Proton Pump Inhibitors - An Overview

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Dr.N. Udupa
Dr.N. Udupa

Proton pump inhibitors were introduced in 1980 for the treatment of heartburn, ulcers and Gastroesophageal reflux disease (GERD).

Omeprazole was the first drug in this class, introduced in 1989. Since then, four other PPIs viz lansoprazole, rabeprazole, pantoprazole and esomeprazole have been introduced in 1995, 1999, 2000 and 2001 respectively.

OMEPRAZOLE 1

Description

Omeprazole (PRILOSEC) is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1Hbenzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42.

The Structure

 Omeprazole Chemical structure 

Omeprazole is a white to off-white crystalline powder which melts with decomposition at about 155°C. It is a weak base, freely soluble in ethanol and methanol, and slightly soluble in acetone and isopropanol and very slightly soluble in water. The stability of omeprazole is a function of pH; it is rapidly degraded in acid media, but has acceptable stability under alkaline conditions.

Mechanism of Action

Omeprazole belongs to a new class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or H2 histamine antagonistic properties, but that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.

Indications

-  Treatment of gastric ulcer (GU), erosive esophagitis (EE), gastroesophageal reflux disease (GERD) with or without esophageal lesion.

-  Maintenance therapy of EE.

-  Eradication of Helicobacter pylori in triple therapy with clarithromycin and amoxicillin or in double therapy with clarithromycin only.

LANSOPRAZOLE 2

Description

Lansoprazole (PREVACID) is a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl] sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C16H14F3N3OS with a molecular weight of 369.37.

The Structure

Lansoprazole  Chemical Sructure 

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water. Lansoprazole is stable when exposed to light for up to two months. The compound degrades in aqueous solution, the rate of degradation increasing with decreasing pH. At 25°C the t½ is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0.

Mechanism of action

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but that suppress gastric acid secretion by specific inhibition of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus.

Indications

-  Treatment of duodenal ulcer (DU), both H. pylori positive and negative, active benign GU, GERD, EE and pathological hypersecretory conditions, including Zollinger-Ellison syndrome (ZES).

-  Maintenance therapy of DU and EE.

-  Eradication of H. pylori in triple therapy with clarithromycin and amoxicillin, or in double therapy with amoxicillin only.

PANTOPRAZOLE 3

Description

Pantoprazole sodium (PROTONIX) is a substituted benzimidazole, sodium 5-(difluoromethoxy)-2-[[(3,4-dimethoxy-2-pyridinyl)methyl] sulfinyl]-1H-benzimidazole sesquihydrate, a compound that inhibits gastric acid secretion. Its empirical formula is C 16H14F2N3NaO4 S x 1.5 H2O, with a molecular weight of 432.4.

The Structure

Pantoprazole sodium Chemical Sructure 

Pantoprazole sodium sesquihydrate is a white to off-white crystalline powder and is racemic. Pantoprazole has weakly basic and acidic properties. Pantoprazole sodium sesquihydrate is freely soluble in water, very slightly soluble in phosphate buffer at pH 7.4, and practically insoluble in n-hexane. The stability of the compound in aqueous solution is pH-dependent. The rate of degradation increases with decreasing pH. At ambient temperature, the degradation half-life is approximately 2.8 hours at pH 5.0 and approximately 220 hours at pH 7.8.

Mechanism of Action

Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by forming a covalent bond to two sites of the (H+,K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (H+,K+)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours.

Indication 

-  Treatment of EE associated with GERD.

The manufacturer of pantoprazole IV is also pursuing the GERD indication for this formulation.

RABEPRAZOLE 4

Description

Rabeprazole sodium (ACIPHEX) is a substituted benzimidazole that inhibits gastric acid secretion. Rabeprazole sodium is known chemically as 2-[[[4-(3-methoxypropoxy)-3-methyl-2- pyridinyl]-methyl] sulfinyl]-1H–benzimidazole sodium salt. It has an empirical formula of C18H20N3NaO3S and a molecular weight of 381.43.

The Structure

Image 

Rabeprazole sodium is a white to slightly yellowish-white solid. It is very soluble in water and methanol, freely soluble in ethanol, chloroform and ethyl acetate and insoluble in ether and n-hexane. The stability of rabeprazole sodium is a function of pH; it is rapidly degraded in acid media, and is more stable under alkaline conditions.

