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The development of cimetidine as a treatment for peptic ulcer
A peptic ulcer is defined as being an erosion of the mucous membrane of the gastrointestinal tract, around 80% of cases are caused by chronic inflammation due to Helicobacter pylori that colonizes in the stomach. Having an ulcer in such an acidic area of course there is a lot of pain and discomfort, and if left untreated this can result in internal bleeding and death. Until as late as the 1970s having a peptic ulcer was a serious condition and very difficult to manage. Before the development of cimetidine the course of treatment would be to follow a milky, bland diet and take to antacids to try and neutralise the gastric acid and allow healing to take place. However if the condition became very severe then surgery to remove the ulcerated area was the only option. The development of cimetidine, trade name Tagamet, was a major breakthrough in the treatment of peptic ulcer and really transformed the lives of millions of people.
In 1964 a team of research scientists at the UK base of Smith Kline & French, made up of George Palet, William Duncan and James Black, began a project to prove the existence of a second histamine receptor (H2), one that wasn't antagonised by antihistamines. They also hoped to prove that it was possible to inhibit the stimulation of acid secretion by histamine, by antagonising these H2 histamine receptors and this would be a treatment of peptic ulcers as it would decrease gastric acid secretion. When the project started there was no consensus regarding the physiological role of histamine in acid secretion, there was evidence that there was a second receptor but it was yet to be found. James Black, after his recent successful discovery of the ß-adrenergic receptor and development of propranolol, had the initial idea to alter the histamine molecule to form the H2 receptor antagonist. During this initial search for a H2 receptor antagonist an agonist, 4-methylhistamine, was produced which stimulated acid secretion but had none of the other histamine responses, thus proving the existence of the second histamine receptor. Extension of the side chain of 4-methylhistamine increased its antagonistic properties and finally a compound was that lacked all agonistic effect was produced. This was burimamide. It was shown in dogs that burimamide inhibited acid secretion after stimulation with histamine, pentagastrin or food. This was the very first H2 histamine receptor antagonist and a patent for burimamide was applied for in June 1971. However this drug was not very well absorbed and therefore not orally active, so structural changes were made to the burimamide compound and an orally active analogue was developed. This drug was called metiamide and a patent was applied for in March 1972. Early testing showed the same results in dogs as burimamide, but it was five times more active and much more easily absorbed. It was suggested that metiamide acted as a competitive antagonist of H2 receptors in the gastric mucosa. Clinical trials of the drug started in 1973. These clinical trials showed impressive results, with some ulcers healing within 3 weeks. The early safety testing of metiamide showed a lot of potential, but during these trials it was discovered that this drug caused agranulocytosis as a side effect, and all clinical trials in the UK were halted immediately. However clinical trials in the USA and South America were continued with close haematological monitoring.
The research team set about developing a similar compound but exchanged the thiourea group of metiamide with a cyanoguanidine moiety hoping that this would stop the agranulocytosis side effect as guanidines occur naturally in the body therefore should be well tolerated. The compound produced was called cimetidine, and the patent application was filed in September 1973. Cimetidine had 10 times more activity than burimamide.
Initial clinical trials showed promise: a study was undertaken to observe the effects of cimetidine over a twenty four hour period in a group of 9 normal men. Results showed that cimetidine at a dose of 0.25grams four times a day produced a consistent and remarkable inhibition of gastric acid secretion. And although variation in when the drug was taken in relation to meals did not affect the decrease in acid secretion, the absorption data suggested that patients should take the drug after meals. (Pounder, R. E. et al. 1976)
The real turning point for the development cimetidine came when a patient with a 7 year history of peptic ulcer disease was admitted to hospital in August 1975. His condition was critical and he underwent emergency surgery, however this made no difference. His physician contacted the team at Smith Kline & French and arranged for a supply of metiamide to be sent to treat the patient, he was advised at the time of the occurrence of agranulocytosis in patients taking metiamide. Within a week of daily metiamide there was a remarkable recovery in the patient, and by October 1975 the patient was discharged. However in November 1975 the patient was readmitted gravely ill with total neutropenia and metiamide was stopped. A request for cimetidine was made, and was started the next day. His condition improved, and white blood cell count returned to normal within a few days. The decision to give the patient cimetidine put the entire H2 receptor project at risk, as if the patient had died it would have been very difficult to prove whether it was caused by the peptic ulcer or the cimetidine. However there was now proof that the agranulocytosis was due to the metiamide and not due to H2 receptor antagonism. Cimetidine was on the road to success!
In May 1976 the first controlled trial with positive results in treating patients was published. Eight male patients with peptic ulcers were used in a trial to test cimetidine's ability to suppress overnight gastric acid secretion. In the double-blind investigation the patients received 100, 200, or 300 mg of cimetidine or a placebo randomly over four consecutive nights. Single-dose oral administration of 300 mg of cimetidine showed the optimal inhibition of overnight gastric acid secretion during an 8-hr period, with the gastric pH staying between 3.5 and 6.0. No untoward side effects of the drug were found. (Hollander, D. et al. 1976)
Cimetidine was hailed a wonder drug, it passed all clinical trials without a hitch and in November 1976 was launched under the trade name Tagamet, with larger and longer clinical trials still ongoing.
