piperidines and troxipide

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Bicarbonates; Carnosine; Chalcone; Chalcones; Diterpenes; Enprostil; Gastric Mucosa; Helicobacter Infections; Helicobacter pylori; Humans; Mucus; Organometallic Compounds; Peptic Ulcer; Piperidines; Prostaglandins; Sucralfate

Cytoprotective agents are mainly used to protect the gastrointestinal tract linings and in the treatment of gastric ulcers. These agents are devoid of appreciable cytotoxic or cytostatic effects, and medicinal chemistry efforts to modify them into anticancer agents are rare. A drug repurposing campaign initiated in our laboratory with the primary focus of discovering brain cancer drugs resulted in drug-dye conjugate 1, a combination of the cytoprotective agent troxipide and heptamethine cyanine dye MHI 148. The drug-dye conjugate 1 was evaluated in three different patient-derived adult glioblastoma cell lines, commercially available U87 glioblastoma, and one paediatric glioblastoma cell line. In all cases, the conjugate 1 showed potent cytotoxic activity with nanomolar potency (EC

Topics: Antineoplastic Agents; Brain Neoplasms; Carbocyanines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Design; Drug Repositioning; Drug Therapy, Combination; Glioblastoma; Humans; Indoles; Molecular Structure; Piperidines; Temozolomide

Topics: Antineoplastic Agents; Apoptosis; Cell Movement; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Repositioning; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Piperidines; Structure-Activity Relationship

Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the C

Topics: Administration, Oral; Animals; Biological Availability; Biomarkers; Case-Control Studies; Disease Models, Animal; Male; Metabolomics; Piperidines; Rats; Stomach Ulcer; Tandem Mass Spectrometry; Tissue Distribution; Treatment Outcome

The purpose of this research aimed at preparing gastro-floating sustained-release tablets of troxipide and a further study on in vitro release and in vivo bioavailability. Under the circumstances of direct powder compression, the floating tablets were successfully prepared with HPMC as main matrix material, Carbopol as assistant matrix material, octadecanol as floating agent and sodium bicarbonate as foaming agent to float by gas-forming. The floating time and accumulative release amount as evaluation indexes were utilized to perform pre-experiment screening and single-factor test, respectively, while central composite design response surface method was applied for formulation optimization, followed by in vivo pharmacokinetic study in beagles after oral administration for floating tablets and commercial tablets used as the control. The results indicated that the floating sustained-release tablets held a better capability for floating and drug release and more satisfactory pharmacokinetic parameters, such as a lower Cmax, a prolonged Tmax, but an equivalent bioavailability calculated by AUC0-24 compared to commercial tablets. So a conclusion was finally drawn that the floating sustained-release tablets possessing a good release property could be suitable for demands of design.

Topics: Acrylic Resins; Administration, Oral; Animals; Anti-Ulcer Agents; Area Under Curve; Biological Availability; Chemistry, Pharmaceutical; Delayed-Action Preparations; Dogs; Drug Compounding; Drug Delivery Systems; Drug Liberation; Excipients; Female; Gastric Mucosa; Hypromellose Derivatives; Male; Piperidines; Tablets

We report a patient who presented with multiple small submucosal nodules with granulomatous inflammation in the minor salivary glands of the oral cavity. A 43-year-old woman presented with a 1-week history of multiple small submucosal nodules in her oral cavity after having taken medicine for abdominal pain. The patient did not have a history of fever, rectal bleeding, skin lesions or arthritis, but did have a history of drug allergy and bronchial asthma. Histopathological examination of the submucosal nodules showed sialadenitis with marked infiltration of lymphocytes, eosinophilic cells, macrophages and Langhans-type or foreign-body-type multinucleate giant cells. The macrophages tended to be aggregated and appeared to have caused immature granuloma formation without caseous necrosis. Degranulated eosinophilic cells were numerous. Sarcoidosis, Crohn's disease, tuberculosis and atypical mycobacterial infection were not identified by medical examination. Three weeks after discontinuing the medication the patient was seen again at a follow-up visit. Multiple submucosal small nodules and other symptoms were not evident at that time. This case report may represent a new entity of salivary gland disease that we tentatively refer to as 'allergic granulomatous sialadenitis'.

