omeprazole, Prilosec
The efficacy of extended-interval dosing of omeprazole in keeping gastroesophageal reflux disease patients symptom free.

Bieszk N, Kale-Pradhan PB.

Wayne State University, Detroit, MI, USA.

The potential economic advantage of alternate-day therapy for GERD maintenance must be weighed against the potential cost of failure before it can be widely instituted. The studies presented have helped develop a clinical picture of the patients who may benefit from alternate-day therapy without risk of complications or potential increases in management costs. Bank et al., reporting on a group of patients, found that patients with Grade II-IV disease had a 61% success rate at two to eight years. Bank defined success as both maintenance of endoscopic healing and symptom control. Ladas et al. found a 66.7% success rate defined as clinical and endoscopic remission in Grades II-III disease. Kurucar et al. monitored symptom control and esophageal complications in his patients and found the regimen to have a 26% success rate in Grades III-IV disease. Lind et al. found that 83% of patients could remain symptom free with on-demand therapy if they were endoscopy-negative at baseline. The results of the Mantides et al. study are important because they imply that alternate-day omeprazole therapy may be more effective than alternatives for step-down treatment, such as ranitidine or cisapride. Furthermore, patients can be educated to increase their frequency of use if symptoms should arise. Not only does this give the patient a sense of self-empowerment over his or her disease state, but it avoids the cost of switching to a PPI due to failure with an H2RA or a motility agent. Alternate-day use of omeprazole should be attempted only during the maintenance phase of GERD therapy. Patients requiring >20 mg/d to achieve healing appeared to be poor candidates for alternate-day omeprazole maintenance therapy. Based on available studies, it would seem that patients with Grades 0-II GERD would benefit most from alternate-day therapy. A role for alternate-day therapy in Grades III-IV is apparent from the results presented but requires greater caution in view of the differing success rates (26-61%) in various studies. With Grades II-III esophagitis, a mean 24-hour gastric pH >6 and a gastric pH <4 less than 10% of the time during the initial healing phase with omeprazole 20 mg/d appeared to be associated with success on alternate-day therapy. Evidence that all marketed PPIs have similar success is not available and should not be extrapolated from the data presented. Evidence that downward dosage adjustments of PPIs versus extending dosage intervals are effective in the maintenance of GERD should be recognized. Lansoprazole has been approved for treating erosive esophagitis at 30 mg/d, with the maintenance dose established at 15 mg/d. Studies showing that lansoprazole 15 mg/d is more effective than alternate-day therapy with lansoprazole 30 mg exist, although similar studies with omeprazole have not been performed. The abstracts describing the use of alternate-day omeprazole accounted for all enrollees and included endoscopic grading or pH monitoring to document disease severity at baseline. Most also included these same objective measures as end points in combination with symptom control. This strengthens the data since the positive predictive value of typical symptoms is variable. However, there are also several significant limitations. Abstracts provide only limited information on methods. All studies other than Lind et al. lacked randomization. This study was also the only one that blinded patients to their treatment. Sample sizes for the majority of the trials were quite small. Statistical analyses were not performed on any of the trial results with the exception of the trial by Lind et al. In light of the lack of evidence of statistical significance as well as study design flaws, conclusions should be drawn cautiously. Larger well-designed trials looking at both the efficacy and cost-effectiveness of alternate day omeprazole are required before a definitive recommendation can be made.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10369630&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs.

Uchiyama K, Wakatsuki D, Kakinoki B, Takeuchi Y, Araki T, Morinaka Y.

Medicinal Research Group II, Kazusa Research Laboratories, Tokyo Tanabe Company Limited, Chiba, Japan. k-uchiy kazusa.tokyo-tanabe.co.jp

We have used Heidenhain-pouch dogs to investigate the effects of (+/-)-5-methoxy-2- inverted question mark[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulph inyl inverted question mark-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine. Single oral administration of TU-199 (0.1, 0.2 and 0.4mgkg(-1)) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg(-1)) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K(+)-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg(-1) once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg(-1)) was much longer than that of omeprazole (0.6mgkg(-1)) or lansoprazole (0.9mgkg(-1)). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K(+)-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 microM, respectively. These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K(+)-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10385219&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Gastric acid blockade with omeprazole promotes gastric carcinogenesis induced by duodenogastric reflux.

