Acid suppression, with proton pump inhibitors (PPI), is the mainstay of therapy for reflux disease; despite this, symptoms and injury persist in many patients. Novel approaches have focused on (1) augmenting acid suppression with reformulated current PPIs, new PPIs or new acid pump blockers and (2) preventing reflux with reflux inhibitors. Other strategies to reduce reflux, improve gastric emptying or esophageal clearance, protect the mucosa, or reduce esophageal sensitivity are under investigation alone or in combination with PPIs; however, novel approaches face significant challenges. The safety and efficacy of current PPIs hamper demonstration of clinical superiority for new acid suppressants, and the multifactorial etiology of reflux disease means that monotherapy using a non-acid suppressant is unlikely to match PPI therapy while combination therapy will be superior only if susceptible patients can be identified reliably. Advances will come, not from a ‘one size fits all’ approach but rather from novel pharmaceuticals allied to novel investigations to permit targeted, personalized reflux therapy.
Key points
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Acid suppression remains the cornerstone of pharmacologic therapy for gastroesophageal reflux disease (GERD).
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Traditional proton pump inhibitors (PPIs) are limited by their pharmacologic properties with respect to symptom control, healing, and potential side effects with long-term use.
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Novel acid suppression agents promise to improve GERD therapy for patients with acid-mediated disease.
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Acid suppression does not address the pathogenetic mechanisms underlying GERD.
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The development of novel pharmacologic approaches to GERD therapy is hampered, inevitably, by the multifactorial cause of GERD and by the ubiquity and redundancy of neurohumoral signaling mechanisms that control upper gastrointestinal sensation and motility.
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Advances in the pharmacologic therapy for GERD will require a personalized approach to therapy based on appropriate investigations to identify relevant therapeutic targets.
Background
GERD develops when the reflux of gastric contents into the esophagus results in troublesome symptoms and/or complications. Symptoms are considered to be troublesome if they occur at least twice a week or if they reduce quality of life or affect daily functioning. The refluxate contains varying amounts of acid, pepsin, bile salts, and trypsin, and the injury caused by these noxious agents may manifest as a wide range of symptoms at esophageal and extraesophageal sites. The long-term complications of GERD include Barrett’s esophagus, peptic stricture, and esophageal adenocarcinoma. The classical symptoms of GERD are heartburn and regurgitation. The disease spectrum is wide and depends on the nature, site, and severity of the injury. The choice of therapy depends on the symptom profile, the pathogenesis of the injury, the affordability of the therapy, and individual preferences.
Background
GERD develops when the reflux of gastric contents into the esophagus results in troublesome symptoms and/or complications. Symptoms are considered to be troublesome if they occur at least twice a week or if they reduce quality of life or affect daily functioning. The refluxate contains varying amounts of acid, pepsin, bile salts, and trypsin, and the injury caused by these noxious agents may manifest as a wide range of symptoms at esophageal and extraesophageal sites. The long-term complications of GERD include Barrett’s esophagus, peptic stricture, and esophageal adenocarcinoma. The classical symptoms of GERD are heartburn and regurgitation. The disease spectrum is wide and depends on the nature, site, and severity of the injury. The choice of therapy depends on the symptom profile, the pathogenesis of the injury, the affordability of the therapy, and individual preferences.
Prevalence and impact of GERD
GERD is one of the most common medical conditions with an estimated prevalence of 10% to 20% in the Western world. It is the most frequent outpatient diagnosis in the United States, the most common indication for upper endoscopy, and the most common principal gastroenterology-related diagnosis in primary care. On an annual basis, GERD accounts for 9 million hospital visits and $10 billion expenditure toward direct as well as indirect costs for management. GERD is associated with reduced quality of life and reduced work productivity and places a huge financial burden on society related not only to the typical reflux syndrome but also to other extraesophageal syndromes such as asthma, reflux laryngitis, and dental erosions. GERD is, also, the leading risk factor for esophageal adenocarcinoma, leading to further significant mortality, morbidity, and health care costs. The prevalence, costs of treatment, and costs of adverse outcomes underline the need for appropriate management strategies targeted at the causes and consequences of reflux disease.
