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6/26/2012
Grand Rounds June 29 1, Efficacy and proved safety of PPI (in adults). The legend.
Over‐prescription of proton pump inhibitors and the consequences: the legend, the ignored facts and our recent findings
2, Over‐prescription of PPIs, focus on infants.
3, Consequences of over‐prescription: the already published but ignored facts.
4, Possible link of long‐term PPI use with gastric cancer: our recent findings.
5, Suggestions by Eric Hassall on PPI use in infants.
Lixin Zhu
Women and Children's Hospital of Buffalo, SUNY at Buffalo, Buffalo, NY 14222
Proton Pump Inhibitors (PPI)
The Niagara Falls in the stomach
• Most effective medicine to suppress gastric acid secretion
Omeprazole
• Could be a life‐saving medicine in many circumstances
pH=7
Lansoprazole
Inventions: Hydroelectricity, Alternating current system
pH=1
Invention: Proton pump inhibitors
Pantoprazole
Online pKa calculator:
http://www.chemaxon.com/marvin/sketch/index.php
The mechanism of PPIs
Efficacy of PPIs and their superiority over H2RA
1.
2.
3.
4.
5.
6.
7.
Olbe L, Carlsson E, Lindberg P.
AstraZeneca R&D, 431 83 Mölndal, Sweden. Bonnevie, O. et al. Gastric acid secretion and duodenal ulcer healing during treatment with omeprazole. Scand. J. Gastroenterol. 19, 882–884 (1984).
Lauritsen, K. et al. Effect of omeprazole and cimetidine on duodenal ulcer. A double blind comparative trial. N. Engl. J. Med. 312, 958–961 (1985).
Burget, D. W., Chiverton, S. G. & Hunt, R. H. Is there an optimal degree of acid suppression for healing of duodenal ulcers — a model of the relationship between ulcer healing and acid suppression. Gastroenterology 99, 345–351 (1990).
Walan, A. et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N. Engl. J. Med. 320, 69–75 (1989).
Klinkenberg–Knol, E. C., Jansen, J. M., Festen, H. P., Meuwissen, S. G. & Lamers, C. B. Double‐blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux oesophagitis. Lancet 1, 349–351 (1987).
Havelund, T. et al. Omeprazole and ranitidine in treatment of reflux esophagitis—double‐blind comparative trial. Br. Med. J. 296, 89–92 (1988).
Hetzel, D. J. et al. Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95, 903–
912 (1988).
Nat Rev Drug Discov. 2003 Feb;2(2):132‐9
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Efficacy and short‐term use safety of PPIs in pediatric patients
An important contribution made by Drs. Robert and Susan Baker
No tachyphylaxis
“Tolerance that occurs with H2RAs does not occur with PPIs.”
Welage LS (2005) Overview of pharmacologic agents for acid suppression in critically ill patients. Am J Health Syst Pharm 62(10 Suppl 2):S4‐S10.
1. Gunasekaran TS, Hassall EG. Efficacy and safety of omeprazole for severe gastroesophageal reflux in children. J Pediatr
1993;123:148‐54.
2. Hassall E, Israel D, Shepherd R, Radke M, Dalvag A, Skold B, et al. Omeprazole for treatment of chronic erosive esophagitis in children: a multicenter study of efficacy, safety, tolerability and dose requirements. International Pediatric Omeprazole Study Group. J Pediatr 2000;137: 800‐7.
3. Fiedorek S, Tolia V, Gold BD, Huang B, Stolle J, Lee C, et al. Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and nonerosive gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2005;40:319‐27.
4. Tolia V, Ferry G, Gunasekaran T, Huang B, Keith R, Book L. Efficacy of lansoprazole in the treatment of gastroesophageal
reflux disease in children. J Pediatr Gastroenterol Nutr 2002;35(Suppl. 4): S308‐18.
5. Gold BD, Gunasekaran T, Tolia V, Wetzler G, Conter H, Traxler B, et al. Safety and symptom improvement with esomeprazole in adolescents with gastroesophageal reflux disease. J Pediatr Gastroenterol Nutr 2007;45:520‐9.
