Among PPIs’ indications are gastroesophageal reflux disease (GERD), heartburn and peptic ulcers. As late as the 1970s, peptic ulcers could be life-threatening if left untreated. Doctors could provide some relief from the painful symptoms with antacids, but these frequently only made ulcers worse. The condition often required surgery to remedy.
The development of histamine 2 (H2) blockers in the late 1970s revolutionized the treatment of conditions caused by excess gastric acid. Tagamet (cimetidine), and later H2 blockers such as Pepcid and Zantac, were the first drugs developed specifically to prevent the secretion of gastric acid in the stomach. But the H2 blockers failed to provide long-term relief in many cases.
As early as the 1960s, Astra Hässle, a research subsidiary of what is today AstraZeneca, had been working on other ideas for limiting stomach acid secretion. The company’s research would eventually target the final stage of gastric acid production, the proton pumps in the lining of the stomach, and block, or inhibit production of a key enzyme in stomach acid production, hydrogen potassium ATPase. This research would lead to a new class of drugs called proton pump inhibitors (PPIs).
Development of Proton Pump Inhibitors: A Timeline
Swedish pharmaceutical research company Astra Hässle, a division of what is now AstraZeneca, begins search for a stomach acid inhibiting drug
Research targets the newly discovered proton pump in the stomach’s secretory membrane
Researchers begin tests on a compound they name timoprazole
Studies find that while timoprazole effective inhibits acid secretion in the stomach, it causes thyroid gland enlargement in humans
A modification of timoprazole called picoprazole proves promising in early tests
Researchers identify a derivative of timoprazole and picoprazole, called omeprazole. It will become Prilosec, the first commercially produced PPI
Astra AB (now AstraZeneca) files an Investigational New Drug (IND) application with the FDA for omeprazole
Omeprazole goes to Phase III human trials
Omeprazole human trials briefly halted when tumors develop during animal research
Human trials resume when the tumor link is found to be a part of animal and not human physiology
Astra finds new compound superior to omeprazole called esomeprazole (Nexium), begins new round of trials
FDA approves omeprazole as first PPI to be marketed in the U.S.
Astra releases omeprazole in the U. S. under the brand name Prilosec
1995 to Present
Seven more brand name PPIs are approved and are marketed the U.S.: Prevacid (lansoprazole), AcipHex (rabeprazole), Nexium (esomeprazole), Protonix (pantoprazole), Zegerid (omeprazole), Dexilant (dexlansoprazole), Vimovo (esomeprazole/naproxen)
Timoprazole and the Development of Omeprazole
In the late 1960s, Astra Hässle had isolated a compound the company thought promising. It worked well in suppressing gastric acid production in lab rats, but turned out to be completely ineffective in humans. The early attempt was abandoned.
At the time, scientists had not fully mapped the pathway to acid secretion. No one knew the role of proton pumps in the stomach in producing stomach acid.
In 1972, the company began work with a new compound, CMN 131, but it proved too toxic. Researchers believed restructuring the compound could remove the toxicity. In 1973, their work resulted in an even more potent anti-secretion compound which they named timoprazole.
Timoprazole soon developed its own problems. Long-term toxicological studies found it caused enlargement of the thyroid gland and caused the thymus gland to atrophy. Researchers would later learn that timoprazole not only inhibited gastric acid production, it inhibited the body’s ability to absorb iodine – an element essential to the thyroid’s function.
It was a set-back, but it would later give Astra researchers an advantage in developing the first PPI when the role of proton pumps and hydrogen potassium ATPase in stomach acid was understood a few years later.
After timoprazole, researchers again tried restructuring the compound, but ran into difficulty finding a potential drug that didn’t inhibit both gastric acid and iodine. The best they could find was a compound named picoprazole.
Trials on animals found some dogs given picoprazole developed necrotizing vasculitis – an inflammation of blood vessel walls that can interrupt blood flow, resulting in the death of tissue and organs. However, one of the dogs in the control group – the dogs not given picoprazole – also developed the condition. This led researchers to discover that all the affected dogs were offspring of the same father and all had antibodies related to a deworming medicine. Dogs without the antibodies were unaffected.
