esomeprazole, Nexium
Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities.

Li XQ, Andersson TB, Ahlstrom M, Weidolf L.

DMPK and Bioanalytical Chemistry, AstraZeneca R and D Molndal, S-431 83 Molndal, Sweden.

The human clearance of proton pump inhibitors (PPIs) of the substituted benzimidazole class is conducted primarily by the hepatic cytochrome P450 (P450) system. To compare the potency and specificity of the currently used PPIs (i.e., omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4), we performed in vitro studies using human liver microsomal preparations and recombinant CYP2C19. Sample analysis was done using selected reaction monitoring liquid chromatography/tandem mass spectometry. With several systems for CYP2C19 activity (two marker reactions, S-mephenytoin 4'-hydroxylation and R-omeprazole 5-hydroxylation, tested in either human liver microsomes or recombinant CYP2C19), the five PPIs showed competitive inhibition of CYP2C19 activity with K(i) of 0.4 to 1.5 microM for lansoprazole, 2 to 6 microM for omeprazole, approximately 8 microM for esomeprazole, 14 to 69 microM for pantoprazole, and 17 to 21 microM for rabeprazole. Pantoprazole was a competitive inhibitor of both CYP2C9-catalyzed diclofenac 4'-hydroxylation and CYP3A4-catalyzed midazolam 1'-hydroxylation (K(i) of 6 and 22 microM, respectively), which were at least 2 times more potent than the other PPIs. All PPIs were poor inhibitors of CYP2D6-mediated bufuralol 1'-hydroxylation with IC(50) > 200 microM. The inhibitory potency of a nonenzymatically formed product of rabeprazole, rabeprazole thioether, was also investigated and showed potent, competitive inhibition with K(i) values of 6 microM for CYP2C9, 2 to 8 microM for CYP2C19, 12 microM for CYP2D6, and 15 microM for CYP3A4. The inhibitory potency of R-omeprazole on the four studied P450 enzymes was also studied and showed higher inhibitory potency than its S-isomer on CYP2C9 and 2C19 activities. Our data suggest that, although the inhibitory profiles of the five studied PPIs were similar, lansoprazole and pantoprazole are the most potent in vitro inhibitors of CYP2C19 and CYP2C9, respectively. Esomeprazole showed less inhibitory potency compared with omeprazole and its R-enantiomer. The inhibitory potency of rabeprazole was relatively lower than the other PPIs, but its thioether analog showed potent inhibition on the P450 enzymes investigated, which may be clinically significant.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15258107&dopt=Abstract esomeprozole Nexium



esomeprazole, Nexium
Dysphagia in patients with erosive esophagitis: prevalence, severity, and response to proton pump inhibitor treatment.

Vakil NB, Traxler B, Levine D.

University of Wisconsin Medical School, Aurora Sinai Medical Center, Milwaukee 53201-0342, USA. nvakil wisc.edu

BACKGROUND & AIMS: Dysphagia is considered an alarm symptom, raising the question of stricture or malignancy. We sought to determine the prevalence and severity of dysphagia in patients with uncomplicated erosive esophagitis and its response to therapy. METHODS: A total of 11,945 patients with endoscopically confirmed erosive esophagitis (Los Angeles grades A-D) participated in 5 double-blind, randomized, clinical trials evaluating the efficacy of up to 8 weeks of treatment with either once-daily esomeprazole 40 mg (n = 5068), esomeprazole 20 mg (n = 1243), omeprazole 20 mg (n = 3018), or lansoprazole 30 mg (n = 2616). The severity of dysphagia (4-point scale) was rated at baseline and at week 4. Esophagitis was classified as mild (grade A or B) or severe (grade C or D). RESULTS: At baseline, 4449 of 11,945 patients (37%) had dysphagia-43% of patients with severe esophagitis, and 35% of patients with mild esophagitis (odds ratio, 1.39; 95% confidence interval, 1.27-1.51, P < 0.001). Dysphagia resolved in 83% of patients after 4 weeks of proton pump inhibitor (PPI) treatment. Resolution of dysphagia was associated with a mean healing rate of 90% across all treatments. Seventeen percent of patients reported persistent dysphagia, and in these patients the healing rates were decreased significantly (mean 72%; P < 0.0001). CONCLUSIONS: Dysphagia is common in patients with erosive esophagitis but is not a reliable clinical predictor of severe erosive esophagitis. Dysphagia resolved with PPI therapy in most cases, but persistent dysphagia may indicate failed healing.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15290658&dopt=Abstract esomeprozole Nexium



esomeprazole, Nexium
Effect of the H, K-ATPase inhibitor, esomeprazole magnesium, on gut total antioxidant capacity in mice.

Koch TR, Petro A, Darrabie M, Opara EC.

