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Amtolmetin: A Reappraisal of NSAID with Gastroprotection. ARTHRITIS 2016; 2016:7103705. [PMID: 27092274 PMCID: PMC4820613 DOI: 10.1155/2016/7103705] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 03/06/2016] [Indexed: 11/17/2022]
Abstract
Aim. To assess the gastrosparing effect of amtolmetin guacyl (AMG) against other nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with osteo-/rheumatoid arthritis. Methods. A literature search was done in the electronic databases (PubMed, Google Scholar, Embase, and Scopus) with key words “amtolmetin guacyl”, “amtolmetin”, and “arthritis”; filters were applied to obtain publications between 01-Jan-1985 and 01-Oct-2015, which were “clinical trials” in osteo-/rheumatoid arthritis patients and in “English language.” Studies were assessed using the Jadad criteria and trials with score ≥ 3 were included in the analysis to compare the safety and efficacy of AMG against other NSAIDs. Results. Search yielded 19 publications of which 3 were included for analysis. Baseline characteristics of patients were comparable between the AMG group and other NSAIDs (diclofenac, celecoxib, and piroxicam) groups in all trials. Efficacy of AMG was similar to the other NSAIDs compared in the trials. The number of adverse events (AEs) reported was similar between both the groups; however, severe AEs reported were significantly lower in the AMG group. Of note was the significant lower number of duodenal ulcers after treatment in the AMG group. Conclusions. AMG has efficacy similar to other NSAIDs and a safer gastrointestinal AE profile when compared to the other NSAIDs.
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Synthesis, spectroscopic and DFT structural characterization of two novel ruthenium(III) oxicam complexes. In vivo evaluation of anti-inflammatory and gastric damaging activities. J Inorg Biochem 2014; 134:25-35. [DOI: 10.1016/j.jinorgbio.2014.01.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 01/15/2014] [Accepted: 01/16/2014] [Indexed: 11/19/2022]
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Abstract
Many prodrug reviews describe specific examples of the successful application of prodrug technology to produce blockbuster drugs, such as simvastatin, omeprazole, acyclovir and enalapril. These reviews are helpful to understand the previous success stories and case histories of prodrug technology. The aim of the current review seeks to more clearly define quantitative trends in the changes in the physicochemical property parameters between the successful prodrug and the active parent molecule. This information can serve to guide medicinal chemists toward more successful pharmaceutical prodrugs in the future.
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Rong Z, Xu Y, Zhang C, Xiang D, Li X, Liu D. Evaluation of intestinal absorption of amtolmetin guacyl in rats: Breast cancer resistant protein as a primary barrier of oral bioavailability. Life Sci 2013; 92:245-51. [DOI: 10.1016/j.lfs.2012.12.010] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 10/05/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023]
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Kirkova M, Alexandova A, Kesiova M, Tsvetanova E, Georgieva A, Todorov S. Potential antioxidant activity of celecoxib and amtolmetin guacyl: in vitro studies. ACTA ACUST UNITED AC 2007; 27:13-8. [PMID: 17199871 DOI: 10.1111/j.1474-8673.2006.00391.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
1. In vitro studies of the potential antioxidant activity of the selective cyclo-oxygenase-2 inhibitor celecoxib and the non-steroid anti-inflammatory drug amtolmetin guacyl (AMG) were carried out. The study included experiments on the ability of these drugs to affect some indices of the oxidative stress [lipid peroxidation (LP), activity of antioxidant enzymes, glutathione (GSH) level] in rat stomach and colon mucosa and in liver. 2. Celecoxib and AMG did not change the activity of the enzymes GSH-peroxidase, oxidased glutathione (GSSG)-reductase and glucose-6-phosphate-dehydrogenase, as well as the GSH level in all tissue preparations. An increased superoxide dismutase (SOD) activity and a tendency to a decreased Fe/ascorbic acid-induced LP in stomach and colon mucosa were found, but only in the presence of AMG. 3. In the liver, both celecoxib and AMG decreased spontaneous and Fe/ascorbic acid-induced LP. SOD activity was enhanced only in the presence of AMG. 4. Experiments aimed at studying celecoxib and AMG in free oxygen radical-generating systems were also carried out. AMG and tolmetin (the main metabolite of AMG) inhibited OH*-provoked deoxyribose degradation in a Fenton system. Celecoxib had no effect on free radicals when tested in the same system. 5. In conclusion, the results of the present in vitro studies suggest that AMG and celecoxib possess antioxidant and metal-chelating abilities, which might contribute to their beneficial effects.
