omeprazole, Prilosec
Cost-minimization analysis of treatment of gastroesophageal reflux disease. Implications of varying holding time on conclusions.

Kivioja A, Linnosmaa I, Vehvilainen A, Vohlonen I.

Department of Social Pharmacy, Center for Pharmaceutical Policy and Economics, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland. akseli.kivioja uku.fi

Gastroesophageal reflux disease (GERD), is a common disorder. The most effective medical treatment for GERD is a proton pump inhibitor (PPI). The aim of this study was to specify the most inexpensive PPI therapy for GERD, and to examine the implications of varying outcome measure, holding time, on the conclusions about the cost-effectiveness of the treatments. Proton pump inhibitors that have holding time of intragastric pH>4 for at least 11h in 24h period (esomeprazole, lansoprazole, omeprazole and rabeprazole), were included. In this cost-minimization analysis (CMA), data on holding times were gathered from scientific publications listed in MEDLINE, prices of proton pump inhibitors from the Finnish database of drug prices and the treatment dosages were taken from the official guide of drug therapies in Finland. A decision tree was applied and the probabilities utilized were acquired from three expert physicians. The cost-minimization analysis was performed in three settings. At first, drugs that had a holding time (pH>4) of 11h or more were included. Secondly, drugs that had a holding time of 12h or more were included, and thirdly, a holding time of 13h or more was required. In the first analysis, the least expensive PPI treatment was lansoprazole (average cost of 138.89 per patient). In the second analysis, least expensive treatment was rabeprazole (193.81 per patient), and in the third, rabeprazole again (193.81 per patient). Esomeprazole and omeprazole were not among two of the least expensive alternatives in any of the settings. Which proton pump therapy turns out to be the least expensive for GERD, depends on the length of the holding time desired. Varying the holding time of the drug had a profound effect on the conclusions about the cost-effectiveness of the alternative treatments.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14757488&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Mortality study of 18 000 patients treated with omeprazole.

Bateman DN, Colin-Jones D, Hartz S, Langman M, Logan RF, Mant J, Murphy M, Paterson KR, Rowsell R, Thomas S, Vessey M; SURVEIL (Study of Undetected Reactions, Vigilance Enquiry into Links) Group.

Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.

BACKGROUND: The long term safety of potent gastric acid suppressive therapy has yet to be established. METHOD: General practice record review at a median interval of 26 months followed by retrieval of details of all deaths within four years using the UK National Health Service Central Registers in 17 936 patients prescribed omeprazole in 1993-1995. Death rates were compared with general population rates. RESULTS: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received further scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. All cause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals (CI) 1.34-1.55); p<0.0001) but had fallen to population expectation by the fourth year. There were significant mortality increases in the first year, falling to or below population expectation by the fourth year, for deaths ascribed to neoplasms (1.82 (95% CI 1.58-2.08); p<0.0001), circulatory diseases (1.27 (95% CI 1.13-1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12-1.64); p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87-3.43); p<0.0001) persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60-6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84-2.18); p=0.075), and trachea, bronchus, and lung (1.64 (95% CI 1.19-2.19); p<0.01) seen in the first year had disappeared by the fourth year but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20-10.09) (p<0.0001) in year 1; 2.88 (95% CI 1.62-4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of Barrett's disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17-4.80)). Six deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37-2.22)) and five in patients without oesophageal disease (O/E 0.77 (95% CI 0.25-1.80)). No relationships were detected with numbers of omeprazole scripts received. CONCLUSIONS: Increases in mortality associated with treatment are due to pre- existing illness, including pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesophageal adenocarcinoma in those without oesophageal mucosal damage recorded at registration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12801948&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Histopathology of the gastric oxyntic mucosa in two different patient groups during long-term treatment with omeprazole.

Hage E, Hendel L, Gustafsen J, Hendel J.

Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Denmark. hage rh.dk

OBJECTIVES: Hypochlorhydria, hypergastrinaemia, inflammation and Helicobacter pylori infection, dose and duration of omeprazole treatment may separately, or in combination, influence the proliferation of enterochromaffin-like (ECL) cells and parietal cell changes in gastric mucosa. To assess the effects of these variables comparisons were carried out in patients with the acid related Zollinger-Ellison syndrome (ZES) versus patients with progressive systemic sclerosis (PSS) and gastro-oesophageal reflux disease. METHODS: Twenty-five patients with PSS and 16 patients with ZES were included and received continuous omeprazole treatment for a mean of 7.5 and 9 years. The patients were investigated every 6-12 months with endoscopy, biopsies and histology, and plasma gastrin measurements. PSS patients were titrated by 24 h pH-metry to oesophageal pH>4, and all ZES patients were titrated to a basal acid output of zero H+. RESULTS: Changes towards diffuse and linear ECL cell hyperplasia were observed in 41% of the PSS patients. Micronodular hyperplasia and neoplasia were not seen. In the ZES patients changes towards linear and micronodular hyperplasia were observed in all patients. Two patients developed ECL cell carcinoids; one of these had MEN-1 syndrome. Also parietal cell changes were more pronounced in the ZES group than in the PSS group. CONCLUSIONS: In patients without intrinsic acid hypersecretion and hypergastrinaemia significant proliferation of ECL cells is not an issue irrespective of gastric mucosal inflammation, omeprazole dose, duration of treatment and acid inhibition. The level of gastrin secretion and high plasma gastrin appear to accelerate ECL cell proliferation and parietal cell changes possibly influenced by chronic gastritis and H. pylori infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12811309&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Stability of esomeprazole capsule contents after in vitro suspension in common soft foods and beverages.

