Allopurinol Antiulcer Anti-Kidney Stone

Allopurinol Protects Against Gastritis and Ulcer

Participation of Xanthine-Xanthine Oxidase System and Neutrophils in Development of Acute Gastric Mucosal Lesions in Rats with a Single Treatment of Compound 48/80, a Mast Cell Degranulator

Authors: Ohta Y.; Kobayashi T.; Ishiguro I.

Source: Digestive Diseases and Sciences, Volume 44, Number 9, 1 September 1999 , pp. 1865-1874(10)

Publisher: Springer

 

Abstract:

The participation of xanthine-xanthine oxidase and neutrophils in the development of acute gastric mucosal lesions was examined in rats injected once with compound 48/80, a mast cell degranulator that releases histamine and gastric acid.

Gastric mucosal lesions (ulcers/gastritis) appeared 30 min. after compound 48/80 injection and developed at 3 hr. The formation of gastric mucosal lesions at 30 min. after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum and NPC 14686, an antiinflammatory agent, but not with allopurinol, a xanthine oxidase inhibitor. The development of gastric mucosal lesions at 3 hr after compound 48/80 injection was prevented by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol. Increases in the activities of gastric mucosal xanthine oxidase and myeloperoxidase, an index of neutrophil infiltration, and the content of lipid peroxide occurred 30 min. after compound 48/80 injection, and these increases were enhanced at 3 hr. The increases in gastric mucosal myeloperoxidase activity and lipid peroxide content at 30 min. after compound 48/80 injection were attenuated by pretreatment with anti-neutrophil antiserum and NPC 14686, while only the increase in gastric mucosal xanthine oxidase activity at the same time point was arrested by allopurinol pretreatment. The increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content at 3 hr after compound 48/80 treatment were attenuated by pretreatment with anti-neutrophil antiserum, NPC 14686, or allopurinol.

When compound 48/80-injected rats were treated with *** allopurinol *** at 30 min. after compound 48/80 injection, the progression of *** gastric mucosal lesions at 3 hr after the injection was almost completely prevented *** with inhibition of the increases in gastric mucosal xanthine oxidase and myeloperoxidase activities and lipid peroxide content.

These results indicate that in rats with a single compound 48/80 treatment neutrophils infiltrated into the gastric mucosa participated in the development of acute gastric mucosal lesions and that the xanthine-xanthine oxidase system in the gastric mucosa participated in the progression rather than the formation of the gastric mucosal lesions.

 

Keywords: COMPOUND 48/40; GASTRIC MUCOSAL LESIONS; XANTHINE OXIDASE; NEUTROPHILS; LIPID PEROXIDE

Language: English

Document Type: Regular paper

 




Eur J Pharmacol. 2001 Feb 9;413(1):121-9.Click here to read Links

Oxygen radicals mediate the final exacerbation of endothelin-1-induced gastric ulcer in rat.

Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Japan

We investigated the role of xanthine oxidase-derived oxygen radicals in the development of endothelin-1-induced gastric ulcer. Mucosal lipid peroxidation showed a peak 24 h after injection, while gastric mucosal haemodynamics were fully restored 26 h after endothelin-1 injection. Allopurinol and oxypurinol, but not superoxide dismutase or catalase, protected the gastric mucosa 24 h after endothelin-1 injection. Oxypurinol antagonized both the vasoconstrictor effect of endothelin-1 and the decrease in gastric ATP. All treatments on the second day after endothelin-1 injection significantly reduced gastric mucosal damage. Xanthine oxidase-derived oxygen radicals contributed largely to the exacerbation but they did not mediate the onset of endothelin-1-induced gastric ulcer. Pretreatment with probucol (500 mg/kg, p.o.) also protected the gastric mucosa from endothelin-1-induced mucosal injury by its antioxidant activity. Oxypurinol was gastroprotective through its vasoactive and energy saving actions. The haemodynamic background of endothelin-1-induced gastric ulcer consists of long lasting ischaemia and subsequent "reperfusion" which may be responsible for the late burst of oxygen radicals.


Digestion. 1989;43(1-2):113-9.Links

Role of oxygen-derived free radicals in the mechanism of chronic gastric ulceration in the rat: implications for cytoprotection.

University Department of Surgery, Royal Infirmary, Glasgow, UK.

