Available online at www.sciencedirect.


Proton pump inhibitors: the beginning of the end or the end of the beginning?
Carmelo Scarpignato1 and Richard H Hunt2
Despite the dramatic success of pharmacological acid suppression in healing peptic ulcers (PUs) and managing patients with gastro-esophageal reflux disease (GERD) a number of challenges remain in the management of acidrelated disorders. Several new drugs are currently being investigated to provide a significant advance over current treatments. These include new drug formulations, novel proton pump inhibitors (PPIs) as well as potassium-competitive acid blockers (P-CABs), which have already reached clinical testing. Some others (like NO-releasing antisecretory compounds) are still in preclinical development and require proof of concept in humans. While H2-receptor antagonists (especially soluble or OTC formulations) will become the ‘antacids of the third millennium’ and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. Since an increasing proportion of patients fail to respond to the best PPI treatment, more potent and long-acting drugs and more effective regimens are needed.
Addresses 1 Laboratory of Clinical Pharmacology, Department of Anatomy, Pharmacology & Forensic Sciences, School of Medicine & Dentistry, University of Parma, Via Volturno 39, 43100 Parma, Italy 2 Division of Gastroenterology, Department of Medicine & Intestinal Disease Research Programme, McMaster University Health Science Centre, Hamilton, Ontario L8N 3Z5, Canada Corresponding author: Scarpignato, Carmelo (scarpi@tin.it)

the proton pump inhibitors (PPIs), which allowed effective and safe treatment of PU and other acid-related disorders [2]. The clarification of the etiological role of Helicobacter pylori infection [3] has further improved the treatment of PU that can be now cured rather than healed. Although antisecretory therapy has advanced dramatically since the introduction of cimetidine in the mid-1970s, there are several identifiable unmet needs especially in the management of gastro-esophageal reflux disease (GERD), where an antisecretory therapy with rapid onset of action and sustained antisecretory effect would be desirable [4,5]. A meta-analysis [6] has shown that in about two-thirds of patients reflux symptoms are not adequately controlled after the first dose of PPI, and nearly half of the patients are still bothered by symptoms after three days standard dose PPI therapy. A rapid onset of action would be desirable also in the management and prevention of nonvariceal upper GI bleeding and may be increasingly important in patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) [5,7]. According to a recent survey [8], although most prescription PPI users are on a QD regimen, a substantial proportion of patients take these drugs twice daily. Patients on PPI therapy often still experience GERD symptoms and supplement their prescription PPIs with other GERD medications. One in four patients are not satisfied with PPI therapy for GERD [8]. Indeed, despite their clinical efficacy, when given once daily, currently available PPIs may not adequately control intragastric acidity during the night in a significant proportion of both healthy subjects and GERD patients, in whom symptom relief remains suboptimal [9]. In particular, nocturnal acid breakthrough (NAB) continues to be a significant issue and in addition to giving rise to symptoms may also contribute to the development of erosive esophagitis [10]. Up to 79% of patients with GERD experience nocturnal symptoms associated with their condition and improvement in nocturnal symptoms associated with a reduction in gastric acidity by PPIs is well documented [11]. The clinical importance of specifically reducing NAB, however, is controversial. In addition, NAB should be considered a misnomer in our view. Indeed, this term should not be used because the pattern of nocturnal acid secretion observed between midnight and 08:00 hours occurs when there is no drug available to inhibit acid secretion. All current PPIs have a short plasma half-life (1–1.5 hours) and even when a second dose of PPI is given before the evening meal (between 5 and 7 hours before midnight) there is no drug available to inhibit acid pumps synthesized and inserted into the secretory membrane
Current Opinion in Pharmacology 2008, 8:677–684

Current Opinion in Pharmacology 2008, 8:677–684 This review comes from a themed issue on Gastrointestinal Edited by Guy Boeckxstaens Available online 24th October 2008 1471-4892/$ – see front matter # 2008 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2008.09.004

The discovery of gastrin by John Edkins and the elucidation of the role of histamine by Sir Henry H Dale triggered the scientific exploration of the regulation of gastric acid secretion and led to the understanding of the pathogenic basis of peptic ulcer (PU) and its subsequent treatment [1]. Following this breakthrough, the identification of the cellular regulators of acid secretion culminated in the development of novel pharmacotherapeutic agents, namely the H2-receptor antagonists (H2RAs) and

