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1.
Ann Neurol ; 89(2): 199-211, 2021 02.
Article in English | MEDLINE | ID: mdl-33159466

ABSTRACT

Advances in genetic discoveries have created substantial opportunities for precision medicine in neurodevelopmental disorders. Many of the genes implicated in these diseases encode proteins that regulate gene expression, such as chromatin-associated proteins, transcription factors, and RNA-binding proteins. The identification of targeted therapeutics for individuals carrying mutations in these genes remains a challenge, as the encoded proteins can theoretically regulate thousands of downstream targets in a considerable number of cell types. Here, we propose the application of a drug discovery approach originally developed for cancer called "transcriptome reversal" for these neurodevelopmental disorders. This approach attempts to identify compounds that reverse gene-expression signatures associated with disease states. ANN NEUROL 2021;89:199-211.


Subject(s)
Gene Expression Regulation/genetics , Neural Stem Cells/drug effects , Neurodevelopmental Disorders/drug therapy , Neurons/drug effects , Transcriptome/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Anticonvulsants/pharmacology , Antidepressive Agents/pharmacology , Antipsychotic Agents/pharmacology , Carbamazepine/pharmacology , Computer Simulation , Drug Discovery , Epirizole/pharmacology , Gene Expression Profiling , Humans , Induced Pluripotent Stem Cells , MCF-7 Cells , Mice , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Neural Stem Cells/metabolism , Neurodevelopmental Disorders/genetics , Neurons/metabolism , PC-3 Cells , Perphenazine/pharmacology , Primary Cell Culture , RNA-Seq , Risperidone/pharmacology , Single-Cell Analysis , Trazodone/pharmacology , Trimipramine/pharmacology
2.
Dig Dis Sci ; 59(2): 297-306, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24385009

ABSTRACT

OBJECTIVES: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that directly upregulates VEGF, Ref-1, p21, and anti-apoptotic genes such as Bcl-xL. In this study, we hypothesized that STAT3 signaling is activated and provides a critical protective role that is required for enterocyte survival during the early phases of cysteamine-induced duodenal ulcers. METHODS: We studied the effect of inhibition of STAT3 activity on cysteamine-induced duodenal ulcers in rats and egr-1 knockout mice using STAT3/DNA binding assay, immunohistochemistry, immunoblot, and quantitative reverse transcriptase PCR analyses. RESULTS: We found that G-quartet oligodeoxynucleotides T40214, a specific inhibitor of STAT3/DNA binding, aggravated cysteamine-induced duodenal ulcers in rats 2.8-fold (p < 0.05). In the pre-ulcerogenic stage, cysteamine induced STAT3 tyrosine phosphorylation, its translocation to nuclei, an increased expression and nuclear translocation of importin α and ß in the rat duodenal mucosa. Cysteamine enhanced the binding of STAT3 to its DNA consensus sequences at 6, 12, and 24 h after cysteamine by 1.5-, 1.8-, and 3.5-fold, respectively, and activated the expression of STAT3 target genes such as VEGF, Bcl-xL, Ref-1, and STAT3-induced feedback inhibitor, a suppressor of cytokine signaling 3. We also demonstrated that egr-1 knockout mice, which are more susceptible to cysteamine-induced duodenal ulcers, had lower levels of STAT3 expression, its phosphorylation, expression of importin α or ß, and STAT3/DNA binding than wild-type mice in response to cysteamine. CONCLUSIONS: Thus, STAT3 represents an important new molecular mechanism in experimental duodenal ulceration.


Subject(s)
Duodenal Ulcer/metabolism , Duodenum/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction , alpha Karyopherins/metabolism , beta Karyopherins/metabolism , Active Transport, Cell Nucleus , Animals , Apoptosis , Cysteamine , Disease Models, Animal , Duodenal Ulcer/chemically induced , Duodenal Ulcer/genetics , Duodenal Ulcer/pathology , Duodenal Ulcer/prevention & control , Duodenum/drug effects , Duodenum/pathology , Early Growth Response Protein 1/deficiency , Early Growth Response Protein 1/genetics , Epirizole , Female , Gene Expression Regulation , Mice , Mice, Knockout , Oligodeoxyribonucleotides/pharmacology , Phosphorylation , Rats , Rats, Sprague-Dawley , STAT3 Transcription Factor/antagonists & inhibitors , Signal Transduction/drug effects , Time Factors , Tyrosine
3.
Proc Natl Acad Sci U S A ; 108(48): 19264-9, 2011 Nov 29.
Article in English | MEDLINE | ID: mdl-22084084

ABSTRACT

Pancreatic ß-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing ß-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of ß-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in ß-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis.