Oxygen-derived free radicals are cytotoxic and mediate tissue damage. Allopurinol prevents the formation of superoxide radicals and dimethyl sulphoxide (DMSO) scavenges the hydroxyl ones. Intraperitoneal reserpine (5 mg/kg every day for 5 days) produced chronic gastric ulceration in all rats after 4 weeks. Animals gavaged with 1 ml/day of each of 1% allopurinol and 1% DMSO for 4 weeks developed ulceration in 60% of cases; however this ulceration developed in only 20% of animals similarly gavaged with 2% solutions. Rats gavaged with 1 ml/day of each of 5% allopurinol and 5% DMSO for 4 weeks were completely protected against the reserpine-induced chronic gastric ulceration. This protection was not associated with any significant effect on the H+ output of the rat stomach. The results suggest that in the rat, oxygen-derived free radicals are responsible for the development of chronic gastric ulceration and that removing these radicals protects against the said ulceration without influencing acid secretion, i.e. cytoprotection.



J Lab Clin Med. 2002 Sep;140(3):142-51.Click here to read Links

Role of acid back-diffusion, glutathione, oxyradical, and histamine in antral hemorrhagic ulcer in rats: the protective effect of lysozyme chloride and antioxidants.

Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan, Taiwan. crchung@mail.ncku.edu.tw

The pathogenesis of gastric antral hemorrhage and ulceration is unclear. This paper first proposes that antral hemorrhagic ulcers produced in rats are associated with attenuation of defensive parameters (such as mucosal glutathione levels and histamine release, as well as aggravation of aggressive factors) including gastric acid back-diffusion and oxyradical generation. The protective effects of lysozyme chloride and antioxidants on this ulcer model were also evaluated. After being deprived of food for 24 hours followed by refeeding for 1 hour, rats were injected with 1.0 mol HCl/L intragastrically under potent analgesia of diethylether-anesthesia to induce antral ulcer. Control rats received a normal saline solution only. Rats were then given free access to water and food for 4 days. Before the experiment began, rats were again deprived of food for 24 hours. Following anesthetization, their stomachs were irrigated for 3 hours with either normal saline or a physiological acid solution containing 100 mmol HCl/L and 54 mmol NaCl/L. Aggravation of various aggressive and defensive parameters in antral mucosa was observed in refed rats that had received 1.0 mol HCl/L. A high relationship of mucosal glutathione level (r = -0.8754, P <.05) or lipid peroxides generation (r = 0.8198) to antral ulceration was obtained in those ulcerated rats. Intragastric lysozyme chloride (50-200 mg/kg) injected three times daily produced a dose-dependent attenuation of various gastric parameters in the acid-irrigated stomachs of antral ulcer rats. Intraperitoneal injections of various antioxidants, including exogenous glutathione, allopurinol, or dimethylsulfoxide also attenuated antral ulcer. In conclusion, the imbalance of aggressive factors, such as acid back-diffusion and oxyradicals-as well as defensive factors including glutathione and histamine-is important in modulating antral hemorrhagic ulcers that can be ameliorated by lysozyme chloride or antioxidants in rats.

Eur J Pharmacol. 2004 Apr 26;491(1):61-8.Click here to read Links

Gastric oxidative stress and hemorrhagic ulcer in Salmonella typhimurium-infected rats.

Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 70101, Taiwan. crhung@mail.ncku.edu.tw

Infection of Salmonella typhimurium (Salmonella typhi) can lead to various organ diseases. This research first proposed that Salmonella typhi-infection could result in gastric oxidative stress and hemorrhagic ulcers that were ameliorated by ofloxacin, lysozyme chloride and several antioxidants, including exogenous glutathione (GSH), allopurinol and dimethylsulfoxide (DMSO). Male Wistar rats were given intrajejunally the live culture of Salmonella typhi [1 x 10(10) colony-forming unit (CFU)/rat] and followed by deprivation of food for 36 h. Age-matched control rats received vehicle only. Rat stomachs were irrigated for 3 h with either normal saline or a simulated gastric juice containing 100 mM HCl, 17.4 mM pepsin and 54 mM NaCl. Infection of Salmonella typhi produced an aggravation of ulcerogenic factors, including enhancing gastric acid back-diffusion, mucosal lipid peroxide generation and hemorrhagic ulcer as well as an attenuation of mucosal GSH level. Intragastric irrigation of gastric juice caused further aggravation of these gastric biochemical parameters. This exacerbation of ulcerogenic factors was abolished by pretreatment of ofloxacin and lysozyme chloride. Antioxidants, such as reduced GSH, allopurinol and DMSO also produced significant (P<0.05) amelioration of gastric damage in Salmonella typhi-infected rats. In conclusion, infection of Salmonella typhi substantially caused gastric oxidative stress and disruption of gastric mucosal barriers, consequently resulted in gastric hemorrhagic ulcerations that were effectively ameliorated by ofloxacin, lysozyme chloride and various antioxidants.


