Guest Editorial Drugs 11: 241-244 (1976) © ADIS Press 1976
Carbenoxolone Sodium: Its Role in Ulcer Healing
M.J.S. Langman Department of Therapeutics, City Hospital, Nottingham
The value of carbenoxolone sodium in promoting the healtng of gastric ulcer was reported 14 years ago (Doll et aI, 1962). Since then the fundamental observation that the drug works has been substantiated many times, and the results have been extended to suggest that duodenal ulcer healing may also be accelerated (Archambault et aI, 1975; Hunt, 1975; Gheorghiu et al., 1975). As carbenoxolone is the first drug which has been unequivocally shown to be of benefit in ulcer, and it is one of the most tested of gastro-intestinal drugs, it is initially surprising to find that further assessment continues prior to licensing its release in many countries where it has not hitherto been used. There are at least four reasons for the delay, two general and two specific. Firstly, many licensing authorities require testing within the country of their jurisdiction, a blanket ruling resulting in much senseless repetitive work and which is of doubtful benefit. Such testing inevitably delays the free release of any drug since it seldom takes less than 2 years to conduct an adequate clinical trial (quite apart from any animal testing requested). It also suffers from the formidable disadvantage that once a drug's properties are known it becomes increasingly difficult to obtain satisfac-
tory studies conducted by interested and well qualified investigators. Results which are obtained tend not unnaturally to mirror those already available or, if similar results are not obtained, there is often a suspicion that this stems from fundamental problems in trial conduct rather than from an inadequate initial appraisal if already performed by competent investigators elsewhere. Secondly, all ulcers have a tendency to heal spontaneously and in such circumstances there is correspondingly less clinical pressure to obtain a remedy which may be beneficial, but only in a proportion of patients. At least a third of all gastric ulcers will heal without specific treatment, and virtually all duodenal ulcer symptoms will remit temporarily. A third factor which may be important is that there is so far no reason for believing that short term ulcer healing radically alters the course of the disease. Carbenoxolone sodium has been clearly shown to make gastric ulcers heal faster and a higher proportion of ulcers heal completely during treatment than when a dummy preparation is used. However, there is no conclusive evidence that this effect is associated with a better overall prognosis. A quarter to a half of all ulcers are fmally treated surgically and there is no good
Carbenoxolone Sodium: Its Role in Ulcer Healing
242
evidence that the introduction of short term heal- carbenoxolone capsules (,Duogastrone'), there is ing agents has greatly changed this proportion. some doubt as to whether this initial benefit is Maintenance treatment might logically have been maintained (Brown et a1., 1972; Montgomery et expected to have been thoroughly tested by now al., 1968). The measurement of duodenal ulcer but the fragmentary evidence available does not response is impeded however, because initial definitely confirm that long-term benefit ensues. symptomatic improvement often bears no relationFinally, the drug has undoubted side-effects, ship to the observed endoscopic changes in the mainly of salt and water retention, but occasion- duodenal mucosa (Brown et al., 1972), and judgeally of hypokalaemia and hypertension. The sign- ments made radiographically are often impOSSible. ificance of these relative to the benefits of the Whether short-term treatment is of long-term value drug are a matter of individual judgement, but the is unknown, but there is a strong suggestion that natural caution of licensing agencies, often based patients recelvmg placebos may ultimately upon terms of reference to prevent harm rather improve symptomatically and thus catch up on than to try and weigh profit against loss, inevitably those given test remedies (Montgomery et al., 1968; Brown et al., 1972). also tends to produce delays. Carbenoxolone has been widely used in the The precise mode of action of carbenoxolone is United Kingdom for 10 years, and this experience unclear. It does not seem to inhibit acid secretion, should allow some balanced judgement of its although it appears to have some antipeptic activity (Berstad, 1972). Its effect in prolonging value. From the published clinical trial series reviewed epithelial cell life span (Upkin, 1971) and in this issue (p.245) it would seem that of every inducing mucosal glycoprotein synthesis (Shilling100 gastric ulcers considered for treatment ford et al., 1974) may be of more significance. approximately one-third will have healed in the Side-effects are common, and occur in up to a period intervening between diagnosis and re- third of patients treated. The frequency is related examination prior to entry to any trial (Doll et al., to three factors: (1) drug dose; (2) age, and (3) 1962; Turpie et al., 1964; Langman et al., 1973). concomitant disease, particularly of the cardioOnce included in the treatment group, between a respiratory system. If patients are poorly superthird and a half will heal completely (compared vised then the cumulative effects of salt and water with less than a fifth in the control group) during retention and reduction in serum potassium levels 4 to 8 weeks treatment, leaving about a quarter of can give rise to severe hypertension with papilloethe original group unhealed. High overall healing dema, congestive heart failure and hypokalaemic rates are recorded in the USA and Australia by myopathy and quadruparesis (Davis et al., 1974). inpatient treatment without specific drug treat- Such alarming adverse effects should be preventment, but such results probably reflect, at least in able by proper supervision of treatment. If part, the inclusion by the selection procedure of patients are seen every 1 to 2 weeks then any rise patients whose ulcers would have healed naturally in blood pressure or undue weight gain associated (Herrmann and Piper, 1973; Sun and Stempien, with fluid retention should be recognised early. 