Subject(s)
Cell Differentiation/drug effects , Drug Discovery/methods , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/drug effects , Pharmaceutical Preparations/metabolism , Acetanilides/pharmacology , Animals , Animals, Genetically Modified , Caffeic Acids/pharmacology , Cell Line, Tumor , Cell Proliferation , DNA Primers/genetics , Dimethyl Sulfoxide , Dose-Response Relationship, Drug , Epirizole/pharmacology , Fluorescent Antibody Technique , Green Fluorescent Proteins , Guanosine Triphosphate/biosynthesis , HMGB1 Protein/metabolism , Larva/drug effects , Microscopy, Confocal , Mycophenolic Acid/pharmacology , Real-Time Polymerase Chain Reaction , Sulfanilic Acids/pharmacology , Tretinoin/metabolism , Zebrafish , p-Aminoazobenzene/analogs & derivatives , p-Aminoazobenzene/pharmacology
4.
Arzneimittelforschung ; 54(4): 221-9, 2004.
Article in English | MEDLINE | ID: mdl-15146935

ABSTRACT

The effects of a new benzimidazole derivative, ME3407 (n-butyl-2-(thiazolo-[5,4-b]pyrid-2-yl) sulfinylacetate, CAS 133903-90-9), on gastric acid secretion and gastric and duodenal ulcers in rats were examined. ME3407, given orally, inhibited dose-dependently (0.3-30 mg/kg) the incidence of gastric lesions such as Shay ulcers, and water-immersion stress-, acetylsalicylic acid (ASA)- and histamine-induced erosions. In addition, ME3407 showed marked therapeutic effect on HCl- and ASA-induced lesions. In the lumen-perfused rats, oral administration of ME3407 inhibited dose-dependently (1-100 mg/kg) gastric acid secretion induced by histamine and tetragastrin with ED50 values of 3.02 and 3.37 mg/kg, respectively. Oral administration of ME3407 at a dose of 30 mg/kg also inhibited the elevation of serum gastrin level. The development of duodenal ulcers caused by mepirizole and systeamine was also potently inhibited by ME3407 at an oral dose of 0.1-30 mg/kg. However, when given at 30 mg/kg intraduodenally, subcutaneously or intravenously, ME3407 did not inhibit these acutely induced gastric elosion and acid output. ME3407 was not detected in the serum upon oral administration. These results indicated that ME3407 was active only by oral administration, and exerts direct action on the ulcers and acid secretion from the gastric membrane.


Subject(s)
Anti-Ulcer Agents/pharmacology , Benzimidazoles/pharmacology , Gastric Acid/metabolism , Gastric Mucosa/metabolism , Pyridines/pharmacology , Thiazoles/pharmacology , Animals , Anti-Inflammatory Agents , Aspirin , Cysteamine , Duodenal Ulcer/chemically induced , Duodenal Ulcer/prevention & control , Epirizole , Gastric Fistula/physiopathology , Gastric Mucosa/drug effects , Gastrins/blood , Histamine , Immersion/adverse effects , Indomethacin , Male , Pepsin A/metabolism , Pylorus/physiology , Rats , Stomach Ulcer/chemically induced , Stomach Ulcer/prevention & control
5.
Inorg Chem ; 42(25): 8328-36, 2003 Dec 15.
Article in English | MEDLINE | ID: mdl-14658885

ABSTRACT

A novel mu-pyrazolato-mu-hydroxo-dibridged copper(II) complex has been synthesized and structurally characterized: [(Cu(mepirizole)Br)2(mu-OH)(mu-pz)] (mepirizole=4-methoxy-2-(5-methoxy-3-methyl-1H-pyrazol-1-yl)-6-methylpyrimidine; pz=pyrazolate). The title compound crystallizes in the monoclinic system, space group P2(1)/c, with a=15.618(2) A, b=15.369(3) A, c=16.071(3) A, and beta=112.250(1) degrees. The structure is built up of dinuclear [(Cu(mepirizole)Br)2(mu-OH)(mu-pz)] units with five-coordinated copper(II) ions (CuBrN3O chromophores) linked by mu2-OH and mu2-pyrazolato bridges that are well separated from each others. The intramolecular copper-copper distance is 3.378(3) A. Magnetic susceptibility data show that the copper atoms are strongly antiferromagnetically coupled with J=-770 cm(-1). The obtained triplet-singlet energy gap is compared with those reported for a series of related dimers. The strong antiferromagnetic coupling arising from the complementarity of the hydroxo and pyrazolato bridges has been discussed on the basis of DFT calculations.


Subject(s)
Epirizole/chemistry , Iron/chemistry , Chemical Phenomena , Chemistry, Physical , Crystallography, X-Ray , Indicators and Reagents , Ligands , Magnetics , Models, Molecular
6.
Int J Pharm ; 245(1-2): 55-65, 2002 Oct 01.
Article in English | MEDLINE | ID: mdl-12270242

ABSTRACT

Modifications of the structure of pBR322 DNA caused by interaction with cisplatin, transplatin and Pd(II) and Pt(II) mepirizole derivatives were studied. The compounds were incubated with the plasmid DNA for 24 h at 37 degrees C and then observed with an atomic force microscope. Circular DNA was used because the small tertiary structural changes are easy to monitor. Likewise, its superhelical nature mimics DNA better than certain forms of intracellular DNA such as chromatin. AFM images clearly reveal that the complexes induce changes in the topological forms of fully relaxed pBR322 DNA. Most of the compounds produce a more compact DNA structure with modified writhing number. Analysis of gel migration of the relaxed pBR322 DNA incubated with the platinum complexes provides complementary information, which is in good agreement with AFM results.