Free Radic Res. 2004 Feb;38(2):147-55.Links

Non-invasive analysis of reactive oxygen species generated in rats with water immersion restraint-induced gastric lesions using in vivo electron spin resonance spectroscopy.

Department of Bio-function Science, Graduate School of Pharmaceutical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.

Reactive oxygen species (ROS) are reportedly associated with gastric ulcer. We previously reported the use of an in vivo 300-MHz electron spin resonance (ESR) spectroscopy/nitroxyl probe technique to detect *OH generation in the stomachs of rats with gastric ulcers induced by NH4OH. However, this is an acute ulcer model, and the relationship between in vivo ROS generation and lesion formation remains to be clarified. To address this question, the same technique was applied to a sub-acute water immersion restraint (WIR) model. A nitroxyl probe that was less membrane-permeable was orally administered to WIR-treated rats, and the spectra in the gastric region were obtained by in vivo ESR spectroscopy. The signal intensity of the orally administered probe was clearly changed in the WIR group, but no change occurred in the control group. Both enhanced signal decay and neutrophil infiltration into mucosa were observed 2h after WIR with little formation of any mucosal lesions. The enhanced signal decay was caused by *OH generation, based on the finding that the decay was suppressed by mannitol, desferrioxamine and catalase. Intravenous treatment with either anti-neutrophil antibody or allopurinol also suppressed the enhanced signal decay, and allopurinol depressed neutrophil infiltration into the mucosa. In rats treated with WIR for 6 h, lesion formation was suppressed by 50% with all antioxidants used in this experiment except anti-neutrophil antibody. These findings suggest that *OH, which is generated in the stomach via the hypoxanthine/xanthine oxidase system upon neutrophil infiltrated into the mucosa, induces mucosal lesion formation, but that it accounts for only half the cause of lesion formation.

Cochrane Database Syst Rev. 2007 Apr 18;(2):CD001973.Click here to read Links
Update of:
Cochrane Database Syst Rev. 2004;(2):CD001973.

Interventions for treating oral mucositis for patients with cancer receiving treatment.

BACKGROUND: Treatment of cancer is increasingly effective but associated with short and long term side effects. Oral side effects, including oral mucositis (mouth ulceration), remain a major source of illness despite the use of a variety of agents to treat them. OBJECTIVES: To assess the effectiveness of interventions for treating oral mucositis or its associated pain in patients with cancer receiving chemotherapy or radiotherapy or both. SEARCH STRATEGY: Computerised searches of Cochrane Oral Health Group's Trials Register; Cochrane Pain, Palliative and Supportive Care Group's Trials Register; CENTRAL; MEDLINE and EMBASE were undertaken. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.Date of the most recent searches June 2006: CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: All randomised controlled trials comparing agents prescribed to treat oral mucositis in people receiving chemotherapy or radiotherapy or both. Outcomes were oral mucositis, time to heal mucositis, oral pain, duration of pain control, dysphagia, systemic infection, amount of analgesia, length of hospitalisation, cost and quality of life. DATA COLLECTION AND ANALYSIS: Data were independently extracted, in duplicate, by two review authors. Authors were contacted for details of randomisation, blindness and withdrawals. Quality assessment was carried out on these three criteria. The Cochrane Oral Health Group statistical guidelines were followed and risk ratio (RR) values calculated using fixed effect models. MAIN RESULTS: Twenty-six trials involving 1353 patients satisfied the inclusion criteria. Four agents, each in single trials, were found to be effective for improving (allopurinol RR 3.33, 95% confidence interval (CI) 1.06 to 10.49; granulocyte macrophage-colony stimulating factor RR 4.23, 95% CI 1.35 to 13.24; immunoglobulin RR 1.81, 95% CI 1.24 to 2.65; human placentral extract RR 4.50, 95% CI 2.29 to 8.86) or eradicating mucositis (allopurinol RR 19.00, 95% CI 1.17 to 307.63). Three of these trials were rated as at moderate risk of bias and one as at high risk of bias. The following agents were not found to be effective: benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and 'magic' (lidocaine solution, diphenhydramine hydrochloride and aluminum hydroxide suspension). Six trials compared the time to heal and mucositis was found to heal more quickly with two interventions: granulocyte macrophage-colony stimulating factor when compared to povidone iodine, with mean difference -3.5 days (95% CI -4.1 to -2.9) and allopurinol compared to placebo, with mean difference -4.5 days (95% CI -5.8 to -3.2).Three trials compared patient controlled analgesia (PCA) to the continuous infusion method for controlling pain. There was no evidence of a difference, however, less opiate was used per hour for PCA, and the duration of pain was shorter. One trial demonstrated that pharmacokinetically based analgesia (PKPCA) reduced pain compared with PCA: however, more opiate was used with PKPCA. AUTHORS' CONCLUSIONS: There is weak and unreliable evidence that allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin or human placental extract improve or eradicate mucositis. There is no evidence that patient controlled analgesia (PCA) is better than continuous infusion method for controlling pain, however, less opiate was used per hour, and duration of pain was shorter, for PCA. Further, well designed, placebo-controlled trials assessing the effectiveness of allopurinol mouthwash, granulocyte macrophage-colony stimulating factor, immunoglobulin, human placental extract, other interventions investigated in this review and new interventions for treating mucositis are needed.