1971). Once healed, relapse may still occur; there Prompt treatment with thiazide diuretics will are few figures available, but it seems to be equally almost always reverse the changes, even during likely in those who received carbenoxolone continued carbenoxolone administration. Measurecompared with those who did not. ment of serum potassium concentrations is The value of duodenal ulcer treatment is harder unnecessary at more than 3 week intervals. Howto gauge. Though there is reason for believing that ever, it should be remembered that thiazide initial responses are improved by treatment with diuretics are kaliuretic and regular measurements
243
Carbenoxolone Sodium: Its Role in Ulcer Healing
and potassium supplementation are essential during diuretic treatment. The side-effects of carbenoxoloneare reminiscent of aldosterone-like activity but though spironolactone will prevent the fluid retention induced by carbenoxolone it also inhibits the healing effect (Doll et aI., 1968). Potassium sparing diuretics such as amiloride are logical alternatives, but have yet to be shown to be effective and to allow healing to proceed unhindered. The precise mechanism by which side-effects are induced is unclear. Carbenoxolone concentrations in plasma are often very high, but such findings, probably only reflect the high degree of drug protein binding. Though the side-effects resemble the action of aldosterone there is no evidence to suggest that aldosterone plasma binding is reversed to any significant extent by carbenoxolone displacement. (Hayes and Langman, 1974). A direct action of carbenoxolone on aldosterone receptors seems a more likely mechanism. Elderly patients may be more prone to side-effects because they have a reduced number of plasma binding sites (with lowered serum albumin levels) and reduced hepatic clearance rates compared with younger people (Hayes and Langman, 1974). So far a single analogue which promised to be free of side-effects has been tested, but its healing properties were unimpressive (Fraser et al., 1972). A variety of other drugs including anticholinergic agents, antipepsins, bismuth chelates, metoclopramide, substituted prostaglandins and deglycyrrhizinised liquorice have been suggested as beneficial in promoting ulcer (particularly gastric ulcer) short-term healing. However, the evidence in support of all of these is as yet less substantial than favouring carbenoxolone. They do, however, have the advantage of a general freedom from serious side-effects (with some exceptions). In summary, carbenoxolone is a useful drug in accelerating short-term ulcer healing during ambulatory treatments. Provided treatment is
responsibly controlled the adverse effects should not present frequent or severe problems; however, there is a clear need for an analogue which is su"stantially side-effect free.
References Archambault, A; Farley, A.; Gosselin, D. and Martin, F.: Multicentere double blind study of duogastrone in the treatment of duodenal ulcers; in Fourth Symposium on Carbenoxolone Sodium Avery-Jones and Parke (Eds) p.251 (Butterworths, London, 1975). Berstad, A.: Inhibition of peptic activity in man by carbenoxolone sodium. Scandinavian Journal of Gastroenterology 7: 129 (1972). Brown, P.: Salmon, P.R.; Htut, T. and Read, A.E.: Double blind trial of carbenoxolone sodium capsules in duodenal ulcer therapy based on endoscopic diagnosis and follow up. British Medical Journal 3: 661 (1972). Davies, G.J.; Rhodes, J. and Calcraft, B.J.: Complications of Carbenoxolone therapy. British Medical Journal 3: 400 (1974). Doll, R.; Hill, I.D.; Hutton, C.F. and Underwood, D.J.: Clinical trials of a triterpenoid liquorice compound in gastric and duodenal ulcer. Lancet 2: 793-796 (1962). Doll, R.; Langman, M.J.S. and Shawdon, H.H.: Treatment of gastric ulcer with carbenoxolone: antagonistic effect of spironolactone. Gut 9: 42 (1968). Fraser, P.M.; Doll, R.; Langman, M.J.S.; Misiewica, J.J. and Shawdon, H.H.: Clinical trial of a new carbenoxolone analogue (BX24), zinc sulphate, and vitamin A in the treatment of gastric ulcer. Gut 13: 459 (1972). Gheorghiu, T.; Frotz, H. and Dole, A: The therapeutic effect of carbenoxolone in duodenal ulcer. Preliminary analysis of a multi-centre double- blind trial; in AveryJones and Parke (Eds) Fourth Sympsium on Carbenoxolone Sodium, p.257 (Butterworths, London 1975). Hayes, M.J. and Langman, M.J.S.: An analysis of carbenoxolone plasma binding and clearance in young and elderly people; in Avery-Jones and Parke (Eds) Fourth Symposium on Carbenoxolone Sodium, p.107 (Butterworths, London 1975). Herrmann, R.P. and Piper, D.W.: Factors influencing the healing rate of chronic gastric ulcer. American Journal of Digestive Diseases 18: 1 (1973).
