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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Acid suppression therapy with proton pump inhibitors is associated with well-established benefits in the management of gastro-oesophageal reflux (GERD) and other acid-related disorders. However, a number of issues still remain unsettled. Despite their clinical efficacy, when given once daily, currently available proton pump inhibitors 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.

Although some novel proton pump inhibitors have been synthesized, only few reached clinical testing. Amongst them, tenatoprazole represents a true advance displaying a long half-life (five to seven times longer than that of currently available drugs) and extended acid suppression covering both day and night. All the available clinical studies suggest both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. As this last compound provides – amongst the members of the class – the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing proton pump inhibitors.

Tenatoprazole appears to be a promising proton pump inhibitor for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Acid suppression therapy with proton pump inhibitors (PPIs) is associated with well-established benefits in the management of gastro-oesophageal reflux disease (GERD) and other acid-related disorders. The dramatic success of pharmacological acid suppression in healing ulcers and managing patients with GERD has been reflected in the virtual abolition of elective surgery for ulcer disease,1 a reduction in non-steroidal anti-inflammatory drug (NSAID)-associated gastropathy,2 and the decision by most patients with reflux symptoms to continue medical therapy rather than undergo surgical intervention.

However, a number of challenges remain in the management of acid-related disorders. These include management of patients with gastro-oesophageal symptoms who do not respond adequately to PPI therapy, optimal treatment and prevention of NSAID-related gastrointestinal (GI) injury, the best combination of antisecretory and antibiotic therapy for the eradication of Helicobacter pylori infection and treatment of patients with non-variceal upper GI bleeding.3, 4 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.5 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 oesophagitis.6 Up to 79% of patients with GERD experience nocturnal symptoms associated with their condition and improvement in nocturnal symptoms associated with reduction in gastric acidity by PPIs is well documented.7 The clinical importance of reducing NAB, is however, controversial. In patients with GERD, recovery of nocturnal gastric acid secretion is of little importance if it is not accompanied by exposure of the oesophagus to acid. Patients with severe forms of chronic GERD however, especially those with Barrett's oesophagus, are more likely to have acid reflux during NAB.5 A recent report8 has shown >70% of patients had improved night-time symptoms after addition of an H2-receptor antagonist (H2RA) to a twice-daily PPI regimen, thus emphasizing the clinical impact of controlling NAB.

The administration of current delayed-release (DR) PPIs is recommended 30 min to 1 h prior to a meal in order to ensure that proton pumps are activated in the parietal cell while drugs are available in plasma.9 As all PPIs have similar plasma half-lives of 1–2 h, any proton pump synthesized after drug levels fall will not be blocked from secreting acid. As a consequence, their failure to provide extended antisecretory activity depends on their short half-life, speed of disassociation from the proton pump, together with activation or synthesis of the pumps.10 The clinical efficacy of the PPIs is related to the degree of acid suppression,11 consequently, PPIs with a longer half-life resulting in extended acid suppression would be expected to offer improved clinical efficacy.

Recent improvements in PPI technology

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Currently available PPIs are orally administered as gastroprotected preparations. The different enteric coatings, which are necessary to protect the acid-labile PPI from acid degradation within the stomach, have the potential disadvantage of delaying PPI absorption and, as a consequence, the available PPI formulations are considered delayed release (DR) preparations.

Delayed-release oral dosage forms are supplied as enteric-coated granules encapsulated in a gelatine shell (e.g. omeprazole capsules and lansoprazole capsules) or as enteric-coated tablets (e.g. pantoprazole tablets, rabeprazole tablets and omeprazole multiple unit pellet system). An alternative oral formulation of lansoprazole – the lansoprazole orally disintegrating tablet (ODT) – has recently been introduced.12 It is easy to swallow and can be taken with or without water. This feature greatly improves compliance when patients are away from home (and water is not readily available) and in those patients with odynophagia or dysphagia as well as swallowing disorders. However, the absorption kinetics still depend on the enteric coating; the oral pharmacokinetics of lansoprazole after dosing with the ODT are essentially identical to that observed after dosing with capsules of enteric-coated granules.13 The bioequivalence between these two formulations will translate into a similar pharmacodynamics and clinical efficacy. And indeed, despite the ODT being preferred by a higher proportion of patients, no significant difference in symptom relief between lansoprazole ODT and other PPIs (namely esomeprazole) was reported in patients with non-erosive reflux disease.14