6. Tolia V, Youssef NN, Gilger MA, Traxler B, Illueca M. Esomeprazole for the treatment of erosive esophagitis in children: an international, multicenter, randomized, parallel‐group, double‐blind (for dose) study. BMC Pediatr 2010;10:41.
A great success!
1, Efficacy and proved safety of PPI (in adults). The legend.
2, Over‐prescription of PPIs, focus on infants.
3, Consequences of over‐prescription: the already published but ignored facts.
4, Possible link of long‐term PPI use with gastric cancer: our recent findings.
5, Suggestions by Eric Hassall on PPI use in infants.
Saved lifes.
Reduced incidence of GI surgeries.
1. Zed PJ, Loewen PS, Slavik RS, & Marra CA (2001) Meta‐analysis of proton pump inhibitors in treatment of bleeding peptic ulcers. Ann Pharmacother 35(12):1528‐1534.
2. Leontiadis GI, Sharma VK, & Howden CW (2007) Proton pump inhibitor therapy for peptic ulcer bleeding: Cochrane collaboration meta‐analysis of randomized controlled trials. Mayo Clin Proc 82(3):286‐296.
Sales totalling $13.6 billion worldwide in 2009.
RYAN D. MADANICK, MD, Cleve Clin J Med. 2011 Jan;78(1):39‐49.
PPIs are the second most commonly prescribed drug class in US. Mullin et al., 2009, Drug Discovery Today, 14:647
1. Van Boxel, O.S. et al. (2009) Sociodemographic factors influence chronic proton pump inhibitor use in a large population in the Netherlands. Aliment Pharmacol. Ther. 29 (5), 571–579
2. Choudhry, M.N. et al. (2008) Overuse and inappropriate prescribing of proton pump inhibitors in patientswith Clostridium difficile‐associated disease. QJM 101, 445–448
3. Slattery, E. et al. (2007) Intravenous proton pump inhibitor use in hospital practice. Eur. J. Gastroenterol. Hepatol. 19, 461–
464
4. Forgacs, I. and Loganayagam, A. (2008) Overprescribing proton pump inhibitors is expensive and not evidence based. BMJ 336, 2–3
“…between 53% and 69% of PPI prescriptions are for inappropriate indications.”
‐‐‐Katz, Mitchell, Failing the acid test. Arch Intern Med. 2010 May 10;170(9):747‐8.
A very recent report in Clinical Gastroenterology and Hepatology
Similar attitude
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Over‐prescription of PPI in infants
From 1999 to 2004, there was a >7‐fold increase in PPI prescription.
One of the PPIs, available in a child‐friendly liquid formulation, saw a 16‐fold increase in use during that 6‐year period.
1, Efficacy and proved safety of PPI (in adults). The legend.
2, Over‐prescription of PPIs, focus on infants.
3, Consequences of over‐prescription: the already published but ignored facts.
4, Possible link of long‐term PPI use with gastric cancer: our recent findings.
5, Suggestions by Eric Hassall on PPI use in infants.
Barron JJ, Tan H, Spalding J, Bakst AW, Singer J. Proton pump inhibitor utilization patterns in infants. J Pediatr Gastroenterol Nutr 2007;45: 421‐7.
Many infants spit up on a daily basis—some 40% to 70%.
Many infants are irritable or have ‘‘unexplained crying”.
Over‐prescription of PPI unnecessarily removes/affects
An important defense against infection.
Protein digestion by pepsin.
Nutrition absorption (Ca, Fe, Mg, VB12)
Milk coagulation by acid/pepsin.
?
GERD
Treatment with PPIs is no better than placebo.
Orenstein SR, Hassall E, Furmaga‐Jablonska W, Atkinson S, Raanan M. Multicenter, double‐blind, randomized, placebo‐controlled trial assessing efficacy & safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease. J Pediatr
2009;154. 514‐520 e4.
Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, Davidson GP. Double‐blind placebo‐controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003;143:219‐23.
AND adds side effects.