Subject(s)
Epirizole/analogs & derivatives , Epirizole/chemistry , Palladium , Plasmids/chemistry , Platinum Compounds/chemistry , Antineoplastic Agents/chemistry , Cisplatin/chemistry , Electrophoresis, Gel, Two-Dimensional , Humans , In Vitro Techniques , Microscopy, Atomic Force , Nucleic Acid Conformation
7.
Can J Physiol Pharmacol ; 77(5): 330-8, 1999 May.
Article in English | MEDLINE | ID: mdl-10535682

ABSTRACT

The biochemical and pharmacological characteristics of a newly synthesized H+-K+ ATPase inhibitor, 2-amino-4,5-dihydro-8-phenylimidazole[2,1-b]thiazolo[5,4-g]benzothiazole (YJA20379-1), were investigated. In the pig gastric microsomes, YJA20379-1 inhibited the gastric H+-K+ ATPase regardless of pH condition, IC50 values being 21 and 24 microM at pH 6.4 and 7.4, respectively. The inhibitory activity of YJA20379-1 was antagonized by dithiothreitol treatment but could not be reversed by dilution and washing of the enzyme preparation. In Sprague-Dawley rats, YJA20379-1, administered i.d., p.o, i.v., or s.c., significantly inhibited basal gastric acid secretion, with ED50 values of 4.7, 20.2, 6.3, and 13.4 mg/kg, respectively. The antisecretory action of YJA20379-1 was short lasting (less than 7 h at an oral dosing of 30 mg/kg). Oral administration of YJA20379-1 also prevented the formation of ethanol, indomethacin, and water immersion stress induced gastric lesions and mepirizole-induced duodenal ulcers in rats. Furthermore, YJA20379-1 accelerated the healing of acetic acid induced chronic gastric ulcers in rats. In conclusion, these results suggest that YJA20379-1 has a potent inhibitory activity on the gastric H+-K+ ATPase but much shorter duration of antisecretory action than omeprazole, thereby exerting its anti-ulcer effects partly with cytoprotective activity.


Subject(s)
Anti-Ulcer Agents/pharmacology , Imidazoles/pharmacology , Proton Pump Inhibitors , Thiazoles/pharmacology , Animals , Benzothiazoles , Dithiothreitol/pharmacology , Epirizole/toxicity , Ethanol/toxicity , Female , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Indomethacin/toxicity , Male , Rats , Rats, Sprague-Dawley , Swine , Time Factors
8.
J Inorg Biochem ; 75(3): 205-12, 1999 Jun 30.
Article in English | MEDLINE | ID: mdl-10474205

ABSTRACT

Pd(II) and Pt(II) complexes of formulae [MLCl2], where L = mepirizole, were synthesized and characterized. Two complexes were obtained and studied by different techniques: IR, 1H and 13C NMR and XPS spectroscopies and mass spectrometry (electrospray). The crystal structure of the complex cis-dichloro-4-methoxy-2-(5-methoxy-3-methyl- pyrazol-1-yl)-6-methyl-pyrimidinepalladium(II), [Pd(mep)Cl2], was studied by crystal X-ray diffraction. It consists of discrete molecules with planar geometry. Pd(II) ions are four-coordinated by two mepirizole nitrogen atoms (N1 from the pyrazole ring and N4 from the pyrimidine ring) and two chlorine atoms. The geometry of the PdN2Cl2 chromophore is a distortion of the square-planar coordination. Data from powder pattern X-ray diffraction of cis-dichloro-4-methoxy-2-(5-methoxy-3-methyl-pyrazol-1-yl)-6-methyl- pyrimidineplatinum(II), [Pt(mep)Cl2], demonstrated that the two complexes are isostructural. The cytotoxic activity of both Pd and Pt complexes was checked for six different tumor cell lines and was lower than that of cisplatin. The Pt bound to DNA was also checked and only a low percentage is able to cross the cell membrane.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Epirizole/chemistry , Epirizole/pharmacology , Palladium/chemistry , Platinum/chemistry , Animals , Cell Division/drug effects , Cell Line, Transformed , Chlorocebus aethiops , Crystallography, X-Ray , HL-60 Cells , Humans , Jurkat Cells , Ligands , Mice , Spectrum Analysis , Structure-Activity Relationship , Vero Cells
9.
J Gastroenterol Hepatol ; 14(3): 251-7, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10197495

