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==Medical uses==
==Medical uses==
These drugs are used in the treatment of many conditions, such as:
These drugs are used in the treatment of many conditions, such as:
* [[Dyspepsia]]<ref name="Overview">{{cite journal|last1=Zajac|first1=P|last2=Holbrook|first2=A|last3=Super|first3=ME|last4=Vogt|first4=M |title=An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia|journal=Osteopathic Family Physician |volume=5 |issue=2 |pages=79–85 |date=March–April 2013 |pmid=|doi=10.1016/j.osfp.2012.10.005}}</ref><ref name="pmid17174612">{{cite journal| author=Wang WH, Huang JQ, Zheng GF, Xia HH, Wong WM, Liu XG et al.| title=Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials. | journal=Clin Gastroenterol Hepatol | year= 2007 | volume= 5 | issue= 2 | pages= 178-85; quiz 140 | pmid=17174612 | doi=10.1016/j.cgh.2006.09.012 | pmc= | url= }} </ref>
{{div col|2}}
* [[Dyspepsia]]<ref name="Overview">{{cite journal|last1=Zajac|first1=P|last2=Holbrook|first2=A|last3=Super|first3=ME|last4=Vogt|first4=M |title=An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia|journal=Osteopathic Family Physician |volume=5 |issue=2 |pages=79–85 |date=March–April 2013 |pmid=|doi=10.1016/j.osfp.2012.10.005}}</ref>
* [[Peptic ulcer]] disease including after endoscopic treatment for bleeding<ref name="pmid25201154">{{cite journal| author=Sachar H, Vaidya K, Laine L| title=Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. | journal=JAMA Intern Med | year= 2014 | volume= 174 | issue= 11 | pages= 1755-62 | pmid=25201154 | doi=10.1001/jamainternmed.2014.4056 | pmc=4415726 | url=}}</ref>
* [[Peptic ulcer]] disease including after endoscopic treatment for bleeding<ref name="pmid25201154">{{cite journal| author=Sachar H, Vaidya K, Laine L| title=Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. | journal=JAMA Intern Med | year= 2014 | volume= 174 | issue= 11 | pages= 1755-62 | pmid=25201154 | doi=10.1001/jamainternmed.2014.4056 | pmc=4415726 | url=] </ref>
* As part of [[Helicobacter pylori]] eradication therapy<ref name="pmid24338763">{{cite journal| author=Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI et al.| title=Optimum duration of regimens for Helicobacter pylori eradication. | journal=Cochrane Database Syst Rev | year= 2013 | volume= 12 | issue= | pages= CD008337 | pmid=24338763 | doi=10.1002/14651858.CD008337.pub2 | pmc= | url= }} </ref>
* As part of [[Helicobacter pylori]] eradication therapy<ref name="pmid24338763">{{cite journal| author=Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI et al.| title=Optimum duration of regimens for Helicobacter pylori eradication. | journal=Cochrane Database Syst Rev | year= 2013 | volume= 12 | issue= | pages= CD008337 | pmid=24338763 | doi=10.1002/14651858.CD008337.pub2 | pmc= | url= }} </ref>
* [[Gastroesophageal reflux disease]] (GERD or GORD) including symptomatic endoscopy-negative reflux disease<ref name="pmid23728637">{{cite journal| author=Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME| title=Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. | journal=Cochrane Database Syst Rev | year= 2013 | volume= 5 | issue= | pages= CD002095 | pmid=23728637 | doi=10.1002/14651858.CD002095.pub5 | pmc= | url= }} </ref> and
* [[Gastroesophageal reflux disease]] (GERD or GORD)
::associated [[laryngopharyngeal reflux]] causing [[laryngitis]]<ref name="pmid17037995">{{cite journal| author=Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP, Wo JM et al.| title=Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. | journal=Am J Gastroenterol | year= 2006 | volume= 101 | issue= 11 | pages= 2646-54 | pmid=17037995 | doi=10.1111/j.1572-0241.2006.00844.x | pmc= | url= }} </ref> and [[chronic cough]]<ref name="pmid16330475">{{cite journal| author=Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske LA| title=Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux. | journal=BMJ | year= 2006 | volume= 332 | issue= 7532 | pages= 11-7 | pmid=16330475 | doi=10.1136/bmj.38677.559005.55 | pmc=1325125 | url= }} </ref>
* [[Laryngopharyngeal reflux]]
* [[Barrett's esophagus]]<ref name="pmid24221456">{{cite journal| author=Singh S, Garg SK, Singh PP, Iyer PG, El-Serag HB| title=Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis. | journal=Gut | year= 2014 | volume= 63 | issue= 8 | pages= 1229-37 | pmid=24221456 | doi=10.1136/gutjnl-2013-305997 | pmc=PMC4199831 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24221456 }} </ref>
* [[Barrett's esophagus]]
* [[Eosinophilic esophagitis]]
* [[Eosinophilic esophagitis]]
* Stress [[gastritis]] and ulcer prevention in [[critical care]]<ref name="pmid23318494">{{cite journal| author=Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ| title=Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis. | journal=Crit Care Med | year= 2013 | volume= 41 | issue= 3 | pages= 693-705 | pmid=23318494 | doi=10.1097/CCM.0b013e3182758734 | pmc= | url= }} </ref>
* Stress [[gastritis]] prevention
* [[Gastrinoma]]s and other conditions that cause hypersecretion of acid including [[Zollinger–Ellison syndrome]] (often 2–3x the regular dose is required)
* [[Gastrinoma]]s and other conditions that cause hypersecretion of acid including [[Zollinger–Ellison syndrome]] (often 2–3x the regular dose is required)

