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April 2000
345
PIRENZIPINE OR FAMOTIDINE CONTROLS NOCTURNALGASTRIC ACID BREAKTHROUGH DURING BID PROTONPUMP INHIBITOR (PPI) TREATMENT.Fernando Sierra, Diana P. Torres, John Cuervo, Jose A. Fernandez,SANTA FE OF BOGOTA Fdn, Bogota, Colombia; SAINT IGNACIOHosp, Bogota, Colombia; Institute of Social Security, Bogota, Colombia;Institute of Social Security, Valledupar, Colombia.
Background: Recently, Peghini and collaborators have shown that nocturnal acid breakthrough (nABT), defined as drop of intragastric pH < 4 for>I hr overnight, occurs in 3/4 of individuals during treatment with PPI bid (Gastroenterology 1997; lI2:A255). Aim: To compare the efficacy of threetreatments to abolish nABT on therapy with PPI bid. Methods: 10 patients(6M, 4F), mean age 36 y, were treated with omeprazole 20 mg (020) bidac (breakfast and dinner) for 7 days. Beginning on day 8, three additionaltreatments, Pirenzipine 150 mg (PI50) or Famotidine 40 mg (F40) or 020were given at 20:30 in different sequence. Studies were completed whilemaintaining 020 bid over the next 4 to 30 days. Intragastric pH wasrecorded 10 cm below LES from 02:00 PM until 8:30 AM. A standardizeddinner was given at 7:00 PM. RESULTS: Pl50 and F40 were both superiorto additional 020 in suppressed nocturnal acid breakthrough. The figureshow median % time intragastric pH < 4 and < 3 from 10:00 PM until7:00 AM. PLACE GRAPHIC HERE CONCLUSION: Adding 150 mg ofPirenzipine or 40 mg of Famotidine at night to 020 bid reduces nABTmore effectively than a third dose of 020. These data suggest that besidehistamine, acetilcholine plays an important role in nocturnal acid secretion,because in this study we show that a specific MI cholinergic receptorantagonist, Pirenzipine, beside histamine H2 receptor antagonist, Famotidine suppressed nocturnal acid breakthrough efficiently.
AGAA21
347
ALGINATES INHIBIT PEPSIN ACTIVITY IN VITRO; A JUSTIFI·CATION FOR THEIR USE IN GASTRO·OESOPHAGEAL REFLUX DISEASE (GORD).Andrew M. Sunderland, Peter W. Dettmar, Jeffrey P. Pearson, Univ ofNewcastle Upon Tyne, Newcastle, United Kingdom; Reckitt & ColmanProducts Ltd, Hull, United Kingdom.
Introduction: Reflux of gastric contents into the oesophagus may give riseto damage to the squamous epithelium of the oesophagus if the pH is 4 orless, which in the long term may predispose to Barrett's oesophagus andoesophageal carcinoma, with the main aggressors of gastric refluxate beingpepsin and hydrochloric acid. The acid can be rapidly alkalized by sodiumbicarbonate but the pepsin can remain active at pH's up to 5 and is onlyirreversibly inhibited at pH's above 7. Consequently pepsin may still havea persistant damaging effect. An effective non-systemic treatment ofchronic gastric reflux is with Gaviscon, which contains alginate, the raftforming component of the product formulation. As well as a physicalbarrier to reflux, Gaviscon may further protect the oesophagus by an abilityto inhibit peptic activity. In this study we have investigated the ability ofalginates to inhibit pepsin. Methods: Total pepsin activity was determinedby the N-terminal assay. Succinyl albumin substrate (8mg/ml,pH2.2) andpepsin was incubated for 30 minutes at 3rC either in the presence orabscence of alginate. Activity was arrested by the addition of 4%(w/v)sodium bicarbonate. Triphenylation of the new N-terminals formed wasachieved by the addition of 0.05%(w/v) trinitrobenzenesulphonic acid.Colour was developed by incubation at 50·C for 10 minutes followed bythe addition of IO%(w/v) sodium dodecyl sulphate and 1.0M hydrochloricacid. Absorbance was measured at 340nm. Results: At a wide range ofalginate concentrations pepsin activity was inhibited with a mean percentage inhibition of 51.50%, (n=58). Discussion: Alginates have been shownto strongly inhibit pepsin activity which further justifies their use ingastro-oesophageal reflux disease, and the possiblity of tailor-making alginates may give better oesophageal protection against gastric refluxate,
346
PHARMACOKINETICS OF ESOMEPRAZOLE IN PATIENTSWITH LIVER CIRRHOSIS.Henrik Sjovall, Irrnelin Hagman, Johan Holmberg, Kerstin Rohss, Mohammed Hassan-Alin, Sahlgrenska Univ Hosp, Goteborg, Sweden; AstraZeneca R&D Molndal, Molndal, Sweden.