Topics: Abdominal Pain; Adult; Anti-Ulcer Agents; Diagnosis, Differential; Enzymes; Female; Granuloma; Humans; Hypersensitivity; Inflammation; Liver Diseases; Piperidines; Ranitidine; Salivary Glands, Minor; Sialadenitis

We previously reported that the gastric mucosa emits fluorescence of porphyrins at the onset of gastric lesions induced by hemorrhagic shock. In this study, we investigated whether the fluorescent substance concerns with the gastric mucosal injuries induced by diflofenac, a nonsteroidal antiinflammatory drug (NSAID). In the gastric mucosa treated with diclofenac, lesions were generated and myeloperoxidase activity increased. Diclofenac administration also increased thiobarbituric acid-reactive substances, a index of tissue peroxidation. After diclofenac treatment, the gastric mucosal fluorescence intensities rose. HPLC analysis demonstrated that the fluorescent substances were mesoporphyrin and protoporphyrin, which were the same as found in hemorrhagic shock. Pretreatment of the tissue with radical scavenging substances, catalase and troxipide, restrained the increase of mucosal fluorescence intensity, tissue peroxidation, and lesion formation. These findings indicate that diclofenac treatment induced the generation of porphyrins as well as tissue peroxidation in gastric mucosal tissue. This study suggests that autofluorescence observation is a useful tool to identify diclofenac-induced gastric injury.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Catalase; Chromatography, High Pressure Liquid; Diclofenac; Disease Models, Animal; Fluorescence; Free Radical Scavengers; Gastric Mucosa; Gastritis; Lipid Peroxidation; Male; Piperidines; Porphyrins; Rats; Rats, Wistar; Spectrometry, Fluorescence

Neutrophils are considered to be involved in the pathogenesis of Helicobacter pylori-associated gastroduodenal diseases on account of their potent biological functions as effector cells. Troxipide, a new antiulcer compound used for patients with gastric ulcer or gastritis, has been shown to inhibit migration and activation of guinea pig neutrophils, but little is known about the pharmacological effects on human neutrophils.. To study the effects of troxipide on chemotactic migration and superoxide generation by human neutrophils.. The chemotactic response of neutrophils was determined in a multi-well chamber with a polycarbonate filter and the generation of O2- by neutrophils was measured using a chemiluminescence method. Concentrations of troxipide in gastric mucosa were measured by high-performance liquid chromatography.. Incubation of neutrophils with 10(-6) to 10(4) M troxipide caused inhibition of recombinant interleukin-8-induced migration. These concentrations of troxipide also inhibited superoxide generation by neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine or platelet activating factor. These phenomena were not simply due to the direct cytotoxic effects since the above concentrations of troxipide did not induce neutrophil apoptosis. The concentrations of troxipide detected in the gastric mucosa after oral administration were in the range able to inhibit chemotactic migration and superoxide generation by neutrophils in vitro.. These results suggest that troxipide may exert its therapeutic effect in patients with gastric ulcer or gastritis by inhibiting inflammatory responses and mucosal injury mediated by neutrophils in gastric mucosa.

Topics: Adult; Anti-Ulcer Agents; Cell Culture Techniques; Cell Movement; Chemotaxis; Chromatography, High Pressure Liquid; Helicobacter Infections; Humans; Inflammation; Intestinal Mucosa; Neutrophils; Piperidines; Stomach Ulcer; Superoxides

The effects of three drugs for the treatment of gastritis and gastric ulcer--gefarnate, ecabet sodium, and troxipide--on periodic acid Schiff (PAS) positive cell density in rabbit conjunctiva in vivo were investigated.. Eye drops containing gefarnate (0.1%, 1%), ecabet sodium (0.1%, 1%), or troxipide (0.1%, 1%) were instilled in both eyes of rabbits, six times a day for 7 days. On the eighth day, filter paper was gently pressed on the bulbar and palpebral conjunctiva, and impression cytology was performed with PAS staining. Three points in each specimen were selected randomly, and PAS stained cells were counted.. The instillation of gefarnate increased PAS positive cell density significantly at the concentration of 1% (p < 0.05). In contrast, instillation of ecabet sodium or troxipide failed to change PAS positive cell density.. These results demonstrated that gefarnate stimulates PAS positive cell density in rabbit conjunctiva.