ABSTRACT

BACKGROUND: Pantoprazole, 2-[(2-pyridylmethyl) sulphinyl] benzimidazole, is a new substituted benzimidazole that inhibits the parietal cell H+/K+-ATPase. METHODS: In the present study, the anti-secretory and anti-ulcer activities of pantoprazole were compared with those of omeprazole and lansoprazole in rats. RESULTS: Pantoprazole (0.3-3 mg/kg, p.o.) as well as omeprazole (1-10 mg/kg, p.o.) and lansoprazole (1-10 mg/kg, p.o.) dose-dependently decreased both basal acid secretion in pylorus-ligated rats and the stimulated acid secretion induced by mepirizole in acute fistula rats, and the effects of pantoprazole were more potent than those of omeprazole and lansoprazole, the ED50 values for the stimulated acid secretion being 0.8, 2.0 and 1.2 mg/kg, respectively. Neither of these drugs had any effect on duodenal HCO3- secretion. These pump inhibitors prevented the development of duodenal lesions in response to mepirizole in a dose-related manner, the ED50 values for pantoprazole, omeprazole and lansoprazole being 0.4, 2.0 and 1.3 mg/kg, respectively. Likewise, pantoprazole showed the healing promoting action on chronic duodenal ulcers induced by acetic acid, and this effect was also more potent when compared to omeprazole or lansoprazole. CONCLUSIONS: We conclude that pantoprazole exhibited both anti-ulcer and healing promoting effects on duodenal ulcers in rats, and the effects may be attributable to its potent anti-secretory action. Other pump inhibitors such as omeprazole and lansoprazole were almost equally effective as pantoprazole, yet this drug was most potent on the basis of ED50 values.


Subject(s)
Anti-Ulcer Agents/therapeutic use , Benzimidazoles/therapeutic use , Duodenal Ulcer/drug therapy , Omeprazole/analogs & derivatives , Omeprazole/therapeutic use , Proton Pump Inhibitors , Sulfoxides/therapeutic use , 2-Pyridinylmethylsulfinylbenzimidazoles , Acetic Acid , Animals , Bicarbonates/metabolism , Dose-Response Relationship, Drug , Duodenal Ulcer/chemically induced , Enzyme Inhibitors/therapeutic use , Epirizole , Gastric Acid/metabolism , Lansoprazole , Male , Pantoprazole , Rats , Rats, Sprague-Dawley , Wound Healing/drug effects
10.
Aliment Pharmacol Ther ; 13(1): 87-96, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9892884

ABSTRACT

BACKGROUND: S-0509, 2-[(tert-butoxycarbonylmethyl) [(m-(carboxy-phenyl)-ureidomethyl-carbonyl]] aminobenzo phenone, was developed as a potent and selective CCKB/gastrin receptor antagonist that does not affect the central nervous system. METHODS: We evaluated the effects of S-0509 on gastric acid secretion and duodenal ulcerogenic and healing responses in rats comparing it with L-365,260, another CCKB/gastrin receptor antagonist. RESULTS: S-0509 (0.1 approximately 10 mg/kg, i.d.) was able to dose-dependently decrease basal acid secretion and inhibit the acid secretory responses induced by both pentagastrin (60 microg/kg/h, i.v.) and peptone (10%, i.g.) but not histamine (4 mg/kg/hr, i.v.) or carbachol (60 microg/kg/h, i.v.). L-365,260 (10 and 30 mg/kg, i.d.) caused only partial a suppression of the acid secretory response to pentagastrin but not to other stimuli, including peptone treatment. On the other hand, a duodenal ulcerogen, mepirizole (200 mg/kg, s.c. ) caused an increase in acid secretion and resulted in penetrating ulcers in the proximal duodenum, and these ulcers gradually healed over 3 weeks. S-0509 significantly inhibited both the acid secretory (> 1.0 mg/kg, i.d.) and ulcerogenic (> 3 mg/kg, p.o.) responses induced by mepirizole when it was given as a pre-treatment. It also promoted significantly the healing of these ulcers (> 3 x 2 mg/kg, p. o.) when it was given twice daily for 14 days. In contrast, L-365, 260 (30 mg/kg) tended to reduce the severity of mepirizole-induced duodenal ulcers, with a slight inhibition of acid secretion, but it caused no influence on the healing response of these ulcers. CONCLUSION: These results confirmed that S-0509 is a selective CCKB/gastrin receptor antagonist with potent antisecretory action in vivo conditions, and further demonstrated that this agent not only prevents the development of duodenal ulcers but also shows healing promoting action on duodenal ulcers, probably through the blockade of CCKB/gastrin receptors.