Conversely, the recently FDA-approved immediate-release (IR) omeprazole formulation displays a different pharmacokinetics and pharmacodynamics compared with the standard, DR preparation.15 This formulation consists of pure, non-enteric-coated omeprazole powder (40 or 20 mg per unit dose) along with 1680 mg of sodium bicarbonate (containing 460 mg of sodium). It is flavoured with peach and peppermint and is designed to be constituted with water prior to administration. Comparative pharmacokinetic studies16 have shown that the antisecretory effect of IR omeprazole is quicker than that observed with classical DR formulation while the duration of the acid lowering activity is similar. The early increase in intragastric pH is likely due to the neutralizing capacity of sodium bicarbonate, which also accelerates and enhances absorption of omeprazole whose increased bioavailability translates into a more profound acid suppression. Bedtime dosing with 40 mg of IR-OME suspension provides better control of nocturnal gastric acidity than once-daily dosing with the DR PPIs17, 18 and also decreases NAB more effectively than DR omeprazole 20 mg b.d. and lansoprazole 30 mg b.d. or pantoprazole 40 mg b.d. Night-time control of gastric acidity with IR-OME suspension is comparable with that achieved by twice-daily dosing of DR esomeprazole 20 mg.18

The next generation of drugs which suppress gastric acidity will most likely be acid pump antagonists which are K+-competitive inhibitors of the ATPase.19 While the PPIs have a unique mechanism of action based on their chemistry, the so called potassium-competitive acid blockers (P-CABs) have a structural specificity for their target, the K+-binding region of the H+,K+-ATPase. P-CABs, despite sharing the same mechanism of action, represent an heterogeneous class of drugs. Indeed, they belong to four different chemical classes, namely imidazopyridines, pyrimidines, imidazonaphthyridines and quinolones.19 Both animal and human studies have shown that P-CABs rapidly achieve peak plasma concentrations after oral administration. This is partly due to their stability at low pH allowing their administration as IR formulations. All the compounds studied to date exhibit a linear pharmacokinetic pattern.19 The rapid absorption of P-CABs is mirrored by a fast onset of acid inhibition. Four representative members of the P-CAB class (AZD0865, CS526, revaprazan and soraprazan) have been studied in humans. Despite a number of papers presented at the recent DDW (Chicago 2005) and UEGW (Copenhagen 2005) and two clinical trials on GERD successfully completed,20 AZD0865 was discontinued, as was the development of CS526. Results of phase III clinical trials with one of such compounds (namely revaprazan) are eagerly awaited to determine whether the favourable pharmacodynamic properties will really translate into clinical benefits.

Development of novel PPIs: the case for tenatoprazole

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Currently available PPIs have similar pharmacokinetic profiles with relatively short plasma elimination half-lives (typically 1–2 h).21 As previously emphasized, only active proton pumps can be blocked during this limited period, and any pumps synthesized after plasma PPI levels fall will be free to secrete acid.10, 11 This may explain the finding that many PPIs do not achieve adequate control of nocturnal acidity even when given twice-daily.5, 22

Tenatoprazole (compound also marked TU-199) has been developed by Mitsubishi Pharma 23 and is now under active development by Negma-Gild. Unlike all the other PPIs, this compound is not a benzimidazole derivative, consisting of one imidazopyridine ring connected to a pyridine ring by a sulfinylmethyl chain (Figure 1). It therefore represents a new chemical entity. In vitro studies, performed in gastric microsomes, have shown that tenatoprazole displays an inhibitory action on proton pump comparable with that of omeprazole and lansoprazole.24 The inhibitory activity of this novel compound on gastric H+,K+-ATPase has been thoroughly characterized by George Sachs’ Team 25, 26 and is reviewed elsewhere in this supplement.

image

Figure 1.  Structural formula of tenatoprazole (TU-199). (RS)-5-methoxy-2-[[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulfinyl]1Himidazo [4,5b] pyridine [CAS Registry No: 113712-98-4].