Arne Brandstrom et al, 1989, Acta Chemica Scandinavica 43: 536
Once activated (in the form of sulphenamide), omeprazole can “react with SH groups in the acidic stomach contents, and with SH groups in the neutral contents of the intestine.”
Hassle is a division of Astra
Constant liquid flow
Abundant rearrangement products of omeprazole
at acidic environment
Arne Brandstrom et al, 1989, Acta Chemica Scandinavica
43: 536
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Omeprazole accumulates in organs other than the stomach
Herlander et al., 1985, Localization of omeprazole and metabolites in the mouse. Scand J Gastroenterol Suppl. 1985;108:95‐104.
If the stomach has a pH so much lower than the rest of the body, does not PPI only trapped at the stomach?
No.
Omeprazole cause gastric carcinoids in rat. Ekman et al., 1985, Toxicological studies on omeprazole. Scand. J. Gastroenterol. Suppl. 108: 53‐69; Havu, 1986, ECL carcinoids of gastric mucosa in rats after life‐long inhibition of gastric secretion. Digestion 35 (suppl.1): 42‐55
Omeprazole treatment
Control
Low dose
Medium dose
High dose Side‐effects due to inhibition of CYP2C19 PPIs are removed in the liver by cytochrome P450: CYP2C19 and CYP3A4.
CYP2C is also responsible for the metabolism of other drugs: diazepam, S‐warfarin, and tolbutamide, etc.
It is unethical to perform a similar controlled study with patients.
Clopidogrel: prodrug used to inhibit platelet aggregation. After absorption, it requires activation by CYP 2C19, before becoming active against platelets.
Clopidogrel (marketed as Plavix) and Omeprazole (marketed as Prilosec) ‐ Drug Interaction
Audience: Cardiovascular healthcare professionals, pharmacists
[Posted 11/17/2009] FDA notified healthcare professionals of new safety information concerning an interaction between clopidogrel (Plavix), an anti‐clotting medication, and omeprazole (Prilosec/Prilosec OTC), a proton pump inhibitor (PPI) used to reduce stomach acid. New data show that when clopidogrel and omeprazole are taken together, the effectiveness of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots will not get the full effect of this medicine if they are also taking omeprazole. Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction.
Other drugs that are expected to have a similar effect and should be avoided in combination with clopidogrel include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.
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Effect on osteoclast: inhibition of bone resorption in vitro and in vivo
Previous research of PPI effect on lysosomal enzymes
1. Burdan F, Siezieniewska Z, Maciejewski R, Madej B, Radzikowska E, Wojtowicz Z. Hepatic lysosomal enzymes activity and liver morphology after short‐time omeprazole
administration. Exp Toxicol Pathol 2002;53:453‐9.
2. Fujisaki H, Oketani K, Nagakawa J, Takenaka O, Yamanishi Y. Effects of rabeprazole, a gastric proton pump inhibitor, on biliary and hepatic lysosomal enzymes in rats. Jpn J Pharmacol
1998;76:279‐88.
3. Grinpukel S, Sewell R, Yeomans N, Mihaly G, Smallwood R. Lack of effect of omeprazole, a potent inhibitor of gastric (H+ + K+) ATPase, on hepatic lysosomal integrity and enzyme activity. J Pharm Pharmacol 1986;38:158‐60.
No effect observed!
All studies performed with liver!!!
Liver is where PPIs are removed.
1. Tuukkanen J, Väänänen HK, Omeprazole, a specific inhibitor of H+‐K+‐ATPase, inhibits bone resorption in vitro. Calcif Tissue Int. 1986 Feb;38(2):123‐5. 2. Anderson RE, Woodbury DM, Jee WS, Humoral and ionic regulation of osteoclast acidity. Calcif Tissue Int. 1986 Oct;39(4):252‐8. 3. Mizunashi K, Furukawa Y, Katano K, Abe K. Effect of omeprazole, an inhibitor of H+,K(+)‐ATPase, on bone resorption in humans. Calcif Tissue Int. 1993 Jul;53(1):21‐5. 1, Efficacy and proved safety of PPI (in adults). The legend.