{{div col end}}


Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.<ref name="AGAfive">{{cite web |title=Five Things Physicians and Patients Should Question |publisher=[[American Gastroenterological Association]] |url=http://www.choosingwisely.org/doctor-patient-lists/american-gastroenterological-association/}}</ref><ref name="refluxstate">{{cite journal |doi=10.1053/j.gastro.2008.08.045 |title=American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease |year=2008 |last1=Kahrilas |first1=Peter J. |last2=Shaheen |first2=Nicholas J. |last3=Vaezi |first3=Michael F. |journal=Gastroenterology |volume=135 |issue=4 |pages=1383–1391, 1391.e1–5 |pmid=18789939 |last4=Hiltz |first4=SW |last5=Black |first5=E |last6=Modlin |first6=IM |last7=Johnson |first7=SP |last8=Allen |first8=J |last9=Brill |first9=JV}}</ref> In the United States, the [[Food and Drug Administration]] advises that no more than three 14-day treatment courses should be used in one year.<ref name="fda"/>
Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.<ref name="AGAfive">{{cite web |title=Five Things Physicians and Patients Should Question |publisher=[[American Gastroenterological Association]] |url=http://www.choosingwisely.org/doctor-patient-lists/american-gastroenterological-association/}}</ref><ref name="refluxstate">{{cite journal |doi=10.1053/j.gastro.2008.08.045 |title=American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease |year=2008 |last1=Kahrilas |first1=Peter J. |last2=Shaheen |first2=Nicholas J. |last3=Vaezi |first3=Michael F. |journal=Gastroenterology |volume=135 |issue=4 |pages=1383–1391, 1391.e1–5 |pmid=18789939 |last4=Hiltz |first4=SW |last5=Black |first5=E |last6=Modlin |first6=IM |last7=Johnson |first7=SP |last8=Allen |first8=J |last9=Brill |first9=JV}}</ref> In the United States, the [[Food and Drug Administration]] advises that no more than three 14-day treatment courses should be used in one year.<ref name="fda"/>

Revision as of 21:29, 20 August 2015

Proton-pump inhibitor
Drug class
General structure of a proton-pump inhibitor
Class identifiers
UseReduction of gastric acid production
ATC codeA02BC
Biological targetHydrogen potassium ATPase
Clinical data
Drugs.comDrug Classes
WebMDMedicineNet 
External links
MeSHD054328
Legal status
In Wikidata