Subject(s)
Benzophenones/pharmacology , Duodenal Ulcer/physiopathology , Phenylurea Compounds/pharmacology , Receptors, Cholecystokinin/antagonists & inhibitors , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzodiazepinones/pharmacology , Benzodiazepinones/therapeutic use , Benzophenones/therapeutic use , Dose-Response Relationship, Drug , Duodenal Ulcer/drug therapy , Epirizole/pharmacology , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/metabolism , Hydrogen-Ion Concentration , Male , Pentagastrin/pharmacology , Peptones/pharmacology , Phenylurea Compounds/therapeutic use , Rats , Rats, Sprague-Dawley
11.
Chin J Physiol ; 42(3): 129-35, 1999 Sep 30.
Article in English | MEDLINE | ID: mdl-10707886

ABSTRACT

Effects of endothelin-1 on gastric acid secretion, duodenal HCO3- secretion, and duodenal mucosal integrity were investigated in anesthetized rats, in comparison with those of TY-10957, a stable analogue of prostacyclin. A rat stomach mounted on an ex-vivo chamber or a proximal duodenal loop was perfused with saline, and gastric acid or duodenal HCO3- secretion was measured using a pH-stat method and by adding 100 mM NaOH or 10 mM HCl, respectively. Duodenal lesions were induced by mepirizole (200 mg/kg) given subcutaneously. Intravenous administration of endothelin-1 (0.6 and 1 nmol/kg) caused an increase of duodenal HCO3- secretion with concomitant elevation of blood pressure; this effect was antagonized by co-administrahon of BQ-123 (ET(A) antagonist; 3 mg/kg, i.v.) and significantly mitigated by vagotomy. Likewise, endothelin-1 caused a significant decrease in histamine-stimulated acid secretion, and this effect was also significantly antagonized by BQ-123. Although TY-10957 (10 and 30 mg/kg, i.v.) produced a temporal decrease of blood pressure, this agent caused not only an increase of duodenal HCO3- secretion, independent of vagal nerves, but also a decrease of acid secretion as well. In addition, both endothelin-1 and TY-10957 significantly prevented mepirizole-induced duodenal lesions at the doses that caused an increase of duodenal HCO3- secretion and a decrease of gastric acid secretion. These results suggest that endothelin-1 affects the duodenal mucosal integrity by modifying both gastric acid and duodenal HCO3- secretions, the effects being mediated by ET(A) receptors.


Subject(s)
Bicarbonates/metabolism , Duodenum/drug effects , Duodenum/metabolism , Endothelin-1/pharmacology , Intestinal Mucosa/metabolism , Animals , Anti-Inflammatory Agents, Non-Steroidal , Anti-Ulcer Agents/pharmacology , Antihypertensive Agents/pharmacology , Duodenal Ulcer/chemically induced , Duodenal Ulcer/metabolism , Duodenal Ulcer/pathology , Duodenum/pathology , Epirizole , Epoprostenol/analogs & derivatives , Epoprostenol/metabolism , Epoprostenol/pharmacology , Gastric Acid/metabolism , Hydrogen-Ion Concentration , Male , Peptides, Cyclic/pharmacology , Rats , Rats, Sprague-Dawley , Vagotomy
12.
Dig Dis Sci ; 43(8): 1657-64, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9724147

ABSTRACT

The role of active oxygen species and lipid peroxidation in the pathogenesis of duodenal ulcers induced by mepirizole was investigated in rats. Oral administration of mepirizole (200 mg/kg) resulted in ulcer lesions in the proximal duodenum. Thiobarbituric acid-reactive substances (TBA-reactive substances), an indicator of lipid peroxidation, also significantly increased in the duodenal mucosa. Myeloperoxidase (MPO) activity in the duodenal mucosa, a sign of polymorphonuclear leukocyte (PMN) accumulation, significantly increased. Combination treatment with polyethylene glycol-modified Serratia Mn-SOD and catalase significantly decreased the size of the ulcers and TBA-reactive substances in the duodenal mucosa. Allopurinol, a xanthine oxidase inhibitor, also reduced the size of duodenal ulcers. Both the size of the ulcers and the increase in TBA-reactive substances in the duodenal mucosa were significantly lower in PMN-depleted rats. Mepirizole increased the surface expression of adhesion molecule CD18 on PMNs in vitro. These results suggest that lipid peroxidation, mediated by active oxygen species generated from xanthine oxidase and PMNs, plays an important role in the pathogenesis of duodenal ulcers induced by mepirizole.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/toxicity , Duodenal Ulcer/metabolism , Epirizole/toxicity , Lipid Peroxidation , Reactive Oxygen Species/metabolism , Allopurinol/pharmacology , Animals , CD18 Antigens/analysis , Catalase/pharmacology , Duodenal Ulcer/chemically induced , Duodenal Ulcer/pathology , Free Radical Scavengers/pharmacology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Neutrophils/pathology , Peroxidase/metabolism , Polyethylene Glycols/pharmacology , Rats , Rats, Wistar , Superoxide Dismutase/metabolism , Superoxide Dismutase/pharmacology , Thiobarbituric Acid Reactive Substances/analysis , Xanthine Oxidase/antagonists & inhibitors , Xanthine Oxidase/metabolism
13.
Life Sci ; 63(5): 317-25, 1998.
Article in English | MEDLINE | ID: mdl-9714419

