Kalaitzakis and Björnsson in its pharmacokinetic properties (Hatlebakk 2003; Kendall 2003). PPIs are the drugs of choice in the treatment of GERD (Moayyedi and Talley 2006). Esomeprazole is considered to have a somewhat higher potency in acid inhibition than other PPIs (Hatlebakk 2003; Kendall 2003; Hellstrom and Vitols 2004). However, previous reports have reported variable results in comparing its efﬁcacy in healing erosive GERD, in maintenance therapy of healed erosive GERD, and in therapy of NERD compared with other PPIs. Some systematic reviews and meta-analyses have been published on the efﬁcacy of esomeprazole in the therapy of erosive GERD (Klok et al 2003; Vakil and Fennerty 2003; Edwards et al 2006; Gralnek et al 2006). The aim of the current systematic review was to provide an update on the efﬁcacy of esomeprazole in acid suppression, in the acute and maintenance therapy of erosive GERD and NERD as well as in improving health-related quality of life (QoL) in GERD. Comparison with other PPIs in this context was also undertaken. Data selection We performed a structured electronic search of PuBMed to identify English-language, randomized clinical trials from 2000 to 2006 comparing esomeprazole vs alternative PPIs in the treatment of GERD. The bibliography of systematic reviews and meta-analyses performed comparing the efﬁcacy of esomeprazole vs other PPIs in GERD was searched manually for references not found by the strategy described above. Abstracts from presentations at conferences, animal studies, or data from the manufacturers not published as full- text articles were not included. A review of the literature on esomeprazole and Barrett’s esophagus or extraesophageal manifestations of GERD was beyond the scope of this article. Acid suppression Although investigators agree that GERD is associated with dysmotility and results from an imbalance between normal defensive factors such as esophageal clearance, lower esophageal sphincter tone, and aggressive factors such as acid and pepsin, it has become increasingly clear that the key to controlling symptoms and to healing esophagitis is decreasing the duration of exposure to the acidic reﬂuxate (Hunt 1999). The duration of esophageal exposure to a reﬂuxate with a pH of 4.0 or less has been shown to be correlated to mucosal injury and to a reduced ability of the injured mucosa to proliferate and heal (Bell et al 1992; Hunt 1999). Controlling GERD symptoms and healing erosive GERD can be best 654 achieved by increasing the gastric pH to 4.0 or above for as long a duration as possible (Bell et al 1992; Hunt 1999). Furthermore, it has been suggested that in patients with more severe grades of esophagitis, there are abnormally high levels of nocturnal acid exposure (Bell et al 1992). Also, ulcerative esophagitis, esophageal strictures, and Barrett’s esophagus are characterized by high levels of supine nocturnal percentage acid reﬂux time (Frazzoni et al 2003), indicating that control of nocturnal acid secretion is important. PPIs reduce gastric acid secretion by inhibiting activity of the gastric H+/K+-ATPase. They are protonated in the acidic gastric environment to active forms, which irreversibly bind to the H+/K+-ATPase and inactivate it (Hunt 1999; Hatlebakk 2003; Hellstrom and Vitols 2004). As PPIs block the last step in the pathway to gastric acid secretion, they are effective in both basal and stimulated acid secretion (Hunt 1999; Hellstrom and Vitols 2004). The effects of esomeprazole on gastric acidity Recently, acid control with esomeprazole has been compared with that of other PPIs in several cross-over studies in either patients with GERD or in healthy individuals. As shown in Table 1, all studies showed that esomeprazole 40 mg od was more effective in maintaining intragastric pH at 4.0 or lower compared with all other PPIs given at standard doses. The same studies demonstrated that esomeprazole 40 mg od is superior to all other PPIs at standard doses in terms of achieving higher 24-hour median intragastric pH and in terms of the number of patients achieving intragastric pH 4.0 for at least 12 hours per day. Nocturnal pH was measured in one of these studies, comparing esomeprazole 40 mg with pantoprazole 40 mg bd (Miehlke et al 2005). During night-time the proportion of time with intragastric pH 4.0 was 85.4% with esomeprazole and 63.6% with pantoprazole (p = 0.0001). Nocturnal acid breakthrough, deﬁned as intragastric pH 4.0 for at least one consecu- tive hour between 10 pm and 6 am, was observed in 26.7% of subjects receiving esomeprazole and in 73.3% of those receiving pantoprazole (p = 0.009) (Miehlke et al 2005). Data on the effect of esomeprazole on nocturnal pH in comparison with other PPIs are otherwise largely lacking. In certain situations, it is reasonable to use higher than approved doses of PPIs, often divided in two doses. These include a diagnostic trial for noncardiac chest pain, empiric treatment trial for supraesophageal symptoms of GERD, cases of partial response to standard dose therapy, cases with breakthrough symptoms, GERD patients with severe Therapeutics and Clinical Risk Management 2007:3(4)