Proton-pump inhibitors (PPIs) are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available. This group of drugs followed and largely superseded another group of medications with similar effects, but a different mode of action, called H2-receptor antagonists. These drugs are among the most widely sold drugs in the world, and are generally considered effective.[1]

Medical uses

These drugs are used in the treatment of many conditions, such as:

associated laryngopharyngeal reflux causing laryngitis[7] and chronic cough[8]


Specialty professional organizations recommend that people take the lowest effective dose possible to achieve the desired therapeutic result when using proton pump inhibitors to treat gastroesophageal reflux disease long-term.[11][12] In the United States, the Food and Drug Administration advises that no more than three 14-day treatment courses should be used in one year.[13]

The effectiveness of PPIs has not been demonstrated in every case, despite their widespread use for these conditions. For example, they do not change the length of Barrett's esophagus.[14] The most objective test to assess success of PPI therapy in patients with GERD is esophageal pH monitoring.

Adverse effects

In general, proton pump inhibitors are well tolerated, and the incidence of short-term adverse effects is relatively low. Long-term use of PPIs has been less studied than short-term use, and the lack of data makes it difficult to make definitive statements.[15] The range and occurrence of adverse effects are similar for all of the PPIs, though they have been reported more frequently with omeprazole. This may be due to its longer availability and, hence, clinical experience. Common adverse effects include: headache, nausea, diarrhea, abdominal pain, fatigue, and dizziness.[16]

Infrequent adverse effects include rash, itch, flatulence, constipation, anxiety, and depression. Also infrequently, PPI use may be associated with occurrence of myopathies, including the serious reaction rhabdomyolysis.[17]

Gastrointestinal

Gastric acid is important for breakdown of food and release of micronutrients, and some studies have shown possibilities for interference with absorption of iron, calcium, magnesium, and Vitamin B12. With regard to iron and vitamin B12 the data are weak and several confounding factors have been identified.[15] Reduction in calcium absorption has been especially concerning, which led the FDA to include a warning on PPI drug labels in 2010.[15] Interference with magnesium absorption is accepted as a class effect and people who have low levels of magnesium as a result of PPI therapy are switched to H2-receptor antagonist drugs.[15] High dose or long-term use of PPIs carries a possible increased risk of bone fractures.[13]

Some studies have shown a correlation between use of PPIs and Clostridium difficile infections. While the data are contradictory and controversial, the FDA had sufficient concern to include a warning about this adverse effect on the label of PPI drugs.[15] Concerns have also been raised about small intestinal bacterial overgrowth and spontaneous bacterial peritonitis in older people taking PPIs and in people with irritable bowel syndrome taking PPIs; both types of infections arise in these populations due to underlying conditions and it is not clear if this is a class effect of PPIs.[15]

Long-term use of PPIs is associated with the development of benign polyps from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. There is no association between PPI use and cancer[15] or pre-cancer.[18] There is concern that use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.[15]

Other

Associations have been shown between PPI use and an increased risk of pneumonia, particularly in the 30 days after starting therapy, where it was found to be 50% higher in community use.[19][20]

Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these are confounded by other factors.[21][22] PPIs are commonly used in cardiovascular patients for gastric protection when aspirin is given for its antiplatelet actions.[21][23] An interaction with the metabolism of the platelet inhibitor clopidogrel is known and this drug is also often used in patients with cardiac disease.[24][25]

One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit dimethylargininase, the enzyme that degrades asymmetric dimethylarginine (ADMA), resulting in higher ADMA levels and a decrease in bioavailable nitric oxide.[26]

Mechanism of action

The activation of PPIs
Micrograph of the gastric antrum showing G cell hyperplasia, a histomorphologic change seen with PPI use (H&E stain)

Proton pump inhibitors act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H+/K+ ATPase, or, more commonly, the gastric proton pump) of the gastric parietal cells.[2] The proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H+ ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.