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Affiliation(s)
- M Kirkova
- Institute of Physiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev st, 1113 Sofia, Bulgaria
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Kirkova M, Alexandova A, Kesiova M, Todorov S. In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems. Comparison with non-selective and COX-2 selective NSAIDs. ACTA ACUST UNITED AC 2007; 27:99-104. [PMID: 17391279 DOI: 10.1111/j.1474-8673.2007.00395.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
1. The in vivo effects of the non-steroid anti-inflammatory drug (NSAID) amtolmetin guacyl, a pro-drug of the NSAID tolmetin, on lipid peroxidation, glutathione levels and activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase) in rat gastric mucosa, colon mucosa and liver, were compared with the effects of non-selective (indomethacin, diclofenac) and COX-2 selective (celecoxib) NSAIDs. 2. Indomethacin treatment led to an increase in lipid peroxidation, glutathione peroxidase and glucose-6-phosphate dehydrogenase activities and to a decrease in catalase activity and glutathione levels in gastric mucosa. In contrast, amtolmetin guacyl treatment was without effects in gastric and colon mucosa, or liver from control animals. Like amtolmetin guacyl, celecoxib had no effect on the lipid peroxidation, or on enzyme and non-enzyme antioxidant defence systems in gastric mucosa. 3. It is suggested that the lack of pro-oxidant effects in vivo associated with amtolmetin guacyl treatment contribute improved gastric tolerability.
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Affiliation(s)
- M Kirkova
- Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
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Kirkova M, Kesiova M, Konstantinova S, Alexandrova A, Petrov L, Tsvetanova E, Todorov S. In vivo effects of amtolmetin guacyl on lipid peroxidation and antioxidant defence systems in different models of gastrointestinal injury. ACTA ACUST UNITED AC 2007; 27:63-70. [PMID: 17199877 DOI: 10.1111/j.1474-8673.2006.00390.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
1. The in vivo effects of the non-steroid anti-inflammatory drug (NSAID) amtolmetin guacyl (AMG) on lipid peroxidation (LP) and on antioxidant enzyme and non-enzyme defence systems were investigated in models of stomach and colon damages, induced by other NSAIDs, by ethanol or by 2,4,6-trinitrobenzenesulfonic acid (TNBS). 2. Indomethacin increased LP, glutathione peroxidase (GSH-PX) and glucose-6-phosphate dehydrogenase (Glu-6-P-DH) activities and decreased glutathione levels in gastric mucosa. Pretreatment with AMG normalized some of the parameters affected by indomethacin. 3. Treatment of rats with ethanol for 0.5 h led to a decrease in glutathione levels as well as activities of glutathione reductase and Glu-6-P-DH in gastric mucosa. AMG, administered 0.5 h before ethanol, limited the adverse actions of ethanol. 4. Amtolmetin guacyl failed to abolish the TNBS-induced changes in the followed-up parameters in colon mucosa and liver, but additional alterations (as with tolmetin) were not observed. 5. The beneficial profile of AMG in the various experimental models of free radical-induced damage investigated in this study suggests the possibility that this drug might possess antioxidant activity.
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Affiliation(s)
- M Kirkova
- Institute of Physiology, Bulgarian Academy of Sciences, 23 Acad. G. Bonchev St, 1113 Sofia, Bulgaria
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Abstract
AIM: To investigate the gastroprotective effect and mechanism of amtolmetin guacyl (AMG, MED15) in mice.
