Christopher P. Farrell

Proton pump inhibitors: actions and reactions

Proton pump inhibitors are the second most commonly prescribed drug class in the United States. The increased utilization of PPIs parallels the rising incidence of reflux disease. Owing to their clinical efficacy and relative lack of tachyphylaxis, PPIs have largely displaced H-2 receptor antagonists in the treatment of acid peptic disorders. The elevation of intragastric pH and subsequent alterations of gastric physiology induced by PPIs may yield undesired effects within the upper GI tract. The ubiquity of the various types of H(+), K(+)-ATPase could also contribute to non-gastric effects. PPIs may influence physiology in other ways, such as inducing transepithelial leak.

Overuse of stress ulcer prophylaxis in the critical care setting and beyond.

BACKGROUND Patients admitted to the intensive care unit (ICU) are susceptible to stress ulcers. We hypothesize that despite recommendations, stress ulcer prophylaxis (SUP) is still overused in the ICU and often continued after resolution of risk factors for bleeding. METHODS We retrospectively studied all ICU admissions for 4 months. Risk factors for stress ulcer bleeding were collected. Patients were categorized into 4 groups: (1) >or=1 major risk factor; (2) >or=1 minor risk factors; (3) no risk factors; (4) preadmission use of acid-suppressive medication. The rate of SUP was calculated by group during ICU stay, on transfer from the ICU, and at hospital discharge. RESULTS Two hundred ten patients were studied. Of all the ICU admissions, 87.1% received SUP. Among patients with no risk factors, 68.1% were placed on prophylaxis on ICU admission; 60.4% continued on treatment upon transfer from the ICU; 31.0% were discharged home on an agent without a new indication. CONCLUSIONS Although judicious use of SUP in high-risk patients can decrease the incidence of gastrointestinal bleeding, inappropriate use may increase drug reactions, unnecessary hospital costs, and personal monetary burden. Our findings argue for improvement measures to reduce initial inpatient overuse of SUP and to prompt discontinuation before hospital discharge.

Tumor necrosis factor blockade for treatment of inflammatory bowel disease: efficacy and safety.

Inflammatory bowel disease (IBD), including Crohns Disease (CD) and Ulcerative Colitis (UC), is characterized by inflammation of the gastrointestinal tract. In UC, inflammation is confined to the mucosa, initially involving the rectum, and may extend proximally to involve the entire colon. In CD, transmural inflammation may affect any portion of the GI tract. The etiology of these disease processes has remained unclear. Therapies are aimed at reducing inflammation and thereby improving symptomatology and morbidity. Traditional medical therapies have included corticosteroids, aminosalicylates, and immunomodulators. Within the past decade, another class of medications has been utilized targeting Tumor Necrosis Factor (TNF), a key, early signaling molecule in the inflammatory cascade. Increased levels of TNF have been found in the blood, epithelial tissue, and stool of patients with active IBD. Anti-TNF medications can not only have direct effects on immune system components, but they also can ameliorate apoptotic cell death and tight junction compromise in the gastrointestinal epithelium. Several randomized, placebo controlled studies have demonstrated the efficacy of these medications in achieving induction and maintaining remission of disease. Their safety profile, however, remains a concern. There has been a reported association of biologic therapy and increased opportunistic infections. A link between biologic therapy and the development of certain malignancies has also been described. Despite these associations, TNF blockade remains an important therapeutic development in the modern therapy of IBD. The role of barrier breakdown at the tight junction level in IBD, and of TNF induction of barrier disruption, is also discussed.

Proton Pump Inhibitors Interfere With Zinc Absorption and Zinc Body Stores

Background Proton pump inhibitors (PPIs) cause a sharp elevation of gastro-duodenal luminal pH which in turn has resulted in reports of reduced absorption of magnesium and certain other nutrients. Methods Gastroesophageal reflux disease (GERD) patients on long-term PPI therapy (> 6 months) or healthy test subjects (not on any acid preventive or neutralizing medication) were administered oral doses of zinc gluconate (26.2 mg zinc, twice daily) for 14 days followed by 5 cc venous blood samples. Plasma was analyzed for total zinc content by atomic absorption spectrophotometry. Baseline plasma and red blood cell zinc levels were also measured in these two groups when not taking any zinc supplementation. Results Plasma zinc levels of healthy controls increased by 126% during the period of zinc supplementation compared to only a 37% increase for individuals on long-term PPI therapy. On their normal diet (with no zinc supplementation), PPI-users had a 28% lower plasma zinc level than healthy controls (P < 0.005). Conclusions PPI use dramatically reduces supplemental zinc uptake and can result in decreased zinc body stores. Certain individuals on long-term PPI therapy, such as infants being treated for colic, may be at risk for decreased systemic levels of trace metals needed for developmental, regenerative and immunological requirements.

Drug delivery of zinc to Barrett’s metaplasia by oral administration to Barrett’s esophagus patients

BACKGROUND Delivery of a pharmacologically effective drug dosage to a target tissue is critical. Barretts epithelia are a unique challenge for drug delivery of orally administered zinc due to rapid transit down the esophageal lumen, incomplete absorptive differentiation of these epithelia, and the use of proton-pump inhibitor drugs abrogating intestinal uptake of supplemental zinc. METHODS Barretts esophagus patients were administered oral zinc gluconate (26 mg zinc twice daily) for 14 days prior to biopsy procurement. Barretts biopsies were analyzed for total zinc content by atomic absorption spectroscopy and by western immunoblot for cellular proteins known to be regulated by zinc. RESULTS Cellular levels of both the Znt-1 transport protein and the alpha isoform of PKC were over 50% lower in the zinc treatment group. CONCLUSION Oral zinc administration can result in effective delivery of zinc to Barretts epithelia with resulting effects on intracellular signal transduction.

Transepithelial leak in Barrett's esophagus patients: The role of proton pump inhibitors

AIM To determine if the observed paracellular sucrose leak in Barretts esophagus patients is due to their proton pump inhibitor (PPI) use. METHODS The in vivo sucrose permeability test was administered to healthy controls, to Barretts patients and to non-Barretts patients on continuous PPI therapy. Degree of leak was tested for correlation with presence of Barretts, use of PPIs, and length of Barretts segment and duration of PPI use. RESULTS Barretts patients manifested a near 3-fold greater, upper gastrointestinal sucrose leak than healthy controls. A decrease of sucrose leak was observed in Barretts patients who ceased PPI use for 7 d. Although initial introduction of PPI use (in a PPI-naïve population) results in dramatic increase in sucrose leak, long-term, continuous PPI use manifested a slow spontaneous decline in leak. The sucrose leak observed in Barretts patients showed no correlation to the amount of Barretts tissue present in the esophagus. CONCLUSION Although future research is needed to determine the degree of paracellular leak in actual Barretts mucosa, the relatively high degree of leak observed with in vivo sucrose permeability measurement of Barretts patients reflects their PPI use and not their Barretts tissue per se.