Chemistry:Pantoprazole

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Short description: Stomach acid suppressing medication
Pantoprazole
Pantoprazole.svg
Clinical data
Trade namesProtonix, others[1]
AHFS/Drugs.comMonograph
MedlinePlusa601246
License data
Pregnancy
category
Routes of
administration		By mouth and intravenous
Drug classproton pump inhibitor
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) / S2
  • UK: POM (Prescription only) [3]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability77%
Protein binding98%
MetabolismLiver (CYP2C19, CYP3A4)
Elimination half-life1-2 hours
ExcretionUrine, feces
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC16H15F2N3O4S
Molar mass383.37 g·mol−1
3D model (JSmol)
ChiralityRacemic
  (verify)

Pantoprazole, sold under the brand name Protonix, among others, is a proton pump inhibitor used for the treatment of stomach ulcers, short-term treatment of erosive esophagitis due to gastroesophageal reflux disease (GERD), maintenance of healing of erosive esophagitis, and pathological hypersecretory conditions including Zollinger–Ellison syndrome.[4][5] It may also be used along with other medications to eliminate Helicobacter pylori.[6] Effectiveness is similar to other proton pump inhibitors (PPIs).[7] It is available by mouth and by injection into a vein.[4]

Common side effects include headaches, diarrhea, vomiting, abdominal pain, and joint pain.[4][5] More serious side effects may include severe allergic reactions, a type of chronic inflammation known as atrophic gastritis, Clostridium difficile colitis, low magnesium, and vitamin B12 deficiency.[4] Use in pregnancy appears to be safe.[4] Pantoprazole is a proton pump inhibitor that decreases gastric acid secretion.[4] It works by inactivating (H+/K+)-ATPase function in the stomach.[8][4]

Study of pantoprazole began in 1985, and it came into medical use in Germany in 1994.[9] It is available as a generic medication.[4][10] In 2021, it was the nineteenth most commonly prescribed medication in the United States, with more than 27 million prescriptions.[11][12]

Medical uses

Pantoprazole is used for short-term treatment of erosion and ulceration of the esophagus for adults and children five years of age and older caused by gastroesophageal reflux disease.[13] It can be used as a maintenance therapy for long-term use after initial response is obtained, but there have not been any controlled studies about the use of pantoprazole past a duration of 12 months.[13] Pantoprazole may also be used in combination with antibiotics to treat ulcers caused by Helicobacter pylori.[14] It can also be used for long-term treatment of Zollinger-Ellison syndrome.[13] It may be used to prevent gastric ulcers in those taking NSAIDs.[6]

For improved efficacy of pantoprazole, the oral tablet formulation is taken half an hour prior to ingestion of food.[5] In the hospital, intravenous administration is indicated when patients are unable to take the medication by mouth.[15]

Children

Pantoprazole is only indicated for the short-term treatment of erosive esophagitis in children ages seven and older; and the safety and effectiveness of pantoprazole have only been established in the treatment of erosive esophagitis in children.[13]

Elderly

The incidence of adverse effects occurring in people aged 65 years and older was similar to that in people aged 65 years and less.[13]

Pregnancy

In reproductive studies using doses largely greater than the recommended doses performed on rats and rabbits, there was no evident harm on the development of the baby.[13][2]

Breast feeding

Pantoprazole has been found to pass through the breast milk. Additionally, in rodent cancer studies, pantoprazole has been shown to potentially cause tumor growth. The clinical relevance of the finding is unknown, but risks and benefits are recommended for consideration in determining the use of therapy for the mother and child.[13][2]

Adverse effects

  • Infection: Stomach acid plays a role in killing ingested bacteria. Use of pantoprazole may increase the chance of developing infections such as pneumonia, particularly in hospitalized patients.[16]

Common

Rare

Long-term use

  • Osteoporosis and bone fracture have been observed in people on high-dose and/or long-term (over one year) prescription proton pump inhibitors.[19]
  • Hypomagnesia has been observed in people on medications like pantoprazole when taken for longer periods of time (generally one year or more, although cases have been reported with regimens as short as three months).[20]
  • Deficiencies such as vitamin B12 deficiency, iron deficiency, and calcium deficiency may be seen with long term use.[5] Vitamin B12 deficiency is due to the change in the acidic environment within the stomach with the use of pantoprazole which prevents peptidases from being activated.[21] This prevents the cleaving of R-factor from vitamin B12 and prevents its absorption.[21]
  • Rebound hypergastrinemia may be seen when stopping the medication after long term use.[22][21]