Current therapeutic strategies and their limitations
At present, acid suppression using traditional delayed-release PPIs, is the mainstay of GERD therapy. PPIs are effective in healing esophagitis, improving symptoms, and preventing complications and are generally well-tolerated with a convenient dosing schedule. PPIs produce higher healing and symptom relief rates than histamine receptor antagonists (H 2 RAs) and antacids, and they have become the primary agents in the management of GERD. Antacids and H 2 RAs, available over the counter in most countries, still have a role in the management of episodic and mild symptoms because they can provide rapid symptom relief, particularly for infrequent symptoms. Antireflux surgery remains an option for patients who are intolerant of PPIs or who have volume reflux; it is less clear that surgery is beneficial for those who achieve poor control with PPIs or who have extraesophageal GERD syndromes, especially in the absence of documented reflux.
Although PPIs are effective in most situations, there are certain problems that are being increasingly recognized. First, although PPIs lead to healing in 88% to 96% of patients with mild erosive esophagitis over 8 weeks, the overall efficacy in symptom control is suboptimal. With 4 weeks of standard dose PPI therapy, the pooled symptom response rate was only 36.7% in patients with nonerosive reflux disease (NERD) and 55.5% in those with erosive esophagitis. Among those on long-term PPIs, 59% of patients with GERD, 40% of those with NERD, and 40% of those with extraesophageal disease have persistent symptoms on standard once a day PPI therapy. Thus, PPI failure is a common problem whose causes need to be identified and addressed. Identified causes of PPI failure include poor compliance, low bioavailability, rapid metabolism, lack of sustained acid suppression, presence of duodenogastric reflux, delayed gastric emptying, hiatus hernia, visceral hypersensitivity, and psychological comorbidities. Second, the pharmacokinetic and pharmacodynamic profiles of currently available PPIs are suboptimal, leading to lack of sustained acid suppression, delay in onset of effect, nocturnal breakthrough symptoms, and requirement of intake at an appropriate time relative to meals to maximize benefit. Third, although PPIs target acid secretion to treat GERD, increased acid production is not the key underlying pathogenetic mechanism. The key pathophysiological mechanisms for GERD such as frequent transient lower esophageal sphincter relaxations (TLESRs), esophageal and gastric dysmotility, and visceral hypersensitivity are not addressed by PPI therapy. Fourth, because GERD is a chronic condition, the overall costs of management are substantial. Fifth, there are increasing concerns about harms from long-term PPI therapy or acid suppression, such that the US Food and Drug Administration ( http://www.fda.gov ) and the UK Medicines and Healthcare products Regulatory Agency ( http://www.mcha.gov.uk ) have recently issued public warnings and changed labeling recommendations for these drugs. There is, therefore, a need and an opportunity to innovate, rationalize, and individualize therapy for patients with GERD to improve outcomes, including quality of life, to save costs, and to minimize adverse events.
Objective of this review
Improvements over current treatment strategies must be based on an understanding of the pathophysiology of GERD in relation to the potential roles of novel pharmaceutical approaches; this approach will permit therapies targeted at specific pathophysiological mechanisms to lead to rational therapeutic strategies based on symptom assessment and investigations. Recent advances in the fields of GERD pathogenesis and drug development have opened up newer options, which now require exploration. An electronic search was conducted in MEDLINE and EMBASE from January 2009 to October 2012 for key search terms “gastroesophageal reflux and its variants,” “esophagitis,” “heartburn,” or “proton pump inhibitors” to obtain recent relevant articles for review.
