacological studies. This paper summarizes the different steps from the basic physiological and pharmacological notes (in animals), plant cultivation, chemistry of substance(s), animal (general and germinative) acute and chronic toxicology, human actions, basic clinical pharmacology of natural capsaicin (capsaicinoids) to introduce and to develop a new drug (or drug combinations) in the human medical therapy.

Recent advances in endoscopic techniques such as capsule endoscopy have revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the small intestine in humans, but there are few effective agents for treatment of small intestinal ulcers. Although the pathogenesis of NSAID-induced intestinal ulcer has been widely studied, dietary factors have seldom been considered. In the present review, the role of dietary fiber (DF) in the formation of NSAID-induced intestinal ulcers is discussed. In previous studies, small intestinal lesions were not observed when NSAIDs were administered to fasted rats, dogs, and cats, but were observed in conventionally-fed animals, suggesting the importance of feeding in the formation of intestinal lesions induced by NSAIDs. However, in animals fed diets containing low or no DF, indomethacin (IND) did not produce lesions in the small intestine, but did produce lesions in animals fed diets supplemented with insoluble dietary fiber (IDF, cellulose). The results suggest that IDF in the diet plays an important role in the formation of NSAID-induced intestinal lesions. On the other hand, addition of soluble dietary fibers (SDFs) such as pectin or mucin to regular diet markedly decreased NSAID-induced intestinal lesions. Thus, IDF and SDF have opposing effects on IND-induced intestinal lesions, i.e., IDF is harmful while SDF is protective. SDFs potentially represent a novel and safe means for protecting the small intestine against NSAID-induced intestinal lesions.

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

The significance of cytoprotection and adaptive cytoprotection and the peptides importance remained to be not completely determined. BPC 157 is an anti-ulcer peptidergic agent, proven in clinical trials to be both safe in inflammatory bowel disease (PL-10, PLD-116, PL 14736) and wound healing, and stable in human gastric juice, with no toxicity being reported. It has a prominent effect on alcohol- lesions (i.e., induced acutely and chronically) and non-steroidal anti-inflammatory drugs-lesions (while interestingly BPC 157 may both prevent and reverse adjuvant arthritis). To review the importance of BPC 157, this review focused on Robert's cytoprotection concept described in rat stomach, reviewing our evidence that may resolve whether the cytoprotection and adaptive cytoprotection is an uniform phenomenon or not; whether the phenomenon or phenomena are endogenous or not, depending on nature of the irritants (mild or strong); whether this may contribute to stomach mucosa defense either when threaten by various ulcerogens or afforded by various antiulcer agents; whether these phenomena are uniform in whole gastrointestinal tract or not; whether they are interrelated or not. Finally, the importance of the cytoprotection phenomena and cytoprotection activity for skin wound healing, and wound healing in general was challenged. Thereby, this review focused on BPC 157 role in cytoprotection and adaptative cytoprotection suggesting that it may be the essential endogenous mediator able to mediate both cytoprotective and adaptive cytoprotective response in stomach and the whole gastrointestinal tract with significant importance in wound healing as well.

Gastric acid secretion has been sometimes inadequately expressed as pH value rather than amount of gastric H+ secreted per unit time. Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three messenger pathways: gastrin-histamine, CCK-somatostatin, and neural network. These pathways have been largely validated and further characterized by phenotyping a series of knockout mouse models. The complexity of gastric acid secretion is illustrated by both expected and unexpected phenotypes of altered acid secretion. For examples, in comparison with wild-type mice, gastrin and CCK double knockout and somatostatin receptor subtype 2 (SSTR2) knockout mice displayed a shift in the regulation of ECL cells from somatostatin-SSTR2 pathway to galanin-Gal1 receptor pathway; a shift in the regulation of parietal cells from gastrin-histamine pathway to vagal pathway; and a shift in the CCK2 receptors on parietal cells from functional silence to activation. The biological function of glycine-extended gastrin in synergizing gastrin-17 has been revealed in gastrin knockout mice. The roles of gastric acid secretion in tumorigenesis and ulceration have not been fully understood. Transgenic hypergastrinemic INS-GAS mice developed a spontaneous gastric cancer, which was associated with an impaired acid secretion. Gastrin knockout mice were still able to produce acid in response to vagal stimulation, especially after H. pylori infection. Taken together, phenotyping of a series of genetically engineered mouse models reveals a high degree of complexity of gastric acid secretion in both physiological and pathophysiological conditions.

Gastroduodenal HCO3 - secretion is a key process that aids in preventing acid-peptic injury. The HCO3 - secretion in rats and mice was increased in response to PGE2 as well as mucosal acidification, the latter response occurring with a concomitant enhancement of mucosal PG production. The duodenal responses to PGE2 and acid were decreased in mice lacking EP3 receptors and reduced by coadministration of an EP3 or EP4 antagonist in rats, complete inhibition being observed when the EP3 and EP4 antagonists were given together. By contrast, the gastric responses disappeared in EP1-knockout mice and were prevented by an EP1 antagonist but not other EP antagonists. Furthermore, duodenal HCO3 - secretion was stimulated by the EP3 and EP4 agonists, whereas gastric HCO3 - secretion was increased only by the EP1 agonist. In addition, the HCO3 - stimulatory effect of sulprostone (an EP1/EP3 agonist) in the duodenum was inhibited by verapamil, a Ca2+ antagonist, and enhanced by isobutyl- methylxanthine, a phosphodiesterase (PDE) inhibitor, but the response in the stomach was inhibited by verapamil and not affected by isobutylmethylxanthine. In the mouse duodenum but not stomach, the response to PGE2 was potentiated by both vinpocetine (a PDE1 inhibitor) and cilostamide (a PDE3 inhibitor). These results suggest that the HCO3 - stimulatory effect of PGE2 in the duodenum is mediated by both EP3 and EP4 receptors, being coupled intracellularly with Ca2+ and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca2+. In addition, both PDE1 and PDE3 are involved in the regulation of duodenal HCO3 - secretion.

α,β-Diamino acids have attracted considerable attention recently due to their growing importance in pharmaceutical and biochemical research. For example, this special class of diamino acids has become the components of enzyme inhibitors, and has been incorporated into peptides which are used to modulate secondary and tertiary structural conformations. Although their widely occurrence in nature, optically active α,β-diamino acids are hard to isolate and purify from available natural resources on large scale. Therefore, their asymmetric synthesis becomes a great interest for organic and medicinal chemists. However, there still exist great challenges for enantioselective synthesis of α,β-diamino acids, especially those with two vicinal chiral centers. This review highlights the recent promising methodologies for enantioselective synthesis of α,β-diamino acids, with special emphasis on catalytic asymmetric reactions, as well as methods for natural chiral compound derivatization, and chiral auxiliaries.