Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach

Alpha-2 receptor activation mediates the inhibition of a number of gastrointestinal functions including gastric and intestinal secretions. Alpha-2 receptors are located in the brain and presynaptically on cholinergic nerve terminals; activation of either inhibits vagus nerve activity. Intestinal secretions are inhibited by postsynaptic alpha-2 receptors located on intestinal epithelial cells. Agents which selectively activate alpha-2 receptors in the gut may therefore be beneficial in treating gastric ulcers and diarrheal states. Two such agents which activate alpha-2 receptors in the gut are WHR-1370A [1-n-butoxy-3-(2,6-dimethylphenylcarbamoyl) guanidine hydrochloride] and lidamidine. WHR-1370A is a potent gastric antisecretory and antiulcer agent which inhibits the release of acetylcholine from the vagus nerve. WHR-1370A's activity is blocked by yohimbine. Lidamidine is a clinically effective antidiarrheal agent. Lidamidine's response is partially inhibited by yohimbine in animal diarrheal models. Alpha-2 agonists represent a new class of drugs which have a promising future in the treatment of gastrointestinal disorders.     

Role of nitric oxide in the gastrointestinal tract

Worldwide osteoarthritis (OA) affects more than 9.6% of men and 18% of women older that 60 years. Treatment for OA often requires chronic use of selective or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which have been associated with gastrointestinal and cardiovascular complications. An increased risk for upper gastrointestinal bleeding with NSAIDs alone and when combined with low-dose aspirin has been described in numerous studies. Although cyclo-oxygenase-2 inhibitors have been shown to carry a lower risk for gastrointestinal injury than nonselective NSAIDs, research continues to identify new treatments that not only are effective but also provide an improved benefit/risk profile, including better gastrointestinal tolerability. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract. In preclinical studies NO was shown to help maintain gastric mucosal integrity, to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Recent studies have shown that cyclo-oxygenase inhibiting NO-donating drugs (CINODs), in which a NO molecule is chemically linked to an NSAID, are effective anti-inflammatory agents and may result in less gastrointestinal damage than is associated with NSAID use. Therefore, these agents provide a potential therapeutic option for patients with arthritis who require long-term NSAID therapy.     

Hispolon induces apoptosis in human gastric cancer cells through a ROS-mediated mitochondrial pathway

Severe side effects and complications such as gastrointestinal and hematological toxicities because of current anticancer drugs are major problems in the clinical management of gastric cancer, which highlights the urgent need for novel effective and less toxic therapeutic approaches. Hispolon, an active polyphenol compound, is known to possess potent antineoplastic and antiviral properties. In this study, we investigated the efficacy of hispolon in human gastric cancer cells and explored the cell death mechanism. Hispolon induced ROS-mediated apoptosis in gastric cancer cells and was more toxic toward gastric cancer cells than toward normal gastric cells, suggesting greater susceptibility of the malignant cells. The mechanism of hispolon-induced apoptosis was that hispolon abrogated the glutathione antioxidant system and caused massive ROS accumulation in gastric cancer cells. Excessive ROS caused oxidative damage to the mitochondrial membranes and impaired the membrane integrity, leading to cytochrome c release, caspase activation, and apoptosis. Furthermore, hispolon potentiated the cytotoxicity of chemotherapeutic agents used in the clinical management of gastric cancer. These results suggest that hispolon could be useful for the treatment of gastric cancer either as a single agent or in combination with other anticancer agents.     

Pharmacological Modification of Gastric Emptying: Effects of Propantheline and Metoclopromide on Paracetamol Absorption

The rate of paracetamol absorption depends on the rate of gastric emptying. Propantheline delayed gastric emptying and markedly slowed the absorption of paracetamol in six convalescent hospital patients. Conversely, the absorption of paracetamol in five healthy volunteers was accelerated by metoclopramide, a drug which stimulates gastric emptying. The total 24-hour urinary excretion of paracetamol was not influenced by propantheline or metoclopramide. Other similar absorption interactions probably occur since drugs are poorly absorbed from the stomach and many therapeutic agents influence gastrointestinal motility.     