ACIPHEX is available for oral administration as delayed-release, enteric-coated tablets containing 20 mg of rabeprazole sodium. Inactive ingredients are mannitol, hydroxypropyl cellulose, magnesium oxide, low-substituted hydroxypropyl cellulose, magnesium stearate, ethylcellulose, hydroxypropyl methylcellulose phthalate, diacetylated monoglycerides, talc, titanium dioxide, carnauba wax, and ferric oxide (yellow) as a coloring agent.

Mechanism of Action

Rabeprazole belongs to a class of antisecretory compounds (substituted benzimidazole proton-pump inhibitors) that do not exhibit anticholinergic or histamine H2-receptor antagonist properties, but suppress gastric acid secretion by inhibiting the gastric H+, K+ATPase at the secretory surface of the gastric parietal cell. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, rabeprazole has been characterized as a gastric proton-pump inhibitor. Rabeprazole blocks the final step of gastric acid secretion.

Indications

- Treatment of erosive or ulcerative GERD, DU and hypersecretory syndromes including ZES.

- Maintenance of erosive or ulcerative GERD.

ESOMEPRAZOLE 5

Description

Esomeprazole sodium (NEXIUM) for Injection is (S)-5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]- 1 H-benzimidazole sodium a compound that inhibits gastric acid secretion. Esomeprazole is the S-isomer of omeprazole, which is a mixture of the Sand R- isomers. Its empirical formula is C17H18N3O3SNa with molecular weight of 367.4 g/mol (sodium salt) and 345.4 g/mol (parent compound).

Esomeprazole sodium is very soluble in water and freely soluble in ethanol (95%).

The Structure

Esomeprazole sodium  chemical structure 

Mechanism of Action

Esomeprazole is a proton pump inhibitor that suppresses gastric acid secretion by specific inhibition ofthe H+/K+-ATPase in the gastric parietal cell. The S- and R-isomers of omeprazole are protonated and converted in the acidic compartment of the parietal cell forming the active inhibitor, the achiral sulphenamide. By acting specifically on the proton pump, esomeprazole blocks the final step in acid production, thus reducing gastric acidity. This effect is dose-related up to a daily dose of 20 to 40 mg and leads to inhibition of gastric acid secretion.

Indications

GERD, healing of EE, maintenance of healing of EE, H. pylori Eradication to reduce the risk of duodenal ulcer recurrence in triple therapy with clarithromycin and amoxicillin

{mospagebreak title=Pharmacokinetics, dosing, and drug interactions}

PHARMACOKINETICS6-9

Absorption- 

Omeprazole and lansoprazole are formulated as enteric-coated granules, whereas rabeprazole and pantoprazole are enteric-coated tablets. Upon leaving the stomach, the granules and tablets are rapidly absorbed once the preparation enters the small intestine. All the products achieve peak concentrations of approximately 0.5 to 2mg/ml. All of the PPI’s undergo low rates of hepatic first pass metabolism. The absolute bioavailability of pantoprazole is approximately 77% due to the first pass effect. Omeprazole shows a saturable first pass effect such that at doses greater than 40mg, the maximum concentration and the absolute bioavailability are greater than would be expected. NEXIUM Delayed-Release Capsules contain an enteric-coated pellet formulation of esomeprazole magnesium. After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax). The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once- daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 mmol*hr/L on day 1 to 11.2 mmol*hr/L on day 5 after 40 mg once daily dosing.

Distribution

Protein binding of all the PPI’s is 95% or greater. Rabeprazole, omeprazole and lansoprazole have been found in the breast-milk of lactating humans. The approximate volume of distribution of pantoprazole is 11 to 23.6L (mean 0.16L/kg) indicating distribution mainly in the extracellular fluid, and limited tissue distribution. Omeprazole is found in fetal tissues at concentrations similar to that achieved in maternal plasma. In animal studies the highest concentrations of omeprazole were found in the liver, kidneys, duodenum, stomach and thyroid gland following intravenous administration of omeprazole. Penetration into red blood cells was found to be low, as well as penetration across the blood-brain barrier. Following oral administration the stomach and duodenal tissues had the highest concentrations of omeprazole. The volume of distribution of omeprazole is 0.24L/kg in elderly, and 0.34-0.37L/kg in adult subjects. The volume of distribution of lansoprazole is ~0.39L/kg. Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2-20 mmol/L. The apparent volume of distribution at steady state in healthy volunteers is approximately 16 L.