Targeting the terminal step in acid production, as well as the irreversible nature of the inhibition, results in a class of drugs that are significantly more effective than H2 antagonists and reduce gastric acid secretion by up to 99%. ("Irreversibility" refers to the effect on a single copy of the proton pump; the effect on the overall human digestive system is reversible, as the proton pump protein is rendered non-functional and can be replaced with new copies.)

Decreasing the acid in the stomach will aid in the healing of duodenal ulcers, and reduces the pain from indigestion and heartburn, which can be exacerbated by stomach acid. Low amounts of stomach acid, also called hypochlorhydria, is the lack of sufficient hydrochloric acid, HCl, which is required for the digestion of proteins and the absorption of nutrients, in particular vitamin B12 and calcium.

The PPIs are given in an inactive form, which is neutrally charged (lipophilic) and readily crosses cell membranes into intracellular compartments (like the parietal cell canaliculus) with acidic environments. In an acid environment, the inactive drug is protonated and rearranges into its active form. As described above, the active form will covalently and irreversibly bind to the gastric proton pump, deactivating it.

Pharmacokinetics

The rate of omeprazole absorption is decreased by concomitant food intake. In addition, the absorption of lansoprazole and esomeprazole is decreased and delayed by food. It has been reported, however, that these pharmacokinetic effects have no significant impact on efficacy.[27][28]

PPIs have a rather short half-life in human plasma (60–90 min), but because they covalently bind to the pump, their half-life of inhibition of gastric acid secretion is substantially longer. The half-life at the site of action is estimated to be approximately 24 hours. Dissociation of the inhibitory complex is probably due to the effect of the endogenous antioxidant glutathione which leads to the release of omeprazole sulfide and reactivation of the enzyme.[29][30]

Examples

Clinically used proton pump inhibitors:

  • Omeprazole (OTC; brand names: Gasec, Losec, Prilosec, Zegerid, ocid, Lomac, Omepral, Omez, Omepep, UlcerGard, GastroGard, Altosec)
  • Lansoprazole (brand names: Prevacid, Zoton, Monolitum, Inhibitol, Levant, Lupizole)
  • Dexlansoprazole (brand name: Kapidex, Dexilant)
  • Esomeprazole (brand names: Nexium, Esotrex, esso)
  • Pantoprazole (brand names: Protonix, Somac, Pantoloc, Pantozol, Pantomed, Zurcal, Zentro, Pan, Controloc, Tecta)
  • Rabeprazole (brand names: AcipHex, Pariet, Erraz, Zechin, Rabecid, Nzole-D, Rabeloc, Razo, Superia. Dorafem: combination with domperidone[citation needed]).
  • Ilaprazole (not FDA approved as of October 2013; brand names: Noltec, Yili'an, Ilapro, Lupilla, Adiza)

History

See also: Discovery and development of proton pump inhibitors

PPIs were developed in the 1980s with omeprazole being launched in 1988. Most of these drugs are benzimidazole derivatives, related to omeprazole, but imidazopyridine derivatives such as tenatoprazole have also been developed.[31] Potassium-competitive inhibitors such as revaprazan reversibly block the potassium-binding site of the proton pump, acting more quickly, but are not available in most countries.[32]