2, Over‐prescription of PPIs, focus on infants.
3, Consequences of over‐prescription: the already published but ignored facts.
A discovery by accident: PPIs are activated at pH5!
Mass spectrum of the omeprazole-peptide adduct
4, Possible link of long‐term PPI use with gastric cancer: our recent findings.
PPI + Peptide‐SH
At pH5
PPI‐S‐S‐peptide !
5, Suggestions by Eric Hassall on PPI use in infants.
I wanted to do the experiment at pH2, but ……
Omeprazole‐laminin (925‐933) adduct was produced at pH5:
Collision-induced dissociation mass spectrum of the omeprazole-peptide adduct
y1 y2 y3 y4 y5 y6 y7 y9
R S G I Y G P [D C] Omeprazole
Similar results were obtained with lansoprazole
and pantoprazole.
PPI + Peptide‐SH
At pH5
PPI‐S‐S‐peptide !
The majority of the peptide was converted into omeprazole‐peptide adduct !
How did it happen? PPI is active at pH5? PPI react with peptides other than the proton pump?
2500
2000
Given that the pKa of the PPIs are in the range of 4‐5,
Starting material:
omeprazole
1500
1000
The following reaction is expected at pH5:
500
0
Intensity, counts
Omeprazole
10% for pKa of 4, 50% for pKa of 5
PPI
2500
2000
protonated PPI
Activated PPI pH5
Starting material:
laminin (925-933)
1500
Peptide‐SH
1000
500
0
Laminin
(925-933)
PPI‐S‐peptide adduct
2500
Product from
omeprazole and
laminin (925-933)
2000
1500
1000
500
0
Omeprazole
Laminin
(925-933)
drug-peptide
adduct
The total ion intensities of each molecule were determined using the Bayesian peptide reconstruction module provided in the BioAnalyst
extension of the Analyst QS software version 2.0
This reaction is rather complete,
and removing activated PPI,
and shifting the balance of the above reactions
Arne Brandstrom et al, 1989, Acta Chemica Scandinavica 43: 536
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pH5 means everywhere in our body:
Lansoprazole and pantoprazole also inhibit lysosomal enzymes
lysosomes in every cell !
***
***
100
Control
80
10 µM
60
30 µM
40
20
0
A549
Caco2
HEK293
***
**
120
***
***
***
*
**
*
100
Control
80
10 µM
60
30 µM
***
***
***
***
***
***
***
NS
100
Control
80
10 µM
60
30 µM
40
20
0
A549
40
Caco2
HEK293
β‐N‐Acetylglucosaminidase Activity ***
***
120
120
***
***
***
***
***
***
***
***
100
Control
80
10 µM
60
30 µM
40
20
0
A549
HepG2
Caco2 HEK293 HepG2
20
0
A549
HepG2
*,p<0.05; **, p<0.01; ***, p<0.001 (Tukey’s honest significance test)
Error bars: standard errors
A549
Caco2
HEK293
HepG2
Pantoprazole effects on NAG activity
Pantoprazole effects on AP activity
Caco2 HEK293 HepG2
human adenocarcinomic alveolar epithelial cell
human colorectal adenocarcinoma epithelial cell
human embryonic kidney cell
hepatocellular carcinoma cell
140
***
***
120
***
*
Control
100
10 µM
80
30 µM
60
40
20
0
A549
Caco2
HEK293
β‐N‐Acetylglucosaminidase Activity ***
***
Acid Phosphatase Activity Acid Phosphatase Activity ***
**
120
β‐N‐Acetylglucosaminidase Activity Omeprazole effects on NAG activity
Omeprazole effects on AP activity
Lansoprazole effects on NAG activity
Lansoprazole effects on AP activity
Acid Phosphatase Activity Lung, kidney, skin, vagina, and importantly ***
***
120
***
***
100
Control
80
10 µM
60
30 µM
40
20
0
A549
HepG2
Caco2 HEK293 HepG2
Summary of our findings
Mice treated with PPIs
PPIs are readily activated at pH5.