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The in vivo antisecretory potency of tenatoprazole, evaluated in different animal models (Shay rat preparation, acute fistula rats and Heidenhain pouch dogs), proved to be two to four times higher than that observed with omeprazole. As a consequence, the healing activity of the compound on experimentally induced gastric and duodenal ulcers appeared similarly higher.24 Unlike omeprazole, which delays gastric emptying,27 tenatoprazole was unable to affect emptying rate.28 In addition, experiments carried out in gastric fistula dogs revealed an elevation of intragastric pH lasting 20% longer than that observed with omeprazole or lansoprazole.29

The pharmacokinetics of tenatoprazole were investigated in Helicobacter pylori-negative healthy Caucasian subjects in a randomized, double-blind, dose-ranging study (10–80 mg, either single or repeated administration). A linear correlation between tenatoprazole dose and AUC was found, and the long half-life of tenatoprazole was confirmed for every dose, reaching 8.7 ± 2.6 h for repeated administration of 40 mg.30 This novel PPI therefore displays a half-life that is five- to sevenfold longer than that of the currently available PPIs21, 31 (Table 1). The antisecretory effect of PPIs is known to be related to the AUC.32, 33 By achieving greater AUCs, PPIs with a prolonged half-life, such as tenatoprazole, are expected to exhibit an extended duration of antisecretory action with limited, if any, difference between day- and night-time activities. In keeping with these pharmacokinetic findings, pharmacodynamic studies have shown tenatoprazole to provide similar acid suppression to esomeprazole during the day, but to better control night-time intragastric acidity.34–36

Table 1.   Pharmacokinetics of currently available proton pump inhibitors (PPIs) compared with that of tenatoprazole
PPI (dose)t1/2 (h)AUC0−∞ (μmol h/L)
  1. Data concerning the current PPIs have been obtained in a crossover study on healthy volunteers31 while those regarding tenatoprazole are from a pharmacokinetic investigation devoted to this novel PPI.30 The linear correlation (r2 = 0.983) between the dose and the AUC for tenatoprazole indicates a linear pharmacokinetic pattern.

Omeprazole 20 mg1.5 ± 0.82.0 ± 1.5
Esomeprazole 40 mg1.1 ± 0.37.3 ± 3.8
Lansoprazole 30 mg1.1 ± 0.35.2  ± 2.6
Pantoprazole 40 mg1.2 ± 0.415.9 ± 8.5
Rapeprazole 20 mg1.1 ± 0.52.2 ± 0.7
Tenatoprazole 20 mg7.8 ± 2.035.9 ± 18.8
Tenatoprazole 40 mg8.7 ± 2.675.2 ± 27.6
Tenatoprazole 80 mg9.2 ± 2.3218.4 ± 108.8

A 7-day crossover study34 reported the increase of intragastric pH with tenatoprazole 40 mg daily for 7 days was significantly higher (P < 0.05) than that observed with the same regimen of esomeprazole, the median pH values being 4.6 ± 0.9 and 4.2 ± 0.8 respectively. In addition, after tenatoprazole administration, the time spent above pH 4 during night-time was significantly longer than that observed with esomeprazole (Table 2). The intragastric pH during the night was similarly higher (4.7 ± 1.1 with tenatoprazole and 3.6 ± 1.4 with esomeprazole, P < 0.01).34 The better control of intragastric acidity achieved with tenatoprazole during the night was evident from the first dose (Figure 2).35

Table 2.   Intragastric acidity in healthy volunteers given esomeprazole or tenatoprazole once-daily for 7 days. Each value refers to the mean (±S.E.M.) of the values obtained from 18 Helicobacter pylori-negative subjects.34
% of time with pH>4Esomeprazole 40 mgTenatoprazole 40 mg
  1. *Tenatoprazole vs. esomeprazole, P < 0.01.

24 h (08:00–08:00 hours)56.2 ± 16.5%6.3 ± 17.8%
Daytime (08:00–20:00 hours)65.6 ± 17.7%62.2 ± 18.5%
Night-time (20:00–08:00 hours)46.8 ± 19.7%64.3 ± 21.7%*
image

Figure 2.  Mean intragastric acidity (expressed as percentage of time with night-time pH over 4) in 24 Helicobacter pylori-negative subjects given tenatoprazole or esomeprazole for 2 consecutive days.35***P < 0.0001 vs. esomeprazole 40 mg.