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Ave., Milwaukee, WI 53295, USA. TimKoch worldnet.att.net

Antioxidant depletion is believed to be a mechanism involved in the pathophysiology of several upper gastrointestinal disorders, and H, K-ATPase inhibitors can alter free radical production by neutrophils. We hypothesized that the H, K-ATPase inhibitor esomeprazole magnesium would decrease gut free radical production with a concomitant increase in gut total antioxidant capacity. A/J mice (n = 10/group) received either vehicle (control) or one of three concentrations of esomeprazole magnesium in vehicle by once-daily gavage for 10 days. Using tissue extracts from stomach and colon, total antioxidant capacity, lipid peroxide levels, and constitutive Cu/Zn-superoxide dismutase were measured using validated assays. There was a dose-related increase in total antioxidant capacity (analysis of variance, P < 0.001) in stomach, but there was no change in the colon. In the assessment of free radical production, there was a trend toward decreased lipid peroxide levels in stomach from mice receiving esomeprazole. In stomach, Cu/Zn-superoxide dismutase activity was increased (ANOVA: p=.03) in mice receiving esomeprazole. In conclusion, gastric total antioxidant capacity and Cu/Zn-superoxide dismutase activity are increased by esomeprazole, and these changes may result in part from decreased free radical production. The present results support the notion that the pharmacological effects of this agent on upper intestinal tissue are more complex than previously thought, and appear to involve both enzymatic and nonenzymatic tissue antioxidants.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15350983&dopt=Abstract esomeprozole Nexium



esomeprazole, Nexium
Effect of proton pump inhibitor pretreatment on resistance of solid tumors to cytotoxic drugs.

Luciani F, Spada M, De Milito A, Molinari A, Rivoltini L, Montinaro A, Marra M, Lugini L, Logozzi M, Lozupone F, Federici C, Iessi E, Parmiani G, Arancia G, Belardelli F, Fais S.

Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Nazionale dei Tumori, Milan, Italy.

BACKGROUND: Resistance to antitumor agents is a major cause of treatment failure in patients with cancer. Some mechanisms of tumor resistance to cytotoxic drugs may involve increased acidification of extracellular compartments. We investigated whether proton pump inhibitors (PPIs), currently used in the anti-acid treatment of peptic disease, could inhibit the acidification of the tumor microenvironment and increase the sensitivity of tumor cells to cytotoxic agents. METHODS: We pretreated cell lines derived from human melanomas, adenocarcinomas, and lymphomas with the PPIs omeprazole, esomeprazole, or pantoprazole and tested their response to cytotoxic drugs in cell death assays. We also evaluated extracellular and intracellular pH and vacuolar-H+-ATPase (V-H+-ATPase) expression, distribution, and activity in PPI-pretreated cells by using western blot analyses, immunocytochemistry, laser scanning confocal analysis, and bioluminescence assays. Finally, we evaluated human melanoma growth and cisplatin sensitivity with or without omeprazole pretreatment in xenografted SCID/SCID mice. RESULTS: PPI pretreatment sensitized tumor cell lines to the effects of cisplatin, 5-fluorouracil, and vinblastine, with an IC50 value reduction up to 2 logs. PPI pretreatment was associated with the inhibition of V-H+-ATPase activity and increases in both extracellular pH and the pH of lysosomal organelles. PPI pretreatment induced a marked increase in the cytoplasmic retention of the cytotoxic drugs, with clear targeting to the nucleus in the case of doxorubicin. In in vivo experiments, oral pretreatment with omeprazole was able to induce sensitivity of human solid tumors to cisplatin. CONCLUSION: Our results open new possibilities for the treatment of drug-resistant tumors through combination strategies based on the use of well-tolerated pH modulators such as PPIs.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15547183&dopt=Abstract esomeprozole Nexium



esomeprazole, Nexium
Effect of Lactobacillus casei supplementation on the effectiveness and tolerability of a new second-line 10-day quadruple therapy after failure of a first attempt to cure Helicobacter pylori infection.

Tursi A, Brandimarte G, Giorgetti GM, Modeo ME.

Digestive Endoscopy Unit, "Lorenzo Bonomo" Hospital, Andria (BA), Italy.

Background: Probiotics have never been used as second-line treatment in patients resistant to a first course of anti-H. pylori treatment. Material/Methods: 70 consecutive patients with persistent H. pylori infection were enrolled and treated with ranitidine bismuth citrate (RBC) 400 mg b.d, esomeprazole or pantoprazole 40 mg/day, amoxycillin 1 g t.d, tinidazole 500 mg b.d. with (group A) or without (group B) supplementation with 750 mg daily containing 16 billion bacteria Lactobacillus casei subsp. casei DG. Esomeprazole or pantoprazole 40 mg/day was administered for a further 4 weeks in cases of active peptic ulcer or severe gastritis detected at endoscopy. In these cases endoscopy was repeated one month after conclusion of therapy. The remaining patients were checked by alC-urea breath test. Results: Sixty-six patients completed the study, 34 in group A and 32 in group B. One group A patient (2.85%) was excluded for protocol violation and one group B patient (2.85%) was lost to follow-up. 33/34 group A patients were H. pylori-negative [per-protocol: 97.05%, on intention-to-treat: 94.28%]. 5/34 patients (14.7%) showed side-effects, but all of them completed the treatment. In group B, two patients (5.71%) showed severe side-effects and were withdrawn from the study. 30/32 patients were H. pylori- negative [per-protocol: 93.75%, on intention-to-treat: 85.71% (p=n.s.)]. 11/32 patients (34.37%) showed side-effects, but all of them completed the study (p<0.05). Conclusions: This 10-day quadruple therapy obtains a high eradication rate, but probiotic supplementation reduces side-effects and permits a slight improvement in eradicating H. pylori.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15567983&dopt=Abstract esomeprozole Nexium