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Drug Information Rounds Combination Drug Therapy for Gastroesophageal Reflux Disease L Brian Cross and Lori N Justice OBJECTIVE: To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine2 receptor antagonists in gastroesophageal reflux disease (GERD). DATA SOURCES: Clinical literature identified through MEDLINE (January 1966–August 2001). Key search terms included gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine2; therapy, combination drug; therapy, combined modality; and combinations, drug. DATA SYNTHESIS: Approximately 80–90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy. Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for ≥60 min during the night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid breakthrough. However, the clinical significance of this finding is not clear. CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine2 receptor antagonists to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far — nocturnal acid breakthrough — has not been proven to correlate with improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs. KEY WORDS: combination therapy, gastroesophageal reflux disease, histamine2 receptor antagonists, proton-pump inhibitors. Ann Pharmacother 2002;36:912-6. REQUEST What is the role of combination therapy with proton-pump inhibitors (PPIs) and histamine2 receptor antagonists (H2RAs) in gastroesophageal reflux disease (GERD)? RESPONSE BACKGROUND The use of pharmacologic agents to decrease the production of, or neutralize, gastric acid in the treatment of GERD has continued to increase as more effective agents are being made available. With the 1986 approval of cimetidine, the first available H2RA, clinicians had access to an agent that was a significant improvement over previously available therapies. The approval of omeprazole, the proto- Author information provided at the end of the text. 912 ■ The Annals of Pharmacotherapy ■ typical benzimidazole in 1989, brought further understanding of the function of the parietal cell and the final common pathway of gastric acid production through the H+/K+ adenosine triphosphatase (ATPase) pump. Many trials1-5 have studied the use of various combination therapies for the treatment of GERD; however, none of these trials studied the use of combination therapy with PPIs and H2RAs. This article reviews the available literature about this combination of PPIs and H2RAs in the treatment of GERD. Understanding parietal cell physiology during the production of gastric acid and how the pharmacology of different agents affects that physiology helps to define the role of combination therapy with PPIs and H2RAs. It is known that the parietal cell membrane undergoes a significant morphologic change when stimulated to secrete acid.6 Three important changes occur in the activated cell: (1) intracellular tubovesicular membranes significantly decrease in number, (2) apical canalicular membranes significantly 2002 May, Volume 36 Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016 www.theannals.com increase in number, and (3) long apical microvilli become apparent.7 Some evidence suggests that the H+/K+ ATPase conductances are transported from the tubulovesicles to the apical secretory canaliculus before acid secretion.8 Activation of H+/K+ ATPase is the final step in the secretion of acid; blocking its action with a PPI should therefore inhibit acid secretion from all sources. PPIs are weak base prodrugs that become concentrated in the secretory canaliculi of the parietal cells, where they are protonated to their active forms. This activated form then binds the luminal α subunit of the H+/K+ ATPase by irreversible covalent sulfhydryl bonds. PPIs can only effectively inhibit parietal cells in the stimulated state described above. Therefore, the degree of acid secretion activation at the time of PPI administration will dictate the effectiveness of the medication.9 Increased effectivness has been reported when PPIs were given with a meal compared with a fasting state.10 Decreased efficacy would be expected in fasting patients because significant numbers of parietal cells would be in the unstimulated phase and therefore unable to trap and activate the PPI. H2RAs are reversible, competitive antagonists of the actions of histamine on H2 receptors, thereby decreasing the production of acid from the parietal cell. It has been suggested7 that cimetidine, as well as the anticholinergic