Prevacid
Effects of rabeprazole, lansoprazole and omeprazole on intragastric pH in CYP2C19 extensive metabolizers.

Saitoh T, Fukushima Y, Otsuka H, Hirakawa J, Mori H, Asano T, Ishikawa T, Katsube T, Ogawa K, Ohkawa S.

Department of Internal Medicine, Tokyo Women's Medical University, Daini Hospital, Japan. ssumiko fa2.so-net.ne.jp

AIM: To investigate the inhibitory effects on gastric acid secretion of three proton pump inhibitors, omeprazole, lansoprazole and rabeprazole, using a three-way crossover design in healthy Helicobacter pylori-negative,S-mephenytoin 4'-hydroxylase (CYP2C19) homo- and hetero-extensive metabolizers. METHODS: Eight healthy Japanese male volunteers were enrolled. After the administration of rabeprazole (10 mg/day), lansoprazole (30 mg/day) or omeprazole (20 mg/day), intragastric pH monitoring was commenced from 24 h before the first proton pump inhibitor dose, and continued for days 1-3 after proton pump inhibitor administration. The pH electrode was used for 48 h and changed just before pH monitoring on day 2. RESULTS: For the administration of 10 mg/day rabeprazole, the mean ratios of the 24-h pH > or = 3 holding time were 5.7 +/- 1.1%,13.6 +/- 2.2%, 35.3 +/- 2.7% and 62.8 +/- 3.1% for the pre-treatment day and days 1, 2 and 3, respectively. The same ratios for lansoprazole (30 mg/day) were 5.7 +/- 0.7%, 7.4 +/- 1.5%, 13.6 +/- 3.4% and 26.6 +/- 4.9%; the same ratios for 20 mg/day omeprazole were 5.9 +/- 0.9%, 6.1 +/- 1.2%, 11.4 +/- 2.8% and 16.4 +/- 4.6%. The mean ratio of the 24-h pH > or = 3 holding time of days 1-3 increased significantly compared to the pre-treatment day (P < 0.01) with the administration of rabeprazole and lansoprazole. The magnitude of inhibition of gastric acid secretion after rabeprazole administration was stronger than that after lansoprazole. A significant elevation of the mean ratio of the 24-h pH > or = 3 holding time was demonstrated on days 2 and 3 with omeprazole (P < 0.01). CONCLUSIONS: In H. pylori-negative CYP2C19 extensive metabolizers, rabeprazole (10 mg/day) shows a faster onset of rising intragastric pH and a stronger inhibition of gastric acid secretion than do lansoprazole (30 mg/day) or omeprazole (20 mg/day).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12269976&dopt=Abstract lansoprazole Prevacid



Prevacid
Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole.

Furuta T, Shirai N, Watanabe F, Honda S, Takeuchi K, Iida T, Sato Y, Kajimura M, Futami H, Takayanagi S, Yamada M, Ohashi K, Ishizaki T, Hanai H.

First Department of Medicine, Hamamatsu University School of Medicine, Japan. furutat mail,nih.gov

BACKGROUND AND OBJECTIVES: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD. METHODS: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients. RESULTS: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups. CONCLUSIONS: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12386647&dopt=Abstract lansoprazole Prevacid



Prevacid
Lansoprazole induces mucosal protection through gastrin receptor-dependent up-regulation of cyclooxygenase-2 in rats.

Tsuji S, Sun WH, Tsujii M, Kawai N, Kimura A, Kakiuchi Y, Yasumaru S, Komori M, Murata H, Sasaki Y, Kawano S, Hori M.

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. tsuji medone.med.osaka-u.ac.jp

Proton pump inhibitors (PPIs) are antiulcer agents that have both gastric antisecretory and mucosal protective actions. The mechanisms of PPI-induced gastric mucosal protection are not known. The present study was designed to examine the mechanism for lansoprazole-induced gastric mucosal protection in rats. Rats were given 0.5, 5, and 50 mg/kg/day lansoprazole alone or both lansoprazole (50 mg/kg/day) and a specific gastrin receptor antagonist 3R-1-(2,2-diethoxyethyl)-((4-methylphenyl)amino-carbonyl methyl)-3-((4-methylphenyl)ureidoindoline-2- one) (AG-041R) (3, 10, and 30 mg/kg/day) for 14 days. Serum gastrin concentrations were measured. The expression of cyclooxygenases (COX-1 and COX-2) in the gastric mucosa was analyzed using Western blotting and immunohistochemical staining. Another series of rats was used to examine the 1) levels of prostaglandin (PG) E2 in gastric mucosa, 2) influences of the drugs on gastric damage caused by absolute ethanol, and 3) effects of a COX-2-specific inhibitor on PGE2 in the gastric mucosa and the mucosal protection afforded by lansoprazole. Lansoprazole dose dependently increased the serum gastrin concentration and enhanced the mucosal expression of COX-2 but not that of COX-1. Lansoprazole increased gastric mucosal PGE2 and reduced gastric damage caused by ethanol. Concomitant administration of AG-041R abolished the lansoprazole-induced COX-2 expression, and increased mucosal PGE2 and mucosal protection. A specific COX-2 inhibitor blocked the lansoprazole-induced increase in mucosal PGE2 and mucosal protection. Activation of gastrin receptors by endogenous gastrin has a pivotal role in the effects of lansoprazole on COX-2 up-regulation and mucosal protection in the rat stomach.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12438555&dopt=Abstract lansoprazole Prevacid



Prevacid
Lansoprazole quantification in human plasma by liquid chromatography-electrospray tandem mass spectrometry.