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A recent pharmacodynamic and pharmacokinetic investigation36 confirmed and extended previous data showing the prolonged duration of acid suppression with tenatoprazole (Figure 3). The proportion of healthy volunteers spending at least 16 h above pH 4 in the 24-h period was considerably higher with tenatoprazole than with esomeprazole (81.5% vs. 34.5%, P < 0.001) while the proportion of subjects with NAB was lower (73.1% vs. 93.1%, P = 0.06), although this difference fell just short of statistical significance in this relatively small study. Even 3 days after treatment was discontinued, mean 24 h pH, and the percentage of time at pH > 3 and pH > 4 were significantly higher with tenatoprazole, indicating a sustained control of intragastric acidity with this novel PPI compared with esomeprazole. After 7 days repeated dosing the maximal plasma concentration of tenatoprazole was almost six times higher than that of esomeprazole while AUC was 32 times higher. A significant correlation between AUC and time intragastric pH > 4 was observed with tenatoprazole not only during, but also after stopping, treatment.36

image

Figure 3.  Mean 24-h intragastric pH profiles (on day 7) in 30 Helicobacter pylori-negative healthy volunteers giving tenatoprazole (40 mg) or esomeprazole (40 mg) orally once a day. It is evident that the mean duration of nocturnal acid breakthrough is shorter with tenatoprazole than with esomeprazole (4.3 h vs. 6.5 h, P < 0.0001) (from Hunt et al.36).

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In summary, the available studies indicate both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. As this last compound provides – amongst the members of the class – the most effective control of intragastric pH whatever the parameter considered,37 it is likely that tenatoprazole could similarly be better than the other existing PPIs. Tenatoprazole therefore appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.

Potential benefits of tenatoprazole in acid-related diseases

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Gastro-oesophageal reflux disease

Current PPIs maintain the intragastric pH above 4 for between 10 and 14 h when given as a single morning dose.37 While this allows healing of erosive oesophagitis with a single morning dose in the majority of patients, healing of higher grade disease is lower.38 In addition, nocturnal heartburn occurs in approximately 15% of erosive oesophagitis patients 39 and around 40% of those with uninvestigated heartburn.40 Although the use of PPIs twice-daily can improve control of acid secretion, a significant number of patients (approximately 70%) will continue to have NAB on intragastric pH monitoring.5 Although this may not give rise to symptoms in all patients, around half of GERD patients report nocturnal heartburn 41 and this may be associated with progression to Barrett's.42, 43 The combination of a twice-daily PPI with an H2RA given at bedtime may be useful in some patients with poor symptom control.44 However, long-term use of H2RAs leads to the development of tolerance and their effect on NAB is lost with prolonged therapy.45 In addition, it must be emphasized that no study in patients with GERD has yet demonstrated that addition of H2-RAs to twice-daily PPI therapy provides any further benefit above that derived from PPIs alone.46, 47 Data from published clinical trials support the effect of tenatoprazole as a true once-daily PPI providing 24-h control of intragastric acid exposure from a single dose. Therefore, this novel PPI may offer improved symptom control in a substantial proportion of patients with GERD or non-erosive disease (NERD). Finally, the prolonged control of oesophageal exposure to acid should allow an improved healing rates of severe (grade C and D according to Los Angeles classification) oesophagitis and may exert a chemopreventive effect in columnar-lined oesophagus.48–50

Although no randomized clinical trials in acid-related diseases are yet available, it is worth mentioning that a preliminary analysis of a phase II dose-ranging (10, 20 and 40 mg daily) Canadian study, performed in patients with reflux oesophagitis (grade A–C), demonstrated that this novel PPI effectively heals mucosal lesions regardless of the dose [Alan B. Thomson, personal communication]. After 4 weeks of treatment with all doses of tenatoprazole, the healing rate was greater than that reported with esomeprazole (40 mg daily) in a historic cohort.