agent atropine, blocks the transformational change of the parietal cell mentioned above. Whether this is a class effect with all H2RAs is not known. In addition, one report11 has shown a significant decrease in the effect of omeprazole in dogs when acid secretion was inhibited by H2RAs. This complex relationship between parietal cell physiology and the pharmacology of these 2 drug classes is important to consider when reviewing the available literature on the use of combination therapy with PPIs and H2RAs. LITERATURE REVIEW Two reviews12,13 address the treatment of GERD patients who were refractory to normal doses of PPIs and who received combination therapy with PPIs and H2RAs. Hatlebakk et al.13 discuss many issues that should be considered in a patient who seems to be refractory to PPI therapy. Some of these include variability in bioavailability of the PPI, inappropriate dosage timing (PPI therapy is significantly more effective when given prior to or with a meal because more proton pumps will be in the active phase of secreting acid and therefore able to be inhibited), reduced efficacy of PPIs in Helicobacter pylori–negative patients and in rapid metabolizers of omeprazole, decreased PPI effects in acid hypersecretors, and omeprazole resistance (possible abnormality with the proton pump). Patients who seem refractory to acid suppression therapy should also be evaluated for such conditions as presence of peptic strictures, Barrett’s esophagus mistaken for unhealed esophagitis, gastric stasis, lower esophageal sphincter dysfunction, ineffective esophageal peristalsis, and nonacid gastroesophageal reflux. For the purposes of this article, nondrug issues are not discussed. www.theannals.com Peghini et al.14 studied patients refractory to PPI therapy and normal volunteers. They used intragastric pH monitoring during both upright and supine positions to assess pH control of 3 different groups taking PPIs therapy twice daily before meals. The first group consisted of 17 patients with persistent GERD symptoms who had been taking twice-daily omeprazole for ≥1 month. The second group included 16 healthy male volunteers given omeprazole twice daily, with pH monitoring performed on day 7 of therapy. Group 3 included 12 healthy male volunteers given lansoprazole twice daily, with pH monitoring performed on day 7 of therapy. The investigators showed that as high as 70% of all subjects (GERD patients and volunteers) taking twicedaily PPI therapy had nocturnal acid breakthrough, defined as pH <4 for >60 minutes during the overnight period. Nocturnal acid breakthrough occurred with equal frequency in all 3 groups studied, therefore questioning the clinical significance of this finding. Of further concern is that assessments were not made to determine the association of nocturnal acid breakthrough with esophageal acid exposure; thus, no evidence is given as to the clinical relevance of nocturnal acid breakthrough. It has been reported15 that as many as 50% of patients with Barrett’s esophagus or scleroderma with GERD do have increased overnight esophageal acid exposure during nocturnal acid breakthrough and may therefore represent the subset of patients who would possibly benefit from the improvement in nocturnal acid breakthrough. The severity of mucosal injury in reflux esophagitis highly correlates with the percentage of time within a 24hour period that either the esophagus is exposed to refluxate with a pH <4 or the intragastric contents are at a pH <4.16,17 However, all experimental trials to date assessing combined therapy with PPIs and H2RAs for the treatment of GERD have measured nocturnal acid breakthrough, assuming that improvement in GERD symptom outcomes would follow improvement in pH control. In another trial, Peghini et al.18 compared 4 regimens after 7 days of therapy in 12 healthy, asymptomatic volunteers. The regimens included omeprazole 20 mg twice daily before meals for 7 days, followed by the addition at bedtime on day 8 of (1) placebo, (2) omeprazole 20 mg, (3) ranitidine 150 mg, or (4) ranitidine 300 mg. Each of these were given in random sequence, with the exception that omeprazole was given as the last added bedtime therapy in all patients. All 4 regimens were completed over the following 4 –21 days (median 7). Overnight gastric pH monitoring (from 1700 until 0630 the next morning) was performed in the 12 subjects on day 8 of therapy with each of the various regimens. Median intragastric pH values