METHODS: Male and female Kunming strain mice, weighing 18-22 g, were utilized in the experiment. Normal or ethanol-induced gastric mucosal damage models in mice were successfully established to investigate the gastroprotective effect and mechanism of AMG. In the experiment of gastric mucosal damage after repeated treatment with AMG, the mice were randomly divided into 5 groups: normal group, 3 AMG groups receiving (75, 150 and 300 mg/kg), and tolmetin group receiving 90 mg/kg. The mice were randomly divided into 6 groups as follows: normal group, model group, AMG groups with doses of 75, 150 and 300 mg/kg, respectively, and tolmetin group with a dose of 90 mg/kg in ethanol-induced gastric mucosal damage experiment. The severity of gastric mucosal lesions was scored from 0 to 5. Gastric tissue sections were stained with hematoxylin and eosin (HE) and examined under light microscopy. Also gastric tissue sections were stained with uranyl acetate and lead citrate, and examined under electron microscopy. In addition, nitric oxide (NO) and malondialdehyde (MDA) contents, and nitric oxide synthase (NOS) and superoxide dismutase (SOD) activities in the stomach tissue homogenates were measured by biochemical methods.
RESULTS: Repeated treatment with AMG (75, 150 and 300 mg/kg) for 7 d did not induce any appreciable mucosal damage, and the average score was not significantly different from that of normal mice. In contrast, tolmetin (90 mg/kg) produced significant gastric mucosal lesions compared with the normal group (P < 0.01). AMG (75, 150 and 300 mg/kg) significantly reduced the severity of gastric lesions induced by ethanol in a dose-dependent manner as compared with the model group (P < 0.05, AMG 75 and 150 mg/kg vs model; P < 0.01, AMG 300 mg/kg vs model). Light and electron microscopy revealed that AMG (150 and 300 mg/kg) induced minimal changes in the surface epithelium layer, without vascular congestion or leucocyte adherence. AMG (75, 150 and 300 mg/kg) demonstrated dose-dependent gastroprotective effects on mice in our study. AMG (75, 150 and 300 mg/kg) could significantly increase NO content and NOS level in the stomach homogenates of mice compared with the model group (P < 0.05, AMG 75 mg/kg and 150 mg/kg groups vs model group; P < 0.01, AMG 300 mg/kg vs model group) respectively. Moreover, AMG (150 and 300 mg/kg) not only significantly increased SOD activities but also obviously decreased the MDA content in the stomach homogenates of mice.
CONCLUSION: AMG exerts significant gastroprotective actions on mice and the involved mechanisms may be its antioxidative effect and induction of NO production.
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Affiliation(s)
- Yuan-Hai Li
- School of Pharmacy, Anhui Medical University, Institute of Clinical Pharmacology, Anhui Medical University,Tunxi West Road, Hefei 230032, Anhui Province, China
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Morini G, Guaita E, Lazzaretti M, Grandi D, Coruzzi G. Morphological features of rat gastric mucosa after acute and chronic treatment with amtolmetin guacyl: comparison with non-selective and COX-2-selective NSAIDs. Digestion 2004; 68:124-32. [PMID: 14610345 DOI: 10.1159/000074726] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2003] [Accepted: 08/04/2003] [Indexed: 02/04/2023]
Abstract
BACKGROUND/AIMS The compound amtolmetin guacyl (AMG) has been characterized in both animal and human studies as a novel non-selective non-steroidal anti-inflammatory drug (NSAID) endowed with lower ulcerogenicity in comparison with traditional NSAIDs due to a unique mechanism of action, namely the increase in endogenous production of gastric nitric oxide. METHODS Conscious rats were treated either acutely (4 h) or chronically (3 and 14 days) with intragastric AMG (50 and 150 mg/kg), the non-selective NSAID tolmetin (TOL, 30 and 100 mg/kg) or the COX-2-selective NSAID celecoxib (CXIB, 20 and 60 mg/kg). Macroscopically visible and histologic lesions were evaluated. The ultrastructure of mucosal microvasculature was assessed. RESULTS (1) TOL and CXIB caused quantitatively greater endothelial damage and inflammatory cell infiltration than that induced by AMG; (2) AMG and CXIB, unlike TOL, did not cause epithelial damage after acute or chronic treatment, and (3) gastric lesions induced by TOL underwent adaptation during chronic treatment. CONCLUSION Endothelial cell damage in the gastric microvasculature is an early event following both non-selective and COX-2-selective inhibitors. The low gastric mucosal toxicity of AMG is confirmed after acute and chronic treatment.