Wetscher GJ, Hinder RA, Smyrk T, Perdikis G, Adrian TE, Profanter C.

Department of Surgery, University of Innsbruck, Austria.

Duodenogastric reflux (DGR) in rats causes growth stimulation of the foregut mucosa that is potentiated by gastric acid blockade. It was the aim of this study to investigate if DGR with gastric acid blockade has a higher incidence of carcinomas of the foregut than DGR alone. DGR was induced in 40 Sprague-Dawley rats using a split gastroenterostomy. A cardiomyotomy was performed across the gastroesophageal junction, inducing reflux into the esophagus. Twenty of these rats received omeprazole postoperatively. After one year 18 rats (90%) with DGR + omeprazole treatment and 7 rats (35%) with DGR alone developed adenocarcinoma of the stomach (P < 0.05). None of the rats developed esophageal cancer, but esophageal mucosal hyperplasia was more pronounced in rats receiving omeprazole. Control rats, treated with omeprazole, did not develop carcinomas of the foregut. In conclusion, gastric acid blockade enhanced DGR-induced carcinogenesis of the stomach and promotes growth stimulation of the esophageal mucosa.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10389684&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole may exert both a bacteriostatic and a bacteriocidal effect on the growth of Helicobacter pylori (NCTC 11637) in vitro by inhibiting bacterial urease activity.

Mirshahi F, Fowler G, Patel A, Shaw G.

School of Health and Sports Science, University of North London, UK.

AIMS: To assess the potential antibacterial effect of omeprazole, a benzimidazole proton pump inhibitor, on the growth of Helicobacter pylori in vitro and to evaluate the effect of this compound on bacterial urease activity. METHODS: The growth of H pylori was observed in liquid culture in the presence and absence of omeprazole (0.8 mg/ml). Urease activity was evaluated in aliquots removed from two hour cultures by monitoring the initial change in absorbency at 560 nm in the presence of 0.02% phenol red. RESULTS: The minimum inhibitory concentration of omeprazole against H pylori was 0.8 mg/ml. The concentration of omeprazole required to inhibit growth was dependent on inoculum density: omeprazole (0.8 mg/ml) prevented growth from a 1 x 10(6) cfu/ml inoculum, but not from the higher inocula of 10(7) or 10(8) cfu/ml. This is the first study to demonstrate that omeprazole exerts a bacteriocidal effect against low bacterial densities and a bacteriostatic effect when bacterial density is high. When used at the onset of growth, this concentration of omeprazole has a bacteriocidal effect after four hours, although it exerts a bacteriostatic effect when added to cultures after the exponential phase. Bacterial urease activity is competitively inhibited by omeprazole in a dose dependent manner. CONCLUSION: The results suggest that omeprazole exerts both a bacteriocidal and a bacteriostatic effect against H pylori and competitively inhibits bacterial extracellular urease activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9659264&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Potentiating hypergastrinemic effect by the peroxisome proliferator ciprofibrate and omeprazole in the rat.

Hammer TA, Sandvik AK, Waldum HL.

Dept. of Medicine, Norwegian University of Science and Technology, Trondheim.

BACKGROUND: Profound inhibition of gastric acid secretion induces enterochromaffin-like (ECL) cell carcinoids due to hypergastrinemia. Peroxisome proliferators also lead to hypergastrinemia and ECL cell carcinoids but without reducing gastric acidity. Since the peroxisome proliferator ciprofibrate is still in use as lipid-reducing agent, and proton pump inhibitors are among the most commonly used drugs, we found it of interest to evaluate both the effect of a combination of these drugs on serum gastrin and the expression of gastrin and somatostatin mRNA in antral mucosa. METHODS: The drugs were given by gastric gavage once daily for 4 weeks to female rats. Blood was drawn by vein puncture before and at the end of the 4-week period for determination of gastrin by radioimmunoassay. At death the stomachs were removed, the antral mucosa homogenized, and the density of gastrin and somatostatin mRNA determined by Northern blot, using 32P-labelled probes. RESULTS: Omeprazole dosing increased serum gastrin 4-fold, ciprofibrate 5-fold, and the combination 24-fold. Serum gastrin during ciprofibrate dosing increased gradually, reaching significance after 14 days. Antral gastrin mRNA density increased similarly to the increase in serum gastrin, whereas antral somatostatin mRNA tended to be reduced in the omeprazole and increased in the ciprofibrate-dosed rats. CONCLUSION: A potentiating hypergastrinemic effect of the peroxisome proliferator ciprofibrate and the inhibitor of gastric acid secretion omeprazole is shown, indicating different mechanisms of action.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9669630&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Interference on Helicobacter pylori growth and adhesion by omeprazole and other drugs.