if it is not accompanied by the exposure of the esophagus to acid. controlled-release formulation of omeprazole specifically addressing NAB. What is in the current GI pipeline? Rationalization within the pharmaceutical industry to combat escalating costs has included the close examination of research portfolios. Many existing GI drugs are in a mature stage of their life cycle and some of the leading compounds in the market have been. Takeda. Two proof-of-concept studies have recently been completed and the full results are eagerly awaited [http://www. Together with the big players (e.com . Since PPIs all have similar short plasma half-lives. in a study of 1046 primary care physicians across the US [19]. Clinical efficacy of the PPIs is related to the degree and duration of acid suppression as well as the length of the treatment [15]. a Current Opinion in Pharmacology 2008. The administration of the current delayed-release (DR) PPIs is recommended 0. or are close to patent expiration. a delayed and controlled-release (ChroNAB technology) formulation of omeprazole. In addition.e. who is developing in cooperation with Axcan Pharma AGI-010. speed of disassociation from the proton pump. Consequently.. New formulations Extended-release formulations of PPIs will become an increasingly important strategy used by pharmaceutical companies. As a consequence.g. who discovered the first PPI more than 20 years ago. TPNA) for its modified release version of the lansoprazole R-isomer.678 Gastrointestinal during the nighttime hours [12]. which were at rest in the cytosol or have been newly synthesized after drug levels fall. There is a remarkable lack of clear instructions in practice concerning empirical therapy. PPIs with a longer half-life resulting in extended acid suppression would be expected to offer improved clinical efficacy [16]. will be discussed. A study [13] has shown that more than 70% of patients had improvement in nighttime symptoms after the addition of an H2RA to a twice-daily PPI regimen. will not be blocked from secreting acid.e.7% dosed it optimally (i. there is increasing evidence of both inappropriate prescribing and inappropriate use of these drugs. It has been suggested [4] that – on sudden withdrawal of therapy because of insufficient symptom relief – rebound acid secretion may reactivate GERD-like/dyspeptic symptoms leading to a vicious circle of events [4]. dexlansoprazole (TAK-390MR) [2]. in patients with GERD. synthesized and started the development of esomeprazole (the magnesium salt of the S-isomer of omeprazole) in 1990. the new PPI formulations currently under development or recently introduced into clinical practice as well as the novel compounds targeting the proton pump. Depomed too has employed its proprietary AcuFormTM delivery technology to develop an oral.5–1. the recovery of nocturnal gastric acid secretion is of little importance. 8:677–684 new avenue to control acid secretion through competitive blockade of the proton pump at the K+ exchange sites is being explored [2.20]. The majority of them are in phase II with only three drugs in phase III [22].M. the failure of PPIs to provide an extended antisecretory effect depends on their pharmacokinetics. Furthermore. which stem from their pharmacology [17]. That PPIs are often taken inappropriately is revealed by a US survey [18] showing that only 27% of GERD patients dosed their PPI correctly (i. This formulation has the potential.0 hours before a meal in order to ensure that proton pumps are activated in the parietal cell at a time when drug is available in plasma [14]. 15–60 min before the first meal of the day). Notwithstanding. This is a strategy that is being adopted by AGI Therapeutics. thus emphasizing the clinical impact of controlling nighttime acid secretion. together with the activation or synthesis of pumps [14]. cfm/1338/Gastroesophageal-Reflux-Disease]. which have already reached clinical testing. the upper GI pipeline is small with only 33 products across all stages of development. any proton pumps. However. and Nycomed). the dose is often doubled.depomedinc. when NAB typically occurs. only 36% of them gave their patients advice on when and how to take their medication. Gastroenterology has been one of the casualties of this exercise and few companies currently retain a specific gastrointestinal research program [21]. The same strategy has been used by TAP Pharmaceuticals (now part of Takeda Pharmaceuticals North America. If symptom resolution is limited and patient dissatisfaction continues. empiric therapy in heartburn and dyspepsia patients is based upon PPI therapy with standard dose for two to four weeks. AstraZeneca. An expanding proportion of patients have weak indications for acid suppression. to remain in the stomach for 4–6 hours and then deliver a second dose so that peak blood levels of the drug are achieved at 2– 3 A. when taken with the evening meal. Patients with severe forms of chronic GERD especially those with Barrett’s esophagus are more likely to have acid reflux during NAB [9]. making it available for clinical practice worldwide at the beginning of the third Millennium. Inc. as they will be useful for the potential treatment of nocturnal acid secretion because of their controlled and sustained release [2]. Not uncommonly.sciencedirect.com/view. Although PPIs have a number of shortcomings. new smaller companies have entered the field and are developing either novel formulations of currently available PPIs or novel PPIs [2]. In this section. AstraZeneca. Although proper education can improve PPI use and effectiveness. up to 60 min before any meal of the day) and only 9. Pharmacokinetic studies [23] show that the plasma concentration–time www. to overcome intrinsic limitations of the available drugs novel formulations of current PPIs and novel compounds are being developed [2].