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Affiliation(s)
- Giuseppina Morini
- Department of Human Anatomy, Pharmacology and Forensic Medicine, University of Parma, Parma, Italy
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Tubaro E, Belogi L, Mezzadri CM, Bettelli E. Impact on the bowel of amtolmetin guacyl, a new gastroprotective non-steroidal anti-inflammatory drug. Eur J Pharmacol 2003; 467:173-83. [PMID: 12706472 DOI: 10.1016/s0014-2999(03)01598-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Amtolmetin guacyl (MED15) is a new non-steroidal anti-inflammatory drug (NSAID) which shares anti-inflammatory, analgesic and antipyretic activity with the other drugs of the NSAID family but which shows, unexpectedly, strong gastroprotective activity similar to misoprostol. This effect has been attributed to the presence in its molecule of a vanillic moiety responsible for stimulation of capsaicin receptors present throughout the length of the gastrointestinal tract. MED15 shows antispasmodic activity in the bowel against a number of agonists and compares favourably with reference compounds. In in vivo indomethacin-induced rat ileitis, MED15 heals better than 5-aminosalicylic acid and sulfasalazine, as well as down-regulating intestinal wall myeloperoxidase content. In acetic acid-induced colitis in the rat, levels of malondialdehyde were found to be more markedly reduced with MED15 than with 5-aminosalicylic acid. In contrast with the effect in the stomach, MED15 protective effect in the bowel appears to be unrelated to nitric oxide (NO) production. The MED15 enteroprotective effect is related to stimulation of intestinal capsaicin receptors as demonstrated by the loss of protective effect in the presence of capsazepine, a specific receptor antagonist of capsaicin. In conclusion, following the favourable results obtained in animal models and notwithstanding the pharmacological effects typical of an NSAID, MED15 may rationally be proposed for the treatment of various human colitis conditions and Crohn's disease.
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Affiliation(s)
- Ezio Tubaro
- Research Laboratories, Medosan Ricerca S.r.l., Via Cancelleria, 12, 00040 Albano Laziale, Rome, Italy.
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Coruzzi G, Coppelli G, Spaggiari S, Cavestro GM, Okolicsanyi L, Lo Giudice P, Pisano C, Tepperman BL. Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible gastric nitric oxide synthase. Dig Liver Dis 2002; 34:403-10. [PMID: 12132787 DOI: 10.1016/s1590-8658(02)80037-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The novel non-steroidal anti-inflammatory drug amtolmetin guacyl has been shown to possess markedly reduced ulcerogenic effects and nitric oxide-mediated gastroprotective activity against the damage induced by ethanol in the rat. AIMS To investigate, in the rat, the role of nitric oxide and of inducible nitric oxide synthase isoform in the protective effect of amtolmetin guacyl against the gastric damage induced by ethanol. METHODS The effects of amtolmetin guacyl on gastric transmucosal potential difference and on gastric mucosal blood flow were investigated in the anaesthetised rat; myeloperoxidase activity, inducible and endothelial nitric oxide synthase protein content were determined in rat gastric mucosal homogenates. The anti-inflammatory drug tolmetin and the bacterial lipopolysaccharide from Escherichia coli were studied for comparison. RESULTS In the anaesthetised rat, amtolmetin guacyl, but not tolmetin, reduced by approximately 50% the fall in gastric potential difference and, to a lesser extent, the macroscopic damage induced by ethanol. The effect of amtolmetin guacyl on transmucosal potential difference was prevented by the selective inducible nitric oxide synthase inhibitor 1400W. In amtolmetin guacyl-treated rats, 1400W decreased gastric mucosal blood flow, whereas it was inactive in vehicle- and tolmetin-treated animals. In gastric mucosal homogenates, both amtolmetin guacyl and lipopolysaccharide, but not tolmetin, increased inducible, but not endothelial, nitric oxide synthase protein content, as revealed by Western immunoblotting. CONCLUSIONS These data confirm that amtolmetin guacyl is a non-steroidal anti-inflammatory agent devoid of gastrolesive properties, that can actually reduce the damaging effects of ethanol through the increase in nitric oxide production, via the inducible isoform of nitric oxide synthase.