Oliveira CH, Barrientos-Astigarraga RE, Abib E, Mendes GD, da Silva DR, de Nucci G.

Department of Pharmacology, State University of Campinas, SP, Campinas, Brazil.

An analytical method based on liquid chromatography with positive ion electrospray ionization (ESI) coupled to tandem mass spectrometry detection was developed for the determination of lansoprazole in human plasma using omeprazole as the internal standard. The analyte and internal standard were extracted from the plasma samples by liquid-liquid extraction using diethyl-ether-dichloromethane (70:30; v/v) and chromatographed on a C(18) analytical column. The mobile phase consisted of acetonitrile-water (90:10; v/v)+10 mM formic acid. The method has a chromatographic total run time of 5 min and was linear within the range 2.5-2000 ng/ml. Detection was carried out on a Micromass triple quadrupole tandem mass spectrometer by Multiple Reaction Monitoring (MRM). The intra- and inter-run precision, calculated from quality control (QC) samples, was less than 3.4%. The accuracy as determined from QC samples was less than 9%. The method herein described was employed in a bioequivalence study of two capsule formulations of lansoprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12482488&dopt=Abstract lansoprazole Prevacid



Prevacid
Safety and pharmacokinetics of oral lansoprazole in preadolescent rats exposed from weaning through sexual maturity.

Youssef AF, Turck P, Fort FL.

Department of Drug Safety, TAP Pharmaceutical Products, Inc, 675 North Field Dr, Lake Forest, IL 60045, USA. ashraf.yousse tap.com

Proton pump inhibitors, the reference standard in adults with acid-related disorders, are increasingly being used in children despite limited pediatric safety and pharmacokinetic data. This study evaluated these parameters in rats aged 21-60 days, which approximately correlates with children aged 2-11 years. Lansoprazole at doses of 0, 5, 15, 50, or 150 mg/kg per day was administered to Sprague-Dawley rats from weaning through sexual maturity. Safety assessments included clinical, neurobehavioral, ophthalmologic, and gender-specific developmental milestones, clinical pathology including urinalysis, organ weight (at necropsy), and histopathologic evaluation. Blood samples for pharmacokinetics were collected on the first and last days of treatment. After the end of dosing, decreases in body weight gain, serum total protein and albumin (males), and microcytic hypochromic anemia were observed at doses of > or =50mg/kg per day, and hypoglycaemia (females) at 150 mg/kg per day. Selected groups exhibited increases in absolute and relative duodenal and stomach weights (> or =15 mg/kg per day), decreases in absolute and relative thymus weights (> or =50 mg/kg per day), increased relative liver weights (> or =50 mg/kg per day), and chronic adhesions to the spleen (> or =15 mg/kg per day). No other changes were observed. The area under the curve values in 60-day-old rats was less than those observed in 21-day-old rats. Areas under the curve values for lansoprazole were higher in female than male 60-day-old rats. No unexpected signs of toxicity were observed in the current preadolescent rats relative to those observed in adult rats in previous studies. The NOEL in preadolescent rats was similar to adults and gives a safety margin of one- to five-fold relative to the pediatric dose (0.87 mg/kg in 2-11-year-olds). These results provide comparative evidence for the value of studies in rats to support safety in a pediatric population. Copyright 2002 Elsevier Science Inc.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12507665&dopt=Abstract lansoprazole Prevacid



Prevacid
Characteristics of diarrhoea in 10,008 users of lansoprazole in daily practice: which co-factors contribute?

Claessens AA, Heerdink ER, van Eijk JT, Lamers CB, Leufkens HG.

Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, The Netherlands. angela kendle.com

PURPOSE: Diarrhoea is one of the most frequently reported adverse events during proton pump inhibitor use in any setting. Because of the limited available information, this study was set up with the aim of assessing the incidence and characteristics of diarrhoea and to investigate possible associated co-factors in proton pump inhibitor users in daily practice. METHODS: Data were used from a prospective, observational study in which 10,008 lansprazole users were followed over time (1994-1998). The study was designed according to the SAMM guidelines. A nested case-control design was used to compare proton pump inhibitor users reporting diarrhoea with those reporting no diarrhoea. RESULTS: The frequency of diarrhoea was 3.7% and the incidence density 10.7 per 1000 patients months of proton pump inhibitor use. The diarrhoea was most commonly loose and occurred on average 4.4 times per day. The analysis of co-factors revealed that patients with concomitant use of oral antibiotics and patients reporting neurological and/or dermatological adverse events, were at risk of developing diarrhoea during proton pomp inhibitor use. CONCLUSIONS: In conclusion, diarrhoea was as frequently reported in our study as in clinical trials and observational data of lansoprazole users. We found the concomitant use of oral antibiotics and the reporting of certain other adverse events to be associated with the reporting of diarrhoea during lansoprazole use. Although a relationship with the proton pump inhibitor intake seemed very plausible, we recommend that use of concomitant medicines as a cause of diarrhoea must be taken into consideration in lansoprazole users.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12512247&dopt=Abstract lansoprazole Prevacid