The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puscas (1932-2015).

Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puscas used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the ß-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puscas for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.

Historical perspective of gastric acid inhibition.

The inhibition of gastric secretion has been a therapeutic objective for decades. A variety of pharmacologic and non-pharmacologic approaches have been proposed throughout history. Among the non-pharmacologic proposals, gastric surgery was widely used until effective drugs were available. Initially antacids and later anticholinergics, H2 blockers and proton pump inhibitors took the predominant position. Finally, Helicobacter pylori eradication has been the milestone for the cure of peptic ulcers.

Edkins and a century of acid suppression.

In 1905, John Edkins (1863-1940) undertook the studies of gastrin that have subsequently formed the basis for a century of investigation into the physiological basis of acid secretion and led to the elucidation of a variety of acid-suppressive pharmacological agents that have revolutionized the management of acid peptic disease. Although his name is known to few, his contributions to the physiology of gastric secretion and his study of spiral organisms in the stomach were prescient and to this day remain models of insightful and rigorous research. As a mentor, his educational impact was exemplified by the fact that he was the first to teach physiology to women in the United Kingdom. Gastrin has evolved from an initially unaccepted phenomenon, to be recognized as an important hormone and a fundamental component of regulatory biology as well as a clinically relevant biomarker of disease. Its critical role in the modulation of acid secretion has become a sine qua non and has been extended to include a broad regulatory proliferative role in the mucosa of the gastrointestinal tract. The pivotal role of gastrin in gastric physiology, biology and clinical medicine is now well accepted and reflects the fundamental contributions that Edkins made to the identification of the agent and the elucidation of its function. As a result of the delineation of the neural and hormonal regulatory mechanisms of acid secretion, the scientific basis of acid peptic disease has become apparent. The identification of histamine receptors and proton pumps has led to the discovery of novel pharmacotherapeutic agents capable of producing acid suppression of such efficacy that surgery has become virtually obsolete in the treatment of the disease process. A century after the initial observations by Edkins of gastrin, the identification of Helicobacter pylori and the ability to eradicate it, as well as the use of the proton pump inhibitor class of drugs, have revolutionized the management of gastroduodenal ulceration and gastroesophageal reflux disease. Both patients and physicians owe a great debt to Edkins, whose seminal observations regarding gastrin initiated an era of gastrointestinal scientific, clinical and pharmacological advance that has culminated in the ability to treat and cure acid peptic disease.

GERD 2003: issues from the past and a consensus for the future.

Gastroesophageal reflux disease (GERD) has evolved from a scarcely reported, little understood disease process just a century ago to a now highly prevalent disease with up to 25% of the population complaining of symptoms of reflux. Throughout history attempts have been made to delineate the esophagus and related pathologies, but it has not been until relatively recently that enough has been understood about its screening, diagnosis and treatment to make a substantial impact on sufferers. Although the use of antacids and thereafter histamine 2 receptor antagonists dramatically improved the management of GERD, it was the advent of the proton pump inhibitor (PPI) class of drugs that revolutionized medical care. Although the relationship of hiatus hernia to reflux was well accepted, the modest results of open fundoplication fell into further disregard given the efficacy of PPIs. The PPIs are currently the most effective form of therapy and are equivalent on a milligram for milligram basis. While currently no novel drugs or devices are of proven efficacy for GERD, the development of an acid-suppressive agent of equal efficiency to a PPI but with a more rapid onset of action and a greater duration of effectiveness would be of particular clinical utility for the future.

History of acid suppression: focus on the hospital setting.

In the hospital setting, prophylactic acid suppression is an important part of care for many critically ill patients. It may also prevent rebleeding in patients admitted with acute upper gastrointestinal tract bleeding. Effective treatments for these conditions stemmed from our increased understanding of the gastric acid secretory pathway and target pH values. The late 1970s saw the introduction of histamine2-receptor antagonists (H2RAs), which partially suppress basal and meal-stimulated acid secretion. Some of these agents can induce an intragastric pH greater than 3, lasting for approximately 10 hours/day when given twice/day at recommended doses. This level of acid suppression can facilitate healing of duodenal ulcers but has limited efficacy for other indications (e.g., gastrointestinal bleed). In the late 1980s a more potent class of acid-suppressing agents was developed, proton pump inhibitors (PPIs). The PPIs can induce an intragastric pH above 3 lasting for approximately 17 hours/day, and an intragastric pH above 5 for approximately 9 hours/day after once-daily oral administration of recommended doses. It is possible to attain even higher target pH values with large doses and with continuous intravenous infusion. Thus, PPIs are agents of choice for treatment of many acid-related disorders including peptic ulcer disease and moderate-to-severe gastroesophageal reflux disease, and for prevention of rebleeding in patients with upper gastrointestinal bleeding. Availability of an intravenous formulation, pantoprazole, enables hospitalized patients for whom oral administration is not feasible to benefit from the superior potency of PPIs. Preliminary data suggest that intravenous PPIs may be more effective than H2RA prophylaxis against stress-related ulcer bleeding for intensive care patients and should facilitate healing in those with bleeding ulcers of the upper gastrointestinal tract.