Topics: Abietanes; Animals; Anti-Ulcer Agents; Cell Count; Conjunctiva; Diterpenes; Gefarnate; Ophthalmic Solutions; Piperidines; Rabbits

We have developed a unique rat AGML model produced by ischemia/reperfusion plus 0.2% ammonia (I/R.NH3), either treatment which would not induce mucosal injury when used alone. The effects of troxipide and other gastric mucosal defensive drugs were investigated with this I/R.NH3-induced AGML model and other AGML models in rats. The following results were obtained: 1) Like allopurinol, troxipide at 50-200 mg/kg, p.o. dose-dependently prevented I/R.NH3-induced development of AGML and also the ischemia/reperfusion-induced increase of gastric mucosal thiobarbituric acid (TBA)-reactive substances; 2) Troxipide at 10(-6)-10(-4) M, like allopurinol, inhibited concentration-dependently in vitro xanthine oxidase activity in gastric mucosal homogenates; 3) Troxipide at 50-200 mg/kg, p.o. inhibited AGMLs induced by bleeding plus 0.2% ammonia and by 1.0% ammonia alone; and 4) Troxipide and sofalcone were similar in preventing all AGMLs tested and also the increase of mucosal TBA-reactive substances, but somewhat differed from teprenone, cetraxate hydrochloride, azulene plus L-glutamine and sucralfate. These findings suggest that troxipide may inhibit I/R.NH3-induced AGML development by preventing generation of oxygen free radicals and by protecting against mucosal fragility due to reduced energy metabolism from poor blood flow and also against ammonia-induced disruption of the gastric mucosal barrier. Therefore, troxipide may be highly effective for various AGMLs with multifactor involvement.

Topics: Acute Disease; Ammonia; Animals; Disease Models, Animal; Gastric Mucosa; Male; Piperidines; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury; Stomach Ulcer

Effects of troxipide (Ku-54) on various experimental gastric ulcers in rats were studied. Ku-54 showed a dose-dependent antiulcerous action at 100, 200 and 300 mg/kg (particularly 300 mg/kg) p.o. in water-immersion stress, pylorus ligated and acetic acid reduced rats. The effect of cimetidine (CIM) (600 mg/kg) on water-immersion stress rats was significantly higher than that of Ku-54(300 mg/kg). On the other hand, the effect of Ku-54 (300 mg/kg) was higher than that of CIM (600 mg/kg) on the pylorus ligated and acetic acid reduced groups. The antiulcerous action of Ku-54 (300 mg/kg) was not related with the content and the pH of gastric juice.

Topics: Acetates; Acetic Acid; Animals; Anti-Ulcer Agents; Cimetidine; Female; Male; Piperidines; Rats; Rats, Sprague-Dawley; Stomach Ulcer; Stress, Physiological

Effects of troxipide on several acute gastric lesions in rats were investigated in comparison with those of cetraxate. Troxipide (100, 200, 300 mg/kg) and cetraxate (100, 300, 1,000 mg/kg), given orally, dose-dependently protected the gastric mucosa from damage due to ethanol. Aspirin- and 0.6 N HCl-induced gastric lesions were dose-dependently inhibited by troxipide (200, 300 mg/kg), but only significantly inhibited by cetraxate at high dose (1,000 mg/kg). Troxipide (100, 200, 300 mg/kg) dose-dependently prevented the formation of gastric lesions induced by water-immersion stress, whereas cetraxate (600, 1,000 mg/kg) also significantly prevented gastric lesions. That is, protective effects of troxipide were much more potent than those of cetraxate against aspirin-, 0.6 N HCl- and water-immersion stress-induced gastric lesions, whereas both were almost equal against ethanol-induced gastric lesions. In addition, cytoprotective effects of troxipide against ethanol-induced lesions were most remarkable at 10, 30, 60 min after administration (100, 300 mg/kg) and lasted for up to 240 min. These results suggested that troxipide might be useful for the treatment of acute gastric lesions in humans.

Topics: Acute Disease; Animals; Anti-Ulcer Agents; Aspirin; Ethanol; Gastric Mucosa; Hydrochloric Acid; Immersion; Male; Piperidines; Rats; Stomach Diseases; Stress, Physiological; Tranexamic Acid