Discontinuation

In people taking PPIs for longer than six months, a dose taper should be considered prior to discontinuation. For those on a moderate to high dose, this can be done by 50 percent every week until on the lowest dose. After a week it can then be stopped.[23]

Interactions

Due to its effect of reducing stomach acidity, use of pantoprazole can affect absorption of drugs that are pH-sensitive, such as ampicillin esters, ketoconazole, atazanavir, iron salts, amphetamine and mycophenolate mofetil.[13][5] Additional medications that are affected include bisphosphonate derivatives, fluconazole, clopidogrel, and methotrexate.[5]

Pharmacology

Wyeth pantoprazole 20 mg

The mechanism of action of pantoprazole is to inhibit the final step in gastric acid production.[13] In the gastric parietal cell of the stomach, pantoprazole covalently binds to the H+/K+ ATP pump to inhibit gastric acid and basal acid secretion.[13] The covalent binding prevents acid secretion for up to 24 hours and longer.[13]

Pantoprazole is metabolized in the liver by the cytochrome P450 system.[24] Metabolism mainly consists of demethylation by CYP2C19 followed by sulfation. Another metabolic pathway is oxidation by CYP3A4. Pantoprazole metabolites are not thought to have any pharmacological significance. It is usually given with a prokinetic drug because of inactivity in the acidic environment of the stomach. Pantoprazole binds irreversibly to H+K+ATPase (proton pumps) to suppress the secretion of acid. Due to irreversible binding of the pumps, new pumps have to be made before acid production can be resumed.[8] The drug's plasma half-life is about two hours.[25] After administration, the time for the drug to reach peak plasma concentrations is 2 to 3 hours.[15] The percentage of the drug that is protein bound is 98%.[15]

In veterinary medicine, pantoprazole appears to be safe to use in several large animal species.[26] The pharmacokinetics of pantoprazole have been explored in several veterinary species, including calves, alpacas and foals with half lives reported as 2.81, 0.47, and 1.43 hours, respectively.[27][28][29] Pantoprazole appears to be eliminated more quickly in goats when compared to calves, with goats having an elimination half-life of less than one hour.[30]

History

Pantoprazole was discovered by scientists at Byk Gulden, a subsidiary of Altana; the drug discovery program started in 1980, producing pantoprazole in 1985. The compound was actually created by chemists working to scale up a different chemical that had been chosen as a development candidate.[31]:117,129 Byk Gulden partnered with Smith Kline & French in 1984.[31]:124 The compound's development names were BY1029 and SK&F96022.[31]:123 By 1986 the companies had created the sodium salt, pantoprazole sodium sesquihydrate, and decided to develop it as it was more soluble and stable, and was more compatible with other ingredients used in the formulation.[31]:130 It was first marketed in Germany in 1994.[31]:130 Wyeth licensed the US patent from Altana,[32] and obtained marketing approval from the US FDA in 2000 under the trade name Protonix.[33][34]

In 2004, worldwide sales of the drug were $3.65 billion, about half of which were in the US.[32]

In 2007, Altana's drug business was acquired by Nycomed.[35] Nycomed was in turn acquired by Takeda in 2011[36] and Wyeth was acquired by Pfizer in 2009.[37]

The patent protecting the drug was set to expire in 2010, but Teva Pharmaceuticals filed an Abbreviated New Drug Application (ANDA) in 2007, and Wyeth and Nycomed sued Teva for patent infringement, but Teva decided to launch its generic drug "at risk" that year, before the patent had been invalidated.[38][39] Wyeth launched an authorized generic in 2008.[35] Pfizer and Takeda's patent exclusivity expired in 2010, and an administrative exclusivity they had for pediatric use expired in January 2011, and full generic competition began.[40] The litigation between Teva and Pfizer/Takeda was settled in 2013, with Teva paying the patent holders $2.15 billion in damages for its early launch.[41]

Society and culture

(As of 2017), the drug was marketed under many brands worldwide, including as a combination drug with domperidone, a combination with itopride, in combination with both clarithromycin and amoxicillin, in combination with levosulpiride, and in combination with naproxen.[1]

