topiramate and Stomach-Ulcer

Topiramate is an anticonvulsant drug effective against a wide range of seizures and epilepsies. The present study was conducted to investigate the possible protective effect of topiramate on indomethacin-induced gastric mucosal damage in rats. The animals were randomly distributed into four experimental groups with 10 animals in each group. Group 1 was the control group received vehicle only (DMSO at 1:4 (w/v)), group 2 was the model group received indomethacin (50 mg/kg; i.p.), and groups 3 and 4 received topiramate (100 mg/kg; i.p.) and ranitidine (100 mg/kg; i.p.), respectively, 1 h before indomethacin (50 mg/kg; i.p.). The efficacy of topiramate was compared with ranitidine. Animals were euthanized 4 h after indomethacin administration, and gastric tissues were collected for macroscopical, histopathological, and biochemical analyses. The mucosal lesions in the gastric corpus were evaluated by pathological examinations. The results revealed that the administration of indomethacin caused evident gastric mucosal damage with morphological and histological manifestation, whereas topiramate pretreatment extensively ameliorated the gastric injuries. Topiramate pretreatment also reduced the contents of tissue malonaldehyde, enhanced ferric reducing antioxidant power value and glutathione levels, and increased the activity of superoxide dismutase, catalase, and glutathione peroxidase in gastric mucosa compared to the model group. Our results indicate that topiramate might possess a protective role against indomethacin-induced gastric ulcers by inhibition of oxidative stress in gastric tissue.

Topics: Animals; Antioxidants; Indomethacin; Ranitidine; Rats; Stomach Ulcer; Superoxide Dismutase; Topiramate

Topics: Adolescent; Adult; Age Factors; Amitriptyline; Analgesics, Non-Narcotic; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Child; Drug Industry; Duodenal Ulcer; Female; France; Gastroesophageal Reflux; Humans; Male; Migraine Disorders; Pharmacovigilance; Phenytoin; Plasma Substitutes; Polygeline; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Sex Factors; Stomach Ulcer; Topiramate

DNA clones for the beta-class carbonic anhydrase (CA, EC 4.2.1.1) of Helicobactor pylori (hpbetaCA) were obtained. A recombinant hpbetaCA protein lacking the N-terminal 15-amino acid residues was produced and purified, representing a catalytically efficient CA. hpbetaCA was strongly inhibited (K(I)s in the range of 24-45 nM) by many sulfonamides/sulfamates, among which acetazolamide, ethoxzolamide, topiramate, and sulpiride, all clinically used drugs. The dual inhibition of alpha- and/or beta-class CAs of H. pylori might represent a useful alternative for the management of gastritis/gastric ulcers, as well as gastric cancer. This is also the first study showing that a bacterial beta-CA can be a drug target.

Topics: Amino Acid Sequence; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chemistry, Pharmaceutical; Cloning, Molecular; Drug Design; Enzyme Inhibitors; Helicobacter pylori; Humans; Molecular Sequence Data; Recombinant Proteins; Sequence Homology, Amino Acid; Stomach Neoplasms; Stomach Ulcer; Sulfonamides

We have cloned and sequenced Helicobacter pylori alpha-class carbonic anhydrase (hpCA) from patients with different gastric mucosal lesions, including gastritis (n=15), ulcer (n=6), and cancer (n=16). Although several polymorphisms were newly identified such as 12Ala, 13Thr, 16Ile, and 168Phe, there was no significant relevance of any polymorphism with gastric mucosal lesion types. A library of sulfonamides/sulfamates has been investigated for the inhibition of hpCA, whereas new derivatives have been obtained by attaching 4-tert-butyl-phenylcarboxamido/sulfonamido tails to benzenesulfonamide/1,3,4-thiadiazole-2-sulfonamide scaffolds. All types of activity for inhibition of hpCA have been detected. Dorzolamide and simple 4-substituted benzenesulfonamides were weak inhibitors (KI 873-4360 nM). Sulfanilamide, orthanilamide, some of their derivatives, and indisulam showed better activity (KI 413-640 nM), whereas most of the clinically used inhibitors, such as methazolamide, ethoxzolamide, dichlorophenamide, brinzolamide, topiramate, zonisamide, etc., acted as medium-potency inhibitors (KI 105-378 nM). Some potent hpCA inhibitors were detected too (KI 12-84 nM) among acetazolamide, 4-amino-6-chloro-1,3-benzenedisulfonamide and some newly designed compounds incorporating lipophilic tails. Some of the newly prepared derivatives had selectivity ratios for inhibiting hpCA over hCA II in the range of 1.25-3.48, showing thus some selectivity for inhibiting the bacterial enzyme. Since hpCA is essential for the survival of the pathogen in acid, it might be used as a new pharmacologic tool in the management of drug-resistant H. pylori.

Topics: Amino Acid Sequence; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cloning, Molecular; DNA, Bacterial; Gastric Mucosa; Gastritis; Helicobacter pylori; Humans; Molecular Sequence Data; Polymorphism, Genetic; Stomach Neoplasms; Stomach Ulcer; Sulfonamides; Sulfonic Acids