Pathophysiology: implications for management
Transient relaxation of the lower esophageal sphincter (LES) is a normal physiologic phenomenon that occurs, intermittently, to allow gastric decompression. Under normal physiologic conditions, air, accompanied by varying amounts of acid, may reflux into the esophagus, depending on the mechanical alterations of the gastroesophageal junction (GEJ). In health, refluxed acid and gastric contents are cleared rapidly by esophageal peristalsis, complemented by neutralization of residual acid by saliva and local mucous secretions. GERD occurs when the defensive factors that protect the esophagus (antireflux barrier, esophageal clearance, squamous epithelial resistance, mucus and bicarbonate secretion, as well as saliva and salivary bicarbonate) are overwhelmed by aggressive factors (volume, frequency, and constituents of gastroesophageal reflux [GER]).
Role of Acid and Pepsin
Gastric acid and pepsin, activated at pH less than 4, are the key components of the refluxate implicated in the causation of esophagitis. Although acid or pepsin alone can cause mucosal injury, it is the presence of acid and acid-activated pepsin that results in significant tissue injury. Acid suppression not only renders the refluxate benign but also reduces the number of reflux episodes because it decreases the overall gastric volume. However, acid suppression does, also, compromise the detection of reflux episodes using current pH monitoring techniques and diagnostic criteria. Despite the central role of acid in the pathogenesis of GER-related injury and symptoms, gastric acid secretion per se is not increased in most individuals with GERD.
Role of the Proximal “Acid Pocket”
Recent studies have demonstrated a proximal “acid pocket” extending from the gastric cardia to the distal esophagus in normal subjects and in patients with GERD. The mean pH in this pocket can be as low as 1.6, and the acid in this pocket is unbuffered by meals. This pocket has been found to play a key role in postprandial acid reflux and in severe reflux disease.
Role of Gastric Contents
Gastric distension triggers the occurrence of TLESRs, which permit GER. Delayed gastric emptying has been noted in 40% of patients with GERD. Diabetic gastroparesis, gastric outlet obstruction, and gastric dysmotility are all associated with prolonged gastric emptying and, in some cases, with persistent dyspeptic symptoms despite adequate acid suppressive therapy, and it is tempting to postulate that prokinetic agents and measures to relieve delayed gastric emptying will have a role in relieving reflux symptoms in this subgroup of patients. Patients with hypersecretory states such as Zollinger-Ellison syndrome are likely to produce large volumes of acid, and they will, often, require potent high-dose antisecretory agents to control acid-related symptoms, including those of GERD.
Role of Duodenal Contents
In patients with increased duodenogastroesophageal reflux (DGER), bile salts and pancreatic enzymes can cause esophageal injury. Although conjugated bile acids are more injurious in the presence of acid and pepsin, deconjugated bile acids and trypsin can cause damage even at neutral pH. With the advent of technology to measure bilirubin levels in addition to esophageal luminal pH levels, reflux episodes can now be characterized, with some accuracy, as acidic, weakly acidic, alkaline, or bile reflux. The finding of DGER in 95% of patients with Barrett’s esophagus, 79% of those with erosive esophagitis, and 50% of those with NERD, and data implicating DGER in the pathogenesis of esophageal adenocarcinoma, suggest that bile reflux is a marker for more severe GERD and that this might allow better targeting of therapy. However, although aggressive acid suppression may reduce bile-mediated injury, it does not eliminate it; other potential methods to reduce DGER include agents that can increase gastroduodenal motility, target mucosal protection or, like cholestyramine and rikkunshito, sequester bile acids. This approach to treating severe GERD will require the development of effective therapeutic strategies and a better understanding of the potential benefit for reducing the severity and complications of GERD.
Role of Antireflux Barrier
The principal component of the defense mechanism is the antireflux barrier, a high pressure zone, created by the LES and the crural diaphragm. The functional integrity of the GEJ depends on the tone and alignment of these 2 muscular structures. During a TLESR, the tone of both LES and crural diaphragm is inhibited to allow belching. TLESRs account for all reflux episodes in healthy individuals and nearly 80% of reflux episodes in patients with GERD. Thus, agents that inhibit TLESR, such as γ-aminobutyric acid (GABA) agonists, glutamate antagonists, cholecystokinin (CCK) antagonists, anticholinergic agents, nitric oxide (NO) inhibitors, and serotonin (5-hydroxytryptamine [5-HT 3 ] or 5-HT 4 ) agonists or antagonists may have a role to play in the management of GERD. A wide range of agents that may reduce TLESR are currently in various stages of investigation.
