Integrated gastric acidity can predict the prevention of naproxen-induced gastroduodenal pathology in normal subjects

Plachetka, John R.; Morelli, Gaetano; Hines, Carolyn; Borland, Julie; Lyke, Alison; Littlefield, D.; Gardner, Jerry D.

doi:10.1016/s0016-5085(03)82584-2

Cited by 9 publications

(10 citation statements)

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“…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 indeed pH-dependent [58, 59]. Acid not only injures the mucosa, by H + ion back diffusion from the lumen causing tissue acidosis, but also increases drug absorption, which is inversely proportional to drug ionization.…”

Section: Towards a Gi Safer Piroxicammentioning

confidence: 99%

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Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Scarpignato

2013

CMC

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Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro-duodenal mucosa possesses many 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. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called “inclusion complexes” that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition t...

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Section: Towards a Gi Safer Piroxicammentioning

confidence: 99%

“…Upper GI injury is often (albeit not always) pH-dependent: the lower the intragastric pH, the higher the mucosal damage [58, 59]. Buffered solution will quickly increase intragastric pH thus leading to mucosal protection.…”

Section: Formulations Of Piroxicam-β-cyclodextrinmentioning

confidence: 99%

Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Scarpignato

2013

CMC

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“…Low intragastric pH enhances the diffusion of NSAIDs into the gastric mucosa and may facilitate mucosal injury. 25 Moreover, H 2 RAs have been associated with variations in 24-hour acid suppression. 26 The profound and sustained acid suppressive effects exhibited by proton pump inhibitors have revolutionized the treatment of acid-related gastrointestinal diseases.…”

Section: Medical Therapy For Nsaidassociated Peptic Ulcer Diseasementioning

confidence: 99%

Treatment and chemoprevention of NSAID-associated gastrointestinal complications

Go¹

2008

TCRM

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Abstract:The use of non-steroidal anti-infl ammatory drugs has become ubiquitous worldwide and remains a common source of gastrointestinal morbidity. Antisecretory medications, particularly proton pump inhibitors, are effective in the treatment and prevention of NSAID-related gastrointestinal complications, including peptic ulcer disease and non-ulcer dyspepsia. A careful assessment of patients' risk factors for developing NSAID-related gastrointestinal complications should be undertaken prior to initiation of any NSAIDs. Patients who are considered at risk for developing gastrointestinal complications should receive concurrent antisecretory medical therapy to minimize the risk for GI complications.

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“…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 severity 51 as well as the probability of mucosal damage (Figure 4).…”

Section: Potential Benefits Of Tenatoprazole In Acid‐related Diseasesmentioning

confidence: 99%

“…Indeed, the higher the intragastric pH, the lower the extent and severity 51 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 H 2 ‐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 …”

Section: Potential Benefits Of Tenatoprazole In Acid‐related Diseasesmentioning

confidence: 99%

Review article: the opportunities and benefits of extended acid suppression

Scarpignato

Pelosini

2006

Aliment Pharmacol Ther

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SUMMARYAcid 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 providesamongst 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.

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Integrated gastric acidity can predict the prevention of naproxen-induced gastroduodenal pathology in normal subjects

Cited by 9 publications

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Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Treatment and chemoprevention of NSAID-associated gastrointestinal complications

Review article: the opportunities and benefits of extended acid suppression

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Integrated gastric acidity can predict the prevention of naproxen-induced gastroduodenal pathology in normal subjects

Cited by 9 publications

References 0 publications

Piroxicam-&#946;-Cyclodextrin: A GI Safer Piroxicam

Piroxicam-&#946;-Cyclodextrin: A GI Safer Piroxicam

Treatment and chemoprevention of NSAID-associated gastrointestinal complications

Review article: the opportunities and benefits of extended acid suppression

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Product

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Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam