Capsaicin-sensitive afferentation represents an indifferent defensive pathway from eradication in patients with H. pylori gastritis.

AIM: To study the role of capsaicin-sensitive afferent nerves in Helicobacter pylori (H. pylori) positive chronic gastritis before and after eradication. METHODS: Gastric biopsy samples were obtained from corpus and antrum mucosa of 20 healthy human subjects and 18 patients with H. pylori positive chronic gastritis (n = 18) before and after eradication. Traditional gastric mucosal histology (and Warthin-Starry silver impregnation) and special histochemical examinations were carried out. Immunohistochemistry for capsaicin receptor (TRVP1), calcitonin gene-related peptide (CGRP) and substance P (SP) were carried out by the labeled polymer immunohistological method (Lab Vision Co., USA) using polyclonal rabbit and rat monoclonal antibodies (Abcam Ltd., UK). RESULTS: Eradication treatment was successful in 16 patients (89%). Seven patients (7/18, 39%) remained with moderate complaints, meanwhile 11 patients (11/28, 61%) had no complaints. At histological evaluation, normal gastric mucosa was detected in 4 patients after eradication treatment (4/18, 22%), and moderate chronic gastritis could be seen in 14 (14/18, 78%) patients. Positive immuno-staining for capsaicin receptor was seen in 35% (7/20) of controls, 89% (16/18, P < 0.001) in patients before and 72% (13/18, P < 0.03) after eradication. CGRP was positive in 40% (8/20) of controls, and in 100% (18/18, P < 0.001) of patients before and in 100% (18/18, P < 0.001) after eradication. The immune-staining of gastric mucosa for substance-P was positive in 25% (5/20) of healthy controls, and in 5.5% (3/18, P > 0.05) of patients before and in 0% of patients (0/18, P > 0.05) after H. pylori eradication. CONCLUSION: Distibution of TRVP1 and CGRP is altered during the development of H. pylori positive chronic gastritis. The immune-staining for TRVP1, CGRP and SP rwemained unchanged before and after H. pylori eradication treatment. The capsaicin-sensitive afferentation is an independent from the eradication treatment. The 6 wk time period might not be enough time for the restituion of chronic H. pylori positive chronic gastritis. The H. pylori infection might not represent the main pathological factor in the development of chronic gastritis.

Production of orally applicable new drug or drug combinations from natural origin capsaicinoids for human medical therapy.

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 anti-inflammatory 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.

Molecular pharmacological approach to drug actions on the afferent and efferent fibres of the vagal nerve involved in gastric mucosal protection in rats.

BACKGROUND: Gastric mucosal protection is associated with the actions of anti-ulcer drugs or agents affecting on the afferent and/or efferent nerve fibres of the vagal nerve. AIMS: 1. To identify the dose-response curves of drugs (compounds) on the afferent vanilloid-receptor (capsaicin or resiniferatoxin-sensitive) and on efferent secretion (atropine, pirenzepine, cimetidine, ranitidine, famotidine, omeprazole, esomeprazole) basal gastric acid and stimulated gastric secretion in relation to the chemically-induced gastric mucosal damage in rats; 2. To determine the ED50 (pD2) and pA2 on the calculation of affinity and intrinsic affinity curves for these agonists/antagonists, as an indication of relative potency of effects. MATERIALS AND METHODS: The observations were carried out in rats (30 different models). RESULTS: The ED50 values for affinities of capsaicin, resiniferatoxin were obtained in nmol/kg b.w. range, whereas the values were in the nmol/kg to micromol/kg b.w. ranges for effects on the gastric basal, stimulated (bethanechol, pentagastrin, histamine) gastric secretion, and the gastric mucosal damage-produced by different ulcerogenic agents (ethanol, HCl, aspirin, indomethacin). CONCLUSION: From the observations, that agents acting on vanilloid (capsaicin) receptors were the most potent inhibitors of acid secretion and gastric lesions from necrotizing agents, suggests that the capsaicin sensitive afferent nerves have a primary place in the efferent regulated events leading to initiation of gastric mucosal damage.

Capsaicin and glucose absorption and utilization in healthy human subjects.

Although many animal experiments (under different experimental circumstances) have been performed, however, to date there have been no human studies of the role of capsaicin-sensitive afferent nerves in carbohydrate metabolism. The glucose loading test (administration of 75 g orally given glucose) was evaluated in 14 human healthy subjects by the simultaneous measurement of plasma level of glucose, C-peptide and glucagon every 15 min for 4 h without and with (ED50) oral application of capsaicin. The plasma level of glucose increased significantly from 30 to 150 min, and the plasma glucagon level increased from 90 to 180 min after the glucose loading when capsaicin administered. The plasma levels of insulin and C-peptide increased from 90 to 165 min after glucose loading but there were no significant difference between the results obtained without and with capsaicin administration. It is concluded that the capsaicin increases the glucose absorption from the gastrointestinal tract and increases the glucagon release (independently of the hormonal antagonist regulation by insulin released after glucose) loading during glucose loading tests carried out in human healthy subjects.