Recent understanding of the dynamics of the GEJ suggests that hiatus hernia is indeed a major risk factor for GERD. In patients with hiatus hernia, the mechanism of reflux is complex. The 2 muscular structures, LES and crural diaphragm, are not aligned. Thus, reflux occurs not only with TLESRs but also during deglutitive LES relaxation and with isolated LES hypotension. The intrathoracic position of the GEJ (negative pressure) in the presence of a hiatus hernia results in a greater pressure gradient during LES relaxation resulting in more reflux. Also, the compliance of GEJ is increased, leading to a larger cross-sectional area at a given pressure gradient and, hence, to increased volume of refluxate. Moreover, if reflux occurs, the refluxate is often acidic because of entrapment of the acid pocket in the hiatal hernia. Patients with a hiatus hernia may require repair using surgical or endoscopic techniques if their disease does not respond to optimal pharmacologic measures.
Recently, patients with GERD have been found to have an altered microbial profile in the distal esophagus, characterized by an increase in gram-negative flora and a decrease in gram-positive flora. The lipopolysaccharide released by the gram-negative bacteria may perpetuate local inflammation and also cause LES relaxation by inducing nitric oxide synthase and delaying gastric emptying via the cyclooxygenase-2 pathway. Probiotic administration has been found to enhance gastric emptying and decrease regurgitation in infants. Further understanding of the role of microbial flora in the causation or perpetuation of GERD may pave the way for using probiotics and antibiotics in the management of GERD.
Role of Esophageal Acid Clearance
The clearance of acid by esophagus has 2 main components: mechanical clearance and chemical neutralization. Reflux of gastric contents may result in esophageal distension and secondary peristalsis, thereby returning refluxed material to the stomach. Patients with esophageal dysmotility have defective clearance resulting in significant mucosal injury because of persistent exposure of the mucosa to noxious agents. Although prokinetic agents have a theoretical role to play in the management of GERD, their overall efficacy in the clinical setting has been relatively disappointing.
Residual acid, which persists after peristaltic volume clearance, is neutralized by saliva and bicarbonate-rich secretions from the submucosal glands of the esophagus. Use of oral lozenges, bethanechol, and smoking cessation are associated with increasing salivation, which helps in improving GER symptoms. Hyposalivation during sleep contributes to prolonged nocturnal reflux episodes. Raising the bed head may be helpful in controlling nocturnal or recumbent GER, but it would be helpful if esophageal clearance could be improved pharmacologically.
Role of Tissue Resistance
Tissue resistance is a function of the buffering capacity of mucus secreted by the submucosal glands, intercellular tight junctions, intracellular defense mechanisms against acidification, frequent cell turnover, and local blood supply. Dilated intercellular spaces (DIS) in the esophageal epithelium is considered an early morphologic marker of acid damage in patients with GERD. DIS is thought to allow passage of water and hydrogen ions, with or without other noxious agents, into the esophageal epithelium, resulting in direct tissue injury as well as activation of the chemosensitive nerve endings located within the mucosa. Recent novel imaging techniques such as narrow band imaging and confocal laser endomicroscopy demonstrate these early changes even in patients who have no obvious damage on standard white light endoscopy.
Role of Visceral Hypersensitivity
Noxious luminal agents as well as inflammatory mediators can stimulate nerve endings that play a key role in visceral hypersensitivity. In some individuals with functional heartburn or NERD and in those with underlying psychological morbidity, symptoms may occur even in the absence of frankly acidic reflux. In these patients, even small quantities of noxious agents are thought to penetrate the DIS and stimulate chemosensitive nociceptors. In these cases, symptoms may be secondary to peripheral sensitization or to central mechanisms resulting in esophageal hyperalgesia. Psychological stress has been shown to increase DIS in the esophageal epithelium, promoting cell injury and chemosensitization. Consequently, various pain modulators are being studied for the management of pain and other symptoms in patients with GERD.