Introduction: Esomeprazole is the first PPI developed as an optical isomerand has proved to be highly effective in the treatment of acid-relateddiseases. The aim of this study was to study the pharmacokinetics ofesomeprazole in patients with liver cirrhosis. Methods: Twelve patientswith mild, moderate and severe liver dysfunction according to Child-Pugh(4 in each class) with a mean age of 51 years (range 40-60 years) and amean weight of 69 kg (range 47-90 kg) completed this open-label study.All patients received esomeprazole capsule 40 mg once daily for five days.Blood samples to determine drug plasma concentration were taken up to 24hours post-dose on day 5 and were analysed using normal-phase liquidchromatography with UV-detection, Pharmacokinetic parameters were estimated by noncompartmental analysis. The pharmacokinetic parameters inthe present study were compared with those obtained in a previous study inpatients with symptoms of GERD with no liver dysfunction. Results: Thetime to reach Cmax was approximately 2 hours, indicating that the time forabsorption is similar to that previously reported in young healthy and inelderly subjects. The AUC, and t l/2 but not Cmax of esomeprazole weresignificantly higher than in patients with symptoms of GERD. The geometric mean AUC, of esomeprazole was 76% (95% CI; 29 to 142%) higherand that of t1/2 was 29% (95%CI; -I to 68%) higher compared to GERDpatients. However, when the patients were grouped according to the degreeof liver dysfunction the AUC, and t l / 2 values in patients with mild andmoderate liver dysfunction were in the same range as those for GERDpatients. No side effects attributable to esomeprazole were noticed. Conclusion: The pharmacokinetics of esomeprazole in patients with mild tomoderate liver dysfunction was similar to that in GERD patients with noliver dysfunction. The plasma levels of esomeprazole were increased inpatients with severe liver dysfunction. Esomeprazole was well tolerated.
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348ESOMEPRAZOLE 20MG MAINTAINS SYMPTOM CONTROL INENDOSCOPY·NEGATIVE GERD: A RANDOMIZED PLACEBOCONTROLLED TRIAL OF ON·DEMAND THERAPY FOR 6MONTHS.Nicholas 1. Talley, Karsten Lauristen, Helena Tunturi-Hihnala, Tore Lind,Bjorn Moum, Christen J. Bang, Tom B. Schulz, Tor M. Omland, MagnusS. Delle, Ola Junghard, The Nepean Hosp, Penrith, Australia; Odense UnivHosp, Odense, Denmark; Seinajoki Hosp, Seinajoki, Finland; Kamsjukhuset, Skovde, Sweden; Ostfold Cent Hosp, Fredrikstad, Norway; Specialistgruppen, Nesttun, Bergen, Norway; Aust-Agder Cent Hosp, Arendal,Norway; Lister Sykehus, Flekkefjord, Norway; AstraZeneca, Molndal,Sweden.
Objectives: Most patients with GERD, regardless of endoscopic status,suffer symptomatic relapse within 6 months of stopping acid suppressanttherapy. This study assessed the efficacy of on-demand treatment of GERDwith esomeprazole, the first PPI developed as an optical isomer. Methods:In this multicenter, double-blind study, 342 endoscopy-negative GERDpatients demonstrating complete resolution of heartburn during the finalweek of a 4-week treatment period with esomeprazole 20mg (E20) oromeprazole 20mg once daily were randomised to receive E20 or placeboon demand (maximum of I dose per day) for the next 6 months. Antacidswere allowed as rescue medication. Primary and secondary efficacy variables were times to study discontinuation due to unwillingness to continueI) for any reason, and 2) for inadequate heartburn control. Dose intake wasassessed using electronic caps on the drug containers. Results: All 342patients (191 males), aged 19-79 (mean 48.9) years, were included in theITT analysis. The proportion of patients who discontinued treatment due toinsufficient control of heartburn was significantly higher among placebocompared to E20 recipients (51% vs 14%; p<O.OOOI). Overall, patientsrandomised to E20 remained in the study longer than those randomised toplacebo (mean 165 vs 119 days). Most patients took the study medicationfor periods of 1-3 consecutive days (E20) or 1-6 consecutive days (placebo). On average, one dose of E20 was taken every third day. The meannumber of antacids taken per day was >2-fold higher in the placebo groupthan in the E20 group (1.06 vs 0.39). The frequency of adverse events wassimilar in the two groups when adjusted for time spent in the study. Clinicallaboratory profiles were similar for the two treatment groups. Conclusions:On-demand therapy with E20 is very efficacious and well-tolerated incomparison with placebo in maintaining symptom control in endoscopynegative GERD. Overall, some 86% of patients continued with on-demandesomeprazole treatment over the 6-month study period.