This cleared the way for trials with picoprazole in human volunteers. By 1976, the drug proved to be the most powerful anti-secretion compound the team had identified so far, but they continued to develop new compounds.
One of these new compounds was omeprazole, later marketed as Prilosec.
Prilosec (omeprazole) Successful in Early Clinical Trials
By 1979, scientists had begun to understand the role of proton pumps in secreting stomach acid. Part of the emerging research found a relationship between acid generation and thyroid activity. Putting this research together with the lessons learned from the failed studies into timoprazole, Astra researchers began closing in on what would become the first proton pump inhibitor.
Research into several compounds between 1972 and 1979 led to omeprazole, which would later be marketed as Prilosec.
With a better idea of what to target, the researchers had zeroed in on omeprazole. The compound was one of several the researchers had developed that proved even more potent than picoprazole. Results from the tests on omeprazole were promising.
Omeprazole was found to produce:
- Potent acid suppression in animal trials
- No effect on iodine uptake
- No atrophy of thymus gland
- No necrotizing vasculitis
- No toxic effects
In 1980, Astra filed an Investigational New Drug (IND) application with the FDA and took omeprazole to human trials in 1982.
Cancer Concerns Delay Human Trials of Prilosec (omeprazole)
In July 1984, the IND was put on hold after a two-year cancer study showed lab rats developing gastric carcinoids. The hold was lifted in September 1985, after Astra and the FDA both agreed that the tumors were a false alarm – the result of “profound and long-lasting acid inhibition” and a reaction with an effect on a particular cell – the EC-L – that behaves differently in rats and humans.
“There is no definite answer to the question of whether OME is tumorigenic in humans,” the FDA reported in a later approval review for Prilosec OTC in 2003.
“There is no definite answer to the question of whether OME is tumorigenic in humans, but the evidence for carcinogenicity in humans is rather weak because the EC-L cell hyperplasia in humans, unlike rats, is not linked to carcinoid tumors.”
- FDA approval review for Prilosec OTC in 2003
The animal trials also suggested that the tumors resulted in part from high-dose, long-term – virtually lifetime – use of omeprazole in the rats.
Carcinoid tumors are rare in humans, but researchers have noticed an uptick in their frequency since PPIs have become one of the most widely used drugs in the world. A 2011 article published in the journal Digestive Diseases and Sciences warned that “[l]ong-term, sometimes lifetime, use is becoming increasingly common, often without appropriate indications” for PPIs.
The authors mentioned “hypergastrinemia and cancer” as potentially resulting from long-term use of the drugs. But it is unlikely that researchers would ever definitively determine whether or not a link between PPIs and certain cancers existed or not.
“Given the low incidence of gastric carcinoid tumors, prospective studies would not be feasible; thus, it is unlikely that the rat hypotheses will ever be proved in humans,” Dr. Neena Abraham, a gastroenterologist at the Michael E. DeBakey Veterans Affairs Medical Center, and professor at Baylor University wrote in the November 2012 edition of Current Opinion in Gastroenterology.
Prilosec (omeprazole) Approved as First Proton Pump Inhibitor
With the resumption of human trials in 1985, omeprazole proved more effective than any of the earlier compounds the Astra researchers had developed. It also proved twice as effective as H2 blockers in healing GERD.
By the mid-2000s, an estimated 12% of the world’s population had taken a PPI.
Branded as Losec in Europe, Astra launched omeprazole in Sweden in 1988. It received FDA approval in 1989 under the brand name Prilosec in the U.S. – after the agency determined Losec was too similar to the name of another, unrelated drug on the market and was concerned the confusion could cause some patients to receive the wrong prescription.
Omeprazole, became the world’s biggest selling prescription pharmaceutical by 1996. By 2004, more than 800 million patients worldwide had used the drug.
In 2003, the FDA approved an over the counter version of Prilosec (Prilosec OTC), making it the first PPI that could be purchased in the U.S. without a prescription.