Stomach, Liver: no inhibitory effect observed with any of those three PPIs.
In vitro and in vivo experiments indicated that PPIs inhibited lysosomal enzymes.
140
*
120
100
80
60
40
20
0
0
0.57
2.85
Omeprazole concentration (mg/kg)
The PPIs effect on lysosomal enzyme is organ/cell specific.
Relative myeloperoxidase activity
Relative acid phosphatase activity
However, in the spleen:
140
Difference exist among different PPIs.
*
120
Lysosome plays key roles in antigen presentation and cytotoxic T lymophocyte function. By interfering with patient immune system, PPIs may increase the risk of tumorigenesis
and infectious diseases.
100
80
60
40
1.
20
Hagiwara T, Mukaisho K, Nakayama T, et al. Long‐term proton pump inhibitor administration worsens atrophic corpus gastritis and promotes adenocarcinoma
development in Mongolian gerbils infected with Helicobacter pylori. Gut 2011;60:624e30.
Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid‐suppressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571‐4.
Doorduyn Y, Van Pelt W, Siezen CL, et al. Novel insight in the association between salmonellosis or campylobacteriosis and chronic illness, and the role of host genetics in susceptibility to these diseases. Epidemiol Infect 2008;136:1225‐34.
4. Neal KR, Briji SO, Slack RC, Hawkey CJ, Logan RF. Recent treatment with H2 antagonists and antibiotics and gastric surgery as risk factors for Salmonella infection. BMJ 1994;308:176.
5. Garcia Rodriguez LA, Ruigomez A, Panes J. Use of acid‐suppressing drugs and the risk of bacterial gastroenteritis. Clin Gastroenterol Hepatol 2007;5:1418‐23.
6. Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT, Wannet WJ, Van Pelt W. Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non‐DT104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect 2006;134:617‐26.
7. Neal KR, Scott HM, Slack RC, Logan RF. Omeprazole as a risk factor for campylobacter gastroenteritis: case‐control study. BMJ 1996;312:414‐5.
8. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol 2007;102:2047‐56; quiz 57.
9. Dial MS. Proton pump inhibitor use and enteric infections. Am J Gastroenterol 2009;104 Suppl 2:S10‐6.
10. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010;170:784‐90.
11. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010;170:772‐8.
2.
3.
0
0
0.57
2.85
Omeprazole concentration (mg/kg)
1, Efficacy and proved safety of PPI (in adults). The legend.
2, Over‐prescription of PPIs, focus on infants.
3, Consequences of over‐prescription: the already published but ignored facts.
4, Possible link of long‐term PPI use with gastric cancer: our recent findings.
5, Suggestions by Eric Hassall on PPI use in infants.
160 (2):193
Spitting up, occationally irritable/crying, usually consolable
Reassurance about the benign natural history of infant regurgitation
Long‐lasting inconsolable crying, with rejection of the bottle or breast, arching or screaming
non‐pharmacological measures should be the first approach
Non‐analgesic, non‐nutritive soothing maneuvers
Position and diet often work
Don’t work?
2 week trial of H2RA
Response observed. GERD. 2week PPI trial
No response? It is not GERD.
Does the child relapse at weaning off PPI?
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H2RA and corporectomy also caused carcinoids, therefore “PPI causing carcinoid” was ignored.
Acknowledgements
University at Buffalo
Wensheng Liu
Susan S. Baker
Robert D. Baker
UC Berkeley
John Forte
Charles Watson
1. Larsson, H. et al. Plasma gastrin and gastric enterochromaffine‐like cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats. Gastroenterology 90, 391–399 (1986). 2. Havu, N., Mattsson, H., Ekman, L. & Carlsson, E. Enterochromaffine‐like cell carcinoids in the rat gastric mucosa following long‐term administration of ranitidine. Digestion 45, 189–195 (1990).
3. Mattsson, H. et al. Partial gastric corporectomy results in hypergastrinemia and development of gastric ECL‐cell carcinoids in the rat. Gastroenterology 100, 311–319 (1991).
UCSF
Alma L. Burlingame
Jonathan Trinidad
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