Gastric mucosal integrity: gastric mucosal blood flow and microcirculation. An overview

The stomach is in a state of continuous exposure to potentially hazardous agents. Hydrochloric acid together with pepsin constitutes a major and serious threat to the gastric mucosa. Reflux of alkaline duodenal contents containing bile and pancreatic enzymes are additional important injurious factors of endogenous origin. Alcohol, cigarette smoking, drugs and particularly aspirin and aspirin-like drugs, and steroids are among exogenous mucosal irritants that can inflict mucosal injury. The ability of the stomach to defend itself against these noxious agents has been ascribed to a number of factors constituting the gastric mucosal defense. These include mucus and bicarbonate secreted by surface epithelial cells, prostaglandins, sulfhydryl compounds and gastric mucosal blood flow. The latter is considered by several researchers to be of paramount importance in maintaining gastric mucosal integrity. The aim of this paper is to review the experimental and clinical data dealing with the role of mucosal blood flow and in particular the microcirculation in both damage and protection of the gastric mucosa.     

CCKB/gastrin receptor antagonists: recent advances and potential uses in gastric secretory disorders.

Cholecystokinin (CCK) and the structurally related peptide, gastrin, have numerous effects on tissues in the central nervous system and gastrointestinal tract. Recent studies show these effect are mediated by a CCKA and CCKB receptor. Knowledge of the physiological role and role of CCKB receptors in pathologic processes has been particularly limited by the availability of selective, potent receptor antagonists. Recently, new members of five different classes of non-peptide CCKB receptor antagonists are reported and are reviewed briefly. these include compounds isolated from Streptomyces (tetronothiodin, virginiamycin analogues), ureido-acetamide analogues (RP 69758, RP 72540, RP 73870), newer benzodiazepine analogues (L-368,935, L-740,093, YM022), pyrazolidimine analogues (LY 262,691) and glutamic acid analogues (CR2194). Many of these compounds have greater than 1000-fold selectivity for the CCKB over the CCKA receptor and some have greater than 10,000-fold selectivity. The pharmacology and effects of CCKB receptor antagonists on gastric acid secretion is briefly reviewed. Furthermore, the possible clinical usefulness of CCKB receptor antagonists in treating disorders of gastric acid secretion, in inhibiting the trophic effects of gastrin and in other clinical conditions is briefly discussed.     

Synthesis and pharmacological evaluation of some dual-acting amino-alcohol ester derivatives of flurbiprofen and 2-[1,1'-biphenyl-4-yl]acetic acid: a potential approach to reduce local gastrointestinal toxicity

The search for safer non-steroidal anti-inflammatory drugs (NSAIDs) continues with the failure of anticipated 'ideal' anti-inflammatory agents, the coxibs, on long-term usage. Increased gastric motility and acidity due to the free carboxy group are involved in the etiology of gastric toxicity, common to conventional NSAIDs. Keeping this fact in mind, it was planned to modify some of the conventional NSAIDs to amino-alcohol ester derivatives, which satisfied the structural requirements for these compounds to possess anticholinergic activity in the intact form. Besides blocking the acidic carboxylic group, incorporation of anticholinergic acivity in these molecules was expected to reduce the gastric toxicity by decreasing gastric acid secretion and motility. Synthesis and pharmacological evaluation of six different N,N-disubstituted amino-ethyl ester derivatives, structurally resembling the amino-alcohol ester class of anticholinergic agents, each for [1,1'-biphenyl]-4-acetic acid (3) and flurbiprofen (10), have been reported as potential substitutes for these NSAIDs, with improved therapeutic profile. All the ester derivatives were found to have sufficient chemical stability in buffers (pH 2.0 and 7.4), ensuring them to be absorbed as intact moieties from the gastrointestinal tract. A significant reduction in ulcerogenic potency in comparison to the parent drugs with a slightly higher anti-inflammatory potency suggests that the majority of these candidates have an improved therapeutic profile over their parent drugs. Hence, a promising novel approach, different from the conventional prodrug concept, has been successfully worked out to overcome the local gastric toxicity, yielding therapeutically better compounds for long-term oral anti-inflammatory therapy.     

Function and regulation of apelin/APJ system in digestive physiology and pathology

Apelin is an endogenous ligand of seven-transmembrane G-protein-coupled receptor APJ. Apelin and APJ are distributed in various tissues, including the heart, lung, liver, kidney, and gastrointestinal tract and even in tumor tissues. Studies show that apelin messenger RNA is widely expressed in gastrointestinal (GI) tissues, including stomach and small intestine, which is closely correlated with GI function. Thus, the apelin/APJ system may exert a broad range of activities in the digestive system. In this paper, we review the role of the apelin/APJ system in the digestive system in physiological conditions, such as gastric acid secretion, control of appetite and food intake, cell proliferation, cholecystokinin secretion and histamine release, gut–brain axis, GI motility, and others. In pathological conditions, the apelin/APJ system plays an important role in the healing process of stress gastric injury, the clinical features and prognosis of patients with gastric cancers, the reduction of inflammatory response to enteritis and pancreatitis, the mediation of liver fibrogenesis, the promotion of liver damage, the inhibition of liver regeneration, the contribution of splanchnic neovascularization in portal hypertension, the treatment of colon cancer, and GI oxidative damage. Overall, the apelin/APJ system plays diversified functions and regulatory roles in digestive physiology and pathology. Further exploration of the relationship between the apelin/APJ system and the digestive system will help to find new and effective drugs for treating and alleviating the pain of digestive diseases.     

Selective effects of serotonergic psychoactive agents on gastrointestinal functions in health

This study evaluated the effects of serotonergic psychoactive agents on gastrointestinal functions in healthy human subjects. Participants received one of four regimens in a randomized, double-blind manner: buspirone, a 5-HT(1A) receptor agonist (10 mg twice daily); paroxetine, a selective serotonin reuptake inhibitor (20 mg daily); venlafaxine-XR, a selective serotonin and norepinephrine reuptake inhibitor (75 mg daily); or placebo for 11 days. Physiological testing performed on days 8-11 included scintigraphic assessment of gastrointestinal and colonic transit, the nutrient drink test, and assessment of the postprandial change in gastric volume. Fifty-one healthy adults (40 females, 11 males) participated in this study. No effects on gastric emptying or colonic transit were identified with any agent. Small bowel transit of a solid meal was accelerated by paroxetine. Buspirone decreased postprandial aggregate symptom and nausea scores. Venlafaxine-XR increased the postprandial change in gastric volume. Buspirone, paroxetine, and venlafaxine-XR affect upper gastrointestinal functions in healthy humans. These data support the need for clinical and physiological studies of these agents in functional gastrointestinal disorders.     

Combined Drug Treatment of Obesity

Pharmacological treatment of obesity has been neglected as a viable therapeutic option for many years. Recent long term studies with combinations of obesity drugs gives promise that drugs may play a role in weight maintenance, which classically has been the most difficult aspect of treating obesity. Currently available obesity drugs include centrally acting adrenergic agents and serotonin agonists. Drugs still in development include a lipase inhibitor that produces fat malabsorption, a combined adrenergic-serotonergic reuptake inhibitor, various gut-central nervous system peptides, and a number of beta-3 agonists. Any of these obesity drugs given alone produces modest weight loss, and for most, weight loss continues for as long as medication is given. The most successful drug regimens to date are combinations of phentermine and fenfluramine or of ephedrine, caffeine, and/or aspirin. The former combination produces reduction in body weight and complications of obesity for 2 to almost 4 years in clinical trials to date. More research is needed to document long term efficacy and particularly the long term safety of these and other combinations.     

Gastric cancer: clinical aspects, epidemiology and molecular background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.     