Carbenoxolone Sodium: Its Role in Ulcer Healing
Hunt, T.: Carbenoxolone and duodenal ulcer: a review; in Avery-Jones and Parke (Eds) Fourth Symposium on Carbenoxolone Sodium, and p.235 (Butterworths, London 1975). Langman, M.J.S.; Knapp, D.R. and Wakely, E.J.: Treatment of chronic gastric ulcer with carbenoxolone and gefarnate; a comparative trial. British Medical Journal 3: 84 (1973). Lipkin, M.: In defence of the gastric mucosa. Gut 12: 599 (1971). Montgomery, R.D.; Lawrence, I.H.; Manton, D.J.; Mendl, K. and Rowe, P.: A controlled trial of carbenoxolone sodium capsules in the treatment of duodenal ulcer. Gut 9: 704 (1968). Shillingford, J.; Lindup, W.E. and Parke, D.V.: The effects of carbenoxolone on the biosynthesis of gastric
244
glycoproteins in the rat and ferret. Biochemical Society Transactions 2: 1104 (1974). Sun, D.C.H. and Stempien, S.J.: The Veterans Administration co-operative study on gastric ulcer. Site and size of the ulcer as determinants of outcome. Gastroenterology 61: 576 (1971). Turpie, A.G.G.; Runcie, 1. and Thomson, T.J.: Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut 10: 299 (1969).
Author's address: Professor MJ.S. Langman, University of Nottingham, Department of Therapeutics, City Hospital, Nottingham NG5 lPB (England).
Carbenoxolone Sodium: Its Role in Ulcer Healing
M.J.S. Langman Department of Therapeutics, City Hospital, Nottingham
The value of carbenoxolone sodium in promoting the healtng of gastric ulcer was reported 14 years ago (Doll et aI, 1962). Since then the fundamental observation that the drug works has been substantiated many times, and the results have been extended to suggest that duodenal ulcer healing may also be accelerated (Archambault et aI, 1975; Hunt, 1975; Gheorghiu et al., 1975). As carbenoxolone is the first drug which has been unequivocally shown to be of benefit in ulcer, and it is one of the most tested of gastro-intestinal drugs, it is initially surprising to find that further assessment continues prior to licensing its release in many countries where it has not hitherto been used. There are at least four reasons for the delay, two general and two specific. Firstly, many licensing authorities require testing within the country of their jurisdiction, a blanket ruling resulting in much senseless repetitive work and which is of doubtful benefit. Such testing inevitably delays the free release of any drug since it seldom takes less than 2 years to conduct an adequate clinical trial (quite apart from any animal testing requested). It also suffers from the formidable disadvantage that once a drug's properties are known it becomes increasingly difficult to obtain satisfac-
tory studies conducted by interested and well qualified investigators. Results which are obtained tend not unnaturally to mirror those already available or, if similar results are not obtained, there is often a suspicion that this stems from fundamental problems in trial conduct rather than from an inadequate initial appraisal if already performed by competent investigators elsewhere. Secondly, all ulcers have a tendency to heal spontaneously and in such circumstances there is correspondingly less clinical pressure to obtain a remedy which may be beneficial, but only in a proportion of patients. At least a third of all gastric ulcers will heal without specific treatment, and virtually all duodenal ulcer symptoms will remit temporarily. A third factor which may be important is that there is so far no reason for believing that short term ulcer healing radically alters the course of the disease. Carbenoxolone sodium has been clearly shown to make gastric ulcers heal faster and a higher proportion of ulcers heal completely during treatment than when a dummy preparation is used. However, there is no conclusive evidence that this effect is associated with a better overall prognosis. A quarter to a half of all ulcers are fmally treated surgically and there is no good
Carbenoxolone Sodium: Its Role in Ulcer Healing
242
evidence that the introduction of short term heal- carbenoxolone capsules (,Duogastrone'), there is ing agents has greatly changed this proportion. some doubt as to whether this initial benefit is Maintenance treatment might logically have been maintained (Brown et a1., 1972; Montgomery et expected to have been thoroughly tested by now al., 1968). The measurement of duodenal ulcer but the fragmentary evidence available does not response is impeded however, because initial definitely confirm that long-term benefit ensues. symptomatic improvement often bears no relationFinally, the drug has undoubted side-effects, ship to the observed endoscopic changes in the mainly of salt and water retention, but occasion- duodenal mucosa (Brown et al., 1972), and judgeally of hypokalaemia and hypertension. The sign- ments made radiographically are often impOSSible. ificance of these relative to the benefits of the Whether short-term treatment is of long-term value drug are a matter of individual judgement, but the is unknown, but there is a strong suggestion that natural caution of licensing agencies, often based patients recelvmg placebos may ultimately upon terms of