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Affiliation(s)
- G Coruzzi
- Institute of Pharmacology, School of Medicine, University of Parma, Italy.
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Riezzo G, Chiloiro M, Montanaro S. Protective effect of amtolmetin guacyl versus placebo diclofenac and misoprostol in healthy volunteers evaluated as gastric electrical activity in alcohol-induced stomach damage. Dig Dis Sci 2001; 46:1797-804. [PMID: 11508686 DOI: 10.1023/a:1010686411837] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Amtolmetin guacyl (AMG) is a nonsteroidal antiinflammatory drug (NSAID) of high therapeutic activity and free of damaging effects on the gastrointestinal tract. Since acute ulcer and nausea have been found to be associated with gastric dysrhythmias, cutaneous electrogastrography and ultrasonographic study of the gastric emptying time were performed simultaneously in 24 healthy volunteers before and for 180 min after a liquid meal with 0.5 g/kg body weight of alcohol in double-blind, placebo-controlled, crossover studies. Before the recording session, each subject had taken placebo, AMG, a standard NSAID, or a gastric protective drug for four days. Alcohol administration increased the tachygastria percentage while diclofenac, AMG, and misoprostol alone did not induce gastrointestinal symptoms and gastric dysrhythmias. As regards alcohol-induced gastric dysrhythmia, placebo and diclofenac showed a clear increase in tachygastria while AMG and misoprostol did not. AMG is able to induce a normalization of gastric dysrhythmia induced by alcohol administration probably due to its peculiar mechanism of action, which involves capsaicin and CGRP pathways.
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Affiliation(s)
- G Riezzo
- Laboratory of Experimental Pathophysiology, Scientific Institute of Gastroenterology, Castellana Grotte, Bari, Italy
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Lazzaroni M, Anderloni A, Bianchi Porro G. The effects on gastroduodenal mucosa of a new nonsteroidal anti-inflammatory drug, amtolmetin-guacyl, versus piroxicam in healthy volunteers: a short-term, double-blind, endoscopically controlled study. Eur J Gastroenterol Hepatol 2001; 13:833-9. [PMID: 11474314 DOI: 10.1097/00042737-200107000-00012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
AIM Amtolmetin-guacyl (AMG) (2-[2[1-methyl-5-(4-methylbenzoyl) pyrrol-2-yl] acetamido] acetic acid 2-methoxyphenyl ester) is a recent drug that, in preliminary studies, has shown effective anti-inflammatory properties with improved gastrointestinal safety. Our study was designed to investigate the effects of AMG and piroxicam on gastroduodenal mucosa in healthy volunteers. MATERIALS AND METHODS Forty-two healthy volunteers aged 18--45 years were randomized in a double-blind manner to AMG 1200 mg for 2 days and 600 mg for 12 days, or piroxicam 40 mg for 2 days and 20 mg for 12 days. Endoscopic evaluation and laboratory tests were performed at baseline and at the end of the treatment. The mucosa was evaluated by endoscopy using a predefined scale: the score could range from 0 to 4. Only volunteers with endoscopy grade 0-1 entered the trial. RESULTS The median post-treatment endoscopy gastric injury scores were 1 (range 0--4) in the AMG-treated volunteers and 3 (range 0--4) in the piroxicam-treated volunteers (P = 0.04). There were two cases with an endoscopic gastric score of 4 in the AMG group, and seven in the piroxicam group (P = 0.1). The corresponding values in the duodenum were 1/21 volunteers in the AMG group and 1/21 in the piroxicam group. Eight out of 11 subjects with an endoscopic score of 4 were Helicobacter pylori negative, and 3/11 were infected by the micro-organism. Different adverse reactions were reported by 15/21 volunteers (71%) in the AMG group and by 12/21 (57%) in the piroxicam group. None of these events resulted in interruption of the study. CONCLUSIONS AMG is a new anti-inflammatory drug with limited gastric toxicity. If these findings are confirmed on a wider scale in long-term trials, then the drug might become a valid alternative to current treatments, especially for patients such as those with rheumatoid arthritis who need steroids and second-line drugs simultaneously.