List of brand names

(As of 2017), it was marketed under many brands worldwide, including: Acernix, Aciban, Acida, Acido-X, Acidrol, Acidwell, Acilib, Acilibre, Acillect, Acipan, Acrid, Alapanzol, Amphoter, Anagastra, Anesteloc, Antaxid, Antopral, Anulacid, Anxel, Apazol, Appryo, Aptizole, Apton, Armcid, Asoprazole, Aspan, Aurizol-P, Awamed, Azatol, Biotop V, Brandocare, Branzol, Buffet, Buscopan Reflusso, Caprol, Ciprazol, Citrel, Clessol, Comenazol, Conoran, Contix, Contracid, Contraflux, Contro-Cap, Controloc, Cool Pan, Delpanto EC, Digene Total, Digespan, Dosanloc, Empaflun, Eracid, Erprazol, Esopan, Eupantol, Exopan, Extream, Extreme, F-Pan, Farmazol, Fenix, Fexmor, Fu Shi Tan, Fulpan, Fupan, Gastblok, Gastenz, Gastrazol-L, Gastriwin, Gastrolan, Gastroloc, Gastromax, Gastronorm, Gastroprozal, Gastrostad, Gastrowell, Gastrozol, Gerdamegh, Gerprazol, Gesoflux, Gondea, Gopan, Hansazol, Hasanloc, Helix, Iboprot, Inipant, Inipepsia, Inipomp, IPP, Ippracid, Ipraalox, Kaiji, Kairol, Letopra, Loxanto, Luoxu, Lupipan, Maalox, Mag, Manez, Marozel, Monpan, Nelgast, Nexpan, Noacid, Noacid, Nolpaza, Nolpaza, Normogastrol, Noxadif, Ntap, Nuosen, Nupenta, Oritop, Osipan, Ozepran, Ozpan, Ozzion, P-20, P-40, P-Bit, P-OD, P-PPI, P-Zole, Pacid, Paciddia, Palio, Palmy, Pamel, Pamtrazol, Pamyl, Pan, Panbloc, Pancleus, Pancrazio, Pandev, Pane, Panfast, Pangest, Panglen, Panlan, Panlisu, Panloc, Panloz, Panmeilu, Panocer, Panogastin, Panopaz, Panor, Panoral, Panore, Panpot, Panpra, Panprabene, Panprax, Panprazol, Panprazox, Panpro, Panproton, Panpure, Panrazol, Panrazole, Panrbe, Panref, Pansa, Pansec, Panso, Pantac, Pantacid, Pantact, Pantagi, Pantakind, Pantaltius, Pantap, Pantasur, Pantaz, Pantazol, Pantecta, Pantex, Pantexel, Pantezol, Panthec, Panthron, Pantid, Pantin, Pantip, Pantium, Panto, Panto-Denk, Panto-Gas, Pantobex, Pantoc, Pantocal, Pantocar, Pantocare, Pantocas, Pantocer, Pantocid, Pantocim, Pantocom, Pantocure, Pantodac, Pantodar, Pantofin, Pantofir, Pantogastrix, Pantogen, Pantogerolan, PantoJenson, Pantokem, Pantokool, Pantolax, Pantoline, Pantoloc, Pantolok, Pantolup, Pantomax, Pantomed, Pantometylentina, Pantomyl, Pantonis, Pantonix, Pantop, Pantopacid, Pantopan, Pantopaz, Pantopep, Pantopi, Pantopra-Q, Pantopraz, Pantoprazal, Pantoprazol, Pantoprazole, Pantoprazolo, Pantoprazolum, Pantoprem, Pantoprix, Pantoprol, Pantopump, Pantor, Pantorc, Pantoren, Pantorica, Pantosal, Pantosan, Pantosec, Pantosid, Pantostad, Pantotab, Pantotis, Pantover, Pantoz, Pantozim, Pantozol, Pantozole, Pantpas, Pantra, Pantrol, Pantroz, Pantul, Pantune, Pantus, Panveda, Panvell, Panz, Panzat, Panzel, Panzilan, Panzilan, Panzol, Panzole, Panzor, Parastamic, Paz, Peblo, Penkool, Penlip, Pentalink, Pentastar, Pentowin, Pentoz, Pentozed, Peploc, Peptac, Peptazol, Peptazole, Pepticaid, Pepticool, Peptix, Peptoloc, Pepzol, Perloc, Pipanzin, Pozola, Praize, Pranza, Praz-Up, Prazobloc, Prazocid, Prazolacid, Prazolan, Prazole, Prazolpan, Prazopant, Pregel, Prevacid, Previfect, Previfect, Progen, Prolex, Promtec, Propanz, Protech, Protinum, Protium, Protocent, Protocid, Protofix, Protoloc, Proton, Proton-P, Protonex, Protonil, Protonix, Protopan, PTA, Pulcet, Pumpisel, Ranloc, Razon, Rcpan, Redacib, Refluxine, Refluxopan, rifun, Ripane, Roxitrol, Sedipanto, Segregam, Seltraz, Sipar, Sodac, Somac, Sozol, Stamic, Stomafor, Stripole, Sumipral, Supacid, Super OM, Suppi, Supracam, Supracid, Surmera, Tai Mei Ni Ke, Tecta, Tonval, Topazol, Topra, Topraz, Topzole, Toraflux, Tropaz, Trupan, Ulceron, Ulcoreks, Ulcotenal, Ulprix, Ulsepan, Ulstop, Ultop, Ultoz, Unigastrozol, Vencid, Ventro-Pant, Vomizole, Wei Di, Wei Ke An, Wonon, Xotepic, Yoevid, Zamotil, Zaprol, Zencopan, Zgaton, Zimpax, Zipant, Zipantol, Zipantola, Ziprol, Zolan, Zolemer, Zolpan, Zolpanz, Zolpra, Zoltex, Zoltum, Zontop, Zoprax, Zovanta, Zurcal, and Zurcazol.[1]