were <4 for all regimens included in the trial. However, when comparing percent of time at pH <4, differences were apparent. Intragastric pH <4 occurred in 48% of the subjects receiving placebo at bedtime, 31% of the subjects receiving omeprazole, 5% of the subjects receiving ranitidine 150 mg, and 6% of the subjects receiving ranitidine 300 mg. Each ranitidine dose was reported to be statistically better The Annals of Pharmacotherapy Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016 ■ 2002 May, Volume 36 ■ 913 LB Cross and LN Justice in pH control versus both the additional third dose of omeprazole (p < 0.01) or placebo (p < 0.0001). The authors speculated that fasting breakthrough nocturnal acid secretion in patients receiving omeprazole twice daily is most likely due to histamine sources. One of the limitations of this study was that it included only a small number of healthy volunteers. As such, no clinical implications to patients with GERD can be drawn from the conclusions of its data. Improvement in pH was compared after only onetime doses of the varied regimens studied, and therefore the applications to clinical practice are unclear. Robinson et al.19 compared 4 regimens in the treatment of 16 heartburn patients in a randomized crossover trial. The regimens included: (1) omeprazole 20 mg in the morning and at bedtime, (2) omeprazole 20 mg in the morning and ranitidine 75 mg at bedtime, (3) omeprazole 20 mg in the morning and placebo at bedtime, and (4) placebo in the morning and at bedtime. The 16 patients received each of the above regimens for 6 days, with a 1-week washout period separating each regimen change. Twenty-four-hour pH monitoring was performed on day 6 of each regimen. No significant difference between the omeprazole twice-daily regimen and the omeprazole in the morning and ranitidine at bedtime regimen was detected with respect to gastric pH profiles for each hour of the day and night. Nocturnal acid breakthrough occurred in 68.75% of patients taking the morning omeprazole/bedtime ranitidine regimen, 87.5% of patients taking both the omeprazole twice-daily regimen and the morning omeprazole/bedtime placebo regimen, and 100% of the patients on the placebo twice-daily regimen. There were no statistical differences found between these regimens. This study has been criticized for administering the second dose of omeprazole at bedtime instead of before the evening meal, since PPIs have been shown to be more effective when given with or before meals. One study20 has since been completed that contradicts the results reported in this trial. A randomized, double-blind, crossover study20 of 20 healthy volunteers investigated omeprazole 20 mg twice daily before meals plus placebo at bedtime compared with omeprazole 20 mg in the morning, placebo before dinner, and ranitidine 150 mg at bedtime. Each treatment arm was completed in 7 days, with a 1-week washout period between study periods. On day 8, gastric pH was measured for 24 hours, and the percentage of time pH was <4 for total, upright, and recumbent positions were compared between the 2 regimens. The median percentage of time that pH was <4 was less with the omeprazole twice-daily regimen (18.9%) than with the morning omeprazole/bedtime ranitidine regimen (29.7%; p = 0.003). Clinical differences between these 2 regimens were not studied. As in other trials assessing the combination of PPI and H2RA therapy, the assumption is that an improvement in nocturnal acid breakthrough in healthy volunteers will correlate to improvement of GERD in patients with active disease. An additional concern is that the duration of therapy in this study and other previously mentioned trials of combination regimens was only 1 week. 914 ■ The Annals of Pharmacotherapy ■ It has been suggested21 that tolerance to H2RA therapy develops over long-term use, a phenomenon that might not be seen in these trials. This subject was addressed by a study presented at the American College of Gastroenterology meeting in October 2000. In this study, Fackler et al. assessed the effect on nocturnal acid breakthrough of the addition of a bedtime dose of ranitidine 300 mg to omeprazole 20 mg twice daily before meals in both healthy volunteers and patients with GERD. Twenty subjects (11 healthy volunteers, 9 pts. with GERD) were given omeprazole 20 mg twice daily for 2 weeks. Ranitidine 300 mg was then added to the PPI regimen at bedtime and measures of nocturnal acid breakthrough were