ABSTRACT

Effects of pituitary adenylate cyclase activating polypeptide (PACAP) on duodenal mucosal HCO3- secretion and ulcerogenic responses induced by mepirizole in anesthetized rats were examined and compared with those of vasoactive intestinal polypeptide (VIP). Animals were given mepirizole (200 mg/kg, s.c.) for induction of duodenal ulcers, and gastric acid and duodenal HCO3- secretions were measured with or without pretreatment of PACAP-27 or VIP. Mepirizole increased acid secretion and induced hemorrhagic lesions in the proximal duodenum within 6 h. Intravenous bolus injection or infusion of PACAP-27 (4 and 8 nmol/kg or 8 nmol/kg/h) increased duodenal HCO3- secretion even in the presence of mepirizole, without effect on acid secretion, and significantly reduced the severity of duodenal lesions caused by mepirizole. In contrast, VIP (8 nmol/kg, i.v.) given by bolus injection significantly decreased acid secretion induced by mepirizole, in addition to stimulation of HCO3- secretion, and prevented duodenal lesions in response to mepirizole. These results suggest that PACAP-27 increases duodenal HCO3- secretion and this action may be important in maintaining the duodenal mucosal integrity against acid, and VIP affords duodenal protection by both increasing duodenal HCO3- secretion and decreasing acid secretion. The reason for the different effects of PACAP and VIP on acid secretion is unknown.


Subject(s)
Bicarbonates/metabolism , Duodenal Ulcer/drug therapy , Duodenum/drug effects , Gastric Acid/metabolism , Intestinal Mucosa/metabolism , Neuropeptides/pharmacology , Neurotransmitter Agents/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Duodenal Ulcer/chemically induced , Duodenal Ulcer/metabolism , Duodenum/metabolism , Epirizole/pharmacology , Intestinal Mucosa/drug effects , Male , Pituitary Adenylate Cyclase-Activating Polypeptide , Rats , Rats, Sprague-Dawley , Vasoactive Intestinal Peptide/therapeutic use
14.
Arch Pharm Res ; 21(3): 241-7, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9875438

ABSTRACT

This study was designed to determine biochemical and pharmacological properties of a newly synthesized benzimidazole derivative, 2-amino-4,5-dihydropyrido [1,2-a] thiazolo [5,4-g] benzimidazole (YJA20379-5) in vitro and in vivo. In the leaky membrane vesicles of pig gastric mucosa, YJA20379-5 inhibited the K(+)-stimulated H+,K(+)-ATPase activity in a concentration- and time-dependent manner, with IC50 values being 43 microM and 31 microM at pH 6.4 and 7.4, respectively. YJA20379-5, given intraduodenally, had a potent inhibitory effect on the gastric acid secretion in pylorus-ligated rats. The ED50 value for acid secretion was 15.4 mg/kg. YJA20379-5, administered orally, also suppressed gastric damages induced by water-immersion stress, indomethacin and ethanol, and duodenal damage induced by mepirizole in rats; the ED50 values were 17.6, 4.7, 3.0 and 18.7 mg/kg, respectively. Furthermore, repeated oral administration of YJA20379-5 accelerated the spontaneous healing of acetic acid-induced gastric ulcers in rats. It is concluded that the antisecretory activity of YJA20379-5 appears to be associated with inhibition of H+,K(+)-ATPase, while its antigastric and antiduodenal lesion activities are primarily related to the antisecretory effect.


Subject(s)
Anti-Ulcer Agents/pharmacology , Benzimidazoles/pharmacology , Gastric Mucosa/enzymology , Proton Pump Inhibitors , Thiazoles/pharmacology , Animals , Anti-Inflammatory Agents, Non-Steroidal , Epirizole , Ethanol , Female , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/pathology , Immersion , Indomethacin , Microsomes/drug effects , Microsomes/enzymology , Omeprazole/pharmacology , Peptic Ulcer/chemically induced , Peptic Ulcer/pathology , Peptic Ulcer/prevention & control , Rats , Rats, Sprague-Dawley , Stress, Psychological/pathology , Swine
15.
Can J Physiol Pharmacol ; 76(9): 921-9, 1998 Sep.
Article in English | MEDLINE | ID: mdl-10066143