reference to prevent harm rather improve symptomatically and thus catch up on than to try and weigh profit against loss, inevitably those given test remedies (Montgomery et al., 1968; Brown et al., 1972). also tends to produce delays. Carbenoxolone has been widely used in the The precise mode of action of carbenoxolone is United Kingdom for 10 years, and this experience unclear. It does not seem to inhibit acid secretion, should allow some balanced judgement of its although it appears to have some antipeptic activity (Berstad, 1972). Its effect in prolonging value. From the published clinical trial series reviewed epithelial cell life span (Upkin, 1971) and in this issue (p.245) it would seem that of every inducing mucosal glycoprotein synthesis (Shilling100 gastric ulcers considered for treatment ford et al., 1974) may be of more significance. approximately one-third will have healed in the Side-effects are common, and occur in up to a period intervening between diagnosis and re- third of patients treated. The frequency is related examination prior to entry to any trial (Doll et al., to three factors: (1) drug dose; (2) age, and (3) 1962; Turpie et al., 1964; Langman et al., 1973). concomitant disease, particularly of the cardioOnce included in the treatment group, between a respiratory system. If patients are poorly superthird and a half will heal completely (compared vised then the cumulative effects of salt and water with less than a fifth in the control group) during retention and reduction in serum potassium levels 4 to 8 weeks treatment, leaving about a quarter of can give rise to severe hypertension with papilloethe original group unhealed. High overall healing dema, congestive heart failure and hypokalaemic rates are recorded in the USA and Australia by myopathy and quadruparesis (Davis et al., 1974). inpatient treatment without specific drug treat- Such alarming adverse effects should be preventment, but such results probably reflect, at least in able by proper supervision of treatment. If part, the inclusion by the selection procedure of patients are seen every 1 to 2 weeks then any rise patients whose ulcers would have healed naturally in blood pressure or undue weight gain associated (Herrmann and Piper, 1973; Sun and Stempien, with fluid retention should be recognised early. 1971). Once healed, relapse may still occur; there Prompt treatment with thiazide diuretics will are few figures available, but it seems to be equally almost always reverse the changes, even during likely in those who received carbenoxolone continued carbenoxolone administration. Measurecompared with those who did not. ment of serum potassium concentrations is The value of duodenal ulcer treatment is harder unnecessary at more than 3 week intervals. Howto gauge. Though there is reason for believing that ever, it should be remembered that thiazide initial responses are improved by treatment with diuretics are kaliuretic and regular measurements
243
Carbenoxolone Sodium: Its Role in Ulcer Healing
and potassium supplementation are essential during diuretic treatment. The side-effects of carbenoxoloneare reminiscent of aldosterone-like activity but though spironolactone will prevent the fluid retention induced by carbenoxolone it also inhibits the healing effect (Doll et aI., 1968). Potassium sparing diuretics such as amiloride are logical alternatives, but have yet to be shown to be effective and to allow healing to proceed unhindered. The precise mechanism by which side-effects are induced is unclear. Carbenoxolone concentrations in plasma are often very high, but such findings, probably only reflect the high degree of drug protein binding. Though the side-effects resemble the action of aldosterone there is no evidence to suggest that aldosterone plasma binding is reversed to any significant extent by carbenoxolone displacement. (Hayes and Langman, 1974). A direct action of carbenoxolone on aldosterone receptors seems a more likely mechanism. Elderly patients may be more prone to side-effects because they have a reduced number of plasma binding sites (with lowered serum albumin levels) and reduced hepatic clearance rates compared with younger people (Hayes and Langman, 1974). So far a single analogue which promised to be free of side-effects has been tested, but its healing properties were unimpressive (Fraser et al., 1972). A variety of other drugs including anticholinergic agents, antipepsins, bismuth chelates, metoclopramide, substituted prostaglandins and deglycyrrhizinised liquorice have been suggested as beneficial in promoting ulcer (particularly gastric ulcer) short-term healing. However, the evidence in support of all of these is as yet less substantial than favouring carbenoxolone. They do, however, have the advantage of a general freedom from serious side-effects (with some exceptions). In summary, carbenoxolone is a useful drug in accelerating short-term ulcer healing during ambulatory treatments. Provided treatment is
responsibly controlled the adverse effects should not present frequent or severe problems; however, there is a clear need for an analogue which is su"stantially side-effect free.