Novel pharmaceutical approaches
Two key facts have emerged from decades of research and clinical practice. First, acid inhibition has been the single most successful approach to the management of GERD. Second, current acid inhibition strategies do not deliver the 3 key outcomes of interest in all patients: symptom relief, mucosal healing, and prevention of complications. Thus, novel strategies must explore the role of drugs for improving acid suppression and for targeting other pathophysiological mechanisms to provide complete symptom relief, mucosal healing, and absence of complications ( Fig. 1 ).
Targeting acid suppression
Traditional PPIs
The traditional delayed-release PPIs—omeprazole, lansoprazole, pantoprazole, and rabeprazole—are prodrugs that are activated by conversion to the sulfenamide form in the acidic environment of the secretory canaliculus. The activated sulfenamide then forms a covalent disulfide bond with a cysteine moiety in the proton pump, blocking the H + K + ATPase exchange pathway. All traditional PPIs are acid labile as prodrugs, and they, therefore, require enteric coating to delay release, with subsequent absorption in the small bowel. After absorption, they are metabolized rapidly, with a short half-life of only 1 to 1.5 hours; fortunately, PPIs bind irreversibly to the proton pump so their effect extends well beyond their plasma residence time. However, because proton pumps are regenerated continuously, acid secretion capacity increases steadily through the day allowing nocturnal acid breakthrough. In addition, traditional PPIs do not achieve maximal acid suppression immediately, generally requiring at least 5 days for peak effect. Acid suppression is optimized if the action of the PPI on the proton pump is maximized by synchronizing ingestion with meal-stimulated acid secretion. Ideally, therefore, a PPI should be taken within 15 to 60 minutes before the first meal of the day. Compliance with this recommendation is adhered to by less than 10% of patients and emphasized by only one-third of the physicians at the time of prescription. Also, the efficacy of the drug depends on the rate of metabolism of the drug by the hepatic cytochrome system. Rapid metabolizers have lower drug levels, translating into reduced acid suppression. These shortcomings of traditional PPIs have resulted in incomplete efficacy, poor compliance, and increasing costs of care.
Newer PPIs
In the past decade, novel pharmacologic approaches have been taken to improve existing molecules or to discover newer agents that might enhance or prolong acid suppression and overcome some of the shortcomings of traditional PPIs ( Tables 1 and 2 ).
| Drug/Type of Modification | Status | Modification | Modified Action |
|---|---|---|---|
| Selective isomeric formulation | |||
| Esomeprazole | Approved | S-enantiomer | Greater bioavailability Increased area under plasma concentration–time curve Lesser interindividual variability |
| Dexlansoprazole MR | Approved | R-enantiomer | |
| Dexrabeprazole | Approved | R-enantiomer | |
| S-pantoprazole | Phase 3 | S-enantiomer | |
| Extended-release formulations | |||
| ER-rabeprazole | Approved | Slow release | Greater plasma residence time Increased area under plasma concentration-time curve |
| CMA-omeprazole (AGN201904-Z) | Approved | Chemically metered release | |
| Dexlansoprazole MR (TAK 390 MR) | Approved | Dual release | |
| Immediate-release preparations | |||
| IR omeprazole | Approved | No enteric coating Combined with NaHCO 3 | Rapid onset and sustained action |
| IR esomeprazole | Approved | ||
| Modified site of action | |||
| Revaprazan | Discontinued | PCABs) Act on K + channel | Higher p K a Greater concentration in secretory canaliculus |
| Soraprazan | Discontinued | ||
| Linaprazan (AZD0865) | Discontinued | ||
| TAK-438 | Phase 2 | ||
| YH4808 | Phase 2 | ||
| Modified chemical structure | |||