It was marketed as a combination drug with domperidone under the brand names Aciban-DSR, Acillect-DSR, Asoprazole-D, Buffet-DXR, Depam, Domelong P, Dycizol, Eracid-D, F-Pan DSR, Fulpan-D, Fulpan-DSR, Gerdom, Gi-Fri, Gopan-D, Gopan-DSR, GR8-OD, Kurepane-DSR, Latop-D, Monpan-D, Monpan-DSR, Nupenta-DSR, Odipan-DSR, Oritop-D, Oritop-DSR, P-Bit-D, P-Bit-DSR, P-Zole DSR, P-Zole-D, PAA-DSR, Palio-D, Pamtrazol-D, Pan-D, Pancrazio-DSR, Pandiff, Pandostal, Pandostal-OD, Panfast-DSR, Panopaz-D, Panor-D, Panpot-DSR, Pansa-D, Pantact-D, Pantin-D, Pantin-RD, Pantocar-D, Pantocom-D, Pantoflux, Pantojoy-DXR, Pantokool-D, Pantolex-DS, Pantopacid-D, Pantopacid-SR, Pantorica-D, Pantozol-D, Pantozol-DSR, Pantra-D, Pantune-D, Panveda-D, Panzo-D, Panzol Plus, Panzol-D, Paz-DN, Peblo-D, Peblo-DSR, Penkool-DSR, Penlip-D, Pentalink-D, Pentastar-D, Pentozed-D, Peptac D, Peptac DSR, Pepticool-DXR, Pintel-DSR, Pop-DSR, Praize-D, Praize-D Forte, Prazole Plus, Prazosan-DSR, Predom, Predom-OD, Prolex-DSR, Prolus-DSR, Protocent-DSR, Protopan-D, Protopan-H, Ripane-D, Ripane-DSR, Trazol-DSR, PTA-D, Ulcicap-PD, Ultop DSR, Ultoz-D, Wonon-D, Wonon-DSR, and Zovanta-D.[1]

It was marketed in combination with itopride under the brand names Ganaton Total, Kurepan-IT, Nupenta-ITR, P-Bit-ISR, Pepnil-ITO, Prolus-ISR, and Protopan-I.[1]

It was marketed in combination with clarithromycin and amoxicillin as Gastrocomb, Klacid Hp7, Panclamox, and ZacPac.[1]

It was marketed in combination with levosulpiride as Panlife-LS and in combination with naproxen as Arthopan.[1]