Metabolism   

All of the PPI’s are extensively metabolized in the liver to inactive metabolites. Certain sub-populations with deficiency of CYP2C19 have been shown to have slow metabolism of pantoprazole.

Elimination 

All of the PPI’s undergo elimination in urine and feces and have elimination halflives of 1.5 hours or less. All of the drugs are cleared mainly as metabolites due to their high degree of metabolism. Certain slow metabolizers of PPI’s clear the drug more slowly than normal metabolizers, and have longer drug elimination half-lives.

PPIs

 

Parameters

Omeprazole

Lansoprazole

Pentoprazole

Rabeprazole

Esomeprazole

IUPAC

5-methoxy-2-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methylsulfinyl]-3H-benzimidazole

2-[(3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methylsulfinyl]-1H-benzoimidazole

5-(difluoromethoxy)-2-[(3,4-dimethoxypyridin-2-yl)methylsulfinyl]-3H-benzoimidazole

2-[(4-(3-methoxypropoxy)-3-methyl-pyridin-2-yl) methylsulfinyl ]-1H- benzoimidazole

(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole

Chemical Name

C17H19N3O3S

C16H14F3N3OS

C 16H14F2N3NaO4 S

C18H20N3NaO3S

C17H19N3O3S

Molecular weight

345.4

369.363

383.371

359.444

345.417

Bioavailability

30–40%

>80%

77%

52%

50–90%

Metabolism

Hepatic (CYP2C19)

Hepatic (CYP2C19, CYP3A4)

Hepatic (CYP2C19,CYP3A4)

Hepatic (CYP2C19,CYP3A4)

Hepatic (CYP2C19, CYP3A4)

Elimination Half-life

1 – 1.2 hours

1 – 1.5 hours

1 hour

1 – 1.5 hours

1–1.5 hours

Tmax

0.5-3.5

1.7

2.5

2-5

0.5-3.5

Excretion

80% Renal
20% Faecal

Renal- 33%

Biliary/feces- 66%

Renal- 71% as metabolites

Feces- 18% as metabolites

Renal- 90% as metabolites

Feces- 10% as metabolites

80% Renal 20% Faecal

Proprietary Name

PRILOSEC

PREVACID

PROTONIX

ACIPHEX

NEXIUM

Year of Approval (USFDA)

Jan 15, 1998

May 10, 1995

Feb 2000

Aug 19, 1999

Feb 20, 2001

Route of Administration

Oral, IV

Oral, IV

Oral, IV

Oral

Oral, IV

DOSING1-5

The dosing regimens for FDA approved indications of the PPI’s are summarized below.

PPIs

Indication

Dosage Regimen

Omeprazole

Treatment of DU

20mg daily x 4 weeks

Treatment of GU

40mg daily x 4-8 weeks

Treatment of GERD

20mg daily x 4 weeks

Treatment of EE

20mg daily x 4-8 weeks

Maintenance of EE

20mg daily

Hypersecretory conditions

60mg daily

H. pylori eradication

-  triple therapy

-  dual therapy

 

20mg twice daily x 10 days

40mg daily x 14 days

Lansoprazole

Treatment of DU

15mg daily x 4 weeks

Maintenance of healed DU

15mg daily

Treatment of GU

30mg daily x 8 weeks

Treatment of GERD

15mg daily x 8 weeks

Treatment of EE

30mg daily x 8 weeks

Maintenance of EE

15mg daily

Hypersecretory conditions

60mg daily

H. pylori eradication

-  triple therapy

-  dual therapy

 

30mg q12h x 10-14 days

30mg q8h x 14 days

Pantoprazole

Treatment of EE

40mg daily x 8 weeks

Rabeprazole

Treatment of DU

20mg daily x 4 weeks

Treatment of GERD

20mg daily x 4-8 weeks

Maintenance of GERD

20mg daily

Treatment of EE

20mg daily x 4-8 weeks

Maintenance of EE

20mg daily

Treatment of hypersecretory conditions

60mg daily

Side Effects and Precautions

PPIs are generally well tolerated. The frequency of adverse effects associated with PPIs is similar to that of placebo, with an overall incidence of less than 5 percent11. The most common adverse effects are headache, diarrhea, abdominal pain, and nausea. Except for diarrhea, the adverse effects of PPIs do not appear to be related to age, dosage, or duration of treatment11,12 The diarrhea seems to be related to the profound acid suppression, which has been shown to alter the bacterial content of the gut. Nevertheless, the overall incidence of diarrhea is less than 5 percent, and this effect appears to be dosage and age-related11. Short-term safety (less than 12 weeks of treatment) of the oldest agents, omeprazole and lansoprazole, has been well established10. PPIs are only contraindicated if the patient has a known history of hypersensitivity to them, and they should be used with caution in patients with severe hepatic disease. Omeprazole is a pregnancy category C agent; the others are pregnancy category B medications. PPIs are not recommended for use in breastfeeding mothers13-17.