K+-ATPase has been thoroughly characterized [32]. Tenatoprazole (TU-199) has been developed by Mitsubishi Pharma in Japan and is now under active development by SIDEM (France). tenatoprazole is a prodrug (pKa = 4. The recently FDA-approved immediate-release (IR) omeprazole formulation displays different pharmacokinetics and pharmacodynamics compared with the standard. AGN 201904-Z. the available PPI formulations are considered delayed release (DR) preparations. Its antisecretory activity proved to be two to three times higher and its half-life two to three times longer than that of omeprazole.53 hours. and 24-hour intragastric pH-recording [24] documented a prolonged acid inhibition across all doses (60. An additional study [26] also showed 30 and 60 mg TAK-390MR to be better than placebo for maintaining healing of esophagitis and relieving heartburn over six months. this compound is not a benzimidazole derivative. which activates omeprazole via gastrin release and also accelerates its absorption and enhances its bioavailability. Vecta Ltd (an Israeli Company) is currently investigating Vecam for the potential treatment of GERD. Both these sites are located in the proton transport pathway. Vecam is a combination of a PPI with a chemical ‘acid pump activator’ (VB101) to allow a meal-independent antisecretory effect (http://www. The majority are still in preclinical www. which is still in phase II [22]. and the median pH never dropped below 5. Current Opinion in Pharmacology 2008. A single morning dose of this formulation provides significantly better control of 24-hour acidity than lansoprazole and pantoprazole [28] while a bedtime dose assures a better control of nocturnal acid secretion than lansoprazole and esomeprazole [29]. Pharmacokinetic studies [31] demonstrated that exposure to prodrug is minimal and that there is essentially quantitative conversion to omeprazole of the absorbed chemical. nonenteric-coated omeprazole powder (40 or 20 mg per unit dose) along with 1680 mg of sodium bicarbonate (containing 460 mg of sodium). as a consequence. is the sodium salt of an acid stable prodrug of omeprazole (Figure 1). This formulation (available as sachets. which are necessary to protect the acid-labile PPI from acid degradation within the stomach. Novel PPIs development or have been abandoned [2]. The binding sites of tenatoprazole were at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. This compound was designed to provide continued metered absorption (CMA) in order to prolong the plasma residence time and thus increase the number of proton pumps within the gastric secretory canaliculus that might be inhibited. Nocturnal acid suppression was also greater by >2 pH units after five days. a phase II clinical trial has been completed (October 2007) in the US (http:// www. although cysteine 822 is found deeper in the TM5/6 membrane domain than cysteine 813 [32]. Following single and repeated doses. All these events translate into a meal-independent antisecretory effect and into a more profound acid suppression. The different enteric coatings (granules encapsulated in a gelatine shell.vecta. consisting of one imidazopyridine ring connected to a pyridine ring by a sulfinylmethyl chain (Figure 1). 8:677–684 Several new PPIs have been synthesized since the discovery of omeprazole. and 120 mg). tablets or multiple unit pellet system [MUPS]). Ambulatory 24-hour intragastric pH recording in healthy.il/products_vecam.Advances in Proton Pump Inhibitor Therapy Scarpignato and Hunt 679 profile is characterized by two distinct peaks.gov/show/NCT00471094). Ilaprazole (IY81149. Although the drug is already on the market in South Korea. or chewable tablets) consists of pure. 90. Oral administration of this compound in humans displays the same acid-stimulating activity of pentagastrin and its combination with either omeprazole or pantoprazole resulted in augmented PPI effects in rats [30].04)..sciencedirect.co.K+-ATPase