Other animals

Pantoprazole has been demonstrated to increase the 3rd compartment pH in alpacas.[42] It has been shown to be generally safe to use in cattle, sheep and goats.[43] The subcutaneous bioavailability is greater than 100% in calves. [44] In calves intravenous and subcutaneous administration has been shown to significantly elevate abomasal pH.[44]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 "Pantoprazole international brand names". Drugs.com. https://www.drugs.com/international/pantoprazole.html. 
  2. ↑ 2.0 2.1 2.2 "Pantoprazole Use During Pregnancy". 26 June 2018. https://www.drugs.com/pregnancy/pantoprazole.html. 
  3. ↑ "Pantoprazole 20mg gastro-resistant tablets - Summary of Product Characteristics (SmPC)". 25 November 2019. https://www.medicines.org.uk/emc/product/450/smpc. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 "Pantoprazole Sodium Monograph for Professionals - Drugs.com". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/pantoprazole-sodium.html. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 "Pantoprazole". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK499945/. Retrieved 27 April 2022. 
  6. ↑ 6.0 6.1 British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. p. 79. ISBN 978-0857112989. 
  7. ↑ "[99 Comparative effectiveness of proton pump inhibitors"]. Therapeutics Initiative. 28 June 2016. http://www.ti.ubc.ca/2016/06/28/99-comparative-effectiveness-proton-pump-inhibitors/. 
  8. ↑ 8.0 8.1 "Proton pump inhibitors. Pharmacology and rationale for use in gastrointestinal disorders". Drugs 56 (3): 307–335. September 1998. doi:10.2165/00003495-199856030-00002. PMID 9777309. 
  9. ↑ Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 130. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA130. 
  10. ↑ "Pantoprazole: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=077056. 
  11. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  12. ↑ "Pantoprazole - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Pantoprazole. 
  13. ↑ 13.00 13.01 13.02 13.03 13.04 13.05 13.06 13.07 13.08 13.09 13.10 13.11 13.12 13.13 13.14 13.15 13.16 13.17 13.18 "Protonix delayed-release- pantoprazole sodium tablet, delayed release Protonix delayed-release- pantoprazole sodium granule, delayed release". 2 May 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=08098cb2-c048-4640-f387-6beec4a38936. 
  14. ↑ "Eradication of H. pylori with pantoprazole, clarithromycin, and metronidazole in duodenal ulcer patients: a head-to-head comparison between two regimens of different duration". Helicobacter 5 (1): 41–51. March 2000. doi:10.1046/j.1523-5378.2000.00006.x. PMID 10672051. 
  15. ↑ 15.0 15.1 15.2 "25 Years of Proton Pump Inhibitors: A Comprehensive Review". Gut and Liver 11 (1): 27–37. January 2017. doi:10.5009/gnl15502. PMID 27840364. 
  16. ↑ "Acid-suppressive medication use in acute stroke and hospital-acquired pneumonia". Annals of Neurology 76 (5): 712–718. November 2014. doi:10.1002/ana.24262. PMID 25164323. 
  17. ↑ "Acute allergic interstitial nephritis after use of pantoprazole". CMAJ 180 (5): 535–538. March 2009. doi:10.1503/cmaj.080456. PMID 19255077. 
  18. ↑ "Acid reflux drugs may lead to heart disease, says Houston study". Houston Chronicle. 10 July 2013. https://blog.chron.com/healthzone/2013/07/acid-reflux-drugs-may-lead-to-heart-disease-says-houston-study/. 
  19. ↑ Center for Drug Evaluation and Research. "Postmarket Drug Safety Information for Patients and Providers - FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors". https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206. 
  20. ↑ Center for Drug Evaluation and Research. "Drug Safety and Availability - FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs)". https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-low-magnesium-levels-can-be-associated-long-term-use-proton-pump. 
  21. ↑ 21.0 21.1 21.2 "Proton Pump Inhibitors (PPI)". StatPearls. Treasure Island (FL): StatPearls Publishing. 2022. http://www.ncbi.nlm.nih.gov/books/NBK557385/. Retrieved 29 April 2022. 
  22. ↑ "Drugs for Treatment of Gastrointestinal Diseases" (in de). Basic Knowledge of Pharmacology. Cham: Springer International Publishing. 2019. pp. 167–180. doi:10.1007/978-3-030-18899-3_13. ISBN 978-3-030-18899-3. 