Preliminary studies of Mammea americana L. (Guttiferae) bark/latex extract point to an effective antiulcer effect on gastric ulcer models in mice

Plant extracts are some of the most attractive sources of new drugs and have shown promising results for the treatment of gastric ulcers. Several folk medicinal plants and herbs have been used to treat gastrointestinal disorders, including gastric ulcers. Mammea americana L. (Guttiferae) fruit is very common in the diet of the population of northern South America. Our research interest in this plant arose because of its potential medicinal value as a tonic and against stomachache, as used in folk medicine. In this paper we evaluated three different extracts (ethanolic/EtOH, methanolic/MeOH and dichloromethane/DCM) obtained from M. americana L., for their ability to protect the gastric mucosa against injuries caused by necrotizing agents (0.3 M HCl/60% EtOH), hypothermic restraint stress, nonsteroidal anti-inflammatory drugs (NSAID, indomethacin) and pylorus ligation. In the HCl/EtOH-induced gastric-ulcer model, EtOH and DCM extracts demonstrated significant inhibition of the ulcerative lesion index by 54% (12.0 +/- 2.6 mm) and 86% (3.7 +/- 1.8 mm), respectively, in relation to the control value (26.0 +/- 1.4 mm) (p<0.0001). In the NSAID/cholinomimetic-induced lesion model, both EtOH and DCM extracts showed antiulcerogenic effects with significant reduction in the damage to these gastric lesions of 36% (8.3 +/- 2.0 mm) and 42% (7.5 +/- 1.4 mm), respectively, as compared to the control group (13.0 +/- 0.9 mm) (p<0.0001). In the gastric ulcer induced by hypothermic-restraint stress, both extracts also showed significant activity, and inhibited the gastric lesion index by 58% and 75%, respectively. The EtOH and DCM extracts also changed gastric juice parameters as well as those of cimetidine, decreased gastric acid secretion significantly (p<0.0001), increased pH values and promoted reduced acid output (p<0.0001). In all gastric-ulcer-induced models, MeOH extract did not show any significant antiulcerogenic activity, nor did it change gastric-juice parameters (p>0.05). The results suggest that EtOH and DCM extracts obtained from M. americana possess excellent antisecretory and/or gastrotective effect in all gastric ulcer models. These results suggest that the antiulcerogenic compound(s) present in M. americana may be clustered in the apolar fraction, which will be investigated by our group for the probable mechanisms of action.     

Antibiotic abuse: the testimony of medical students.

Surveys of the use of antimicrobial drugs on students during antimicrobial drugs on students during their first 15 months in medical or dental school indicate that they have been treated with these agents at least three times as frequently as seems reasonable, and that the tetracyclines, ampicillin, penicillin G and erythromycin are the chief drugs overused. Antimicrobiol therapy is frequently instituted for probable viral respiratory tract infections and without any attempt to establish a bacteriologic diagnosis. It is likely that anitmicrobiol agents are used more widely in treating the general public in Canada than in treating medical students. Improvements in the rational use of this important group of drugs could increase the quality and probably reduced the cost of medical care.     

Balancing the gastrointestinal benefits and risks of nonselective NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of medications to treat pain and inflammation. However, gastrointestinal complications associated with NSAIDs are prevalent, largely due to the frequent use of these agents. Adverse events associated with NSAIDs include minor side effects, such as dyspepsia, as well as serious complications, such as bleeding and perforation. Although the probability that any given individual user of an NSAID will suffer a serious gastrointestinal complication is fairly low, widespread patient exposure can translate into a major national health burden. The increasing use of aspirin in the prevention of cardiovascular events and the availability of select over-the-counter NSAIDs represent additional challenges to clinicians in their efforts to make the most appropriate therapeutic decisions while minimizing the potential gastrointestinal risks associated with the use of these agents. Side effects such as dyspepsia do not provide adequate warning of gastrointestinal complications, because most complications occur without the presence of antecedent symptoms. Therefore, accurate risk assessment and the management of controllable risk factors are crucial to the safe administration of NSAIDs. This review focuses on the gastrointestinal effects of aspirin, acetaminophen, and other nonselective NSAIDs, and discusses those factors that are associated with increased risk for adverse gastrointestinal events in certain individuals.     