NSAID-associated lesions and symptoms

Gastro-duodenal mucosa possesses an array of defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. The presence of acid appears to be a conditio sine qua non for NSAID-injury, which is in fact pH-dependent.51, 52 Indeed, the higher the intragastric pH, the lower the extent and severity51 as well as the probability of mucosal damage (Figure 4).52 There is therefore a strong rationale for PPI use in both treatment and prevention of NSAID associated gastro-duodenal ulcers.53 Unlike H2-blockers, PPIs protect from NSAID-injury not only the duodenum, but also the stomach, where the majority of mucosal lesions are usually located.54–57

image

Figure 4.  pH-dependency of non-steroidal anti-inflammatory drug (NSAID) mucosal injury in healthy volunteers.52 In this investigation naproxen was given to 37 healthy subjects for 6 days, either alone or in combination with a antisecretory agent. Both upper gastrointestinal (GI) endoscopy and measurement of intragastric acidity was performed on day 6. Partial inhibition of gastric acid secretion significantly reduced the incidence of gastric pathology (53%) than those whose gastric acidity had remained unchanged (89%; P = 0.029). The importance of pH in predicting the extent of damage was shown by the individuals’ integrated gastric acidity. Good acid control (i.e. low integrated gastric acidity) was predictive of a lower probability of NSAID-associated gastric damage; high acidity was predictive of the development of gastro-duodenal pathology.

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However, while current PPIs allow healing of NSAID-related lesions, patients with gastric ulcer respond less well than those with duodenal ulcers. In the comparative trial of omeprazole vs. ranitidine (the ASTRONAUT study 58), 81% of those patients with gastric ulcers were healed at 8 weeks with omeprazole compared with 92% of those with duodenal ulcers. This difference was more marked when ‘early healing’ at 4 weeks was assessed. Most patients continue to require their NSAID, and in such patients there is a loss of protection with time, even with continued PPI therapy.58–60 Most NSAIDs inhibitors are taken more than once-daily, or are available as ‘sustained released’ formulations to provide 24 h benefit. In addition, some compounds (like, for instance, naproxen) undergo enterohepatic circulation further extending GI exposure.61 As a result therefore, patients who take an existing PPI once-daily will have residual acid secretion during the 24-h period and will be at risk of GI injury from their NSAID therapy. A PPI with a true 24-h acid suppression effect from once-daily therapy would be expected to displays an improved mucosal protection and clinical trial data with such long-lasting acid inhibitors are awaited with interest.

Helicobacter pylori eradication

Since Warren and Marshall first described the infectious aetiology of peptic ulcer (PU) disease in 1984, a great deal of evidence has accumulated to suggest that H. pylori eradication therapy cures PU disease62, 63 and can be beneficial also to other H. pylori-related diseases.64–66 Today, there is no longer any serious debate about the value or appropriateness of such treatment that is based on overwhelming evidence from clinical trials reinforced by several years of clinical practice. There are however strong indications for treatment that are universally accepted and some other, less well evidence-based (so-called ‘advisable’ indications)65, 66 that are still surrounded by much debate. It is nevertheless clear that, based on an ever increasing number of studies, the indications for treating the infection have gradually increased over the past years.64Helicobacter pylori infection and NSAID use are associated with independent and significant increases in the risk of PU and ulcer bleeding, with synergism reported between these two factors.67

Development of a successful treatment for H. pylori infection has been fraught with difficulty. The survival capabilities of H. pylori within the stomach make it difficult to eradicate. The organism is able to survive over a wide pH spectrum. It is found within the gastric mucus layer, deep within the mucus-secreting glands of the antrum, attached to cells, and even within cells.68 The organism must be eradicated from each of these potential niches and this is a daunting task for any single antibiotic. Initial attempts to cure the infection showed that the presence of antibiotic susceptibility in vitro did not necessarily correlate with successful treatment. It was rapidly recognized that therapy with a single antibiotic led to a poor cure rate and various antimicrobial mixtures were tried resulting in several effective combinations of antibiotics, bismuth, and antisecretory drugs.69

Proton pump inhibitors display several pharmacological actions that give them a place in the eradication regimens (for review see Scarpignato and Pelosini68), that is:

  • 1
    They exert an antibacterial action against H. pylori;70
  • 2
    By increasing intragastric pH, they allow the microorganism to reach the growth phase and become more sensitive to antibiotics such as amoxicillin and clarithromycin;71
  • 3
    They increase antibiotic stability72 and efficacy;73 and
  • 4
    By reducing gastric emptying74 and mucus viscosity,75 they increase the gastric residence time and mucus penetration of antimicrobials.