J Radiat Res (Tokyo). 2008 Jan;49(1):49-54. Epub 2007 Dec 19.Click here to read Links

Allopurinol gel mitigates radiation-induced mucositis and dermatitis.

Department of Physiology, Nippon Dental University, School of Life Dentistry at Tokyo, Tokyo, Japan. kitagawa-j@tokyo.ndu.ac.jp

It has not been verified whether allopurinol application is beneficial in decreasing the severity of radiation-induced oral mucositis and dermatitis. Rats were divided into 4 groups and received 15 Gy irradiation on the left whisker pad. Group 1 received only irradiation. Group 2 was maintained by applying allopurinol/carrageenan-mixed gel (allopurinol gel) continuously from 2 days before to 20 days after irradiation. Group 3 had allopurinol gel applied for 20 days after radiation. Group 4 was maintained by applying carrageenan gel continuously from 2 days before to 20 days after irradiation. The intra oral mucosal and acute skin reactions were assessed daily using mucositis and skin score systems. The escape thresholds for mechanical stimulation to the left whisker pad were measured daily. In addition, the irradiated tissues at the endpoint of this study were compared with naïve tissue. Escape threshold in group 2 was significantly higher than that in group 1, and mucositis and skin scores were much improved compared with those of group 1. Concerning escape threshold, mucositis and skin scores in group 3 began to improve 10 days after irradiation. Group 4 showed severe symptoms of mucositis and dermatitis to the same extent as that observed in group 1. In the histophathological study, the tissues of group 1 showed severe inflammatory reactions, compared with those of group 2. These results suggest that allopurinol gel application can mitigate inflammation reactions associated with radiation-induced oral mucositis and dermatitis.

World J Gastroenterol. 2005 Jul 14;11(26):4032-9.Click here to read Links

Effect of the ulcerogenic agents ethanol, acetylsalicylic acid and taurocholate on actin cytoskeleton and cell motility in cultured rat gastric mucosal cells.

Helsinki University Central Hospital, Department of Surgery, Biomedicum Helsinki, Haartmaninkatu 8, Helsinki 00290, Finland.

AIM: To assess the effects of ulcerogenic agents on actin cytoskeleton and cell motility and the contribution of oxidative stress. METHODS: Rat gastric mucosal cell monolayers were cultured on coverslips. The cells were exposed, with or without allopurinol (2 mmol/L), for 15 min to ethanol (10-150 mL/L), ASA (1-20 mmol/L) or taurocholate (1-20 mmol/L), then the cells were processed for actin and vinculin staining. Cell migration after wounding was also measured. RESULTS: Exposure to 10 mL/L ethanol caused divergence of zonula adherens-associated actin bundles of adjacent cells and decreased rate of migration. These actions were opposed by xanthine oxidase inhibitor allopurinol. Exposure to 50 mL/L ethanol induced degradation and divergence of zonula adherens-associated vinculin from adjacent cells, which was, again, partially reverted by allopurinol. With 1 mmol/L ASA actin filaments became shorter and thicker. However, higher concentrations (10, 20 mmol/L) of ASA returned microfilaments thinner and longer, and decreased rate of migration. Zonula adherens-associated actin bundles were moderately distorted with 10 mmol/L ASA and with 10 mmol/L taurocholate. Exposure to taurocholate provoked changes resembling those of ASA. Taurocholate 5-20 mmol/L decreased the rate of migration dose dependently. The effects of ASA and taurocholate were not prevented by allopurinol. CONCLUSION: All ulcerogenic agents decreased the rate of migration dose dependently and induced divergence of zonula adherens-associated actin bundles of adjacent cells. In addition, ethanol and ASA caused degradation of actin cytoskeleton. Oxidative stress seems to underlie ethanol, but not ASA or taurocholate, induced cytoskeletal damage.



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