References

  1. ^ The Health Strategies Consultancy LLC (March 2005). "Follow The Pill: Understanding the U.S. Commercial Pharmaceutical Supply Chain". The Kaiser Family Foundation.
  2. ^ a b Zajac, P; Holbrook, A; Super, ME; Vogt, M (March–April 2013). "An overview: Current clinical guidelines for the evaluation, diagnosis, treatment, and management of dyspepsia". Osteopathic Family Physician. 5 (2): 79–85. doi:10.1016/j.osfp.2012.10.005.
  3. ^ Wang WH, Huang JQ, Zheng GF, Xia HH, Wong WM, Liu XG; et al. (2007). "Effects of proton-pump inhibitors on functional dyspepsia: a meta-analysis of randomized placebo-controlled trials". Clin Gastroenterol Hepatol. 5 (2): 178–85, quiz 140. doi:10.1016/j.cgh.2006.09.012. PMID 17174612. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  4. ^ Sachar H, Vaidya K, Laine L (2014). "Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis". JAMA Intern Med. 174 (11): 1755–62. doi:10.1001/jamainternmed.2014.4056. PMC 4415726. PMID 25201154.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ Yuan Y, Ford AC, Khan KJ, Gisbert JP, Forman D, Leontiadis GI; et al. (2013). "Optimum duration of regimens for Helicobacter pylori eradication". Cochrane Database Syst Rev. 12: CD008337. doi:10.1002/14651858.CD008337.pub2. PMID 24338763. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ^ Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME (2013). "Short-term treatment with proton pump inhibitors, H2-receptor antagonists and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease". Cochrane Database Syst Rev. 5: CD002095. doi:10.1002/14651858.CD002095.pub5. PMID 23728637.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Qadeer MA, Phillips CO, Lopez AR, Steward DL, Noordzij JP, Wo JM; et al. (2006). "Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials". Am J Gastroenterol. 101 (11): 2646–54. doi:10.1111/j.1572-0241.2006.00844.x. PMID 17037995. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ Chang AB, Lasserson TJ, Kiljander TO, Connor FL, Gaffney JT, Garske LA (2006). "Systematic review and meta-analysis of randomised controlled trials of gastro-oesophageal reflux interventions for chronic cough associated with gastro-oesophageal reflux". BMJ. 332 (7532): 11–7. doi:10.1136/bmj.38677.559005.55. PMC 1325125. PMID 16330475.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Singh S, Garg SK, Singh PP, Iyer PG, El-Serag HB (2014). "Acid-suppressive medications and risk of oesophageal adenocarcinoma in patients with Barrett's oesophagus: a systematic review and meta-analysis". Gut. 63 (8): 1229–37. doi:10.1136/gutjnl-2013-305997. PMC 4199831. PMID 24221456.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  10. ^ Alhazzani W, Alenezi F, Jaeschke RZ, Moayyedi P, Cook DJ (2013). "Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis". Crit Care Med. 41 (3): 693–705. doi:10.1097/CCM.0b013e3182758734. PMID 23318494.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ "Five Things Physicians and Patients Should Question". American Gastroenterological Association.
  12. ^ Kahrilas, Peter J.; Shaheen, Nicholas J.; Vaezi, Michael F.; Hiltz, SW; Black, E; Modlin, IM; Johnson, SP; Allen, J; Brill, JV (2008). "American Gastroenterological Association Medical Position Statement on the Management of Gastroesophageal Reflux Disease". Gastroenterology. 135 (4): 1383–1391, 1391.e1–5. doi:10.1053/j.gastro.2008.08.045. PMID 18789939.
  13. ^ a b "Possible Increased Risk of Bone Fractures With Certain Antacid Drugs". U S Food and Drug Administration. 25 May 2010. Retrieved 26 May 2010.
  14. ^ Cooper, B. T.; Chapman, W.; Neumann, C. S.; Gearty, J. C. (2006). "Continuous treatment of Barrett's oesophagus patients with proton pump inhibitors up to 13 years: Observations on regression and cancer incidence". Alimentary Pharmacology and Therapeutics. 23 (6): 727–33. doi:10.1111/j.1365-2036.2006.02825.x. PMID 16556174.
  15. ^ a b c d e f g h Corleto VD et al. Proton pump inhibitor therapy and potential long-term harm. Curr Opin Endocrinol Diabetes Obes. 2014 Feb;21(1):3-8. doi:10.1097/MED.0000000000000031 PMID 24310148
  16. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3[page needed]