ABSTRACT

This study was designed to determine the effect of a newly synthesized proton pump inhibitor, 2-dimethylamino-4,5-dihydrothiazolo[4,5:3,4]pyridol[1,2-a]be nzimidazole (YJA20379-2), on gastric H(+)-K(+) ATPase activity, acid secretion, and experimental gastroduodenal lesions or ulcers in rats. YJA20379-2 inhibited in a concentration-dependent manner the proton pump (H(+)-K(+) ATPase) activity in isolated hog gastric mucosal microsomes, therefore, confirming its classification as a proton pump inhibitor. The inhibitory efficacy of YJA20379-2 on the proton pump was about eight times higher than that of omeprazole at pH 7.4. The activity of the inhibited enzyme was not restored by dilution and washout method, so this implied that the inhibition of YJA20379-2 is not reversible. YJA20379-2, given intraduodenally or orally, potently suppressed acid secretion in pylorus-ligated rats, with ED50 values of 3.6 and 7.7 mg.kg(-1), respectively. Pretreatment with YJA20379-2 dose dependently protected the gastric mucosa from damage induced by absolute ethanol, water-immersion stress, indomethacin, and the duodenal mucosa from damage induced by mepirizole in rats, with ED50 values of 11.0, 21.0, 0.5, and 18.7 mg.kg(-1), respectively. Repeated administration of YJA20379-2 also dose dependently accelerated spontaneous healing of acetic acid induced gastric ulcers. These results suggest that YJA20379-2 has potent antisecretory and antiulcer effects, which are exerted by suppression of H(+)-K(+) ATPase activity in gastric parietal cells, such that YJA20379-2 may be useful for the clinical treatment of peptic ulcer diseases.


Subject(s)
Anti-Ulcer Agents/pharmacology , Imidazoles/pharmacology , Proton Pump Inhibitors , Animals , Epirizole/toxicity , Ethanol/toxicity , Female , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Gastric Mucosa/enzymology , Indomethacin/toxicity , Male , Microsomes/enzymology , Rats , Rats, Sprague-Dawley , Swine
16.
Chem Pharm Bull (Tokyo) ; 44(9): 1700-6, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8855364

ABSTRACT

(1H-Pyrazol-1-yl)-, (1H-imidazol-1-yl)-, and (1H-1,2,4-triazol-1-yl)pyrimidines were prepared and evaluated for cytoprotective antiulcer activity. Among them, 4-methoxy-6-methyl-2-(1H-pyrazol-1-yl)pyrimidine (18) showed potent inhibition of the HCl-ethanol-induced and water-immersion stress-induced ulcers in rats, as well as low acute toxicity.


Subject(s)
Anti-Ulcer Agents/chemical synthesis , Anti-Ulcer Agents/therapeutic use , Epirizole/chemistry , Pyrimidines/chemistry , Administration, Oral , Animals , Anti-Ulcer Agents/chemistry , Disease Models, Animal , Epirizole/pharmacology , Magnetic Resonance Spectroscopy , Male , Peptic Ulcer/drug therapy , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship
17.
Arzneimittelforschung ; 46(2): 177-84, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8720310

ABSTRACT

The effects of (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3-[2- [[[5-(methylamino)methyl-2-furyl] methyl]thio]ethyl]-2-(methylsulfonyl)guanidine (CAS 140695-21-2, T-593), a new histamine H2-receptor antagonist, on gastric secretion and experimental gastric and duodenal lesion/ulcer models in rats were examined. The drug administered orally or intraduodenally significantly and dose-dependently inhibited both basal and histamine-stimulated acid secretion. Pepsin output was also inhibited by the drug nearly dose-dependently. The acid-inhibitory effect of T-593 persisted for 12 h after a single oral administration. T-593 potently protected the gastric mucosa against water-immersion stress-, indometacin- and HCl.acetylsalicylic acid-induced lesions, but it had no effect on HCl.ethanol-induced lesions. T-593 significantly prevented the development of mepirizole-induced duodenal ulcers. Spontaneous healing of kissing gastric ulcers was significantly enhanced when T-593 was administered for 14 days. The antisecretory and antilesion/antiulcer effects of T-593 were similar to those of ranitidine and omeprazole. It is concluded that T-593 is a potent antisecretory and antiulcer drug.


Subject(s)
Gastric Mucosa/metabolism , Guanidines/pharmacology , Histamine H2 Antagonists/pharmacology , Peptic Ulcer/drug therapy , Sulfones/pharmacology , Animals , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/therapeutic use , Dose-Response Relationship, Drug , Epirizole , Gastric Acid/metabolism , Gastric Mucosa/drug effects , Guanidines/therapeutic use , Histamine/pharmacology , Histamine H2 Antagonists/therapeutic use , Indomethacin , Male , Omeprazole/pharmacology , Omeprazole/therapeutic use , Pepsin A/metabolism , Peptic Ulcer/chemically induced , Peptic Ulcer/etiology , Ranitidine/pharmacology , Ranitidine/therapeutic use , Rats , Rats, Sprague-Dawley , Stomach Ulcer/chemically induced , Stomach Ulcer/prevention & control , Stress, Psychological/complications , Sulfones/therapeutic use
18.
Chem Pharm Bull (Tokyo) ; 43(11): 2021-3, 1995 Nov.
Article in English | MEDLINE | ID: mdl-8575039

ABSTRACT

With a view to finding more effective antiulcer agents, a series of 2-benzylthio-5,6,7,8-tetrahydro-4(3H)-quinazolinones and related compounds were synthesized and evaluated in a histamine-stimulated gastric secretion model. The sodium salt of the 2-(dimethylamino)benzylthio derivative (8) showed gastric mucosal protection and gastric antisecretion activities, and was also effective against experimental gastric and duodenal ulcers induced by some ulcerogenic agents. Based on a comparison of the antiulcer properties of 8 with those of the lead compounds (1 and 2) and cimetidine, it appears that, for improvement of antiulcer activity, the reduction of gastric acidity is a more important factor than the reduction of gastric volume output or gastric total acid output.