resulting in disulfide formation and the inhibition of acid secretion. It represents therefore a new chemical entity. Figure 1) is a benzimidazole compound synthesized at Il-Yang (South Korea) and presently licensed to TPNA. In contrast to all the other PPIs. initially developed by Allergan and now by Alevium Co.com .78 and 4. blood concentrations peaked at about four hours and declined with a mean apparent half-life ranging between 3.0 with AGN.html). Like the other PPIs. DR preparation [27]. have the potential disadvantage of delaying PPI absorption and. This medication may therefore be useful for patients with nocturnal symptoms and patients who need rapid and robust acid suppression. The inhibitory activity of this novel compound on gastric H+. capsules. occurring 1–2 and 4–5 hours after dosing. From the preliminary analysis of the results of two RCTs [25] it seems that both 60 and 90 mg of TAK-390MR are superior to the standard lansoprazole formulation (30 mg) in healing erosive esophagitis. H. pylori-negative male volunteers [31] showed that AGN 201904-Z provides faster and more profound acid suppression than esomeprazole on day 1 and day 5. such as those with refractory GERD. respectively. which is converted to the active sulfenamide or sulfenic acid in the acidic secretory canaliculus of the stimulated parietal cell.clinicaltrials. The antisecretory effect of IR omeprazole is quicker than that observed with classical DR PPIs [27]. Eisai too is developing an extendedrelease version of Pariet/Aciphex (rabeprazole) for the treatment of upper GI disorders. The early increase in intragastric pH is likely due to the neutralizing capacity of sodium bicarbonate. extraesophageal symptoms and PU-related bleeding. Currently available PPIs are orally administered as gastroprotected preparations. This active species binds to luminally accessible cysteines of the gastric H+.

AGN 201904-Z.sciencedirect.680 Gastrointestinal Figure 1 Chemical structure of ilaprazole (upper panel). the median pH being 4. there is a loose packing structure of molecules. respectively [33]. Therefore. Note that ilaprazole and AGN 201904-Z belong – like the current PPIs – to benzimidazole compounds whereas tenatoprazole represents a different chemical entity. Pharmacokinetic studies revealed that tenatoprazole displays a long half-life (8. which derive from the chiral nature of the sulfur atom of the sulfinyl group.8. with its release products (middle panel) and tenatoprazole (lower panel). The crystal form of S-tenatoprazole sodium salt hydrate is indeed quite different from that of S-tenatoprazole free form. Further investigation [34] confirmed and extended the previous data showing the prolonged duration of acid suppression with tenatoprazole. The pharmacokinetics of Stenatoprazole sodium was studied in healthy volunteers and proved to be linear with a dose-related increase in www. which results in rapid water access and hence greater solubility.2 Æ 0.com . 8:677–684 to exploit the features of stereoselective catabolism.05) than that observed with the same regimen of esomeprazole. A careful pharmacokinetic and structural study [32] showed that the oral bioavailability of the S-tenatoprazole sodium salt hydrate is almost twice that of S-tenatoprazole free form. currently under active development.7 Æ 2. the S-isomer was selected for further development.6 hours for repeated administration of 40 mg) and pharmacodynamic investigations in the same subjects have shown an increase of intragastric pH with tenatoprazole 40 mg daily for seven days signicantly higher (P < 0. three novel PPIs. Like the other PPIs. in order Current Opinion in Pharmacology 2008. In the crystal of S-tenatoprazole sodium salt hydrate.9 and 4. The difference in bioavailability can be explained by the better solubility of the sodium salt because of its peculiar crystal structure.6 Æ 0. tenatoprazole is a racemic mixture of two stereoisomers.