DRUG INTERACTIONS 9,18,19

The PPI’s are metabolized by the cytochrome P450 isoenzymes and therefore can be expected to interact with other drugs that are substrates for that enzyme system. Omeprazole is, however, the only PPI with known interactions with drugs that are substrates of the CYP2C19, including diazepam, warfarin and phenytoin. Lansoprazole interacts with theophylline through CYP1A1 isoenyzme induction. The PPI’s may also affect the absorption of certain drugs that require an acidic environment for optimal absorption to occur. The drug interactions of the PPI’s are summarized below.

Proton Pump Inhibitor

Interacting Drug(s)

Nature of Interaction

Omeprazole
Clarithromycin

Increase plasma levels of

omeprazole, clarithromycin and 14-hydroxyclarithromycin

 

Sucralfate

 

Delayed absorption/Decrease bioavailability of omeprazole; administer at least 30 minutes prior to sucralfate.

Diazepam

 

Decrease diazepam clearance 25-50%;130% increase in half-life and increase plasma levels of diazepam

Phenytoin

 

15-20% decrease clearance and 18-25% increase AUC and 17% increase half-life of phenytoin.

Warfarin

Elimination of warfarin may be prolonged

Lansoprazole
Theophylline

10% increase in theophylline clearance and 13% decrease in AUC may require dosage adjustment

Sucralfate

 

Delayed absorption/Decrease bioavailability of lansoprazole; administer

lansoprazole at least 30

minutes prior to sucralfate.

Ketoconazole

Ampicillin esters

Iron salts

 

Absorption of these drugs

may be decrease by the change in gastric pH.

Pantoprazole

It does not significantly affect the kinetics of the drugs as in the case of other PPI’s.  In vivo studies, digoxin, ethanol, glyburide, antipyrine, and caffeine had no clinically relevant interactions with pantoprazole.

Rabeprazole

Digoxin

19% increase in digoxin bioavailability, 20% increase in digoxin trough levels, 29%

increase in digoxin Cmax

 

Ketoconazole

30% decrease in bioavailability of ketoconazole

Cyclosporine

 

Increase cyclosporine plasma

Levels

Esomeprazole

Diazepam

45% decrease in clearance of diazepam.

Warfarin

Increase in INR and prothrombin time

Ketoconazole, iron salts and digoxin

interfere with the absorption

{mospagebreak title=Conclusion and References}

Summary and Conclusion

The proton pump inhibitors are substituted benzimidazoles that inhibit gastric acid secretion via inhibition of the H+/K+ ATPase pump. Although there are some differences in pharmacokinetics and binding affinity for the pump, these drugs are comparatively similar in their efficacy in treatment of gastric diseases. The number of indications for which they are approved differs, but efficacy has been shown to some extent for most in their non-FDA approved indications as well, and it is thought that efficacy for all of the indications can be generalized across the group.

Currently, the PPI’s are the drugs of choice for most gastric acid related diseases because their efficacy has been proven to be superior to the H2 antagonists. This includes H. pylori treatment where ≥ 90% eradication can be achieved with a PPI in combination with 2 antibiotics alone. The PPI’s are also considered the treatment of choice for Zollinger-Ellison Syndrome (ZES). The PPI’s offer convenient once-daily dosing for most indications. Lansoprazole has the largest number of FDA approved indications of the group and for most of those indications is more cost effective than the other agents. Lansoprazole can be administered via nasogastric tube and there is information available regarding administration of omeprazole via enteral tubes. Omeprazole administration via enteral tubes is more cumbersome compared with lansaprazole. Pantoprazole has only one indication at this time, and is the most cost effective of the group for that indication. It also has shown up to this time, no significant drug-drug interactions, unlike omeprazole which has several significant drug interactions, and rabeprazole and lansoprazole which each have a few moderately significant drug interactions. It has shown efficacy in gastric ulcers, duodenal ulcers, and H. pylori eradication in a limited number of studies, and may become more popular once more safety data is generated. The PPI’s, as a class are primarily used for a limited duration of time i.e., 4-8 weeks. Avoiding excessive duration of use should be advocated to minimize drug interactions, long term suppression of gastric acid and potential for severe unexpected toxicity.

