The biochemical and pharmacological properties of a newly synthesized H+-K+ ATPase inhibitor, 2-dimethylamino-4,5-dihydrothiazolo[4,5:3,4]pyridol-[1,2-a]benzimidazole

1998 ◽  
Vol 76 (9) ◽  
pp. 921-929 ◽  
Author(s):  
Young-Kuk Chung ◽  
Man-Sik Chang ◽  
Kyu-Bong Kim ◽  
Sang-Kwon Sohn ◽  
Tae-Wook Woo ◽  
...  
Keyword(s):  
Proton Pump Inhibitor ◽  
Atpase Activity ◽  
Acid Secretion ◽  
Proton Pump ◽  
Water Immersion ◽  
Repeated Administration ◽  
Gastric Ulcers ◽  
Dependent Manner ◽  
Atpase Inhibitor ◽  
Concentration Dependent Manner

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]benzimidazole (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.Key words: antisecretion, cytoprotection, H+-K+ ATPase, YJA20379-2.

Biochemical and pharmacological characteristics of a newly synthesized H+-K+ ATPase inhibitor, YJA20379-1, 2-amino-4,5-dihydro-8-phenylimidazole [2,1-b]thiazolo[5,4-g]benzothiazole

1999 ◽  
Vol 77 (5) ◽  
pp. 330-338
Author(s):  
Sang-Kwon Sohn ◽  
Man-Sik Chang ◽  
Wahn-Soo Choi ◽  
Kyu-Bong Kim ◽  
Tae-Wook Woo ◽  
...  
Keyword(s):  
Acid Secretion ◽  
Inhibitory Activity ◽  
Water Immersion ◽  
Gastric Ulcers ◽  
Sprague Dawley ◽  
Atpase Inhibitor ◽  
Duodenal Ulcers ◽  
Cytoprotective Activity ◽  
Sprague Dawley Rats ◽  
Potent Inhibitory Activity

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 µM 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.Key words: proton pump inhibitor, acid secretion, anti-ulcer effects, cytoprotective activity.

scholarly journals Effect of omeprazole--a gastric proton pump inhibitor--on pentagastrin stimulated acid secretion in man.

Gut ◽  
1983 ◽  
Vol 24 (4) ◽  
pp. 270-276 ◽  
Author(s):  
T Lind ◽  
C Cederberg ◽  
G Ekenved ◽  
U Haglund ◽  
L Olbe
Keyword(s):  
Proton Pump Inhibitor ◽  
Acid Secretion ◽  
Proton Pump ◽  
Gastric Proton Pump

scholarly journals Two Cases of Proton Pump Inhibitor (PPI)-resistant Gastric Ulcers Caused by Gastric Empting Disturbance

2005 ◽  
Vol 54 (2/3) ◽  
pp. 69-74
Author(s):  
Yuki NISHINO ◽  
Jun NISHIKAWA ◽  
Masaaki SATAKE ◽  
Toshihiko MATSUMOTO ◽  
Keiko AKASHI ◽  
...  
Keyword(s):  
Proton Pump Inhibitor ◽  
Proton Pump ◽  
Gastric Ulcers

scholarly journals The gastric H, K-ATPase system also functions as the Na, K-ATPase and Ca-ATPase in altered states

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 165
Author(s):  
Tushar Ray
Keyword(s):  
Atpase Activity ◽  
Acid Secretion ◽  
Proton Pump ◽  
Intracellular Signaling ◽  
Parietal Cells ◽  
Apical Plasma Membrane ◽  
Altered States ◽  
Apparent Lack ◽  
Ca Pump ◽  
Na Pump