Participation of vanilloid/capsaicin receptors, calcitonin-gene-related peptide and substance P in gastric protection of omeprazole and omeprazole-like compounds.

The effects of omeprazole and different omeprazole-like compounds, associated with anti-ischaemic, antioxidant and poly(adenosine-diphosphate-ribose) polymerase (PARP) inhibitory properties, on the gastric acid secretion (4 h pylorus-ligated) and indomethacin-induced gastric mucosal damage connected with the specific immunohistochemical distribution of TRPV1, CRGP and SP during the effects of these compounds, were studied. The observations were carried out in CFY-strain rats (180-210 g), according to the standard methods and the above-mentioned parameters were studied in these experimental circumstances without and with application of different compounds. We found that: (1) all of the compounds dose-dependently inhibited the gastric acid secretion and mucosal damage; (2) the expression of TRPV1 receptor, CGRP and SP decreased significantly in both pylorus-ligated and indomethacin-treated animals and (3) the expression of TRPV1 and CGRP was reduced. Meanwhile, no change was obtained in SP expression during the gastric mucosal protection produced by omeprazole and omeprazole-like compounds. The conclusions were that (1) a functional overlap exists between the capsaicin-sensitive afferent and efferent vagal nerve during omeprazole effects; (2) chemical modification of omeprazole molecule offers a new pathway to obtain a new drug for the introduction in the clinical practice.

Immunohistochemical distribution of vanilloid receptor, calcitonin-gene related peptide and substance P in gastrointestinal mucosa of patients with different gastrointestinal disorders.

The immunohistochemical distribution of capsaicin/vanilloid (transient receptor potential vanilloid 1, TRPV1) receptors and neuropeptides (CGRP, SP) was studied in the gastrointestinal mucosal biopsies of patients with gastritis, erosions, ulcers, polyps, adenocarcinoma, chronic inflammatory bowel diseases, polyps without and with hyperplasia, dysplasia and adenocarcinoma in colon. The studies were carried out in 127 patients and 30 people with only functional dyspepsia (without any histological alteration). The results were: (1) the positivity of TRPV1 receptor and CGRP was detected, and weak participation of SP was detected in patients with different gastric diseases; (2) the presence of TRPV1, CGRP and SP could be detected in chronic inflammation of bowel disease; (3) SP could not detected in patients with colon polyps, dysplasia and adenocarcinoma; (4) the presence of TRPV1 and CGRP was proved in colon dysplasia and adenocarcinoma. We conclude that (1) the immunohistochemical distribution of TRPV1, CGRP and SP differs in gastrointestinal diseases of the upper and lower tract, and (2) the participation of TRPV1, CGRP and SP differs significantly in these different gastrointestinal diseases.

Involvement of serum retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers in Hungary.

AIM: To analyze the serum levels of retinoids and Leiden mutation in patients with esophageal, gastric, liver, pancreatic, and colorectal cancers. METHODS: The changes in serum levels of retinoids (vitamin A, alpha- and beta-carotene, alpha- and beta-cryptoxanthin, zeaxanthin, lutein) and Leiden mutation were measured by high liquid performance chromatography (HPLC) and polymerase chain reaction (PCR) in 107 patients (70 males/37 females) with esophageal (0/8), gastric (16/5), liver (8/7), pancreatic (6/4), and colorectal (30/21 including 9 patients suffering from in situ colon cancer) cancer. Fifty-seven healthy subjects (in matched groups) for controls of serum retinoids and 600 healthy blood donors for Leiden mutation were used. RESULTS: The serum levels of vitamin A and zeaxanthin were decreased significantly in all groups of patients with gastrointestinal (GI) tumors except for vitamin A in patients with pancreatic cancer. No changes were obtained in the serum levels of alpha- and beta-carotene, alpha- and beta-cryptoxanthin, zeaxanthin, lutein in patients with GI cancer. The prevalence of Leiden mutation significantly increased in all groups of patients with GI cancer. CONCLUSION: Retinoids (as environmental factors) are decreased significantly with increased prevalence of Leiden mutation (as a genetic factor) in patients before the clinical manifestation of histologically different (planocellular and hepatocellular carcinoma, and adenocarcinoma) GI cancer.