these novel benzimidazole carboxamides show lower basic properties (pKB) and are chemically as well as metabolically very stable. All these data clearly demonstrate that. tenatoprazole has a longer half-life and a longer duration of antisecretory action.com The next generation of drugs that suppress gastric acidity will most likely be the acid pump antagonists. the existing studies point out both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. and 90 mg daily) pharmacodynamic study have recently been presented [35] and show that all the doses of S-tenatoprazole Na resulted in a significantly higher median pH on day 5 compared to esomeprazole (40 mg daily).20]. A further unpublished study from Professor Galmiche Team (Nantes.0) than in the plasma (pH 7. no randomized clinical trials in acid-related diseases are available as yet. in the evening) with esomeprazole (40 mg twice daily). the K+-binding region of the H+. where it has the potential to address unmet clinical needs [16]. This indicates that these agents will produce more rapid acid inhibition and will be able to elevate gastric pH to a higher level than PPIs. France) compared this compound (60 mg once daily. France]. Despite a number of papers presented at recent GI meetings and two completed clinical trials in GERD [44. 8:677–684 . compared to the existing PPIs. On entering an acidic environment. The main differences between P-CABs and PPIs are summarized in Table 1. In contrast to the previous ones. esomeprazole. The duration of acid suppression achieved with S-tenatoprazole Na once daily was similar to that observed after esomeprazole 40 mg twice daily. during both the day and the night. the intragastric pH control being significantly higher three days after stopping treatment (Figure 2). thus suggesting that the duration of action of PCABs will depend on their half-life. Extensive pharmacological investigation on several compounds has only recently been published in extenso [40– 43]. acid pump antagonists have a structural specificity for their target. both Cmax and AUC (Jean Paul Galmiche and Richard Hunt. P-CABs are instantly protonated and it is in this form that they are thought to bind to and inhibit the enzyme. The drug provided significantly greater and more prolonged as well as dose-dependent acid suppression than the comparator. This combination of properties allows them to concentrate in acidic environments. While the PPIs have a unique mechanism of action based on their chemistry. Nantes. Whether these favorable pharmacodynamic properties will translate into clinical benefits has yet to be demonstrated. they belong to four different chemical classes. in agreement with the current knowledge according to which the antisecretory effect is proportional to the AUC [37]. S-tenatoprazole sodium then appears a promising PPI for the treatment of acid-related diseases. Indeed. Animal studies have shown a close correlation between the maximum inhibition of acid output and the logarithm of Cmax [20]. P-CABs are lipophilic. 60. A further class of compounds with a specifically substituted benzimidazole carboxamide core structure has been patented by Nycomed (now incorporating Altana Pharma) [39]. Since this last compound provides – amongst the members of the class – the most effective control of intragastric pH whatever the parameter considered [38]. and quinolones [20]. It is evident that a P-CAB offers a more rapid elevation of intragastric pH than a PPI (and similar to that achieved by an H2RA) while maintaining the same degree of antisecretory effect. pyrimidines.0 would theoretically be expected to be 100 000fold higher in the parietal cell canaliculus (pH 1. For example. weak bases that have high pKa values and are stable at low pH. Potassium-competitive acid blockers Intragastric 24-hour pH recording in healthy volunteers given esomeprazole (40 mg bid) or S-tenatoprazole Na (60 mg qd) [courtesy of Professor Jean Paul Galmiche. it is probable that tenatoprazole will prove to www.4). unpublished observations).Advances in Proton Pump Inhibitor Therapy Scarpignato and Hunt 681 Figure 2 be better than the other existing PPIs. Although these properties should theoretically translate into a better therapeutic efficacy. but the former drug did show a carry-over effect. Despite sharing the same mechanism of action. the duration of which is dependent on half-life and can easily be prolonged by extended release formulations.K+-ATPase. the concentration of a P-CAB with a pKa of 6. esomeprazole at standard doses (40 mg once daily) and equivalent to esomeprazole given twice daily. namely imidazopyridines. The Current Opinion in Pharmacology 2008. P-CABs represent a heterogeneous class of drugs. which are K+-competitive inhibitors of the ATPase [2. However. The results of a doseranging (30. The concentration of P-CABs in the gastric mucosa is demonstrated by in vitro and in vivo studies with linaprazan (AZD0865) and revaprazan [40.sciencedirect.43]. imidazonaphthyridines. In a meta-analysis of individual subject data from four pharmacodynamic studies [36] we have recently shown that S-tenatoprazole sodium 60 mg once daily is more effective than the currently most effective PPI.45] linaprazan was discontinued [2].

