Disease relevance of Loxtidine

• METHODS: Male hypergastrinemic mice (INS-GAS mice) were infected with Helicobacter felis and given the CCK2/gastrin receptor antagonist YF476 and/or the histamine H2-receptor antagonist loxtidine for 3 or 6 months [1].
• ECL-cell derived gastric cancer in male cotton rats dosed with the H2-blocker loxtidine [2].
• The oral administration of loxtidine to mice at doses of 600, 250, and 50 mg/kg/day for 746 days produced carcinoid tumours of the gastric fundus [3].
• There is no evidence that loxtidine acts as a direct carcinogen and it is suggested that the tumours were the result of prolonged achlorhydria produced by a potent unsurmountable histamine H2 receptor antagonist [4].
• In the VAG+LOX animals endocrine cell neoplasia was seen in 60% and dysplasia in 40% of animals compared to 40% neoplasia, 45% dysplasia and 15% hyperplasia in LOX animals [5].

High impact information on Loxtidine

• RESULTS: Mice treated with YF476 or loxtidine alone showed partial suppression of both gastric acid secretion and progression to neoplasia [1].
• YF476 and/or loxtidine treatment did not alter the overall level of H. felis colonization but did result in significant down-regulation of the growth factors regenerating gene I and amphiregulin [1].
• In the present study, the insurmountable H2-receptor antagonist loxtidine (200 mg/kg/day) was given to male cotton rats for 6 months [2].
• In the dysplastic mucosa of loxtidine-dosed animals there was a marked increase in chromogranin A-positive cells, where numerous groups of cells also stained positive with the Sevier-Munger technique [2].
• Long-term treatment (1 to 32 weeks) with an irreversible histamine 2-receptor blocker (loxtidine) caused a sustained increase in plasma gastrin levels, which was accompanied by a gradual increase in histamine and histidine decarboxylase activity of the gastric oxyntic mucosa [6].

Chemical compound and disease context of Loxtidine

• The very late occurrence of gastric carcinoids in a life-span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long-acting unsurmountable histamine H2-antagonist [7].

Biological context of Loxtidine

• H. felis infection of INS-GAS mice led to increased apoptosis and the development of atrophy, whereas treatment with either YF476 and/or loxtidine strongly inhibited both apoptosis and atrophy [8].
• The parietal cell density was unaffected by omeprazole treatment, whereas it tended to be reduced in the loxtidine-treated rats [9].
• After loxtidine-placebo treatment all values were significantly increased (p < 0.05; 883 +/- 70 microns, 192.8 +/- 10.6 pmol/L, 97 +/- 16.2 cells/visual field, and 51.7 +/- 19.2 cells/visual field, respectively) [10].
• The potential nitrosatability of loxtidine was investigated using an expanded version of the WHO Nitrosation Assay Procedure, and detectable quantities of mutagenic nitroso-species were not formed [11].

Anatomical context of Loxtidine

• The nature of the anti-secretory activity of loxtidine was compared with that of ranitidine on histamine-induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation [7].
• 4. Loxtidine produced a dose-dependent rise in the number of eosinophils in the gastric mucosa of conventional rats [12].
• The major route of metabolism for loxtidine in dog hepatocytes was glucuronidation with oxidation to the carboxylic acid metabolite being of minor importance [13].

Associations of Loxtidine with other chemical compounds

• The results demonstrate that histamine 2-receptor blockade initiated by loxtidine promotes a rapid development of enterochromaffinlike cell tumors in Mastomys and suggest a critical role for gastrin in the formation of these tumors [6].
• The ECL cell density was slightly higher in the loxtidine- than in the omeprazole-treated rats [9].
• Cimetidine, ranitidine and famotidine are competitive antagonists, while the long-acting H2-receptor antagonists, e.g. loxtidine and lamitidine, are insurmountable H2-receptor blockers [14].
• AIMS: To examine the effects of a pepsin inhibitor, pepstatin-A, a long acting H2-receptor blocker, loxtidine, exogenous pepsin and exogenous acid against indomethacin-induced antral ulceration in the rat [15].
• METHODS: The rodent mastomys received the H2-antagonist loxtidine (2 g/l drinking water) alone or in combination with terfenadine (0.5 g/l or 35 mg/l drinking water) for 120 days [16].

Gene context of Loxtidine

• In addition, we studied the effects of the gastrin/cholecystokinin-2 (CCK-2) receptor antagonist YF476 and/or histamine H2 (H-2) receptor antagonist loxtidine on apoptosis and atrophy in INS-GAS mice with or without Helicobacter felis (H. felis) infection [8].
• The Mastomys was utilized as a model for the rapid induction of ECLomas by insurmountable acid secretory blockade induced by the pharmacologically irreversible H2-receptor antagonist, loxtidine [17].
• The results indicate that cyproheptadine, an H1-receptor antagonist, inhibits loxtidine-induced ECL cell hyperplasia independent of any effects on serum gastrin [17].
• In addition, the loxtidine-induced ECL cell tumors expressed a high density of SS and gastrin receptors [18].
• Hypergastrinemia induced by short-term (5 days) histamine2-receptor blockade (loxtidine) resulted in increased histidine decarboxylase (HDC) mRNA expression in the gastric oxyntic mucosa [19].

Analytical, diagnostic and therapeutic context of Loxtidine

• Determination of loxtidine in human serum by capillary column gas chromatography with nitrogen-phosphorus detection [20].
• Untreated animals were compared with animals receiving the histamine2-receptor blocker loxtidine (LOX) and with animals subjected to unilateral subdiaphragmatic vagotomy prior to loxtidine treatment (VAG+LOX) [5].
• 4. In vivo hepatic and intrinsic clearances for loxtidine were determined in rat, dog and human volunteers [13].
• Hypergastrinemia was generated by the irreversible histamine-2 receptor antagonist loxtidine for 8 weeks (hyperplasia) and 16 weeks (neoplasia). p53 expression was evaluated in fundic mucosa from different stages of transformation by Western blot analysis and immunohistochemistry using monoclonal antibodies against wild-type p53 [21].
• An automated continuous flow liquid-liquid extraction procedure is described for the separation of the H2-antagonist loxtidine from plasma samples containing two metabolites which interfere in the radioimmunoassay of the drug [22].

References