What is the cytoprotective action of carbenoxolone?
G.P. Young (Melbourne)
Chemistry of carbenoxolone
Carbenoxolone is a relatively unique compound - hemisuccinate of the natural terpenoid 18ß-glycyrrhetic acid (enoxolone) . It is highly lipophilic, crosses cell membranes readily, and has high affinity for plasma proteins.
Oral administration is followed by rapid absorption from stomach and small intestine. Its plasma half-life in normal subjects <65 years old is 15 h. Ninety-eight per cent of a dose is excreted in bile, as glucuronide conjugates.
Mechanism of action
Studies of its mechanism of action have focused primarily on gastric mucosa, even though it has a therapeutic benefit for duodenal ulcer and esophagitis as well . These actions have been reviewed by Parke , and fall into three broad categories: effects on mucus, on cell kinetics and on the gastric mucosal barrier.
In 1967, it was shown that carbenoxolone-treated patients had increased mucus in gastric pits . Subsequently, it was shown that carbenoxolone increased mucus synthesis in human gastric mucosa, and some animal species [I]. This was particularly attributed to an increase in the N-acetylneuraminic acid-containing mucoproteins, and was suggested to be due to stimulation of microsomal glycosyl transferases by carbenoxolone.
Carbenoxolone has been shown by a number of investigators in the 1970s  to
prolong the half-life of gastric mucosal cells by reducing the rate of cell turnover, to decrease DNA synthesis and to diminish epithelial exfoliation. Importantly, this effect is seen in the inflamed mucosa of patients with astrophic gastritis, when biopsies are treated with carbenoxolone in organ culture .
Carbenoxolone pretreatment reduces peptic activity and acid secretion in pyloric-ligated rats, and reduces the damaging effect of aspirin on gastric mucosal permeability in humans . Carbenoxolone also reduces net H+ back diffusion across human gastric mucosa. Thus, in the stomach, carbenoxolone can be considered as a cytoprotective agent.
Carbenoxolone appears to have less marked effects on duodenal than gastric mucus , and its action on duodenal epithelial kinetics are unknown. There is no information on its action on esophageal squamous mucosa, although interestingly, it is still available in some countries as an oral preparation (Bioral) for treating oral aphthous ulcers.
Delivering carbenoxolone to the esophagus
The route of action of carbenoxolone has long been considered to be topical on the mucosa. The reasons put forward to support this contention are its lipophilic nature and rapid absorption, its improved efficacy in duodenal ulcer when given in a delayed-release capsule , and its lack of effect on gastric mucus secretion when exposure to gastric mucosa is minimized by delivery to duodenum in the delayed-release capsule . The relationship between serum levels and healing of duodenal ulcer does not disprove the concept that it acts topically .
The observations that a liquid carbenoxolone preparation without other additives was of inconsistent value in esophagitis  led to testing of the possibility that more effective delivery of the drug to the esophagus might be of benefit. Thus a combined alginate/carbenoxolone preparation was developed in an attempt to achieve this by reflux of the viscous carbenoxolone-containing alginate gel .
Carbenoxolone in reflux esophagitis
Using a "low-dose" antacid/alginate/carbenoxolone preparation in a single-center controlled trial on 37 patients with reflux esophagitis, carbenoxolone appeared to hasten symptom relief and endoscopic evidence of healing . The number of patients who showed resolution of symptoms was 89% compared to 50% of alginate/ antacid-treated controls (p < 0.025). Healing occurred endoscopically in 95% vs. 67% (p < 0.05). A subsequent uncontrolled study of a large number of patients confirmed these findings .
A subsequent formulation of Pyrogastrone® containing 20 mg carbenoxolone, 600 mg alginic acid, 60 mg magnesium trisilicate, 240 mg aluminum hydroxide and 210 mg sodium bicarbonate was released. Tablets were to be chewed before swallowing, one 3 times daily after meals and two at night. This "high-dose" (in terms of
antacid and alginate) formulation was compared to antacid/alginate alone in a double-blind multicenter study of 59 patients . Carbenoxolone treated patients showed an 82% improvement in symptom grades over 8 weeks compared to 63% in controls -a 50% faster rate of improvement (p < 0.01). Both groups showed similar significant endoscopic evidence of healing during the first 4 weeks but this improvement was sustained during the second 4 weeks, only in the carbenoxolone-treated group (p < 0.05).
In this study, few side effects occurred. No patient developed edema or renal or hepatic failure. Only one patient on carbenoxolone developed mild hypokalemia. Thus, carbenoxolone in alginate/antacid preparations does offer some therapeutic advantage. In carefully selected and observed patients, the side-effect profile is low.
Carbenoxolone - its role in the 1990s
There have been no direct comparisons of carbenoxolone with H2-receptor antagonists, proton-pump inhibitors or prokinetic agents in reflux esophagitis. It may be that Pyrogastrone compares well with the earlier, less potent H2-receptor antagonists, but it seems unlikely that it will compare favorably with the more recent drugs, especially the proton-pump inhibitors. Certainly its side effect profile of mineralocorticoid-like effects (fluid retention, hypokalemia) put it at a disadvantage. There is some information to suggest that carbenoxolone has an antiviral action (Dr S. Gottfried, personal communication); whether such an effect would be sufficient to be of value in viral esophagitis is completely unknown.
Carbenoxolone is a topically active, cytoprotective agent in the upper gastrointestinal tract. It has a modest but significant effect on symptoms and endoscopic evidence of reflux esophagitis. However, with the advent of more effective and safer agents, it can only be viewed from a historical perspective at this time.
1. Parke DV. Some recent advances in the pharmacology of carbenoxolone. In: Jones FA, Langman MJS, Mann RD (eds) Peptic Ulcer Healing Recent Studies on Carbenoxolone. Lancaster: MTP Press Ltd, 1978;l-8.
4. Klein HJ, Frotz H, Gheorghiu T. Mechanism of action of carbenoxolone. Autoradiographic study of proliferation in vitro of epithelial cells from gastric mucosa of carbenoxolone-treated patients In: Jones FA, Parke DV (eds) Fourth Symposium on Carbenoxolone. London: Butterworths, 1975:161-170.
5. Hossenbocus A, Colin-Jones DG. Protection of the human gastric mucosa from aspirin by carbenoxolone. In: Jones FA, Parke DV (eds) Fourth Symposium on Carbenoxolone London: Butterworths, 1975;91-102.
Young GP, Nagy GS, Myren J, Kronborg U, Logan KR, Reed PI, Hopper JL Treatment of reflux oesophagitis with a