The clinical and nutritional implications of lipid-lowering drugs that act in the gastrointestinal tract

PURPOSE OF REVIEW: A new class of cholesterol-lowering therapy that reduces intestinal sterol absorption has recently been introduced. This increases the number of classes of lipid-lowering agents that directly affect gastrointestinal function and raises questions concerning the overall effect of these agents on absorption and nutritional status. RECENT FINDINGS: A recent assessment notes a paucity of information concerning the factors that affect the bioavailability and intestinal absorption of lipophilic nutrients. By contrast, the specificity of the mechanisms of action of new drugs acting on the gastrointestinal tract may circumvent some of the detrimental effects on nutrient and drug bioavailability that have been noted with older forms of treatment. SUMMARY: The clinical imperative for aggressive control of lipid and metabolic risk factors makes widespread use, alone or in combination, of lipid-lowering agents that affect the gastrointestinal tract seem increasingly likely. Whilst the opportunity for therapeutic synergy is attractive, care will be required to avoid interference with intestinal absorptive function.     

Exosomes as a novel cell-free therapeutic approach in gastrointestinal diseases

Cell communication through extracellular vesicles (EVs) has been defined for many years and it is not limited only to neighboring cells, but also distant ones in organisms receive these signals. These vesicles are secreted from the variety of cells and are composed of a distinctive component such as proteins, lipids, and nucleic acids. EVs have different classified subgroups regarding their cell origin, in this context, exosomes are the most appealing particles in cell biology, especially clinical in recent years and are represented as novel therapeutic agents with numerous advantages alongside and/or over cell therapy. However, cell therapy had a hopeful outcome in gastrointestinal diseases which have minimal alternatives in their treatments. Inflammatory bowel disease (IBD), liver fibrosis, gastrointestinal cancers are the examples that cell therapy and immunotherapy were applied in their treatment, therefore, the cell products like exosomes are the beneficial option in their treatment even cancers with promising results in animal models. In this review, we consider the main defined biogenesis, function, and component of secreted exosomes in different cells with a specific focus on the potential application of these exosomes as a cell-free therapeutic approach in gastrointestinal diseases like IBD, gastric cancer, and colon cancer. Additionally, exosomes role as therapeutic reagents mainly mesenchymal stem cells and dendritic cell-derived exosomes in different studies have been under intense investigation and even they are being studied in different clinical trials. Therefore, all these striking functions described for secretome implies the importance of these biocarriers.     

The metabolic effects of inhibitors of 5-lipoxygenase and of cyclooxygenase 1 and 2 are an advancement in the efficacy and safety of anti-inflammatory therapy

Chronic treatment of inflammatory diseases with non-steroidal anti-inflammatory drugs is effective but not always devoid of serious side effects. In particular, the use of traditional non-steroidal aspirin-like drugs has been associated with a high incidence of gastrointestinal bleedings. The development of a new class of drugs, the selective cyclooxygenase type 2 (COX-2) inhibitors, has generated much expectation on the possibility to have safer compounds. After the initial enthusiasm of the scientific community, a re-evaluation of some large, randomized double-blind clinical studies performed with two of these compounds, has disclosed that the late serious gastrointestinal complications are not significantly reduced in comparison with non-selective inhibitors and that cardiovascular concerns might arise particularly if theses drugs are utilized in patients with underlying heart diseases. A new promising class of drugs to control inflammatory diseases is in advanced clinical development. The balanced inhibitors of 5-lipoxygenase (5-LOX) and of cyclooxygenase (both types 1 and 2) block the formation of all the enzymatically arachidonic acid-derived metabolites, both prostaglandins (like COX inhibitors) and leukotrienes (LT); these drugs have been shown to possess a very good anti-inflammatory efficacy without serious side effects. Licofelone, previously known as ML3000, is the molecule in the most advanced phase of clinical development (phase III) among this class of compounds; it is a potent, competitive, and well balanced inhibitor of 5-LOX and COX pathways. The drug has been shown to possess analgesic, anti-inflammatory, antipyretic antibronchocostrictory and antiplatelet properties at doses which are safe for the gastrointestinal tract. Moreover, the newly performed preclinical studies, here briefly reviewed, appear to indicate that the compound seems particularly suitable to protect the articular cartilage and the synovial space in degenerative joint disease and to exert a relevant antithrombotic activity. Preliminary results of clinical studies of licofelone in osteoarthritis indicate that the drug has a comparable or slightly better efficacy than that of naproxen but possesses a much better gastrointestinal safety. This latter important aspect has been also evaluated by an endoscopic study in normal volunteers randomly assigned to a 4-week treatment with licofelone, placebo or naproxen. The results indicate that no ulcers occurred in either licofelone group or the placebo group, while ulcers with unequivocal depth were present in 20% of the naproxen-treated subjects.     