  17. ^ Clark, DW; Strandell J (June 2006). "Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors?". European Journal of Clinical Pharmacology. 62 (6): 473–479. doi:10.1007/s00228-006-0131-1. PMID 16758264.
  18. ^ Song, H; Zhu, J; Lu, D (2 December 2014). "Long-term proton pump inhibitor (PPI) use and the development of gastric pre-malignant lesions". The Cochrane database of systematic reviews. 12: CD010623. doi:10.1002/14651858.CD010623.pub2. PMID 25464111.
  19. ^ Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA (2015). "Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis". PLoS One. 10 (6): e0128004. doi:10.1371/journal.pone.0128004. PMC 4456166. PMID 26042842.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  20. ^ Eom, CS; Jeon, CY; Lim, JW; Cho, EG; Park, SM; Lee, KS (22 February 2011). "Use of acid-suppressive drugs and risk of pneumonia: a systematic review and meta-analysis". CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 183 (3): 310–9. PMID 21173070. {{cite journal}}: Missing pipe in: |journal= (help)
  21. ^ a b Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW; et al. (2013). "Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy". Eur Heart J. 34 (23): 1708–13, 1713a–1713b. doi:10.1093/eurheartj/eht042. PMID 23425521. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  22. ^ Melloni C, Washam JB, Jones WS, Halim SA, Hasselblad V, Mayer SB; et al. (2015). "Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review". Circ Cardiovasc Qual Outcomes. 8 (1): 47–55. doi:10.1161/CIRCOUTCOMES.114.001177. PMID 25587094. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  23. ^ Kwok CS, Nijjar RS, Loke YK (2011). "Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis". Drug Saf. 34 (1): 47–57. doi:10.2165/11584750-000000000-00000. PMID 21047145.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW (2013). "Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review". Heart. 99 (8): 520–7. doi:10.1136/heartjnl-2012-302371. PMID 22851683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Cardoso RN, Benjo AM, DiNicolantonio JJ, Garcia DC, Macedo FY, El-Hayek G; et al. (2015). "Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis". Open Heart. 2 (1): e000248. doi:10.1136/openhrt-2015-000248. PMC 4488889. PMID 26196021. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  26. ^ Schepers E, Speer T, Bode-Böger SM, Fliser D, Kielstein JT (2014). "Dimethylarginines ADMA and SDMA: the real water-soluble small toxins?". Seminars in Nephrology. 34 (2): 97–105. doi:10.1016/j.semnephrol.2014.02.003. PMID 24780466. Retrieved 2015-06-11. It also seems to be the pathophysiological link between the use of proton pump inhibitors and increased cardiovascular event rate because these drugs bind and inhibit DDAH, the enzyme that degrades ADMA, which results in higher ADMA levels and a decrease in bioavailable NO. {{cite journal}}: line feed character in |quote= at position 150 (help)
  27. ^ AstraZeneca Pty Ltd. Nexium (Australian approved prescribing information). North Ryde: AstraZeneca; 2005.
  28. ^ Wyeth Australia Pty Ltd. Zoton (Australian approved prescribing information). Baulkham Hills: Wyeth; 2004.
  29. ^ Shin, Jai Moo; Munson, Keith; Vagin, Olga; Sachs, George (2008). "The gastric HK-ATPase: Structure, function, and inhibition". Pflügers Archiv - European Journal of Physiology. 457 (3): 609–22. doi:10.1007/s00424-008-0495-4. PMC 3079481. PMID 18536934.
  30. ^ Carlsson, E.; Lindberg, P. (2002). "Two of a kind". Chemistry in Britain. 38 (5): 42–5.
  31. ^ Sachs, G.; Shin, J. M.; Howden, C.W. (2006). "Review article: The clinical pharmacology of proton pump inhibitors". Alimentary Pharmacology and Therapeutics. 23: 2–8. doi:10.1111/j.1365-2036.2006.02943.x. PMID 16700898.
  32. ^ Kim HK, Park SH, Cheung DY, Cho YS, Kim JI, Kim SS; et al. (2010). "Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects". J Gastroenterol Hepatol. 25 (10): 1618–25. doi:10.1111/j.1440-1746.2010.06408.x. PMID 20880169. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

External links

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