Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lansoprazole (AG 1749/CG 4801) is an inhibitor of gastric acid secretion by blocking H+,K(+)-ATPase. In this 2:1 randomized, double-blind, multicentre trial lansoprazole 30 mg am was compared to 40 mg famotidine nocte in 264 out-patients suffering from uncomplicated duodenal ulcer. After 2 weeks of treatment ulcer healing was confirmed endoscopically in a significantly higher proportion (P = 0.027) of patients treated with lansoprazole (94/174 = 54.0%) compared to patients receiving famotidine (35/90 = 38.9%). Cumulative healing rates after 4 weeks were 91.4% for the lansoprazole group and 83.3% for the famotidine group (P = 0.065). Pain relief and decrease of concomitant antacid consumption during treatment were comparable in both groups. Both compounds were well tolerated. Rates of recurrent duodenal ulcer in the 6 months after trial treatment were 45/158 (28.5%) after lansoprazole, and 18/69 (26.1%) after famotidine.
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PMID:Lansoprazole versus famotidine: efficacy and tolerance in the acute management of duodenal ulceration. 154 19

The gastric acid antisecretory compound omeprazole (5-methoxy-2-((4-methoxy- 3,5-dimethyl-2-pyridinylmethyl)-sulphinyl)-1H-benzimidazole), a member of the new class of H+, K(+)-ATPase inhibitors, is known to interact with the metabolism of other drugs in vitro and in vivo. In this study, two other substituted benzimidazoles, pantoprazole (5-difluoromethoxy-2-((3,4-di-methoxy-2-pyridinylmethyl)-s ulp hinyl)-1H- benzimidazole) and lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylmethyl)- sulphinyl)-1H-benzimidazole) are compared for their ability to inhibit cytochrome P450 dependent biotransformation in vitro with regard to three representative reactions: O-dealkylation of 7-ethoxycoumarin (EC), N-demethylation of ethylmorphine (EM) and hydroxylation of lonazolac (Lona). These reactions can be seen in microsomes from phenobarbital pretreated rats representing the cytochrome P450IIB1 subfamily. As shown in presence of known inhibitors of cytochrome P450, e.g. SK&F 525A, metyrapone, chlorpromazine and nitrendipine, different enzymes seem to be responsible for these three indicator reactions of the cytochrome P450IIB1 complex. These reactions are inhibited to a different extent by the three H+, K(+)-ATPase inhibitors. Pantoprazole shows the lowest inhibitory activity versus the three reactions (Ki, mumol/L): EC, 138; EM, 104; Lona, 128. A greater effect is observed with omeprazole: EC, 38; EM, 68; Lona, 20. Lansoprazole exceeds omeprazole in inhibiting the three cytochrome P450 dependent enzymes: EC, 17; EM, 34; Lona, 8. In microsomes from untreated rats with the predominant cytochrome P450IIA1 subfamily as well as in microsomes from isopropanol treated rats (induction of cytochrome P450IIE1) which catalyse only lonazolac hydroxylation to a detectable amount, the latter reaction was inhibited by pantoprazole with a somewhat lower Ki of 77 whereas the values for omeprazole and lansoprazole remained unchanged in comparison to those found in microsomes from phenobarbital pretreated rats. The biotransformation rate of the substituted benzimidazoles themselves in microsomes from control and induced rats is lowest for pantoprazole followed by lansoprazole and omeprazole.
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PMID:The H+, K(+)-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole. 165 Feb 12

Lansoprazole (AG 1749) is a novel substituted benzimidazole which inhibits gastric acid secretion by blocking H+,K(+)-ATPase. This randomized, double-blind multicentre trial studied the dose-response relationship of lansoprazole on ulcer healing and compared it with ranitidine in 314 out-patients with endoscopically assessed, symptomatic duodenal ulcer. Cumulative healing rates with Lansoprazole 7.5, 15, and 30 mg o.m. were 48, 59, and 74% at 2 weeks and 75, 84, and 95% at 4 weeks, respectively (intention-to-treat); the difference of the healing rates between 7.5 and 30 mg groups was significant (P less than 0.001). Corresponding healing rates for 300 mg ranitidine nocte were 51 and 89%. Pain relief was similar in all treatment groups. Lansoprazole was well tolerated. During a follow-up of 6 months relapse rates after lansoprazole 7.5, 15, and 30 mg were 21, 29, and 22%, respectively; the relapse rate after ranitidine 300 mg was 20%. In conclusion, lansoprazole provides faster healing of duodenal ulcer than ranitidine and a similar relapse pattern. For further trials in peptic ulcer disease a daily dose of lansoprazole 30 mg o.m. is recommended.
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PMID:Dose-related healing of duodenal ulcer with the proton pump inhibitor lansoprazole. 188 24