Current state of therapy for pain and inflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclo-oxygenase (COX)-2 inhibitors, are among the most widely used medications in the USA. Traditional NSAIDs, although effective at relieving pain and inflammation, are associated with a significant increase in the risk for gastrointestinal adverse events. Throughout the 1990s these events were estimated to result in approximately 100,000 hospitalizations and 16,500 deaths each year nationally. Recent studies have indicated that the risk for serious NSAID gastropathy has declined substantially during the past decade as a result of a number of factors, including lower doses of NSAIDs, the use of gastroprotective agents such as proton pump inhibitors and misoprostol, and the introduction of the selective COX-2 inhibitors. One therapeutic approach that may reduce the risk for gastrointestinal side effects associated with traditional NSAIDs while retaining their efficacy is the inclusion of co-therapy with a proton pump inhibitor; these agents inhibit acid secretion and have been demonstrated to promote ulcer healing in patients with NSAID-related gastric ulcers. Alternatively, COX-2 selective agents have been used to treat patients at high risk for such events. Both nonselective and selective COX-2 inhibitors have now been shown to be associated with an increased risk for cardiovascular events. These studies, together with the outcomes of the recent US Food and Drug Administration decision to require 'black box' warnings regarding potential cardiovascular risks associated with NSAIDs, suggest that the use of COX-2 inhibitors as the sole strategy for gastroprotection in patients with arthritis and other pain syndromes must be reconsidered, particularly among those at risk for cardiovascular events.     

Growth factors in ulcer healing: lessons from recent studies.

Growth factors such as epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF) and more recently vascular endothelial growth factor (VEGF) have been used extensively to heal experimental gastric, duodenal and colonic ulcers in animal models. Encouraging results have been reported in clinical trials with EGF and bFGF. Since our laboratory has been involved with the initial ulcer healing studies with bFGF, PDGF and VEGF, we summarize here the major lessons from these studies and from literature data. These conclusions relate to the role of: 1) gastrointestinal (GI) secretion; 2) epithelial versus vascular components of the healing; 3) efficacy in the upper and lower GI tract; 4) quality of ulcer healing; as well as 5) the endogenous origin; and 6) molar potency of growth factors. Namely, among these growth factors only EGF inhibits gastric acid and stimulates duodenal bicarbonate secretion, while chronic administration of bFGF slightly enhances gastric secretion and PDGF has no effect demonstrating that potent ulcer healing can be achieved without influencing acid base and mucus secretion. This might be related to the fact that these growth factors stimulate with varying potency virtually all the cellular elements needed for ulcer healing, e.g., epithelial cell proliferation and migration by EGF > bFGF > PDGF, fibroblast proliferation by bFGF > PDGF and angiogenesis by VEGF > bFGF > PDGF > EGF. Conceptually, the most interesting results were obtained recently with VEGF which is virtually specific for angiogenesis, illustrating that stimulation of vascular factors is sufficient for ulcer healing because epithelial cells apparently spontaneously proliferate and migrate over a dense granulation tissue to complete the healing process. Since these growth factors directly stimulate the cell components of ulcer healing, it is probably not surprising that they are active in both upper and lower GI tract lesions, produce good quality of ulcer healing in comparison with spontaneously healed duodenal ulcers which are hypovascular and muscle regeneration is not part of natural healing. Contrary to other antiulcer drugs, these growth factors are endogenously derived and play a role in the natural history of ulcer healing, and since these relatively large peptides (18-45 kDa) are active in ng quantities, their molar potency is 2-7 million times superior to cimetidine-like drugs. Thus growth factors are endogenously derived very potent antiulcer drugs which act independently of GI secretion, are active in upper and lower GI lesions, and since they stimulate virtually all the cells of the healing process, they produce an excellent quality of ulcer healing.