This article offers an explanation for the apparent lack of Na, K-ATPase activity in parietal cells although ouabain has been known to inhibit gastric acid secretion since 1962. The gastric H, K-ATPase (proton-pump) seems to be acting in altered states, thus behaving like a Na, K-ATPase (Na-pump) and/or Ca-ATPase (Ca-pump) depending on cellular needs.  This conclusion is based on the following findings. First, parietal cell fractions do not exhibit Na, K-ATPase activity at pH 7.0 but do at pH 8.5. Second, the apical plasma membrane (APM) fraction exhibits a (Ca or Mg)-ATPase activity with negligible H, K-ATPase activity. However, when assayed with Mg alone in presence of the 80 k Da cytosolic proton-pump activator (HAF), the APM fraction reveals remarkably high H, K-ATPase activity, suggesting the observed low affinity of Ca (or Mg)-ATPase is an altered state of the latter. Third, calcium (between 1 and 4 µM) shows both stimulation and inhibition of the HAF-stimulated H, K-ATPase depending on its concentration, revealing a close interaction between the  proton-pump activator and local Ca concentration in gastric H, K-ATPase function. Such interactions suggest that Ca is acting as a terminal member of the intracellular signaling system for the HAF-regulated proton-pump. It appears that during resting state, the HAF-associated H, K-ATPase remains inhibited by Ca (>1 µM) and, prior to resumption of acid secretion the gastric H, K-ATPase acts temporarily as a Ca-pump for removing excess Ca from its immediate environment. This conclusion is consistent with the recent reports of immunochemical co-localization of the gastric H, K-ATPase and Ca-ATPase by superimposition in parietal cells, and a transitory efflux of Ca immediately preceding the onset of acid secretion. These new perspectives on proton-pump function would open new avenues for a fuller understanding of the intracellular regulation of the ubiquitous Na-pump.

Peptic ulcer disease

2020 ◽  
pp. 2849-2861
Author(s):  
Joseph Sung
Keyword(s):  
Peptic Ulcer ◽  
Proton Pump Inhibitor ◽  
Peptic Ulcer Disease ◽  
Proton Pump ◽  
Gastric Ulcers ◽  
High Dose ◽  
Recurrent Bleeding ◽  
Ulcer Disease ◽  
H Pylori ◽  
Line Of Therapy

Helicobacter pylori infection, use of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, and smoking are the most important causes of peptic ulcer disease. Peptic ulcer disease is characterized by a history of waxing and waning symptoms of localized, dull, aching pain in the upper abdomen. Bleeding is the most common complication; free perforation of the stomach or duodenum into the peritoneal cavity is uncommon but serious. The diagnosis of peptic ulcer disease is made by endoscopy, which offers an opportunity for biopsy of gastric ulcers (which may be malignant) and reveals important prognostic indicators in patients with bleeding ulcers. A single daily dose of a proton pump inhibitor gives quick relief of symptoms and effective healing of peptic ulcers in 4 to 6 weeks. The management of patients with upper gastrointestinal haemorrhage requires a multidisciplinary medical and surgical approach. Early risk stratification based on clinical and endoscopic criteria allows delivery of appropriate care, with endoscopic intervention now widely accepted as the first line of therapy. This should be followed by administration of a high dose of an intravenous proton pump inhibitor to further reduce recurrent bleeding. Treatment of H. pylori is a cure for peptic ulcer disease in most patients. This usually requires at least two antimicrobial agents, with the most popular triple therapy combining a proton pump inhibitor with any two of amoxicillin, metronidazole, and clarithromycin for 7 to 14 days. Eradication of H. pylori infection, avoidance of high-dose NSAIDs or aspirin, and the maintenance use of proton pump inhibitors in high-risk individuals are the best ways to prevent recurrence of ulcer and ulcer complications.

scholarly journals A Novel Synthetic Dihydroindeno[1,2-b] Indole Derivative (LS-2-3j) Reverses ABCB1- and ABCG2-Mediated Multidrug Resistance in Cancer Cells

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3264 ◽  
Author(s):  
Chao Guo ◽  
Fangyuan Liu ◽  
Jie Qi ◽  
Jiahui Ma ◽  
Shiqi Lin ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Protein Expression ◽  
Atpase Activity ◽  
Cancer Cells ◽  
Abc Transporter ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Expression Levels ◽  
Chemotherapy Drugs ◽  
Diphenyltetrazolium Bromide

10-oxo-5-(3-(pyrrolidin-1-yl) propyl)-5,10-dihydroindeno [1,2-b] indol-9-yl propionate (LS-2-3j) is a new chemically synthesized indole compound and some related analogues are known to be inhibitors (such as alectinib and Ko143) of ATP-binding cassette (ABC) transporters, especially the ABC transporter subfamily B member 1 (ABCB1) and the ABC transporter subfamily G member 2 (ABCG2). This study aimed to evaluate the multidrug resistance (MDR) reversal effects and associated mechanisms of LS-2-3j in drug-resistant cancer cells. The inhibition of cell proliferation in tested agents was evaluated by the 3-(4,5-dimethylthiazol)-2,5-diphenyltetrazolium bromide (MTT) assay. Accumulation or efflux of chemotherapy drugs was analyzed by flow cytometry. The ATPase activity was measured using an ATPase activity assay kit. The mRNA transcripts and protein expression levels were detected by real-time PCR and Western blot, respectively. In this connection, LS-2-3j significantly enhanced the activity of chemotherapeutic drugs in MDR cells and could significantly increase the intracellular accumulation of doxorubicin (DOX) and mitoxantrone (MITX) by inhibiting the function of the efflux pumps in ABCB1- or ABCG2-overexpressing cells. Furthermore, reduced ATPase activity, mRNA transcription, and protein expression levels of ABCB1 and ABCG2 were observed in a concentration dependent manner in MDR cancer cells.