Peripheral regulation of gastric acid secretion is initiated by the release of gastrin from the G cell. Gastrin then stimulates the cholecystokinin-B receptor on the enterochromaffin-like cell beginning a calcium signaling cascade. An exocytotic release of histamine follows with concomitant activation of a C1- current. The released histamine begins the H2-receptor mediated sequence of events in the parietal cell, which results in activation of the gastric H+/K+ - ATPase. This enzyme is the final common pathway of acid secretion. The H+/K+ - ATPase is composed of two subunits: the larger alpha-subunit couples ion transport to hydrolysis of ATP, the smaller beta-subunit is required for appropriate assembly of the holoenzyme. Both the membrane and extracytoplasmic domain contain the ion transport pathway, and therefore, this region is the target for the antisecretory drugs of the post-H2 era. The 100 kDa alpha-subunit has probably 10 membrane spanning segments with, therefore, five extracytoplasmic loops. The 35 kDA beta-subunit has a single membrane spanning segment, and most of this protein is extracytoplasmic with the six or seven N glycosylation consensus sequences occupied. Omeprazole is an acid-accumulated, acid-activated, prodrug that binds covalently to two cysteine residues at positions 813 (or 822) and 892, accessible from the acidic face of the pump. Lansoprazole binds to cys321, 813 (or 822) and 892; pantoprazole binds to cys813 and 822. The common binding site for these drugs (cys813 or 822) is responsible for the inhibition of acid transport. Covalent inhibition of the acid pump improves control of acid secretion, but since the effective half life of the inhibition in man is about 48 hr, full inhibition of acid secretion, perhaps necessary for eradication of Helicobacter pylori in combination with a single antibiotic, will require prolongation of the effect of this class of drug.
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PMID:Gastric acid secretion: activation and inhibition. 750 35

Lansoprazole is a benzimidazole derivative that effectively decreases gastric acid secretion, regardless of the primary stimulus, via inhibition of gastric H+,K(+)-adenosine triphosphatase (ATPase). It provides effective symptom relief and healing of peptic ulcer and reflux oesophagitis after 4 to 8 weeks of therapy and appears to prevent recurrence of lesions when administered as maintenance therapy. When administered at therapeutic dosages, lansoprazole produced higher healing rates than ranitidine or famotidine in patients with duodenal and gastric ulcers. Lansoprazole heals duodenal ulcers more rapidly than ranitidine or famotidine. Relief of ulcer symptoms in lansoprazole recipients is at least equivalent to, and tends to be more rapid than, that in patients receiving histamine H2-receptor antagonists. In comparisons with omeprazole 20 mg/day, lansoprazole 30 mg/day produced duodenal ulcer healing more rapidly and reduced ulcer pain to a greater extent at 2 weeks, but overall healing rates were similar after 4 weeks of therapy. At therapeutic dosages, lansoprazole produces superior healing and symptom relief of reflux oesophagitis in comparison with ranitidine, and it tends to relieve heartburn more effectively than omeprazole, although both agents produce equivalent healing. Healing of peptic ulcers or reflux oesophagitis refractory to histamine H2-receptor antagonists occurs after 8 weeks in the majority of patients treated with lansoprazole, and lansoprazole and omeprazole demonstrate similar efficacy in patients with refractory peptic ulcers. In patients with Zollinger-Ellison syndrome, lansoprazole effectively controls mean basal gastric acid output. Lansoprazole is generally well tolerated in clinical trials. The incidence of adverse effects is similar to that of omeprazole, ranitidine and famotidine in comparative studies. Combination therapy with lansoprazole and antibacterial agents such as amoxicillin, tinidazole, roxithromycin and/or metronidazole appears to eradicate Helicobacter pylori in 22 to 80% of patients with this organism. Limited data also suggest that lansoprazole may have superior activity against H. pylori in comparison with omeprazole, although the clinical relevance of this preliminary finding requires further confirmation. Thus, lansoprazole may be considered as alternative to existing antisecretory agents available for the treatment of acid-related disorders, particularly because it may provide more rapid healing and relief of symptoms.
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PMID:Lansoprazole. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy in acid-related disorders. 752 61