Life cycle of a block buster drug: discovery and development of omeprazole (Prilosec).

Block buster drugs share a variety of common features, among which is the tendency to create entirely new markets. For example, an early "informed" estimate of the potential market size for the hypothetically "perfect" peptic ulcer drug was thirty-five million dollars. Based on current sales, however, we reckon this hypothesis to have underestimated the actual market demand for omeprazole (Prilosec) by about 400-fold. Similarly, prior to the introduction of the "retired" block busters chlordiazepoxide and diazepam (Librium and Valium), the market for "minor tranquilizers" in the treatment of anxiety and neurosis did not exist. Thus, once an emerging block buster seems to be therapeutically working, it is not unusual for diagnostic rates of the disease for which it is indicated and efficacious to actually increase. Top block buster drugs generally have or appear to have a high margin of safety.

Improving the gastrointestinal safety of NSAIDs: the development of misoprostol--from hypothesis to clinical practice.

Arthritis is a major source of disability for the American population. It results in significant morbidity for the millions of patients affected and costs billions of dollars yearly for diagnosis and management. Nonsteroidal antiinflammatory drugs (NSAIDs) are the principal therapy for the majority of arthritis patients. It has been estimated that more than 15 million people with arthritis take these drugs daily. This use is predicted to increase greatly not only as a result of an aging population, with the consequent increase in the prevalence of arthritis, but also because NSAIDs may prove to have a role in decreasing colonic neoplasia and in reducing the likelihood of conditions such as Alzheimer's disease. It is therefore increasingly important to understand the nature of the side effects associated with these agents as well as ways of decreasing or preventing their occurrence. NSAIDs inhibit the enzymes cyclooxygenase-1 and cyclooxygenase-2. This reduces the synthesis of prostaglandins and therefore decreases joint inflammation, but it may also lead to the development of gastric and duodenal ulcers. For this reason, exogenous prostaglandins have been studied for their potential role in preventing NSAID-associated ulcers and ulcer complications. This paper reviews the development of the prostaglandin E1 analog misoprostol, the theory behind its use as a mucosal protective agent, and the results of studies in animals as well as in normal volunteers and patients with arthritis. Ultimately, a study was performed to evaluate whether misoprostol reduces the incidence of serious ulcer complications in patients taking NSAIDs. It is an interesting story, which promises to be of increasing importance as NSAID use expands to new indications while concern remains about their associated complications, especially those related to the gastrointestinal tract.

[The history of the treatment of chronic duodenal ulcer]. / Historia del tratamiento de la úlcera duodenal crónica.

The author reviews the treatment of duodenal ulcer from its beginnings with gastroenterostomy one hundred years ago. He points out that treatment has changed as it was better understood that hypersecretion of acid was an important ulcerogenic factor. The Sippy regime, with diet and alkali to neutralize acid, and the resection and vagotomy were introduced. He discusses some aspects of the history of these therapies in Panama and points out the importance of the introduction of H2 receptors blocker and other drugs still under investigation.

Historia del tratamiento de la ulcera duodenal crónica / History of the duodenal ulcer chronic treatment

Hemos repasado el tratamiento de la úlcera duodenal desde sus inicios, hace cien años, con la gastroenterostomía. Se señala cómo el tratamiento varió cuando se entendió mejor que la hipersecreción de ácido era factor ulcerogénico. Se introdujo el tratamiento de Sippy, con álcalis y dieta, para neutralizar el ácido; y en cirugía, la resección y la vagotomía. Se hacen algunas consideraciones sobre la historia de estos tratamientos en Panamá. Finalmente, se señala la importancia de los bloqueadores de los receptores H2 y de otros medicamentos todavía en estudio

Discovery and synthesis of rioprostil.

Between 1972 and 1979 a research team at Miles Laboratories produced 1200 prostaglandin analogues as potential pharmaceuticals. Most of these analogues were produced using the Sih synthesis. They were screened in several animal models and a few were found to inhibit gastric acid secretion in the rat. The best compound (TR-4698, rioprostil) is being pursued as an anti-ulcer and cytoprotective agent. An improved synthesis of this compound involves the use of n-butyllithium and copper (I) cyanide in a one-pot conjugate addition of a vinyl tin intermediate with a chiral alkylated cyclopentenone. Multihundred gram lots of rioprostil are produced with only one chromatography, that of the final substance, needed.