“Even though there are some controversial issues and answers to safety questions are yet to be provided, the safety experience with prescription OME (omeprazole) is generally reassuring,” the FDA’s Center for Drug Evaluation and Research wrote in its medical review of Prilosec OTC.
Proton Pump Inhibitors Flood the Market
Following Astra’s success with Prilosec, roughly 40 other pharmaceutical manufacturers rushed into the PPI field. Most failed commercially, but a few would find a part of what was fast becoming a lucrative market for the drugs.
The second PPI approved for sale in the U.S. was Takeda Pharmaceutical’s Prevacid (lansoprazole) in 1995. Byk Gulden’s Protonix (pantoprazole) and Eisai’s AcipHex (rabeprazole) followed.
By 2010, six compounds, under at least eight brand names would be on the market in the U.S. All of them are omeprazole analogues – chemical compounds with molecular structures closely similar to omeprazole. Two, Nexium and Dexilant, were follow-ups to existing patents, improving on companies’ original PPIs.
In 1987, even before Astra took Prilosec to market, the company had begun work on a new PPI. Researchers had found that certain patients in the human trials needed higher or multiple doses of omeprazole to relieve symptoms and heal.
After testing four compounds between 1989 and 1994, only one proved superior to omeprazole – esomeprazole. The FDA approved it under the brand name Nexium in 2000.
Takeda Pharmaceuticals launched Dexilant (dexlansoprazole) as a follow-up to Prevacid in 2009. It was the first of a new generation of proton pump inhibitors.
Similar to Takeda’s lansoprazole compound, dexlansoprazole incorporated a dual-release technology. This allowed the medicine to achieve two peak concentrations in the blood at various times after a patient took it. This extended the inhibitory effect of the drug.
Previous PPIs required patients to take the drug 30 to 60 minutes before a meal. Dexlansoprazole eliminated the strict time regimen.
Aftermarket Research Exposes New Proton Pump Inhibitor Complications
While researchers had navigated around toxicity and cancer concerns in developing PPIs, other serious PPI side effects emerged in multiple studies after the drugs hit the market. The earliest of these was an association with acute interstitial nephritis (AIN) – a kidney condition that can lead to kidney injury and renal failure. Later research would identify potential complications including greater risk of bone fractures and serious bacterial infections.
The FDA has required warnings added to at least some PPI labels after research found the drugs may cause these conditions:
Acute Interstitial Nephritis (AIN)
In 1992, the American Journal of Medicine published an article on what is believed to be the first case of drug-induced AIN due to Prilosec.
In 2004, researchers writing in the journal Nephrology, Dialysis, and Transplantation concluded Prilosec and Prevacid are the “drugs most commonly associated with interstitial nephritis.”
In 2007, other researchers writing in Clinical Nephrology identify an “ever increasing number of cases of acute interstitial nephritis (AIN) associated with PPI therapy” and that “all PPIs have been documented to cause AIN.”
Despite multiple studies finding a connection between PPIs and AIN, the FDA did not require warnings of the risk added to PPI labels until 2014.
A study published in JAMA in 2006 concluded that “[l]ong-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture.”
Subsequent studies have found an association between PPI use and increased risk of osteoporosis and reduced bone density.
In 2011, the FDA required PPI manufacturers to update their labels with warnings about the drugs and an increased risk for fracture of the spine, wrist and hip.
In 2010, Researchers publish an analysis of 21 previous studies which revealed an association between PPI use and an 81 percent increased risk of C. difficile diarrhea.
C. difficile is a serious infection which can lead to potentially life-threatening conditions.
In 2012, the FDA put out a safety communication saying PPI use can increase the risk for C. difficile diarrhea. And in 2014, the agency required some PPI makers to add a warning about the risk to their labels.
Terry Turner is an Emmy-winning, former television journalist. He is an associate member of the American Bar Association, the ABA’s Health Law group and a member of the Alliance of Professional Health Advocates. He holds six certificates in Health Literacy for Healthcare Professionals from the Centers for Disease Control and Prevention. As a Washington-based investigative reporter, he routinely reported on health and medical policy issues before Congress, the FDA and other federal agencies. Terry received his B.A. in Media Arts from Lyon College.