Prevacid
Gastroprotective activity of the novel proton pump inhibitor lansoprazole in the rat.

Morini G, Grandi D, Arcari ML, Bertaccini G.

Institute of Pharmacology, University of Parma, Italy.

1. The protective activity of lansoprazole was evaluated on gastric mucosal lesions induced by intragastric 25% NaCl (1 ml/rat for 1 hr) and by indomethacin (20 mg/kg for 6 hr) in the rat and compared with that of omeprazole. 2. Lansoprazole (3, 10 and 10 mumol/kg i.g.) dose-dependently prevented the formation of indomethacin-induced lesions, the inhibition being 99% at the highest dose. Omeprazole, 10 mumol/kg i.g., enhanced the damage by indomethacin while higher doses caused a reduction, lesion index being reduced by 98% at 100 mumol/kg. 3. Histologically in lansoprazole- as well as in omeprazole-pretreated rats, indomethacin-induced necrosis of the mucosa was absent, luminal epithelium being intact. 4. Lansoprazole (30, 100 and 300 mumol/kg) and omeprazole (30, 100 and 300 mumol/kg) dose-dependently reduced the formation of lesions by hypertonic saline. 5. Present results indicated that lansoprazole and omeprazole protect the gastric mucosa in different experimental models of gastric ulceration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7557244&dopt=Abstract lansoprazole Prevacid



Prevacid
Gastric antisecretory activity of lansoprazole in different experimental models: comparison with omeprazole.

Coruzzi G, Adami M, Bertaccini G.

Institute of Pharmacology, University of Parma, Italy.

1. The activity of the novel proton pump with inhibitor lansoprazole was examined in different gastric secretion models in vitro and in vivo, in comparison with omeprazole. 2. In the conscious cat with gastric fistula lansoprazole (0.25-2 mumol/kg i.v.) caused a dose-dependent reduction of the acid secretion induced by dimaprit, pentagastrin, 2-deoxy-D-glucose and bombesin, being approximately as potent as omeprazole (0.25-1.5 mumol/kg i.v.). Similar to omeprazole, lansoprazole was also more effective when administered in hyperacidic states. 3. In the anaesthetized rat with lumen perfused stomach lansoprazole (0.03-1 mumol/kg i.v.) was approximately 3 times more potent than omeprazole (0.1-3 mumol/kg i.v.) in inhibiting the acid secretion induced by histamine, 2-deoxy-D-glucose and forskolin. 4. In the isolated gastric fundus from the immature rat lansoprazole (1-30 microM) reduced basal acid secretion and the acid response to histamine and forskolin, with a potency not significantly different from that of omeprazole. 5. No significant differences were found in the different species between lansoprazole and omeprazole as for the duration of action. 6. In conclusion, lansoprazole exerts a marked antisecretory effect in a variety of gastric secretion models from different species. However, it did not significantly differ from omeprazole when considering either the potency or the duration of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7557245&dopt=Abstract lansoprazole Prevacid



Prevacid
Mechanism for species-specific induction of Leydig cell tumors in rats by lansoprazole.

Fort FL, Miyajima H, Ando T, Suzuki T, Yamamoto M, Hamashima T, Sato S, Kitazaki T, Mahony MC, Hodgen GD.

Abbott Laboratories, Abbott Park, Illinois 60064, USA.

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.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7589908&dopt=Abstract lansoprazole Prevacid



Prevacid
Effects of lansoprazole on ethanol-induced injury and PG synthetic activity in rat gastric mucosa.

Fukuda T, Arakawa T, Shimizu Y, Ohtani K, Higuchi K, Kobayashi K.

Third Department of Internal Medicine, Osaka City University Medical School, Japan.

Lansoprazole, a proton pump inhibitor, has been reported to inhibit ethanol-induced injury in rats. However, the mechanism of the protective effect is not known. This study was carried out to investigate the role of prostaglandin (PG) in the protective effect of lansoprazole. Male Wistar rats were given either 30 mg/kg of lansoprazole or vehicle alone intragastrically 30 min before administration of ethanol. They were killed to measure the gross mucosal lesions in the stomach as the ulcer index. In another experiment, 5 mg/kg of indomethacin was injected 30 min before administration of lansoprazole. The effects of 16,16-dimethyl PGE2 (dmPGE2) on ethanol-induced injury over time were compared with lansoprazole. PGE2 synthesis in gastric mucosa after administration of lansoprazole was measured by radioimmunoassay. Lansoprazole reduced gastric mucosal injury by lansoprazole. DmPGE2 significantly reduced gastric mucosal injury from 5 min after exposure to ethanol. Lansoprazole did not affect PGE2 synthesis in the gastric mucosa. These results suggest that PG may not be involved in the protective effect of lansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7594340&dopt=Abstract lansoprazole Prevacid



Prevacid
Factors affecting quality of ulcer healing after lansoprazole treatment.

Ito G, Nakagawara M, Watanabe F, Ooi S, Nawano M, Hanai H, Kaneko E.

First Department of Medicine, Hamamatsu University School of Medicine Shizuoka, Japan.

To evaluate endogenous and exogenous factors affecting the quality of ulcer healing produced by proton pump inhibitors, gastric acid pH, serum gastrin, and serum pepsinogen (PG) I and II were measured in peptic ulcer patients before and after treatment with lansoprazole 30 mg once daily. Lansoprazole achieved more rapid scarring in duodenal ulcer (n = 34), with a healing rate of 97.1% after 6 weeks, than in gastric ulcer (n = 56), with a healing rate of 92.8% after 8 weeks. Scarring was the most rapid in gastroduodenal ulcer (n = 8), with a healing rate of 100% after 8 weeks, but the rate of complete scarring was the lowest (37.5%). Lower gastric acidity and lower PG I:II ratio were associated with poor quality ulcer scarring in patients with gastric ulcers, but the opposite was true for those with duodenal and gastroduodenal ulcers. For gastric ulcers, not only ulcer size but also mucosal atrophy was an important factor in ulcer healing. Smoking and alcohol consumption had little effect on the quality of ulcer healing during treatment. These results suggest that there are a number of differences between gastric ulcers and duodenal ulcers in terms of the quality of ulcer healing after lansoprazole treatment.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7594344&dopt=Abstract lansoprazole Prevacid