Subject(s)
Anti-Ulcer Agents/pharmacology , Gastric Mucosa/drug effects , Quinazolines/pharmacology , Animals , Anti-Ulcer Agents/chemistry , Anti-Ulcer Agents/therapeutic use , Aspirin/administration & dosage , Aspirin/toxicity , Cimetidine/administration & dosage , Cimetidine/pharmacology , Cimetidine/therapeutic use , Disease Models, Animal , Duodenal Ulcer/drug therapy , Epirizole/administration & dosage , Epirizole/toxicity , Ethanol/administration & dosage , Ethanol/toxicity , Gastric Acid/metabolism , Gastric Mucosa/injuries , Histamine/administration & dosage , Histamine/toxicity , Indomethacin/administration & dosage , Indomethacin/toxicity , Male , Quinazolines/chemistry , Quinazolines/therapeutic use , Rats , Rats, Sprague-Dawley , Stomach Ulcer/drug therapy , Structure-Activity Relationship
19.
Dig Dis Sci ; 40(5): 1112-7, 1995 May.
Article in English | MEDLINE | ID: mdl-7729273

ABSTRACT

The hyperemia at the duodenal ulcer margin is important for ulcer healing. We studied the effect of tobacco cigarette smoke on the hyperemia at the margin of mepirizole-induced duodenal ulcer. Duodenal mucosal blood flow values measured by iodo[14C]antipyrine (IAP) autoradiography and hydrogen gas clearance (HGC) were compared. Twenty-four hours after rats were injected with an ulcerogenic dose of mepirizole, they were exposed to tobacco cigarette smoke and duodenal mucosal blood flow was measured by IAP autoradiography. There is a significant correlation between the blood flow measurements by HGC and IAP autoradiography. The hyperemia at the ulcer margin previously demonstrated in our laboratory is absent after exposure of the rats to tobacco cigarette smoke. We speculate that the inhibition of ulcer margin hyperemia could explain the aggravation of duodenal ulcer by tobacco cigarette smoke.


Subject(s)
Duodenal Ulcer/physiopathology , Hyperemia/physiopathology , Intestinal Mucosa/blood supply , Nicotiana , Plants, Toxic , Smoke , Animals , Antipyrine/analogs & derivatives , Autoradiography , Carbon Radioisotopes , Duodenal Ulcer/chemically induced , Epirizole , Hydrogen , Male , Rats , Rats, Sprague-Dawley
20.
Dig Dis Sci ; 40(3): 670-7, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7895564

ABSTRACT

The inhibition of nitric oxide (NO) production by NO synthase inhibitors stimulates HCO3- secretion in the rat duodenal mucosa. Therefore, we examined the effects of NG-nitro-L-arginine methyl ester (L-NAME, the NO synthase inhibitor) and nitroprusside (the exogenous NO donor) on the duodenal HCO3- and ulcerogenic responses in anesthetized rats. Animals were administered mepirizole (200 mg/kg, subcutaneously) for induction of duodenal ulcers, and gastric acid and duodenal HCO3- secretions were measured with or without pretreatment with L-NAME (5 mg/kg, intravenously) or nitroprusside (4 mg/kg, intravenously). Mepirizole increased acid secretion, decreased the acid-induced duodenal HCO3- secretion, and induced hemorrhagic lesions in the proximal duodenum. The inhibition of NO production by L-NAME potentiated the acid secretory response, increased the duodenal HCO3- secretion, and prevented the duodenal lesions, and these changes were all antagonized by simultaneous administration of L-arginine (200 mg/kg, intravenously) but not D-arginine. On the other hand, nitroprusside slightly reduced the acid response but further decreased the HCO3- output, resulting in aggravation of duodenal lesions induced by mepirizole. These data suggest that the inhibition of endogenous NO production by the NO synthase inhibitor L-NAME increases duodenal HCO3- secretion and protects the duodenal mucosa against acid injury.


Subject(s)
Arginine/analogs & derivatives , Duodenal Ulcer/chemically induced , Duodenum/metabolism , Epirizole/adverse effects , Nitric Oxide/physiology , Animals , Arginine/pharmacology , Bicarbonates/metabolism , Duodenal Ulcer/metabolism , Duodenal Ulcer/prevention & control , Duodenum/drug effects , Gastric Acid/metabolism , Intestinal Secretions/chemistry , Intestinal Secretions/drug effects , Male , NG-Nitroarginine Methyl Ester , Nitric Oxide/antagonists & inhibitors , Nitroprusside/pharmacology , Rats , Rats, Sprague-Dawley
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