In a crossover clinical trial [48] the hypothesis that the coadministration of famotidine (10 mg daily) and omeprazole (20 mg daily) would lead to a rapid onset of the action of acid suppression without the loss of efficacy of the PPI was tested. continually appear on the horizon. Both mediators are also capable of inhibiting neutrophil adherence and activation and mast cell degranulation. will become the ‘antacids of the third millennium’ and will be particularly useful for on-demand symptom relief. are still in preclinical development and require proof of concept in humans.K+-ATPase Duration of effect related to half-life of drug in plasma Full effect from first dose + + PPIs Requires transformation to the active form Concentrate in parietal cell acid space (1000-fold higher than those in plasma) Sulfenamide binds covalently to H+. The NO-enhanced PPI NMI-826 (synthesized by NitroMed via the use of the so-called NitRx technology) was significantly more effective than their parent molecule. both pharmaceutical and invasive. In this connection a fast-dissolving oral tablet containing a fixed dose combination of a PPI and an H2RA (product labelled OX 17) has been developed by Orexo AB (Uppsala.22]. new potential therapies. new formulations. even using twice daily regimens of the currently available PPIs [52] represent an unmet clinical need that requires to be addressed with newer agents capable of achieving rapid and long-lasting acid suppression [16]. and better acid-suppressing regimens are welcome. Current Opinion in Pharmacology 2008. A number of new drugs are currently being investigated to provide a significant advance on current treatments. or nitrosothiol groups) added through a chemical spacer to conventional antisecretory drugs result in different physico-chemical properties and different NO-releasing capacities of the hybrid molecules. The different NO-releasing moieties (nitroxybutyl. On day 1 famotidine and omeprazole in combination improved the duration of and the time to reach intragastric pH > 4 compared to omeprazole alone [48]. lansoprazole. always with great initial enthusiasm. but the rate of NO release is much slower in comparison with other NO donors. Similar results have more recently been reported in Italy with furoxan-derived PPIs (namely rabeprazolerelated compounds) [51]. exerting many of the same actions as PGs in the GI tract [49].com A look to the future Nitric oxide (NO) is now recognized as a critical mediator of GI mucosal defense. NO is capable of exerting cytoprotective effects similar to those observed with PGs [49]. mucus release. In gastroenterology. As a consequence. Over a seven-day period. NMI-826 healed 90% of gastric ulcers versus a corresponding 50% for the parent molecule. NO-PPIs require metabolic degradation by tissue enzymes (mainly esterases of the intestinal wall and liver) to release NO. [2]). However. as in other medical specialties. 8:677–684 . there are some follow-up compounds of soraprazan. As organic nitrates. While H2-receptor antagonists.K+-ATPase Duration of effect related to half-life of the sulfenamide–enzyme complex Full effect after repeated doses same holds true for CS526. For instance. both PGs and NO are capable of modulating mucosal blood flow.sciencedirect. Conclusions In acid-related disorders. A combination of an H2RA with the novel PPI tenatoprazole has also been patented [47].K -ATPase enzyme Superconcentrates in parietal cell acid space (100 000-fold higher than those in plasma) P-CABs binds competitively to the potassium binding site of H+. in healing acid-induced gastric ulcers in rats. P-CABs Acts directly on the H . furoxan. one of which is currently under clinical investigation [2]. much attention has recently been focused on NO-donating antisecretory compounds. such as the NO-donating antisecretory drugs.682 Gastrointestinal Table 1 P-CABs and PPIs: main differences in the mechanism of action (from Scarpignato et al. A survey [13] found that the majority of GERD patients report persistent improvement of nighttime symptoms from bedtime H2RA use (in addition to PPI therapy) and the authors suggested that possible clinically important tolerance does occur in a small number of patients. particularly at night. When faced with promising www. especially soluble or OTC formulations. Sweden) and phase II clinical trials with this formulation are presently under way in Europe [2. which would also possess a mucosal protective activity. these either will prove to be failures or will find their appropriate level of use in our therapeutic armamentarium. In experimental models of gastric injury. lansoprazole [50]. there is still a place for H2RAs in the era of PPIs [46]. novel compounds. Over time. The difficulties encountered in attaining effective symptomatic control. healing is directly related to the degree and duration of acid suppression and the length of treatment [14]. PPI-H2RA combination Despite all their intrinsic limitations. clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. In this connection. Novel PPIs and P-CABs have already reached clinical testing while some others. and repair of mucosal injury.

