امپرازول

از ویکی‌پدیا، دانشنامهٔ آزاد
پرش به: ناوبری، جستجو
فارسی English
امپرازول
امپرازول
امپرازول
نام آیوپاک (RS)-۶-methoxy-۲-((۴-methoxy-۳٬۵-dimethylpyridin-۲-yl) methylsulfinyl)-۱H-benzo[d]imidazole
شمارهٔ CAS ۷۳۵۹۰-۵۸-۶
فرمول شیمیایی C17H19N3O3S
گروه دارویی مشتقات بنزوایمیدازول
طبقه بندی درمانی شیمیایی تشریحی ضد زخم پپتیک
PubChem ۴۵۹۴
جرم مولی (گرم بر مول) ۳۴۵٫۴ گرم در مول
نیمه عمر یک ساعت (ویکی انگلیش: ۱ تا ۱٫۲ ساعت)
متابولیسم کبدی، بوسیله آنزیمهای CYP2C۱۹ و CYP3A۴
دفع ۸۰ درصد کلیوی (از راه ادرار) ، ۲۰ درصد از راه مدفوع
زیست فراهمی ۳۵ تا ۷۶ درصد
مکانیسم اثر از طریق مهار سیستم آنزیمی H+/K+/ATPase در سطح ترشحی سلول پاریتال معده، باعث مهار ترشح اسید معده می‌شود.
عوارض جانبی ترمور، توهم، بی خوابی، طپش قلب، راش، تهوع، اسهال، استفراغ، بی اشتهایی، نفریت بینابینی، هماچوری، آنمی.
موارد مصرف درمان کوتاه مدت زخم دئودنوم، ازوفاژیت شدید، ریفلاکس گاستروازوفاژیال، سندرم زولینگر-الیسون، زخم معده
راه استعمال خوراکی
اشکال دارویی کپسول ۲۰ میلی گرمی، محلول ۲۰ میلی گرم در ساشه
مصرف در بارداری گروه C

امپرازول (به انگلیسی: Omeperazole)

نامهای تجارتی : Losec - Lorsec -Exiprazol - Merazole - Omezole - Pilozec

رده درمانی: ضد زخم پپتیک .

رده فارماکولوژیک: مشتقات بنزایمیدازول

اشکال دارویی: کپسول ۲۰ میلی گرمی، ساشه ۲۰ میلی گرمی برای تهیه سوسپانسیون (محلول)

مکانیسم اثر[ویرایش]

امپرازول یک بلوک کننده پمپ پروتون بوده واز طریق مهار سیستم آنزیمی H+/K+/ATPase در سطح ترشحی سلول پاریتال معده، باعث مهار ترشح اسید معده می‌شود.

  • نکته از فارماکولوژی کاتزونگ : امپرازول سردسته مهار کننده‌های پمپ پروتون می‌باشد که به صورت برگشت ناپذیر عملکرد پمپ H+/K+/ATPase را، مهار می‌کند.
  • نکته دیگر : اثر امپرازول ظرف یک ساعت شروع می‌شود و ظرف دو ساعت به اوج اثر خود می‌رسد و مدت اثر آن تا ۷۲ ساعت خواهد بود.

موارد مصرف[ویرایش]

طریقه مصرف[ویرایش]

  • جهت درمان کوتاه مدت زخم دئودنوم:

دربالغین : ۲۰ میلی گرم (یک کپسول)، از راه خوراکی، یک بار در روز تجویز می‌شود . درمان باید به مدت چهار هفته ادامه یابد. بعضی از بیماران نیاز به یک دوره درمانی چهار هفته‌ای دیگر نیز دارند.

  • جهت درمان ازوفاژیت اروزیو شدید و درمان ریفلاکس شدید گاستروازوفاژیال:

دربالغین : ۲۰ میلی گرم (یک کپسول)، از راه خوراکی، یک بار در روز تجویز می‌شود و درمان ۴ تا ۸ هفته ادامه می‌یابد.

  • جهت درمان سندرم زولینگر-الیسون:

در بالغین : روزانه ۶۰ تا ۷۰ میلی گرم، از راه خوراکی و در دوزهای منقسم تجویز می‌شود. بعضی بیماران ممکن است روزانه تا ۱۲۰ میلی گرم از راه خوراکی در دوزهای منقسم نیاز داشته باشند.

  • جهت درمان زخم معده:

در بالغین : روزانه ۴۰ میلی گرم از راه خوراکی، به مدت ۴ تا ۸ هفته تجویز می‌شود.

موارد منع مصرف[ویرایش]

  • حساسیت مفرط نسبت به دارو و ترکیبات آن.