performed at the end of 1 week of the combination regimen. The combination of omeprazole 20 mg twice daily before meals and ranitidine 300 mg at bedtime was continued, and measures of nocturnal acid breakthrough were performed again after 3 more weeks of therapy. Forty-five percent of subjects had suppressed nocturnal acid breakthrough after 1 week of combination therapy; however, this had decreased to 25% by the end of 4 weeks with combination therapy. The authors suggested that bedtime ranitidine did not eliminate nocturnal acid breakthrough, and the effect of ranitidine on nocturnal gastric acid reduction was minimal and lessened with prolonged therapy. As with other trials in this review, small subject numbers limit the clinical application of the trial. DISCUSSION Since the advent of PPIs, the treatment and healing rates of reflux disease have improved significantly compared with those of former therapies.12 Healing rates for reflux esophagitis using standard PPI doses (omeprazole 20 mg once daily or lansoprazole 30 mg once daily) have been reported to be 80–90% after 8 weeks. A small portion of patients is refractory to standard once-daily PPI therapy; this group may be at increased risk for more serious complications of reflux disease, such as Barrett’s esophagus. For this reason, discovering why the patient is refractory to therapy is paramount. According to the results by Khoury et al.20 adding an H2RA to once-daily PPI therapy would not be appropriate. The overwhelming majority of patients should respond to twice-daily PPI therapy given before the morning and evening meals. The clinician should first eliminate patient-specific and medication-specific causes of treatment failure. Current American College of Gastroenterology practice guidelines22 for the diagnosis and treatment of GERD recommend reconsidering the diagnosis, current therapy, or both for patients who present with GERD refractory to twice-daily PPI therapy. In the small minority of true treatment failures of twice-daily PPI therapy, the next step in medical management is not completely clear. One option would be to simply further increase the dose of the PPI. In a limited number of patients, Leite et al.23 found that by increasing the dose of omeprazole to 80 mg/d, improvement of omeprazole resistance was seen. This would only be useful if pH monitoring indicates a continued low pH despite standard doses of PPI therapy. Due to the sig- 2002 May, Volume 36 Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016 www.theannals.com Drug Information Rounds nificant interpatient variability in response to PPI therapy, a second option would be to change to a different PPI.24 Many patients who seem refractory to twice-daily PPI therapy might be considered for fundoplication. This approach is probably incorrect. The most appropriate surgery candidate is the patient who is a complete responder to PPI therapy but prefers surgery. Patients who are PPI resistant as proven by pH monitoring and patients who are suggestive of nonacid reflux may also be appropriate surgery candidates.13 However, due to recent results of a long-term outcome trial25 comparing medical management and surgery for the treatment of GERD that showed an unexpected increase in mortality at 10-year follow-up in the surgically managed patients, the appropriate time to refer patients for surgical management of GERD is in question now more than ever. Finally, a trial of twice-daily PPI with the addition of an H2RA could be considered. However, to date, no trials have compared the efficacy of regimens beyond twice-daily PPI therapy in GERD patients. SUMMARY No studies in patients with GERD demonstrate that the addition of H2RAs to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far — nocturnal acid breakthrough — has also not been proven to correlate to improvement of GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in patients refractory to standard doses of PPIs. L Brian Cross PharmD CDE, Assistant Professor, Department of Pharmacy Practice & Pharmacoeconomics, College of Pharmacy, University of Tennessee, Memphis, TN Lori N Justice PharmD, Assistant Professor, Department of Pharmacy Practice & Pharmacoeconomics; Interim Director, Drug Information Center, College of Pharmacy, University of Tennessee Reprints: L Brian Cross PharmD CDE, College of Pharmacy, University of Tennessee, 847 Monroe Ave., Ste. 205 C, Memphis, TN 38163-2109, FAX 901/448-1221, E-mail [email protected] We thank the following colleagues for their review of this article: Patricia B Amadio MD, J Richard Brown PharmD, Kenneth DeVault MD, and J Douglas Wurtzbacher PharmD. References 1. McKenna CJ, Mills JG, Goodwin C. Combination of ranitidine and cisapride in the treatment of reflux oesophagitis. Eur J Gastroenterol Hepatol 1995;7:817-22. 