The importance of pH control in the management of H. pylori infection is attested by the MACH-2 study,76 which clearly showed that the cure rates achieved by treatment with two antibacterial agents, namely amoxicillin plus clarithromycin or clarithromycin plus metronidazole, are significantly lower than those achieved by the same two agents given concomitantly with omeprazole. A similar finding has been reported when the combination of clarithromycin and tinidazole was tested with or without concomitant lansoprazole.77

A recent investigation78 examined the effect of nocturnal intragastric pH, measured 7 days after administration of triple therapy (i.e. lansoprazole, clarythromycin and amoxicillin), on H. pylori eradication rate. As expected, neither the morning nor the divided dose regimen of the PPI (namely lansoprazole) were able to control nocturnal acidity and the occurrence of NAB. NAB did not influence H. pylori eradication in PU patients, but the duration of NAB and 24-h median intragastric pH were found to influence the success of the therapy (Figure 5). The median pH in those patients who become H. pylori-negative after treatment was 5.7 ± 0.2 whereas it reached only the value of 4.2 ± 0.4 (P < 0.05) in patients in whom eradication was not achieved.78 These data therefore suggest that the success of eradication therapy depends not only on intragastric pH, but also on the duration of NAB. Controlling intragastric acidity both during the day and the night should therefore achieve better eradication rates. As matter of fact, in a recent study79 with twice-daily (40 mg) esomeprazole-based triple therapy the eradication rate did approach 96% on intention-to-treat analysis. Indeed, McColl's team80 has shown that this regimen almost completely suppresses 24-h intragastric acidity reaching a median pH on treatment of 6.75 (6.3–7.1) and exhibiting little, if any, NAB.

image

Figure 5.  Effect of NAB on Helicobacter pylori Eradication Rate in 67 PU Patients (from Kim et al.78). The median intragastric pH of the Helicobacter pylori eradication and persistence group was 5.7 ± 0.2 and 4.2 ± 0.4, respectively (P < 0.05).

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Besides achieving higher eradication rates, PPIs which offer superior control of both day and night acidity could also improve compliance. Current PPIs must be taken at high doses, twice-daily, while a long-acting PPI could perhaps be given once-daily thus simplifying the regimen without impairing efficacy. Finally, although not yet studied in the clinic, it might also be possible to achieve with such a long-lasting acid inhibitor acceptable eradication rates even with dual therapy (e.g. amoxicillin plus PPI).

Upper gastrointestinal bleeding

Although initial rates of haemostasis are high following endoscopic therapy, a substantial incidence of recurrent bleeding is seen.81 Combination of endotherapy with acid suppression is superior to monotherapy in reducing bleeding and surgery and superior to endotherapy alone in minimizing re-bleeding but not surgery.82

The goal of medical therapy for bleeding ulcers has been traditionally to sustain intragastric pH > 6, in order to promote platelet aggregation, clot formation and stability.83, 84 Indeed, platelet function is improved at high pH (Figure 6) 85 and pepsin promotes clot lysis below 5.86

image

Figure 6.  Effect of plasma pH on platelet aggregation. Buffer or HCl is added at point A; pH shown was determined at the end of each 5-min experiment. At a pH below 6.0, platelet aggregation is almost completely abolished. Adapted from Green et al.85

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H2RAs show little benefit in patients with PU bleeding,87–89 which reflects their inadequate pH control and the rapid onset of tolerance (see above). Several meta-analyses87, 88, 90–92 have shown that treatment with a PPI reduces the risk of re-bleeding and the requirement for surgery after ulcer bleeding but has no benefit on overall mortality, an effect seen only with intravenous administration of high doses to high-risk patients.93, 94 One of these systematic reviews94 actually suggested a significant benefit only for patients having endoscopic high-risk stigmata for re-bleeding.