scholarly journals Effect of Proton Pump Inhibitor Therapy on NOX5, mPGES1 and iNOS expression in Barrett’s Esophagus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dan Li ◽  
Deepthi Deconda ◽  
Aihua Li ◽  
Fadlallah Habr ◽  
Weibiao Cao
Keyword(s):  
Proton Pump Inhibitor ◽  
Barrett’S Esophagus ◽  
Proton Pump ◽  
Barrett's Esophagus ◽  
Acid Treatment ◽  
Inos Expression ◽  
Prostaglandin E ◽  
Inos Mrna ◽  
Dependent Manner ◽  
Induced Changes

Abstract Acid reflux may contribute to the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA). However, it is not clear whether the molecular changes present in BE patients are reversible after proton pump inhibitor (PPI) treatment. In this study we examined whether PPI treatment affects NOX5, microsomal prostaglandin E synthase (mPGES)-1 and inducible nitric oxide synthase (iNOS) expression. We found that NADPH oxidase 5 (NOX5), mPGES-1 and iNOS were significantly increased in BE mucosa. One-month PPI treatment significantly decreased NOX5, mPGES1 and iNOS. In BAR-T cells, NOX5 mRNA and p16 promoter methylation increased after pulsed acid treatment in a time-dependent manner. Four or eight-week-acid induced increase in NOX5 mRNA, NOX5 protein and p16 methylation may be reversible. Twelve-week acid treatment also significantly increased NOX5, mPGES1 and iNOS mRNA expression. However, twelve-week-acid-induced changes only partially restored or did not recover at all after the cells were cultured at pH 7.2 for 8 weeks. We conclude that NOX5, mPGES1 and iNOS may be reversible after PPI treatment. Short-term acid-induced increase in NOX5 expression and p16 methylation might be reversible, whereas long-term acid-induced changes only partially recovered 8 weeks after removal of acid treatment.

scholarly journals Ciprofloxacin Enhances the Chemosensitivity of Cancer Cells to ABCB1 Substrates

2019 ◽  
Vol 20 (2) ◽  
pp. 268 ◽  
Author(s):  
Pranav Gupta ◽  
Hai-Ling Gao ◽  
Yunali Ashar ◽  
Nishant Karadkhelkar ◽  
Sabesan Yoganathan ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Hematological Malignancies ◽  
Scintillation Counter ◽  
Dependent Manner ◽  
Intracellular Accumulation ◽  
Concentration Dependent Manner ◽  
Cytotoxic Effects ◽  
Docking Analysis ◽  
Atpase Assay ◽  
Major Drug

ABCB1 is one of the major drug efflux transporters that is known to cause multidrug resistance (MDR) in cancer patients receiving chemotherapy for the treatment of solid tumors and hematological malignancies. Inhibition of ABCB1 efflux function is important for maintaining the intracellular concentration of chemotherapeutic drugs. Here, we evaluated ciprofloxacin for its ability to reverse MDR caused by the overexpression of ABCB1. Cytotoxicity of ciprofloxacin was determined by the MTT assay. The chemosensitizing effects of ciprofloxacin were determined in combination with ABCB1 substrates. The intracellular accumulation and efflux of ABCB1 substrates was measured by a scintillation counter, and protein expression was determined by the Western blotting. Vanadate-sensitive ATPase assay was performed to determine the effect of ciprofloxacin on the ATPase activity of ABCB1, and docking analysis was done to determine the interaction of ciprofloxacin with ABCB1. Ciprofloxacin significantly potentiated the cytotoxic effects of ABCB1 substrates in ABCB1-overexpressing cells. Furthermore, ciprofloxacin increased the intracellular accumulation and decreased the efflux of [3H]-paclitaxel without altering the expression of ABCB1. Ciprofloxacin stimulated the ATPase activity of ABCB1 in a concentration-dependent manner. Our findings showed that ciprofloxacin potently inhibits the ABCB1 efflux function and it has potential to be developed as a combination anticancer therapy.

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