2. Vigneri S, Termini R, Leandro G. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995;333:1106-10. 3. Richter JE, Sabesin SM, Kogut DG. Omeprazole versus ranitidine or ranitidine/metoclopramide in poorly responsive symptomatic gastroesophageal reflux disease. Am J Gastroenterol 1996;91:1766-72. 4. Lieberman DA. Medical therapy for chronic reflux esophagitis: long term follow-up. Arch Intern Med 1987;147:717-20. 5. Galmiche JP, Fraitag B, Filoche B. Combined therapy with cisapride and cimetidine in severe reflux oesophagitis: a double blind placebo-controlled trial. Gut 1988;29:675-81. 6. Helander HF. Parietal cell structure during inhibition of acid secretion. Scand J Gastroenterol 1984;19(suppl 101):21-6. 7. Redel CA, Zwiener RJ. Anatomy and anomalies of the stomach and duodenum. In: Feldman M, ed. Sleisenger & Fordtran’s gastrointestinal and liver disease. 6th ed. Orlando, FL: WB Saunders, 1998:587-99. www.theannals.com 8. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995;75:155-9. 9. Soll AH. Peptic ulcer and its complications. In: Feldman M, ed. Sleisenger & Fordtran’s gastrointestinal and liver disease. 6th ed. Orlando, FL: WB Saunders, 1998:621-63. 10. Hatlebakk JG, Katz PO, Castell DO. Proton pump inhibitors: better before breakfast than without breakfast (abstract). Am J Gastroenterol 1998;93:1636. 11. De Graef J, Woussen-Colle M. Influence of the stimulation state of the parietal cells on the inhibitory effect of omeprazole on gastric acid secretion in dogs. Gastroenterology 1986;91:333-7. 12. DeVault KR. Overview of medical therapy for gastroesophageal reflux disease. Gastroenterol Clin North Am 1999;28:831-46. 13. Hatlebakk JG, Katz PO, Castell DO. Medical therapy: management of the refractory patient. Gastroenterol Clin North Am 1999;28:847-60. 14. Peghini PL, Katz PO, Bacy NA, Castell DO. Nocturnal recovery of gastric secretion on twice daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763-7. 15. Katz PO, Tutuian R. Histamine receptor antagonists, proton pump inhibitors and their combination in the treatment of gastro-oesophageal reflux disease. Best Pract Res Clin Gastroenterol 2001;15:371-84. 16. Dent J. Roles of gastric acid and pH in pathogenesis of gastro-oesophageal reflux disease. Gastroenterol 1994;29(suppl 201):55-61. 17. Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate acid suppression for management of gastro-oesophageal reflux disease. Digestion 1992;51(suppl 1):59-67. 18. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115:1335-9. 19. Robinson M, Rodriguez-Stanley S, Miner PB. Zantac 75 = Prilosec 20 mg to block nighttime acid (abstract)! Am J Gastroenterol 1998;93:1623. 20. Khoury RM, Katz PO, Hammond R, Castell DO. Bedtime ranitidine does not eliminate the need for a second daily dose of omeprazole to suppress nocturnal gastric pH. Aliment Pharmacol Ther 1999;13:675-8. 21. Fackler WK, Vaezi MF, Ours TM, Richter JE. Nocturnal acid breakthrough and H2RAs — another viewpoint (abstract). Am J Gastroenterol 2000;95:2419. 22. DeVault K, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999;94: 1434-42. 23. Leite LP, Johnston BT, Just RJ. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol 1996;91:1527-31. 24. Hatlebakk JG, Camacho-Lobato L, Katz PO. Omeprazole 20 mg b.i.d. vs. lansprazole 30 mg b.i.d. in control of intragastric acidity (abstract). Am J Gastroenterol 1998;93:1636. 25. Spechler SJ. Long-term outcome of medical and surgical therapies for gastroesophageal reflux disease: follow-up of a randomized controlled trial. JAMA 2001;285:2331-8. EXTRACTO OBJETIVO: Evaluar el rol de la terapia combinada de los inhibidores de la bomba de protones con los antagonistas de los receptores de histamina 2 en el tratamiento de reflujo gastroesofágico. FUENTES DE INFORMACIÓN: Se identificó la literatura clínica utilizando MEDLINE (enero 1966–agosto 2001). Los términos utilizados en la búsqueda incluyeron reflujo gastroesofágico, benzimidazoles; terapia, combinación de drogas; terapia, modalidad combinada; y combinaciones de drogas. SÍNTESIS: Aproximadamente el 80–90% de los pacientes se curan de la esofagitis por reflujo después de 