Lansoprazole is a substituted benzimidazole which inhibits gastric acid secretion by inhibiting the hydrogen-potassium ATPase (proton pump) in the parietal cell. The finding of Leydig cell hyperplasia and Leydig cell tumors in 2-year oral studies in Sprague-Dawley rats but not in CD-1 mice prompted investigative studies to determine the mechanism for the Leydig cell changes. hCG challenge studies in Sprague-Dawley rats revealed decreased testosterone responsiveness in rats treated orally for 1 or 2 weeks with lansoprazole. After 4 weeks of daily oral treatment increases in serum LH and decreases in serum testosterone were detected within a few hours after dosing. In a study where 9-month-old male F344 rats were given testosterone supplementation via Silastic implants and then treated with lansoprazole for 6 months, a high incidence of Leydig cell tumors was seen in lansoprazole-treated, unsupplemented rats, whereas no Leydig cell tumors were seen in testosterone supplemented rats. This implied that reduction of the normal feedback inhibition at the level of the hypothalamus and/or pituitary due to reduced testosterone levels, thus giving rise to elevated levels of LH, was involved in the induction of Leydig cell tumors by lansoprazole. In vitro studies with Leydig cells from rats using various stimulators and precursors of testosterone biosynthesis demonstrated that the most sensitive site for inhibition of testosterone synthesis by lansoprazole is the transport of cholesterol to the cholesterol side chain cleavage enzyme. The IC50s for inhibition of LH or hCG-stimulated testosterone synthesis in Leydig cells from rats, mice, and monkeys were 11-12, 8, and 24.7 micrograms/ml, respectively. In vitro studies with metabolites of lansoprazole revealed that three metabolites were more potent inhibitors of testosterone synthesis than the parent drug, two of them being at least 10 times more potent. These metabolites are present in rats at substantial levels but are undetectable in humans. The lack of induction of Leydig cell tumors in mice, lower sensitivity of primate Leydig cells, and the absence of testosterone synthesis-inhibiting metabolites in man suggest that Leydig cell tumors found in rats represent a species-specific sensitivity and does not imply a risk for clinical use in man.
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PMID:Mechanism for species-specific induction of Leydig cell tumors in rats by lansoprazole. 758 8

Lansoprazole is an inhibitor of gastric H+,K(+)-ATPase, commonly referred to as the 'proton pump'. The pharmacodynamic effect of proton pump inhibition is to reduce gastric acid secretion. Long experience with H2 antagonists and more recently proton pump inhibitors has demonstrated the value of reducing gastric acid secretion in conditions where acid plays a key role in the pathogenesis of gastrointestinal inflammation and ulceration. The pharmacokinetics, pharmacodynamics and clinical safety of lansoprazole are discussed elsewhere in this supplement, and so this review will focus upon the European and American experience of the efficacy of lansoprazole in the treatment of peptic ulceration and gastro-oesophageal reflux.
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PMID:Clinical review of lansoprazole. 806 Aug 2

This multicenter, randomized, double-blind, 8-wk study compared the new H+/K(+)-ATPase inhibitor, lansoprazole, 30 mg daily, to ranitidine 150 mg bid for treatment of erosive reflux esophagitis resistant to histamine-2 receptor antagonists (H2RA). Patients were evaluated after 2, 4, 6, and 8 wk of treatment by symptom assessment and endoscopy. Healing rates for lansoprazole were 71%, 80%, 88%, and 89% at 2, 4, 6, and 8 wk, respectively, compared to 21%, 33%, 45%, and 38% for ranitidine (p < 0.001 at all points). Lansoprazole was significantly more effective than ranitidine for relief of heartburn and reduction of antacid tablet use. Increases in serum gastrin concentrations between the baseline and the 8-wk visit were greater in lansoprazole-treated than in ranitidine-treated patients. Lansoprazole was safe and well tolerated. In patients with erosive reflux esophagitis resistant to standard doses of H2RA, lansoprazole 30 mg/day is more effective than continuation of an H2RA (ranitidine 150 mg bid) for healing of esophagitis and improvement of symptoms.
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PMID:Treatment of reflux esophagitis resistant to H2-receptor antagonists with lansoprazole, a new H+/K(+)-ATPase inhibitor: a controlled, double-blind study. Lansoprazole Study Group. 810 95

Lansoprazole, a new substituted benzimidazole, is an effective acid proton pump inhibitor acting by inhibiting selectively H+/K+ ATPase of the gastric parietal cell. This study was performed to assess the effect of successive 30, 60, 90 and 120 mg dosages of lansoprazole in 4 patients suffering from Zollinger-Ellison syndrome. The basal gastric acid output was markedly inhibited in comparison with baseline values (mean maximal reduction: 87%; extremes: 75-99%) and was dose-related. Lansoprazole inhibited pepsin output globally with a dose range effect between 30 and 90 mg/day. The treatment induced a rapid relief of clinical symptoms. No biological abnormality was noted. These data proved that lansoprazole is efficient for treating gastric acid hypersecretion in patients suffering from ZES.
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PMID:[Dose-response effect of lansoprazole in patients with Zollinger-Ellison syndrome]. 818 84

Lansoprazole, a new proton pump inhibitor, selectively inhibits the H+/K(+)-ATPase. Its inhibitory effect on basal and gastrin stimulated gastric acid secretion is equal to omeprazole and stronger than that of H2-receptor antagonists. Healing rates concerning gastric and duodenal ulcers and refluxesophagitis are significantly higher compared to H2-receptor antagonists and at least comparable to omeprazole. Regarding pilot studies in H. pylori eradication therapy, lansoprazole in combination with various antibiotics is expected to show good eradication rates. Considering its excellent safety and interaction profile lansoprazole is effective and safe in treating acid related disorders.
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PMID:[Lansoprazole--profile of a new proton pump inhibitor]. 819 67


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