In 1979, endoscopy, clinical assessment, and laboratory studies were used in a month long double-blind multicentre trial on two hundred patients with uncomplicated duodenal ulcers. The study was to compare the effects of cimetidine given at doses of 1 or 2 grams per day compared to a placebo. Ulcer healing occurred in 28% of patients taking the placebo, 61% of patients taking 1 gram of cimetidine a day, and 70% of patients taking 2 grams of cimetidine a day. This showed cimetidine had a significant advantage over the placebo, but the effects of the two doses of cimetidine were not shown to be markedly different. There was noticeable symptomatic improvement of patients given cimetidine early into the trial. As part of the study patients were asked to report all side effects, and the only side effect found which might have been caused by cimetidine was headache in 5% of patients. Biochemical studies showed significant (though slight) rises in serum uric acid, and serum creatinine but no significant changes occurred in the serum levels of liver enzymes. This study confirmed that 1 gram is a suitable daily dose of cimetidine for the treatment of duodenal ulceration. (Bardhan, K. D. et al. 1979)
Studies have also been undertaken to prove cimetidine's use in the prevention of the return of peptic ulcers. In 1978, forty seven patients were used in a double blind trial to evaluate the efficacy of 400mg of cimetidine twice a day in the prevention of recurrent duodenal ulcers over the course of a year. Seven patients were not considered in the final result; six patients withdrew, and one patient did not maintain the prescribed treatment. Of the remaining fourty patients, twenty six took cimetidine and fourteen took the placebo. Within a year ulcers recurred in all patients taking the placebo, and of the cimetidine patients, two had recurrent ulcers within a year, and three had other endoscopic abnormalities at the end of the treatment. The remaining twenty one patients had no abnormalities which could be endoscopically observed at the end of a year. And so from this study it was concluded that a maintenance dose of cimetidine significantly reduces the risk of recurrence of a duodenal ulcer. (Mekel, R. C. 1978)
High doses of cimetidine (more than five grams a day) can cause reversible impotence or gynaecomastia. Cimetidine also interacts with many drugs metabolized by cytochrome P450, for example, tricyclic antidepressants. The safety of long-term cimetidine use has not been officially studied but should be considered in relation to the potential consequences of prolonged acid suppression, including the risk of proliferation of gastric flora and the risk of developing enterochromaffin-like cell hyperplasia, which could in turn, theoretically, lead to gastric malignancy. Although these problems have not been observed in patients taking high or low doses of cimetidine for a prolonged period of time, this is thought be because standard doses of cimetidine allow acid secretion in response to food, and this daily acid tide prevents lasting bacterial colonization. (Sabesin, S. M. 1993)
Cimetidine has a half life of about 2 hours and when taken orally 48% is excreted unchanged in urine.
The Committee on Safety of Medicines regranted a clinical trial certificate for metiamide in 1974 but only for seriously ill patients.
Ten years after its introduction cimetidine had achieved sales of one billion dollars and had become the world's number one presecription drug. It was the world's first “blockbuster drug”. Tagamet closed hospital wards that were no longer needed, something which very few pharmaceutical brands can ever claim. With such high demand for cimetidine it was important to have an economically viable manufacturing process. The production volume reached 1000 tons a year which is a huge amount by pharmaceutical standards. Just as the discovery of cimetidine is a milestone in drug design, the discovery and development of a cost effective synthetic route to make cimetidine is a milestone in process research and development. The initial process used to make cimetidine involved a rate limiting step which required the reduction of an ester intermediate, using lithium aluminum hydride (LAH). The LAH process was difficult and expensive to operate and was threatened by a shortage of LAH supplies. A more economical and effective method of producing cimetidine was developed by using sodium in liquid ammonia for the reduction of the ester. This cleaner, less expensive pathway helped cut tens of millions of dollars per year from the manufacturing cost. However the success of cimetidine was shortlived.
Glaxo launched the second H2 antagonist Zantac (ranitidine) in 1981. It was not a revolutionary drug in terms of it's pharmacology but it was in terms of industry. Glaxo priced Zantac more than 50% higher than Tagamet but marketed the drug aggressively and this strategy paid off and within a few years it was outselling Tagamet.
In May 1994 Tagamet's patent expired. A few years before Tagamet's patent expiry a new class of drugs called proton pump inhibitors were introduced, led by Losec (patent expiry in 2014). They soon replaced all H2 antagonists as the standard of care for peptic ulcer prevention and treatment.
Cimetidine - safety, phase I, II, III, registration, post launch activities, 2010 (patent expiry??)