تداخلات دارویی[ویرایش]

عوارض جانبی[ویرایش]

جستارهای وابسته[ویرایش]

منابع[ویرایش]

  • راهنمای کاربرد داروهای ژنریک ایران، دکتر رامین خدّام، چاپ هفتم،۱۳۸۸، صفحات:۶۹۲و ۶۹۳
  • داروهای ژنریک ایران و دسته بندی داروها، دکتر مصطفی صابر، چاپ هفتم، صفحه :۱۹۷
  • فارماکولوژی کاتزونگ ترور، فصل ۵۶، داروهای مورد استفاده در بیماری‌های گوارشی (مکانیسم اثر)
  • ویکی انگلیش (تکمیل اطلاعات جدول)
Omeprazole
Omeprazole.svg
Omeprazole 3d structure.png
Systematic (IUPAC) name
6-methoxy-2-((4-methoxy-3,5-dimethylpyridin-2-yl) methylsulfinyl)-1H-benzo[d]imidazole
Clinical data
Licence data US FDA:link
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) POM (UK) OTC (US)
Routes Oral, IV
Pharmacokinetic data
Bioavailability 35–76%[1][2]
Protein binding 95%
Metabolism Hepatic (CYP2C19, CYP3A4)
Half-life 1–1.2 hours
Excretion 80% Renal
20% Faecal
Identifiers
CAS number 73590-58-6 YesY
ATC code A02BC01
PubChem CID 4594
DrugBank DB00338
ChemSpider 4433 YesY
UNII KG60484QX9 YesY
KEGG D00455 YesY
ChEBI CHEBI:7772 YesY
ChEMBL CHEMBL1503 YesY
PDB ligand ID 1C6 (PDBe, RCSB PDB)
Chemical data
Formula C17H19N3O3S 
Mol. mass 345.4 g/mol
 YesY (what is this?)  (verify)

Omeprazole (INN) /ˈmɛprəzl/ (Prilosec and generics such as losepine) is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease, gastroesophageal reflux disease, laryngopharyngeal reflux, and Zollinger–Ellison syndrome. Omeprazole is one of the most widely prescribed drugs internationally and is available over-the-counter in some countries.

Medical uses

Omeprazole is used to treat gastroesophageal reflux disease, gastric and duodenal ulceration, and gastritis.

H. pylori-related ulcers

Omeprazole is combined with the antibiotics clarithromycin and amoxicillin (or metronidazole in penicillin-hypersensitive patients) in the 7–14 day eradication triple therapy for Helicobacter pylori. Infection by H. pylori is the causative factor in the majority of peptic ulcers.[3]

Adverse effects

Some of the most frequent side effects of omeprazole (experienced by over 1% of those taking the drug) are headache, diarrhea, abdominal pain, nausea, dizziness, trouble awakening, and sleep deprivation, although in clinical trials the incidence of these effects with omeprazole was mostly comparable to that found with placebo.[4] Other side effects may include iron and vitamin B12 deficiency, although very little evidence supports this.[5]

Proton pump inhibitors may be associated with a greater risk of osteoporosis-related fractures[6][7] and Clostridium difficile-associated diarrhea.[5][8] By suppressing acid-mediated breakdown of proteins, antacid preparations (such as omeprazole) lead to an elevated risk of developing food and drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitisation occurs. It is unclear whether this risk occurs with only long-term use or with short-term use, as well.[9] Patients are frequently administered the drugs in intensive care as a protective measure against ulcers, but this use is also associated with a 30% increase in occurrence of pneumonia.[5][10] The risk of community-acquired pneumonia may also be higher in people taking PPIs.[5]

Since their introduction, proton pump inhibitors (especially omeprazole) have been associated with several cases of acute tubulointerstitial nephritis, an inflammation of the kidneys that often occurs as an adverse drug reaction.[5][11][12]

In 2011, the FDA warned that prolonged use of PPIs could cause low serum magnesium levels.[13] They recommended that prior to initiating long term use, clinicians should consider obtaining baseline magnesium levels, particularly in patients already taking diuretics or digoxin.[13]

PPI use has also been associated with fundic gland polyps,[14] whereas other authors have demonstrated a lack of association [15][16]

The following adverse reactions have been identified during postapproval use of Prilosec Delayed-Release Capsules.[17] Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure.

Systemic: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, fever, pain, fatigue, malaise, hair loss

Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema

Endocrine: Gynecomastia

Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with Prilosec. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors.

Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin]

Metabolism and nutritional disorders: Hypoglycemia, hypomagnesemia, hyponatremia, weight gain

Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture

Nervous system/psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo

Respiratory: Epistaxis, pharyngeal pain

Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis

Special senses: Tinnitus, taste perversion

Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision

Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain

Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis

Interactions

Omeprazole is an inhibitor of the enzymes CYP2C19 and CYP3A4,[18] and will therefore interact with drugs that depend on these enzymes for their metabolism, such as diazepam and alprazolam. Almost all benzodiazepines are metabolised via the CYP3A4 and CYP2D6 pathway and inhibition of these enzymes will result in a higher AUC (bloodlevels of the drug/compound). Other drugs that are dependant on CYP3A4 for their metabolism are escitalopram, warfarin, oxycodone, tramadol, oxymorphone, etc. The concentrations of these drugs may increase if they are used concomitantly with omeprazole.[19] Clopidogrel (Plavix) is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form; inhibition of CYP2C19 blocks the activation of clopidogrel, thus reducing its effects and potentially increasing the risk of stroke or heart attack in people taking clopidogrel to prevent these events.[20][21] Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.[22]

Drugs that depend on an acidic stomach environment (such as ketoconazole or atazanavir) will be poorly absorbed, whereas acid-labile antibiotics (such as erythromycin which is a very strong CYP3A4 inhibitor) will be absorbed to a greater extent than normal due to the more alkaline environment of the stomach.[19]

St. John's wort, an MAO-inhibitor (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.[23]

Omeprazole during breastfeeding

To the moment, no clinical trials have deeply evaluated the potential consequences of the use of omeprazole in breastfeeding. However, the pharmacokietics of omeprazole molecule strongly suggest the safety of omeprazole use during breastfeeding:

  • Omeprazole has a high plasma protein binding rate (95%),[24] indicating that little amount of drug is transferred to the milk duct during breast milk formation.
  • Omeprazole needs to be administrated in an enteric-coated formulation due to its rapid degradation in the acidic conditions of the stomach. This suggests that free molecules of omeprazole uptaken by the rapidly degraded in the acidic conditions of the stomach, that most of the molecules ingested by the infant are degraded before being absorbed.

The safety of omeprazole use in breastfeeding deduced from pharmacokinetic characteristics of the omeprazole molecule agree with a case report in which the presence of omeprazole in breast milk was analysed over 4 hours after omeprazole uptake.[25] The study revealed that the peak omeprazole concentration in breast milk (that occurred 3h after omeprazole ingestion) was 7% of peak serum concentration, which corresponds to less than 1% of the usual adult dose (200 to 400 ug of omeprazole/Kg of body weight) for a 5 kg infant consuming 200 ml of breast milk per day.

Mechanism of action

Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses gastric acid secretion by specific inhibition of the hydrogen–potassium adenosinetriphosphatase (H +, K +-ATPase) enzyme system found at the secretory surface of parietal cells. It inhibits the final transport of hydrogen ions (via exchange with potassium ions) into the gastric lumen. Since the H +, K +-ATPase enzyme system is regarded as the acid (proton) pump of the gastric mucosa, omeprazole is known as a gastric acid pump inhibitor. Its inhibitory effect is dose-related. Omeprazole inhibits both basal and stimulated acid secretion irrespective of the stimulus.[26]

Pharmacokinetics

The absorption of omeprazole takes place in the small intestine and is usually completed within 3–6 hr. The systemic bioavailability of omeprazole after repeated dose is about 60%.

Omeprazole, as well as other proton pump inhibitors, are only effective on active H+/K+ ATPase pumps. These pumps are stimulated in the presence of food to aid in digestion. For this reason, patients should be advised to take omeprazole with a glass of water on an empty stomach about 30–60 minutes before a meal to allow the drug to reach peak levels once food is ingested.[27][28] Additionally, most sources recommend that after taking omeprazole at least 30 minutes should be allowed to elapse before eating[29][30] (at least 60 minutes for immediate-release omeprazole plus sodium bicarbonate products, such as Zegerid),[31] though some sources say that with delayed-release forms of omeprazole it is not necessary to wait before eating after taking the medication.[32] Plasma protein binding is about 95%.

Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver. Identified metabolites are the sulfone, the sulfide and hydroxy-omeprazole, which exert no significant effect on acid secretion. About 80% of an orally given dose is excreted as metabolites in the urine and the remainder is found in the feces, primarily originating from bile secretion.