  23. ↑ "Acid suppression: optimizing therapy for gastroduodenal ulcer healing, gastroesophageal reflux disease, and stress-related erosive syndrome". Gastroenterology 118 (2 Suppl 1): S9-31. February 2000. doi:10.1016/s0016-5085(00)70004-7. PMID 10868896. 
  24. ↑ "Metabolic interactions of the proton-pump inhibitors lansoprazole, omeprazole and pantoprazole with other drugs". European Journal of Gastroenterology & Hepatology 8 (Suppl 1): S21–S25. October 1996. doi:10.1097/00042737-199610001-00005. PMID 8930576. 
  25. ↑ "Novel approaches to inhibition of gastric acid secretion". Current Gastroenterology Reports 12 (6): 437–447. December 2010. doi:10.1007/s11894-010-0149-5. PMID 20924727. 
  26. ↑ "A Retrospective Clinical Investigation of the Safety and Adverse Effects of Pantoprazole in Hospitalized Ruminants". Frontiers in Veterinary Science 7: 97. 2020. doi:10.3389/fvets.2020.00097. PMID 32258063. 
  27. ↑ "Pharmacokinetics and Tissue Levels of Pantoprazole in Neonatal Calves After Intravenous Administration". Frontiers in Veterinary Science 7: 580735. 2020. doi:10.3389/fvets.2020.580735. PMID 33330703. 
  28. ↑ "Pharmacokinetics and pharmacodynamics of pantoprazole in clinically normal neonatal foals". Equine Veterinary Journal 37 (4): 336–341. July 2005. doi:10.2746/0425164054529427. PMID 16028623. 
  29. ↑ "Efficacy and pharmacokinetics of pantoprazole in alpacas". Journal of Veterinary Internal Medicine 24 (4): 949–955. July 2010. doi:10.1111/j.1939-1676.2010.0508.x. PMID 20384953. 
  30. ↑ "Pharmacokinetics of Pantoprazole and Pantoprazole Sulfone in Goats After Intravenous Administration: A Preliminary Report". Frontiers in Veterinary Science 8: 744813. 2021. doi:10.3389/fvets.2021.744813. PMID 34631865. 
  31. ↑ 31.0 31.1 31.2 31.3 31.4 "6. The Development of a New Proton-Pump Inhibitor: The Case History of Pantoprazole". Analogue-based drug discovery. Weinheim: Wiley-VCH. 2006. pp. 115–136. ISBN 9783527608003. https://archive.org/details/analoguebaseddru00jfis. 
  32. ↑ 32.0 32.1 "Wyeth, Nycomed Take Aim At Sandoz Over Protonix". Law360. 20 May 2008. https://www.law360.com/newjersey/articles/56858/wyeth-nycomed-take-aim-at-sandoz-over-protonix. 
  33. ↑ "An update on the use of pantoprazole as a treatment for gastroesophageal reflux disease". Clinical and Experimental Gastroenterology 3: 11–16. 2010. doi:10.2147/ceg.s6355. PMID 21694841. 
  34. ↑ "Drug Approval Package: Protonix (Pantoprazole Sodium) NDA 20987". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20987_Protonix.cfm. 
  35. ↑ 35.0 35.1 "Generic Protonix and Wyeth as Takeover Bait". WSJ. 30 January 2008. https://blogs.wsj.com/health/2008/01/30/generic-protonix-and-wyeth-as-takeover-bait/. 
  36. ↑ "Takeda to Buy Nycomed for $13.7 Billion". DealBook. 19 May 2011. https://dealbook.nytimes.com/2011/05/19/takeda-to-buy-nycomed-for-13-7-billion/. 
  37. ↑ "Pfizer in talks to acquire Wyeth in $60 billion deal: WSJ". 23 January 2009. https://www.marketwatch.com/story/pfizer-in-talks-to-acquire-wyeth-in-60-billion-deal-wsj. 
  38. ↑ "Wyeth Faces Generic Rival to a Heartburn Drug". The New York Times. 7 September 2007. https://www.nytimes.com/2007/09/07/business/07cnd-wyeth.html. 
  39. ↑ "Perspectives on the "generic cliff"--pushing and falling". Journal of Managed Care Pharmacy 14 (3): 318–321. April 2008. doi:10.18553/jmcp.2008.14.3.318. PMID 18439056. 
  40. ↑ "Protonix - Big Patent Expirations of 2010". FiercePharma. http://www.fiercepharma.com/special-report/protonix-big-patent-expirations-of-2010. 
  41. ↑ "Teva loses $2B gamble on generic of Pfizer's Protonix". FiercePharma. 12 June 2013. http://www.fiercepharma.com/legal/teva-loses-2b-gamble-on-generic-of-pfizer-s-protonix. 
  42. ↑ "Efficacy and pharmacokinetics of pantoprazole in alpacas". Journal of Veterinary Internal Medicine 24 (4): 949–955. July 2010. doi:10.1111/j.1939-1676.2010.0508.x. PMID 20384953. 
  43. ↑ "A Retrospective Clinical Investigation of the Safety and Adverse Effects of Pantoprazole in Hospitalized Ruminants". Frontiers in Veterinary Science 7: 97. 2020. doi:10.3389/fvets.2020.00097. PMID 32258063. 
  44. ↑ 44.0 44.1 "Pharmacokinetic and pharmacodynamic properties of pantoprazole in calves". Frontiers in Veterinary Science 9: 1101461. 2023-01-30. doi:10.3389/fvets.2022.1101461. PMID 36794231. 



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