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Montrone F, Santandrea S, Caruso I, Gerli R, Cesarotti ME, Frediani P, Bassani R. Amtolmetin guacyl versus piroxicam in patients with osteoarthritis. J Int Med Res 2000; 28:91-100. [PMID: 10898121 DOI: 10.1177/147323000002800204] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The efficacy and tolerability of amtolmetin guacyl (AMG), a new non-steroidal anti-inflammatory drug, were compared with piroxicam, in patients with osteoarthritis. In a randomized double-blind study patients with arthritis (n = 99) received either 600 mg AMG on an empty stomach or 20 mg of piroxicam on a full stomach, once daily for 30 days. All clinical parameters improved significantly with both drugs; there were no significant differences between the two treatments. Tolerability, assessed by the patients, was significantly better in the AMG group. In the piroxicam group nine of 50 patients withdrew because of side-effects (gastrointestinal) compared with two of 49 (nausea and headache) in the AMG group. There were three cases of perforation, ulcer and bleeding in the piroxicam group but no serious side-effects with AMG. Total numbers of side-effects were similar in the two groups, but epigastric and abdominal pain were more frequent and more intense with piroxicam. AMG was as effective as piroxicam in controlling the symptoms of osteoarthritis, but showed better gastrointestinal tolerability.
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Affiliation(s)
- F Montrone
- Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
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Tubaro E, Belogi L, Mezzadri CM. The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal anti-inflammatory drug. Eur J Pharmacol 2000; 387:233-44. [PMID: 10650165 DOI: 10.1016/s0014-2999(99)00791-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Amtolmetin guacyl (2-methoxyphenyl-1-methyl-5-p-methylbenzoyl-pyrrol-2-acetamido acetate) (MED15) is a new nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic and antipyretic properties similar to the traditional drugs, but with unexpected gastroprotective effects. In an in vivo rat model, amtolmetin guacyl administered orally demonstrates inhibition of gastric acid secretion following stimulation by various agonists, and up-regulation of gastric bicarbonate production. Pretreatment with MED15 also shows a significant reduction of indomethacin-induced gastric damage in the rat. The reason behind this behaviour appears to be bound to the presence in the MED15 molecule of a vanillic moiety known to stimulate capsaicin receptors. In fact, the antisecretive effect of MED15 is blocked by capsazepine (a specific capsaicin receptor antagonist). This effect is confirmed by the interference found with anti-histamine H(1) drugs. Owing to the connection between capsaicin and calcitonin gene-related peptide (CGRP), a possible effect of MED15 on CGRP receptors was hypothesized, considering the leading role played on gastric mucosa by the predominant sensory neuropeptide of the stomach wall, CGRP. In fact, the anti-secretive and gastroprotective effect of MED15 is abolished by CGRP-(8-37) (the specific CGRP receptor antagonist). The unmodified MED15 molecule is found throughout the gastroenteric tract for long periods of time following oral administration, as further confirmation of the mechanism of action being based on the presence of the vanillic moiety at receptor level.
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Affiliation(s)
- E Tubaro
- Medosan Ricerca, Research Laboratories, Via Cancelleria 12, 00040, Albano Laziale, Italy
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Affiliation(s)
- I Coruzzi
- Institute of Pharmacology, University of Parma, Via Volturno 39, Parma, Italy
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