Johnson DA, Roach AC, Carlsson AS, Karlsson AA, Behr DE.

Division of Gastroenterology, Eastern Virginia School of Medicine, Norfolk, Virginia 23505, USA. dajevms aol.com

STUDY OBJECTIVE: To determine the in vitro stability of esomeprazole pellets from an opened capsule after suspension in various common soft foods and beverages. DESIGN: In vitro study. SETTING: Pharmaceutical company research laboratory. MEASUREMENTS AND MAIN RESULTS: Pellets from opened esomeprazole 20-mg capsules were suspended in 100 ml of tap water, milk (1.5% fat), orange juice, apple juice, yogurt, or cultured milk for 30 minutes, then added to 500 ml of hydrochloric acid to simulate gastric acid exposure. After a 2-hour incubation, the mixture was filtered through a sieve, and the collected pellets were dissolved in an alkaline solution. Esomeprazole concentrations were measured using reverse-phase liquid chromatography The stability of the esomeprazole pellets exceeded 98% in all beverages and soft foods except milk. CONCLUSION: Administration of the pellets from an opened esomeprazole capsule shortly after suspending them in tap water, yogurt, cultured milk, orange juice, or apple juice may be a practical alternative for patients who cannot swallow an intact capsule. Bioavailability studies comparing esomeprazole administered as an intact capsule to that of the pellets from an opened capsule suspended in these beverages or soft foods are recommended to confirm these findings.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12820815&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Efficacy of a paste formulation of omeprazole for the treatment of naturally occurring gastric ulcers in training standardbred racehorses in Canada.

Doucet MY, Vrins AA, Dionne R, Alva R, Ericsson G.

Departement de biomedecine veterinaire, Faculte de medecine veterinaire, Universite de Montreal, CP 5000, Saint-Hyacinthe, Quebec J2S 7C6.

The efficacy of a paste formulation of the H+, K+, -ATPase inhibitor omeprazole was evaluated in standardbred racehorses for the treatment and prevention of gastric ulcers. Twenty standardbred racehorses in training, aged 2 to 9 years, were enrolled from 2 training centres in this field trial. Endoscopic examinations confirmed the presence of gastric ulcers in all horses, prior to allocation and treatment and on day 0. Lesions were scored on a scale of 0 to 3 (intact epithelium to extensive ulceration). Replicates were formed, based on training level and location. Within replicates, 1 horse was assigned to group 1 and 3 horses were assigned to group 2, randomly. Horses in group 1 were sham-dosed controls. Horses in group 2 were given omeprazole paste orally at 4 mg/kg bodyweight (BW)/day from day 0 to day 27 and 2 mg/kg BW/day of omeprazole paste orally from day 28 to day 57. Follow-up endoscopies were conducted on post treatment days 28 and 58 or 59. Physical examinations, including BWs, were conducted on all horses prior to treatment and on days 13 or 14, 28, 42 or 43, and 58 or 59. Horses treated with omeprazole had significantly (P < 0.01) more improvement in gastric lesion scores than did controls at day 28 and at study termination on days 58 or 59. All of the omeprazole-treated horses were improved relative to baseline ulcer score at both examinations, and 73.3% were healed (lesion score of 0) at both examinations. None of the controls improved at any point during the study. When the dose was reduced to 2 mg/kg BW, 80% of the horses showed no recurrences or worsening in gastric ulcers. It was concluded that omeprazole paste at 4 mg/kg BW orally, once daily is highly effective in healing gastric ulcers in standardbred racehorses in training and that a dose of 2 mg/kg BW orally, once daily, effectively prevents the recurrence of gastric ulcers in most horses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12892289&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
A screening study on the liability of eight different female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes.

Laine K, Yasar U, Widen J, Tybring G.