Currently available PPIs are not able to maintain the intragastric pH above 6 for prolonged periods. In a recent study in healthy volunteers neither lansoprazole formulations (IV or oral) or IV pantoprazole could achieve an intragastric pH of 6 for a significant period.95 However, Armstrong et al.96 found that oral esomeprazole (40 mg), which provides the most effective control of intragastric pH amongst the different PPI,37 achieves greater acid inhibition than intravenous pantoprazole (40 mg) on both day 1 and day 5. As the available pharmacodynamic studies34–36 have shown a superiority of tenatoprazole over esomeprazole, it is conceivable that a PPI with extended half-life could achieve the same (or even better) outcomes obtained with the intravenous infusion of these acid inhibitors.

Conclusions and perspective for the future

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

In acid-related disorders, healing is directly related to the degree and duration of acid suppression and the length of treatment.11 Taken into account the difficulties encountered in attaining effective symptomatic control, particularly at night, using currently available PPIs once-daily, newer agents that can achieve rapid and potent acid suppression may be advantageous.

A number of new drugs are currently being investigated to provide a significant advance on current treatments (for review see Scarpignato et al.97). Some of them (namely P-CABs and CCK2-receptor antagonists) have already reached clinical testing while some others (like the antigastrin vaccine, H3-receptor ligands or gastrin-releasing peptide receptor antagonists) are still in preclinical development and need the proof of concept in human beings. Of the current approaches to reduce acid secretion, P-CABs and CCK2-receptor antagonists hold some promise, with several compounds already in clinical trials. Although the rapid onset of action of P-CABs (i.e. a full effect from the first dose) is appealing, the results of phase II studies with one such agent (namely AZD0865) did not show any advantages over esomeprazole (M. Sohtell, P. Jansson and P. Lundborg et al., personal communication). Thanks to their limited efficacy and the development of tolerance it is unlikely that CCK2-antagonists will be used alone as antisecretory compounds but, rather, their combination with PPIs will be attempted with aim of reducing the long-term consequences of hypergastrinaemia.98 While H2-receptor antagonists (especially soluble or over the counter 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.98

Like the other PPIs, tenatoprazole is a racemic mixture of two stereoisomers which derive from the chiral nature of the sulphur atom of the sulfinyl group.99 As a consequence, in order to exploit the features of stereoselective catabolism, the S-isomer was selected for further development.100 A careful pharmacokinetic and structural study by George Sachs’ team25 showed that the oral bioavailability of S-tenatoprazole sodium salt hydrate is almost twice that of S-tenatoprazole free form. The difference in bioavailability can be explained by the better solubility of the sodium salt. Some pharmacodynamic and healing studies with S-tenatoprazole sodium have already been planned and will start in the near future.

The prolonged half-life of tenatoprazole has been shown to provide extended acid suppression throughout the entire 24-h dosing period, with effects that are still evident 5 days after treatment withdrawal. In particular, tenatoprazole has demonstrated significant improvements in nocturnal acid control compared with current PPIs.34–36 This superior antisecretory effect and long duration of action indicate that tenatoprazole may offer improved control of the symptoms and complications of GERD even in patients for whom a once-daily PPI is ineffective. A prolonged reduction in oesophageal exposure to acid should facilitate improved healing of severe oesophagitis and may exert a chemopreventive effect in columnar-lined oesophagus. In addition, because of its potent and prolonged antisecretory effect, tenatoprazole may also be useful in the prevention and treatment of NSAID-related gastroduodenal damage, and in H. pylori eradication regimens. This novel PPI may also improve outcomes of PPI therapy of upper GI bleeding by providing continuous 24-h acid suppression. Tenatoprazole (as well as its S-isomer) then appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs. Further clinical studies are of course needed to confirm this hypothesis.

Financial Disclosure

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References

Carmelo Scarpignato is on the Speakers’ Bureau for Negma-Gild and AstraZeneca and has delivered lectures on tenatoprazole or esomeprazole at several educational meetings. Iva Pelosini has no financial interests to disclose.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Recent improvements in PPI technology
  5. Development of novel PPIs: the case for tenatoprazole
  6. Potential benefits of tenatoprazole in acid-related diseases
  7. Conclusions and perspective for the future
  8. Financial Disclosure
  9. References
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