Gismondo MR, Drago L, Lombardi A, Fassina MC, Mombelli B.

L. Sacco Teaching Hospital-University of Milan, Milano, Italy.

Helicobacter pylori is the causative agent of gastritis and a co-agent in other gastroduodenal diseases. Gastroduodenal ulcer and MALT-lymphoma in particular, regress when patients are administered antimicrobial agents to eradicate infection. Sometimes eradication is not definitive and is difficult to check. The aim of our study was to test the antimicrobial activity of omeprazole on H. pylori in comparison with ampicillin and other anti-H2 drugs (ranitidine and famotidine), and to evaluate their interference with bacterial adhesion of H. pylori. We also compared results of the agar dilution antibacterial sensitivity test on H. pylori to those obtained using a bacteria adherence to cell monolayers model, to see if drug activity was different against adhered bacteria. We evaluated omeprazole and ampicillin MIC90s (minimum inhibitory concentrations) against 20 H. pylori isolates by traditional agar dilution method and by exposing previously adhered bacteria to an Hep-2 monolayer to different drug concentrations. The activity against bacteria adhered to cell lines was evaluated by counting viable adhered bacteria after 1, 6, 12 hours of contact with drug. Interference with adherence to Hep-2 cells was also tested. Omeprazole and ampicillin MICs were comparable to other findings (omeprazole MIC90 was 12.5 microg/ml and ampicillin MIC90 was 0.016 microg/ml), while higher concentrations were necessary (4 x MIC90) against adhered bacteria. These findings suggest that MICs evaluated with traditional assays can have different predictivity than tests on adhered H. pylori.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9669648&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
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 omeprozole Prilosec



omeprazole, Prilosec
Somatostatin-14 modulates acid-dependent inhibition of meal-stimulated gastrin via muscarinic pathways in dogs.

Fung LC, Greenberg GR.

Department of Medicine, University of Toronto, Ontario, Canada.

Intraluminal antral acidification inhibits gastrin and stimulates somatostatin-14 (S-14) release, but a functional relationship in the postprandial state has not been established. To examine whether meal-stimulated S-14 mediates inhibition of gastrin release by gastric acid, the effects of omeprazole on circulating levels of S-14 separated from S-28 by gel permeation chromatography, and gastrin were measured without and with atropine in dogs. Compared to controls, pretreatment with omeprazole decreased postprandial plasma levels of S-14 and S-28 (both P<0.01) and increased gastrin (P<0.001). Atropine selectively converted the S-14 response after omeprazole to a peak sixfold increase 40 min after meal ingestion (P<0.001), which was also significantly above S-14 values after atropine alone and controls, but reduced plasma levels of S-28 and gastrin to baseline. Infusions of the somatostatin analogue, cyclo-[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(BZL)] increased postprandial gastrin twofold above controls (P<0.05), and when administered after omeprazole reversed the inhibition of gastrin by atropine, without altering S-14 levels. In contrast, infusions of S-14, which simulated S-14 levels after omeprazole-atropine, and of [D-Trp8]-S-14, which abolished meal-stimulated S-14 responses, did not alter postprandial elevations of plasma gastrin. This study suggests that in conscious dogs muscarinic inhibitory pathways selectively regulate S-14 secretion, are amplified at neutral gastric pH and reciprocally link S-14 to gastrin secretion in the gastric phase of meal ingestion. Postprandial regulation of gastrin release by S-14 includes neurocrine interactions with muscarinic receptor activation; endocrine or paracrine regulation seem less likely.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9712177&dopt=Abstract omeprozole Prilosec