Measurement in body fluids

Omeprazole may be quantified in plasma or serum to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients. Plasma omeprazole concentrations are usually in a range of 0.2–1.2 mg/l in persons receiving the drug therapeutically via the oral route and 1–6 mg/l in victims of acute overdosage. Enantiomeric chromatographic methods are available to distinguish esomeprazole from racemic omeprazole.[33][34]

Chemistry

(S)- and (R)-enantiomers of omeprazole, a racemate (1:1 mixture of both enantiomers)

Omeprazole contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist as either the (S)- or (R)-enantiomers. Omeprazole is a racemate, an equal mixture of the two. In the acidic conditions of the canaliculi of parietal cells, both enantiomers are converted to achiral products (sulfenic acid and sulfenamide configurations) which react with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid.

Omeprazol rearrangement in the body

AstraZeneca has also developed esomeprazole (Nexium) which is a eutomer, purely the (S)-enantiomer, rather than a racemate like omeprazole.

Omeprazole undergoes a chiral shift in vivo which converts the inactive (R)-enantiomer to the active (S)-enantiomer, doubling the concentration of the active form.[35] This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers". The proportion of the poor metabolizer phenotype varies widely between populations, from 2.0–2.5% in African-Americans and white Americans to >20% in Asians; several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status.[36]

History

Omeprazole was first marketed in the United States in 1989 by Astra AB, now AstraZeneca, under the brand names Losec and Prilosec. An over-the-counter brand, Prilosec OTC, is available in the US for treatment of heartburn. It is now also available from generic manufacturers under various brand names.

In 1990, at the request of the U.S. Food and Drug Administration, the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide).[37] The new name has led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.[37]

AstraZeneca markets omeprazole as Losec, Antra, Gastroloc, Mopral, Omepral, and Prilosec. Omeprazole is marketed as Zegerid by Santarus, Prilosec OTC by Procter & Gamble and Zegerid OTC by Schering-Plough and as Segazole by Star Laboratories in Pakistan.[38][39] In the Philippines, Ajanta Pharma markets omeprazole under the brand name Zegacid. Dr. Reddy's Laboratories markets it as Omez in India, Russia, Romania, and South Africa. In Bangladesh, Healthcare Pharmaceuticals Ltd. marketed omeprazole under the brand name Opal, Eskayef Bangladesh Limited marketed it under the brand name Losectil, Acme Laboratories Limited marketed it under the brand name PPI, and Apex Pharma also markets it under the brand name Aspra. It is also available under the brand name Rome 20 marketed by Rephco Pharmaceuticals Ltd. In Argentina, it is made by Laboratorios Bagó S.A. and available there and in Ecuador as Ulcozol.[40] In Indonesia, Darya-Varia Laboratories marketed omeprazole as Ozid. In Brazil, omeprazole is produced by Multilab under the name Lozeprel. In Spain, it is produced by Cantabria Pharma S.L. under the name emeprotón. In Bangladesh, In 1999, antiulcerants were the leading class of therapeutic drugs, with $15.6 billion in global sales. Of that, Prilosec accounted for $5.91 billion, making it the best-selling drug on the market.[41]

Although Prilosec's U.S. patent expired in April 2001, AstraZeneca was able to delay the introduction of generic versions through lawsuits and peripheral patent claims. It introduced Nexium as a patented replacement drug.[42]

Dosage forms

Package of Losec (Omeprazole) 20 mg, purchased in Hong Kong
Omeprazole 10 mg, From U.K.

Omeprazole is available as tablets and capsules (containing omeprazole or omeprazole magnesium) in strengths of 10, 20, 40, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS).

It is also available for use in injectable form (IV) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10-ml clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg, equivalent to 40 mg of omeprazole.

Multiple unit pellet system

Omeprazole tablets manufactured by AstraZeneca (notably Losec/Prilosec) are formulated as a "Multiple Unit Pellet System" (MUPS). Essentially, the tablet consists of extremely small enteric-coated granules (pellets) of the omeprazole formulation inside an outer shell. When the tablet is immersed in an aqueous solution, as happens when the tablet reaches the stomach, water enters the tablet by osmosis. The contents swell from water absorption causing the shell to burst, releasing the enteric-coated granules. For most patients, the multiple-unit pellet system is of no advantage over conventional enteric-coated preparations. Patients for which the formulation is of benefit include those requiring nasogastric tube feeding and those with difficulty swallowing (dysphagia) because the tablets can be mixed with water ahead of time, releasing the granules into a slurry form, which is easier to pass down the feeding tube or to swallow than the pill.[citation needed] The granules are manufactured in a fluid air bed system. Sugar spheres in suspension are sequentially sprayed with aqueous suspensions of omeprazole, a protective layer, an enteric coating and an outer layer to reduce granule aggregation. The granules are mixed with other excipients and compressed into tablets. Finally, the tablets are film-coated to improve the stability and appearance of the preparation.