References

1. http://www.fda.gov/medwatch/SAFETY/2005/Mar_PI/Prilosec_PI.pdf

2. http://www.fda.gov/cder/foi/label/2000/20406S33lbl.pdf

3. http://www.fda.gov/medwatch/SAFETY/2003/03Feb_PI/Protonix_PI.pdf

4. www.fda.gov/cder/foi/label/1999/20973lbl.pdf

5. http://www.fda.gov/medwatch/SAFETY/2003/03Feb_PI/Nexium_PI.pdf

6. Richardson P, Hawkey C, Stack W. Proton pump inhibitors- pharmacology and rationale for use in gastrointestinal disorders. Drugs. 1998;56(3):307-35.

7. Israel D, Hassall E. Omeprazole and other proton pump inhibitors: pharmacology, efficacy, and safety, with special reference to use in children. J Pediatr Gastroenterol Nut. 1998; 27(5): 568-79.

8. Micromedex- Drugdex Evaluations. 2000. 9. Feret B, Quercia R, Cappa J. Rabeprazole: A proton pump inhibitor for the treatment of acid-related disorders. Formulary. 1999;34: 313-23.

10. Welage LS, Berardi RR. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J Am Pharm Assoc 2000;40:52-62.

11. Reilly JP. Safety profile of the proton-pump inhibitors. Am J Health Syst Pharm 1999;56(23 suppl 4):S11-7.

12. Franko TG, Richter JE. Proton-pump inhibitors for gastric acid-related disease. Cleve Clin J Med 1998; 65:27-34.

13. Omeprazole (Prilosec). Package insert. Wayne, Pa.: Astra Pharmaceuticals, 1998. Retrieved May 2002, from: www.astrazeneca-us.com/pi.

14. Lansoprazole (Prevacid). Package insert. Deerfield, Ill.: TAP Pharmaceuticals, 1999. Retrieved May 2002, from: www.prevacid.com.

15. Rabeprazole (Aciphex). Package insert. Titusville, N.J.: Janssen Pharmaceutica, 1999. Retrieved May 2002: http://us.janssen.com/products/pi_files/aci8.5x11.pdf.

16. Pantoprazole (Protonix). Package insert. Philadelphia, Pa.: Wyeth-Ayerst, 2000. Retrieved May 2002, from: www.wyeth.com/products/wpp_ products/protonix_pi.asp.

17. Esomeprazole (Nexium). Package insert. Wilmington, Del.: Astra Pharmaceuticals, 2001. Retrieved May 2002, from: www.astrazeneca-us.com/pi/203647NexiumPI.pdf.

18. Welage L, Berardi R. Evaluation of omeprazole, lansoprazole, pantoprazole, and rabeprazole in the treatment of acid-related diseases. J. Am Pharm. Assoc. 2000;40(1):52-62.

19. Saltiel E, Fask A. Prevalence of potential proton-pump inhibitor drug interactions: A retrospective review of prescriptions in community pharmacies. Clin Ther. 1999;21(10):1812-19.

{mospagebreak title=About Dr.N. Udupa et.al}

About Authors:

D. Sreedhar, Dilip Kumar, Ajay Pise, Manthan D Janodia, G. Subramanian, N. Udupa*

Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, MAHE, Manipal – 576 104

First Author

D. Sreedhar

First author D. Sreedhar did B.Pharm from Roland Institute of Pharmaceutical Sciences, Berhempur, Orissa, M.Pharm (Pharmaceutical Marketing and Administration) from Manipal College of Pharmaceutical Sciences, Manipal, Karnataka and presently working as lecturer in the Department of Pharmacy Management and is registered for PhD under the guidance of Dr N. Udupa, HOD(Department of Pharmacy Management) and Principal, Manipal College of Pharmaceutical Sciences. Papers were published in the reputed national journals.

*Corresponding Author

Dr.N. Udupa

Corresponding author Dr.N. Udupa is HOD (Department of Pharmacy Management) and Principal, Manipal College of Pharmaceutical Sciences. More than 300 papers were published in reputed national and international journals. Received 5 prestigious awards, guided more than 20 PhD candidates, attended over 25 conferences and has 4 patents under his credit.: Emailn.udupa@manipal.edu Phone Number – (0820) 2922482

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