Department of Medical Laboratory Sciences & Technology, Division of Clinical Pharmacology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden. karlai utu.fi

The aim of this study was to screen the inhibitory potential of different clinically used oestrogen and progestin hormones on CYP2C9, 2C19 and 3A4 activities in human liver microsomes. The degree of inhibition by desogestrel, 3-ketodesogestrel, 17-beta-oestradiol, gestodene, aethinyloestradiol, medroxyprogesterone acetate, norethisterone or L-norgestrel were studied at 100 microM on losartan oxidation (CYP2C9), R-omeprazole 5'-hydroxylation (CYP2C19) and R-omeprazole sulphoxidation (CYP3A4) with a 10-min preincubation with NADPH in human liver microsomes prepared from 6 individual genotyped donor livers. Aethinyloestradiol was found to be a potent inhibitor (55% mean inhibition; 95% CI 32% to 79%) of losartan oxidation (CYP2C9) and R-omeprazole 5-hydroxylation (70%; 63% to 77%) (CYP2C19), while it had little effect on R-omeprazole sulphoxidation (CYP3A4) activity. 17-beta-Oestradiol did not produce significant inhibition on any of the studied enzyme activities. Of the progestin hormones studied, gestodene and 3-ketodesogestrel were potent inhibitors of CYP2C19 (57%; 47% to 67% and 51%; 29% to 45%) and CYP3A4 (45%; 30% to 59% and 40%; 19% to 62%), but had little effect on the CYP2C9 activity. In addition, medroxyprogesterone acetate was found to inhibit CYP2C9 (55%; 45% to 65%), while not having significant effect on 2C19 or 3A4. In conclusion, the liability of clinically used female sex steroids to inhibit CYP2C9, 2C19 and 3A4 activities in human liver microsomes is very distinctive and these differences among both the oestrogen and progestin hormones may, at least in part, explain the variable results from clinical trials examining inhibitory effects of hormone replacement therapy and oral contraceptives on drug metabolism.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12899669&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Odds of moderate or severe gastric ulceration in racehorses receiving antiulcer medications.

Orsini JA, Haddock M, Stine L, Sullivan EK, Rabuffo TS, Smith G.

New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA 19348, USA.

OBJECTIVE: To determine the odds of moderate or severe gastric ulceration in racehorses treated with various antiulcer medications. DESIGN: Unmatched case-control study. ANIMALS: 798 horses in active race training (252 Thoroughbreds and 546 Standardbreds). Only horses that had been receiving a single antiulcer medication or no antiulcer medication for at least 2 weeks prior to examination were included. PROCEDURE: Gastroscopy was performed on each horse by a single individual who was not aware of the horses' antiulcer treatments, and severity of gastric ulceration was scored. Signalment and medication history were recorded. Logistic regression was used to determine whether identification of moderate or severe ulceration was associated with treatment, age, breed, or sex. Treatments were grouped as no treatment, buffer, sucralfate, histamine type 2 receptor antagonist, compounded omeprazole, proprietary omeprazole at a low dosage, and proprietary omeprazole at a high dosage. RESULTS: Only proprietary omeprazole was associated with significantly lower odds of moderate or severe ulceration, compared with no treatment. Risks of moderate or severe gastric ulceration in horses receiving a buffer, sucralfate, a histamine type 2 receptor antagonist, or compounded omeprazole were not significantly different from risks in horses receiving no antiulcer medication. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that the proprietary formulation of omeprazole was associated with a significantly lower risk of moderate or severe gastric ulceration, compared with no treatment, in racehorses in active race training, whereas other antiulcer medications were not.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12906229&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism.

Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Tassaneeyakul W, Meyer UA, Birkett DJ.

Clinical Pharmacology, Astra Hassle AB, S-43183 Molndal, Sweden.

1 The in vitro metabolism of omeprazole was studied in human liver microsomes in order to define the metabolic pathways and identify the cytochrome P450 (CYP) isoforms responsible for the formation of the major omeprazole metabolites. 2 The four major metabolites identified in vitro, in tentative order of importance, were hydroxyomeprazole, omeprazole sulphone, 5-O-desmethylomeprazole, and an unidentified compound termed metabolite X. Omeprazole pyridone was also detected but could not be quantitated. Incubation of hydroxyomeprazole and omeprazole sulphone with human microsomes resulted in both cases in formation of the hydroxysulphone. The kinetics of formation of the four primary metabolites studied were biphasic suggesting the involvement of multiple CYP isoforms in each case. Further studies used substrate concentrations at which the high affinity activities predominated. 3 Formation of the major metabolite, hydroxyomeprazole, was significantly correlated with S-mephenytoin hydroxylase and with benzo[a]pyrene metabolism and CYP3A content. Inhibition studies with isoform selective inhibitors also indicated a dominant role of S-mephenytoin hydroxylase with some CYP3A contribution in the formation of hydroxyomeprazole. Correlation and inhibition data for the sulphone and metabolite X were consistent with a predominant role of the CYP3A subfamily in formation of these metabolites. Formation of 5-O-desmethylomeprazole was inhibited by both R, S-mephenytoin and quinidine, indicating that both S-mephenytoin hydroxylase and CYP2D6 may mediate this reaction in human liver microsomes and in vivo. 4 The Vmax/Km (indicator of intrinsic clearance in vivo) for hydroxyomeprazole was four times greater than that for omeprazole sulphone. Consistent with findings in vivo, the results predict that omeprazole clearance in vivo would be reduced in poor metabolisers of mephenytoin due to reduction in the dominant partial metabolic clearance to hydroxyomeprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12959268&dopt=Abstract omeprozole Prilosec