Immediate release formulation

In June 2004 the FDA approved an immediate release preparation of omeprazole and sodium bicarbonate that does not require an enteric coating. This preparation employs sodium bicarbonate as a buffer to protect omeprazole from gastric acid degradation. This allows for the production of chewable tablets. This combination preparation is marketed in the United States by Santarus under the brand name Zegerid. Zegerid is marketed as capsules, chewable tablets, and powder for oral suspension. Zegerid is most useful for those patients who suffer from nocturnal acid breakthrough (NAB) or those patients who desire immediate relief. In India it is marketed by Dr. Reddy's Laboratories as powder formulation with the brand name OMEZ-INSTA (FGP). It is reported to have additional benefits with patients suffering from alcoholic gastritis and life-style associated gastritis.

See also

References

  1. ^ Prilosec Prescribing Information. AstraZeneca Pharmaceuticals.
  2. ^ Vaz-Da-Silva, M; Loureiro, AI; Nunes, T; Maia, J; Tavares, S; Falcão, A; Silveira, P; Almeida, L; Soares-Da-Silva, P (2005). "Bioavailability and bioequivalence of two enteric-coated formulations of omeprazole in fasting and fed conditions". Clin Drug Investig 25 (6): 391–9. doi:10.2165/00044011-200525060-00004. PMID 17532679. 
  3. ^ "What Causes Ulcers?". MedicineNet. 9 October 2009.
  4. ^ "Prilosec Side Effects & Drug Interactions". RxList.com. 2007. Retrieved 2007-06-16. 
  5. ^ a b c d e Madanick RD (Jan 2011). "Proton pump inhibitor side effects and drug interactions: much ado about nothing?". Cleve Clin J Med 78 (1): 39–49. doi:10.3949/ccjm.77a.10087. PMID 21199906. 
  6. ^ Yang YX, Lewis JD, Epstein S, Metz DC (2006). "Long-term proton pump inhibitor therapy and risk of hip fracture". JAMA 296 (24): 2947–2953. doi:10.1001/jama.296.24.2947. PMID 17190895. 
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  8. ^ "Proton pump inhibitors and Clostridium difficile". Bandolier. 2003. Retrieved 2007-07-13. 
  9. ^ Pali-Schöll I, Jensen-Jarolim E; Jensen-Jarolim, E. (April 2011). "Anti-acid medication as a risk factor for food allergy". Allergy 66 (4): 469–77. doi:10.1111/j.1398-9995.2010.02511.x. PMID 21121928. 
  10. ^ Herzig SJ, Howell MD, Ngo LH, Marcantonio ER (May 2009). "Acid-suppressive medication use and the risk for hospital-acquired pneumonia". JAMA 301 (20): 2120–2128. doi:10.1001/jama.2009.722. PMID 19470989. 
  11. ^ Tubulointerstitial Nephritis at Merck Manual of Diagnosis and Therapy Professional Edition
  12. ^ Ray S, Delaney M, Muller AF (2010). "Proton pump inhibitors and acute interstitial nephritis". BMJ 341: c4412–c4412. doi:10.1136/bmj.c4412. PMID 20861097. 
  13. ^ a b http://www.fda.gov/drugs/drugsafety/ucm245011.htm
  14. ^ Thomson AB, Sauve MD, Kassam N, Kamitakahara H (May 2010). "Safety of the long-term use of proton pump inhibitors". World J Gastroenterol 16 (19): 2323–30. doi:10.3748/wjg.v16.i19.2323. PMC 2874135. PMID 20480516. 
  15. ^ Vieth M, Stolte M. Fundic gland polyps are not induced by proton pump inhibitor therapy. Am J Clin Pathol 2001; 116: 716-720
  16. ^ Fiocca R, Mastracci L, Attwood SE, Ell C, Galmiche J-P, Hatleback J, Bärthel A, Långström G, Lind T, Lundell L for the LOTUS trial collaborators. Gastric exocrine and endocrine cell morphology under prolonged acid inhibition therapy: results of a 5-year follow-up: results of a 5-tear follow-up in the LOTUS trial. Aliment Pharmacol Ther 2012; 36:959-971
  17. ^ Drugs.com - "Prilosec"
  18. ^ Inhibition of CYP2C19 and CYP3A4 by omepra... [Drug Metab Dispos. 2013] - PubMed - NCBI. Ncbi.nlm.nih.gov. PMID 23620487. 
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