| Tenatoprazole (TU-199) | Phase 3 | Modified imidopyridine | Prolonged t ½ Increased area under plasma concentration–time curve |
| Ilaprazole | Phase 2 | Modified benzimidazole | |
| Combined with another agent | |||
| 4VB101 | Phase 2b | PPI with pentagastrin | Meal-independent secretory effect |
| NMI-826 | Phase 2 | PPI with NO-releasing moiety | Mucosal protection |
| OX17 | Phase 2 | PPI with H 2 RA | Enhances acid suppression |
| H 2 RA | Patented | Tenatoprazole with H 2 RA | Better nocturnal acid suppression |
| Alginate | Phase 3 | PPI with alginate | Reduces reflux from acid pocket |
| Problem with Traditional PPI | Potential Solution | Drug | Mechanism of Action | Remarks |
|---|---|---|---|---|
| Slow onset (5 d to achieve peak action) | Rapid onset | IR omeprazole IR esomeprazole TAK-438 | Rapid absorption and action PCABs | Useful for rapid relief of symptoms |
| Meal-dependent antisecretory effect | Meal-independent antisecretory effect | Pantoprazole Tenatoprazole Dexlansoprazole IR omeprazole IR esomeprazole Vecam (PPI + VB101) | Action relatively independent of meal timing Gastrin agonist | Meal-independent administration may improve compliance |
| Short half-life (1–2 h) | Sustained action | Tenatoprazole (TU199) Ilaprazole ER-rabeprazole Dexlansoprazole CMA-omeprazole | Prolonged half-life (9 h) Prolonged half-life (6 h) Enteric-coated extended release Dual pH-dependent release Pro-PPI | Useful for chronic symptoms Provides better symptom relief |
| Nocturnal breakthrough | Nocturnal acid suppression Prolonged action, see above | Add night dose Add H 2 -RA Tenatoprazole IR omeprazole | Suppresses nighttime acid secretion | Nocturnal symptoms and for extraesophageal manifestations |
| Breakthrough symptoms | Therapy on pro re nata basis | Step-up dose Add antacids (pro re nata) | Better acid suppression | Rapid short-term symptom relief |
| Rapid metabolizers | Use alternatives or increase dose of PPI in use | Esomeprazole Rabeprazole | Inhibits CYP2C19 Alternate metabolic pathway | In those with cytochrome P450 variant alleles |
| Drug interactions | PPI metabolized by pathways other than P450 | Pantoprazole Rabeprazole Ilaprazole | Alternate metabolic pathway Alternate metabolic pathway Alternate metabolic pathway | Possible role in patients with suspected drug interactions |
Stereoisomers
Isomers of traditional PPIs have been developed to improve bioavailability and efficacy. The common preparations in this category are esomeprazole, dexlansoprazole, dexrabeprazole, and S-pantoprazole. Of these, esomeprazole and dexlansoprazole have been studied in clinical trials and used extensively in routine clinical practice. In general, they have been found to be clinically more effective than their parent racemic formulations, albeit at higher doses, while maintaining similar safety profiles.
Extended-release PPIs
Dexlansoprazole MR (modified release) is an isomeric PPI that, also, has a dual delayed-release delivery system that releases the drug at 2 different pH levels, resulting in absorption over a longer period and sustained serum levels for up to 6.4 hours. As a result, dexlansoprazole MR, 90 mg, has been found to be somewhat more effective than lansoprazole, 30 mg daily. In addition, the effect of dexlansoprazole is not affected significantly by the time of ingestion, relative to food intake, with the potential for greater flexibility in drug dosing.
Extended-release ( ER ) rabeprazole is designed to release the drug throughout the lower gastrointestinal tract. It contains a combination of standard enteric-coated delayed-release tablets and pulsatile-release tablets. Rabeprazole is released from the former in the proximal small intestine and from the latter in the distal gut. In a combined analysis of 2 studies, in patients with moderate to severe erosive esophagitis, ER rabeprazole was reported not to be inferior to esomeprazole, 40 mg daily, with respect to esophagitis healing and symptom relief.