Gastroenterology 2008. 24. Chey WD. 16:441-443. 22. 8. Gastroenterology 2008. Shaheen NJ. delayed-release lansoprazole capsules and delayed-release esomeprazole capsules on nocturnal gastric acidity after bedtime dosing in patients with night-time GERD symptoms. O’Neil JM: TAK390MR. Lancet 1984. 78(Suppl. Gautille TC. Hogan DL. Sharma P. Tutuian R. we should always wonder whether they are effective and safe and whether they are really better than the current ones. 25:197-205. Kothari S. 159:649-657. Digestion 2005. Fendrick AM. 18:370-373. Sachs G. 90 mg. Orr WC. 2. Pratha VS: Comparison of the effects of immediaterelease omeprazole oral suspension. Pankratov O. 11. Inadomi JM. Bagin RG: Control of 24-hour intragastric acidity with morning dosing of immediate-release and delayed-release proton pump inhibitors in patients with GERD. Agrawal A. Atarot T. Gastroenterology 2008. published within the period of review. Mainie I. and management. 26. Gastroenterology 2008. Naveh M: PPI activity is optimized by VB101. Allen ML. Scarpignato C. Tutuian R.com . Eur J Gastroenterol Hepatol 2005. Howden CW: Primary-care physicians’ perceptions and practices on the management of GERD: results of a national survey. Andersson K. 21. Chowers Y. Wright N. Cowen M: Correct and incorrect dosing of proton pump inhibitors and its impact on GERD symptoms. Persson B. 18. Aliment Pharmacol Ther 2005. Yuan Y. 12. Hunt RH: Importance of pH control in the management of  GERD. 13(Suppl 1): S29-S33. 10. Comprehensive review summarizing the current understanding of the role of acid suppression in the management of GERD. Eur J Gastroenterol Hepatol 2004. Data Monitor. Comprehensive review on future developments in the field of antisecretory drugs. Although acid suppression therapy has stood the test of time. Pipeline Insight: Upper GI Disorders. Vakily M. Carlsson E: Potassium-competitive acid  blockade: a new therapeutic strategy in acid-related diseases. 17:113-120. Peura DA: TAK-390MR. Aliment Pharmacol Ther 2006. Robinson M: The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Pilmer B. 20. the final chapter on the pharmacological treatment of acid-related diseases has not yet been written. Excellent historical review summarizing the key achievements in the physiology and pharmacology of gastric acid secretion. Pharmacol Ther 2005. Ballard ED. Modlin IM. Bar-Peled O. Gastroenterology 2008. 23. 23(Suppl 2):23-34. Thoughtful review first addressing the unmet clinical needs in acid-related diseases. 2007. Comprehensive review on a new class of drugs targeting the proton pump. 3. Howden CW: Review article: immediate-release proton-pump inhibitor therapy — potential advantages. Pelosini I: Review article: the opportunities and  benefits of extended acid suppression. Wang C. Katz PO. Mayer MD. Parsons ME. Wang CC. Koch FK. 14. 7. Kostadinov A. Scheiman JM. Perez MC. 15. Larsen LM. 8:677–684 References and recommended reading Papers of particular interest. Am J Gastroenterol 2005. 134(Suppl 1):A-171 [Abstract#S1073]. 134(Suppl 1):A-172 [Abstract#s1076]. Metz DC. Howden CW. Barkun AN: Review article: acid-related disease — what are the unmet clinical needs? Aliment Pharmacol Ther 2006. Seminal paper suggesting the etiological role of Helicobacter pylori in peptic ulcer disease.Advances in Proton Pump Inhibitor Therapy Scarpignato and Hunt 683 new therapies. Huang JQ. in press. Pezanoski J. Critical paper addressing the limitations of current antisecretory regimens. Scarpignato C. Gastroenterology 2003. 17. Tytgat GN: Are there unmet needs in acid suppression? Best  Pract Res Clin Gastroenterol 2004. have been highlighted as:  of special interest  of outstanding interest 1. 100:1237-1242. a dual delayed release formulation of the proton pump inhibitor TAK-390. 6. Am J Gastroenterol 1994. Katz PO. Lee M. 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