8 semanas de tratamiento con inhibidores de la bomba de protones administrados 1 vez al día. Los pacientes que toman los inhibidores de la bomba de protones 2 veces al día pueden sentir episodios de acidez nocturna (períodos de pH gástrico <4 que dura ≥60 min durante la noche) hasta en un 70% de las veces. No se ha demostrado la aplicación clínica de este hallazgo. Un estudio demostró que el omeprazol en las mañanas más ranitidina al acostarse no es tan eficaz para controlar la acidez nocturna como el omeprazol 2 veces al día administrado antes del desayuno y de la cena. Más aún, un estudio menor con personas saludables sin reflujo gastroesofágico demostró que añadir la ranitidina 1 vez al día a la hora de acostarse al The Annals of Pharmacotherapy Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016 ■ 2002 May, Volume 36 ■ 915 LB Cross and LN Justice régimen de omeprazol 2 veces al día puede disminuir la ocurrencia de la acidez nocturna. Sin embargo, la significancia clínica de este hallazgo no se ha esclarecido. CONCLUSIONES: Ningún estudio en pacientes con reflujo gastroesofágico ha demostrado que la adición de un antagonista de los receptores de la histamina 2 a la terapia de un inhibidor de la bomba de protones 2 veces al día provee mayor beneficio que el uso de los inhibidores de la bomba de protones por si solos. El parámetro utilizado hasta el momento, la acidez nocturna, para medir la eficacia de los regímenes para el reflujo gastroesofágico (GERD, por sus siglas en inglés) no ha podido establecer una correlación con la mejoría de los síntomas de esta condición en ningún estudio controlado ni prospectivo. Rafaela Mena RÉSUMÉ Evaluer le rôle d’une association d’inhibiteurs de la pompe à protons (IPP) et d’inhibiteurs des récepteurs H2 de l’histamine (anti-H2) dans le reflux gastro-œsophagien. REVUE DE LITTÉRATURE: Littérature clinique repérée par une recherche sur MEDLINE (janvier 1966–août 2001). Les mots-clefs employés comportaient reflux gastro-œsophagien, benzimidazoles, oméprazole, OBJECTIF: lansoprazole, pantoprazole, rabéprazole, anti-H2, et association. RÉSUMÉ: Environ 80 à 90% des patients présentent une guérison de l’œsophagite par reflux après 8 semaines de traitement par IPP une fois par jour. Le faible nombre de patients réfractaires à ce schéma devrait répondre à un traitement par IPP donné avant les repas du matin et du soir. Cependant, ces sujets présentent encore des périodes d’acidité nocturne (pH <4 pendant au moins 60 min) dans 70% des cas: les conséquences cliniques de cette constatation n’ont pas été démontrées. Un essai de faible taille chez des sujets sains a montré que l’association oméprazole le matin plus ranitidine au coucher n’est pas aussi efficace que l’oméprazole donné avant les repas du matin et du soir pour diminuer les périodes d’acidité nocturne. Un essai de faible taille chez des sujets sains a montré que l’addition d’une dose de ranitidine au coucher à un schéma comportant de l’oméprazole 2 fois par jour est susceptible de diminuer l’occurrence des périodes d’acidité nocturne. Néanmoins, la signification clinique de ces constatations n’est pas claire. CONCLUSIONS: Aucune étude chez des patients atteints de reflux gastroœsophagien n’a montré que l’addition d’anti-H2 à un schéma comportant des IPP 2 fois par jour procure un bénéfice par rapport aux IPP seuls. Bruno Edouard Full text access to the Annals of Pharmacotherapy is available to subscribers only. Personal, Student, and Resident Subscriptions To access full text articles through The Annals Web site (www.theannals.com), simply enter your subscriber number which appears on the mailing label, in both the user name and password boxes. The subscriber number appears in the top row of the label. It starts with the letters TP and includes the first group of numbers. For example, the highlighted portion of this label is the subscriber number. TP TP 34712 34712 0111 1108 John Q Clinician, PharmD. 123 Main St. Cincinnati, OH 45678 You would enter TP34712 (without a space between the letters and numbers) as the user name and password. Institutional Subscriptions Subscriptions have automatic full text access based on the subscriber’s IP address. If you have not submitted your IP address, please contact customer service at [email protected] and provide your IP address and subscriber number. 916 ■ The Annals of Pharmacotherapy ■ 2002 May, Volume 36 Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016 www.theannals.com