References Archambault, A; Farley, A.; Gosselin, D. and Martin, F.: Multicentere double blind study of duogastrone in the treatment of duodenal ulcers; in Fourth Symposium on Carbenoxolone Sodium Avery-Jones and Parke (Eds) p.251 (Butterworths, London, 1975). Berstad, A.: Inhibition of peptic activity in man by carbenoxolone sodium. Scandinavian Journal of Gastroenterology 7: 129 (1972). Brown, P.: Salmon, P.R.; Htut, T. and Read, A.E.: Double blind trial of carbenoxolone sodium capsules in duodenal ulcer therapy based on endoscopic diagnosis and follow up. British Medical Journal 3: 661 (1972). Davies, G.J.; Rhodes, J. and Calcraft, B.J.: Complications of Carbenoxolone therapy. British Medical Journal 3: 400 (1974). Doll, R.; Hill, I.D.; Hutton, C.F. and Underwood, D.J.: Clinical trials of a triterpenoid liquorice compound in gastric and duodenal ulcer. Lancet 2: 793-796 (1962). Doll, R.; Langman, M.J.S. and Shawdon, H.H.: Treatment of gastric ulcer with carbenoxolone: antagonistic effect of spironolactone. Gut 9: 42 (1968). Fraser, P.M.; Doll, R.; Langman, M.J.S.; Misiewica, J.J. and Shawdon, H.H.: Clinical trial of a new carbenoxolone analogue (BX24), zinc sulphate, and vitamin A in the treatment of gastric ulcer. Gut 13: 459 (1972). Gheorghiu, T.; Frotz, H. and Dole, A: The therapeutic effect of carbenoxolone in duodenal ulcer. Preliminary analysis of a multi-centre double- blind trial; in AveryJones and Parke (Eds) Fourth Sympsium on Carbenoxolone Sodium, p.257 (Butterworths, London 1975). Hayes, M.J. and Langman, M.J.S.: An analysis of carbenoxolone plasma binding and clearance in young and elderly people; in Avery-Jones and Parke (Eds) Fourth Symposium on Carbenoxolone Sodium, p.107 (Butterworths, London 1975). Herrmann, R.P. and Piper, D.W.: Factors influencing the healing rate of chronic gastric ulcer. American Journal of Digestive Diseases 18: 1 (1973).
Carbenoxolone Sodium: Its Role in Ulcer Healing
Hunt, T.: Carbenoxolone and duodenal ulcer: a review; in Avery-Jones and Parke (Eds) Fourth Symposium on Carbenoxolone Sodium, and p.235 (Butterworths, London 1975). Langman, M.J.S.; Knapp, D.R. and Wakely, E.J.: Treatment of chronic gastric ulcer with carbenoxolone and gefarnate; a comparative trial. British Medical Journal 3: 84 (1973). Lipkin, M.: In defence of the gastric mucosa. Gut 12: 599 (1971). Montgomery, R.D.; Lawrence, I.H.; Manton, D.J.; Mendl, K. and Rowe, P.: A controlled trial of carbenoxolone sodium capsules in the treatment of duodenal ulcer. Gut 9: 704 (1968). Shillingford, J.; Lindup, W.E. and Parke, D.V.: The effects of carbenoxolone on the biosynthesis of gastric
244
glycoproteins in the rat and ferret. Biochemical Society Transactions 2: 1104 (1974). Sun, D.C.H. and Stempien, S.J.: The Veterans Administration co-operative study on gastric ulcer. Site and size of the ulcer as determinants of outcome. Gastroenterology 61: 576 (1971). Turpie, A.G.G.; Runcie, 1. and Thomson, T.J.: Clinical trial of deglycyrrhizinised liquorice in gastric ulcer. Gut 10: 299 (1969).
Author's address: Professor MJ.S. Langman, University of Nottingham, Department of Therapeutics, City Hospital, Nottingham NG5 lPB (England).