Effects of KU-54 on the biosynthesis of glycoprotein in the gastric mucosa and the liver, as measured by the rate of incorporation of 14C-glucosamine, were investigated in rats under various conditions after a single administration of 14C-glucosamine of (9.88 microCi/animal, ip). 14C-glucosamine was incorporated with relative ease in the acid-insoluble fraction of the gastric mucosa. KU-54 at 100 mg/kg was orally administered twice daily for 5 days in rats (though it was given once on the 5th day) before injection of 14C-glucosamine. The rate of 14C-glucosamine incorporation into the acid-insoluble fraction of the gastric mucosa was significantly increased by KU-54, but that of the hepatic tissue was not increased. In addition, hydrocortisone (20 mg/kg) also produced a drop of incorporation of 14C-glucosamine in the gastric mucosa, but oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given once on the 5th day) significantly inhibited the drop of incorporation of 14C-glucosamine in the gastric mucosa, but that in the hepatic tissue was not inhibited. Therefore, the effects of KU-54 were greater in the gastric mucosa than in the hepatic tissue. On the 5th day of the ulcer produced by acetic acid in rats, the specific radioactivity in the mucosa of the margin of the ulcer increased significantly compared with that in the normal (non-ulcerative) mucosa, but this phenomenon was not affected by KU-54.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Gastric Mucosa; Glucosamine; Glycoproteins; Hydrocortisone; Injections, Intraperitoneal; Liver; Male; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer

Effects of 3,4,5-trimethoxy-N-(3-piperidyl) benzamide (KU-54), an antiulcer drug, on the tissue respiration of the gastric mucosa and the liver were studied in rats. Oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given only once on the 5th day) caused an increase in oxygen consumption of the gastric mucosa in rats, but did not affect that of the liver. Thus the principal active site of KU-54 on tissue respiration was found to be the gastric mucosa. Oral KU-54 at 100 mg/kg once daily for 11 days significantly accelerated the oxygen consumption of marginal gastric mucosa of acetic acid ulcer in rats. The effect of oral gefarnate at 200 mg/kg was about half that of KU-54 at 100 mg/kg, but it was not significant. In addition, oral KU-54 at 100 mg/kg twice daily for 5 days (though it was given only once on the 5th day) significantly inhibited the decrease of oxygen consumption of the gastric mucosa in hemorrhagic shocked rats. The effect of oral gefarnate at 100 mg/kg was not like that at KU-54 at 100 mg/kg in conscious rats. When KU-54 was added in the incubation medium with small gastric mucosal fragments of rats, the increase of oxygen consumption of the gastric mucosa did not occur. Oral KU-54 at 100 mg/kg significantly accelerated a glycogen consumptive stimulation of the gastric mucosa of the corpus in ischemic rats, but the respiration of the antral mucosa was not accelerated under anaerobic incubating conditions. Oral gefarnate at 200 mg/kg accelerated an anaerobic glycolysis of the gastric antral mucosa in rats.

Topics: Animals; Anti-Ulcer Agents; Gastric Mucosa; Gefarnate; Glycolysis; In Vitro Techniques; Liver; Male; Oxygen Consumption; Piperidines; Rats; Rats, Inbred Strains; Stomach Ulcer

In dogs and rabbits anesthetized with pentobarbital sodium or urethane, respectively, the gastric mucosal blood flow was measured by the thermoelectrical method after intravenous administration of 3-(3, 4, 5-trimethoxybenzamido)piperidine(KU-54), an antiulcer drug. In the gastric corpus of rabbits, the maximal mucosal blood flow (11.9%) was attained within 1 min after KU-54(5 mg/kg i.v.) dosing and there was a prolonged increase during 8 min. Administration of KU-54 produced a transitory depression of the blood pressure by about 20%, and induced a beta-adrenergic-like action, presumably because both the blood pressure depression and the gastric mucosal blood flow increment were simultaneous in rabbits. This phenomenon was however, not abolished by pretreatment with propranolol, a beta-adrenergic blocker, therefore KU-54 may not be a beta-adrenergic blocking agent. Administration of gefarnate, a standard antiulcer drug, produced a slight increase in gastric mucosal blood flow and response to this drug was less than that seen with KU-54. Sulpiride, a standard antiulcer drug, two peaks on the gastric mucosal blood flow increment in rabbits and the pattern of blood flow increment differed from that seen with KU-54. The increment of gastric mucosal blood flow produced by KU-54 (5 mg/kg i.v.) was more successive in the gastric antrum than that in the gastric corpus. In fasting rabbits, the main period of gastric mucosal blood flow increment produced by KU-54 (5 mg/kg i.v.) was more successive than that seen in the non-fasting animals. In dogs, the maximal blood flow (16%) was observed at 7 min after KU-54 (5 mg/KG i.v.) dosing and there was a prolonged increase during 6 min.

Topics: Animals; Anti-Ulcer Agents; Blood Pressure; Dogs; Fasting; Female; Gastric Mucosa; Male; Piperidines; Rabbits; Regional Blood Flow