Chemically metered absorption omeprazole ( CMA-omeprazole /AGN 201904-Z) is a slowly absorbed acid-stable prodrug, which is converted into the active drug after absorption. This prodrug is absorbed throughout the length of the small intestine, resulting in a steady and prolonged serum residence time. In a phase I study, it was found to be better than esomeprazole in producing acid suppression at nighttime.
Immediate-release PPIs
Immediate-release (IR) formulations are nonenteric-coated PPIs that are combined with sodium bicarbonate to protect the drug from acid-induced degradation. The uncoated PPI is then rapidly absorbed, from the proximal intestine, resulting in rapid onset of action. In addition, the antacid-induced rise in gastric pH value itself stimulates acid secretion, which facilitates uptake of the PPI prodrug by the activated parietal cell and formation of the active sulfenamide derivative in the secretory canaliculi. As a result, the IR formulation’s efficacy is likely to be less affected by administration before a meal. IR omeprazole and IR esomeprazole have been found to offer a rapid onset of action and sustained acid suppression, associated with decreased nocturnal acid breakthrough, compared with traditional PPIs.
Newer PPIs
Tenatoprazole is an imidazopyridine derivative unlike traditional PPIs, which are benzimidazole derivatives. Tenatoprazole too is a prodrug that requires conversion into the active agent in the acidic environment of the secretory canaliculus of the parietal cell, where it binds at the Cys813 and Cys822 residues of the proton pump. Tenatoprazole has a long half-life of 8.7 ± 2.6 hours, which translates into prolonged acid suppression. Like other traditional PPIs, tenatoprazole is a racemic mixture of 2 stereoisomers, of which the S-isomer has been selected for further development. In addition, it was determined that the sodium salt of S-tenatoprazole offered better solubility and bioavailablity than the free form of S-tenatoprazole. In another phase 1 study, S-tenatoprazole-Na produced significantly greater and more prolonged dose-dependent 24-hour and nocturnal acid suppression than esomeprazole. In a meta-analysis of individual patient data, S-tenatoprazole sodium, 60 mg once a day, was found to be more effective in producing acid suppression than esomeprazole at standard doses (40 mg once a day), its acid suppression being equivalent to that of esomeprazole given twice daily. The efficacy of tenatoprazole is consistent with our current understanding that the antisecretory effect of PPIs is proportional to the area under the curve of plasma drug levels. Given its pharmacologic characteristics, S-tenatoprazole-Na may provide greater clinical efficacy compared with current PPIs for patients in whom once-daily therapy is ineffective.
Ilaprazole is a new substituted benzimidazole PPI that has been reported to produce higher gastric acid suppression and has a more prolonged half-life and a better safety profile than omeprazole. Reports that the metabolism of ilaprazole may differ from that of other PPIs suggests that it may be useful in patients at risk of drug interactions or in those with CYP2C19 variants. Recent studies of ilaprazole in healing gastroduodenal ulcers are promising, but there are no published clinical trials on its use in GERD.
Potassium-competitive acid blockers (PCABs)
PCABs are members of a new class of drugs that specifically target the potassium-binding region of the H + K + ATPase. PCABs are lipophilic weak bases that are stable at low pH values; this feature allows them to concentrate in acidic environment, resulting in 100,000-fold higher levels in the parietal cell canaliculus. The differences from traditional PPIs are highlighted in the Table 3 , which has been modified from the review article by Scarpignato and Hunt. These agents block the H + K + ATPase in a competitive reversible manner resulting in rapid and sustained acid inhibition. Drugs in this class, including revaprazan, soraprazan, linaprazan (AZD0865), and TAK 438, share the same final mechanism of action, but they belong to 4 different chemical classes, namely, imidazopyridines, pyrimidines, imidazonaphthyridines, and quinolones, respectively. Despite excellent pharmacokinetic and pharmacodynamic properties, most of these agents have been discontinued because of safety concerns or because they were not demonstrably superior to standard PPIs in clinical studies. However, evaluation of TAK 438 is still underway and the results of phase 3 trials are awaited.
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