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BRMs 498 29 August 1970 MEDICAL JOURNAL Plasma li-Hydroxycorticoid Levels after Carbenoxolone Sodium Br Med J: first published as 10.1136/bmj.3.5721.498 on 29 August 1970. Downloaded from D. MATTINGLY,* M.B., F.R.C.P. ; CHRISTINE TYLER,t B.SC., PH.D.; ELAINE BILTON,t A.I.M.L.T. British Medical Journal, 1970, 3, 498-500 Summary: A definite rise in plasma l1-hydroxycorti- Methods coid levels has been shown in eight patients with All the tests were carried out in the morning, and a single duodenal ulcer following the oral administration of car- dose of 100 mg. of carbenoxolone sodium was given orally to benoxolone sodium. A similar rise was seen in one patient with sarcoidosis whose pituitary A.C.T.H. secretion had the subjects between 10.30 and 11.30, with the exception of been acutely suppressed with dexamethasone. No such one man who was given only 50 mg. The tablets were given with 20-30 ml. of water. Patients had breakfasted normally at rise, however, was seen in three patients suffering from adrenal insufficiency. It is suggested that carbenoxolone 7.30. Venous blood samples of 5-6 ml. were taken from the antecubital fossa by means of an indwelling cannula. Two acts directly on the adrenal cortex, causing an increased production of corticosteroids. control samples were taken at intervals of one hour before the dose of carbenoxolone, and further samples were taken over the subsequent two and a half hours. Plasma 1l-hydroxycorticoids (11-OHCS) were estimated by the fluorimetric method previously described, 2 ml. of plasma Introduction being used for each estimation (Mattingly, 1962). The presence of carbenoxolone sodium in the plasma in concen- sodium is synthesized from Carbenoxolone (Biogastrone) trations up to 10 mg./100 ml. does not interfere with the glycyrrhizic acid, which is one of the many constituents of measurement of ll-OHCS by this technique. The synthetic liquorice root. Apart from its apparent healing effect on the analogues of cortisol do not fluoresce if this method is used, mucosa, prepara- gastric this compound, like crude liquorice so that endogenous corticosteroid production can be studied tions, has other pharmacological actions which rese;nble during the administration of these compounds. those of certain adrenocortical hormones. In rats it has an anti-inflammatory action which is about one-third that of cor- tisol (hydrocortisone) when given by subcutaneous injection, though, unlike cortisol, it is ineffective in rats when given by Subjects mouth. This effect persists in hypophysectomized animals but is greatly reduced when both adrenal glands are removed The subjects, six men and six women, were all inpatients at (Khan and Sullivan, 1968). the time of study and were resting in bed throughout its This anti-inflammatory action of carbenoxolone has not been duration. The nature and purpose of the investigation was investigated in man, but a significant proportion of patients explained to each patient before inclusion in the series. Their a rise to 62 and in but four instances treated with this drug have developed salt retention, in ages ranged from 25 years, all http://www.bmj.com/ blood pressure, hypokalaemia, and occasionally severe potas- they were suffering from duodenal ulcers. The four excep- sium depletion (Doll et al., 1962; Doll et al., 1965; Horwich and tions are described below. Galloway, 1965; Turpie and Thomson, 1965; Hausmann and Tarnoky, 1966; Mohamed et al., 1966; Forshaw, 1969). These Case 1.-A woman of 43 had Addison's disease. On admission side-effects have also been reported with crude liquorice her morning plasma ll-OHCS level was only 3.9 sg./100 ml., or corticosteroid levels preparations, and resemble those produced by an excess of and there was no rise in plasma urinary she was 1 mg. of intramuscular tetracosactrin depot as seen when given adrenal mineralocorticoids such is in Conn's she was also syndrome. each morning for three days. During this period given prednisolone 2 5 mg. and fludrocortisone 0-2 mg. daily by on 29 September 2021 by guest. Protected copyright. Possibly these pharmacological actions of carbenoxolone are mouth, and next day she was again given these steroids five hours due to direct stimulation of corticosteroid production by the before the carbenoxolone was administered. adrenal cortex, but evidence to support this hypothesis is lacking. In particular, a number of workers have shown that a was found to aldosterone secretion is normal or reduced in patients given Case 2.-A man of 58 with pituitary tumour, two His 11- liquorice or its derivatives (Baron et al., 1969). It has, have had hypopituitarism years ago. morning plasma OHCS level was only 0.4 ig./100 ml., and he had a negligible therefore, been suggested that these results are consistent only adrenal response to exogenous A.C.T.H. Since that time he had with the hypothesis that the mineralocorticoid effect of car- been maintained on oral cortisol and thyroxine, and on the day of benoxolone is due to its possessing intrinsic aldosterone-like the test was given a single dose of 30 mg. of cortisol by mouth properties. This theory, however, fails to take into account five and a half hours before the carbenoxolone was administered. the observations of Borst et al. (1953), who concluded that the favourable effects of liquorice on salt loss in Addison's Case 3.-A man of 57 had Addison's disease. His initial morn- disease were seen only in those patients who still had some ing plasma ll-OHCS level was 8 ,ug./100 ml., which is just within left, and those of et functioning adrenal tissue Elmadjian al. the normal morning range, but there was no rise in plasma or (1956), who found that the mineralocorticoid-like action of urinary steroid levels after three days on tetracosactrin depot in a monoammonium glycyrrhizinate, observed in intact subjects, dose of 1 mg. intramuscularly each morning. During the tests he was absent in two adrenalectomized patients. The work was maintained on oral prednisolone 5 mg. twice daily and reported here provides evidence that the administration by fludrocortisone 0.1 mg. by mouth daily. mouth of carbenoxolone sodium produces a rise in the unconjugated plasma 11-hydroxycorticoid levels, raising once Case 4.-A woman of 48 with sarcoidosis, was about to be again the question of its mode of action. started on corticosteroid therapy. She was given 2 mg. of dexa- methasone by mouth at 11.30 on the night before the administra- * Director. tion of carbenoxolone, and a further oral dose of 2 mg. at 6 a.m. t Research Assistant. t Research Technician. next day in order to ensure acute suppression of pituitary Postgraduate Medical Institute, University of Exeter. A.C.T.H. secretion during the test. BRmsa 29 August 1970 Carbenoxolone Sodium and Duodenal Ulcer-Mattingly et al. MEDICAL JOURNAL 499 Results three patients with adrenal insufficiency, however, this seems unlikely and strongly suggests that this drug has a stimulatory Br Med J: first published as 10.1136/bmj.3.5721.498 on 29 August 1970. Downloaded from In all the subjects with duodenal ulcers the administration effect on the adrenal cortex. Whether this is due to a direct of a dose of carbenoxolone sodium mouth resulted in by a action on the adrenal glands or to stimulation of pituitary rise in plasma ll-OHCS levels which lasted for between one A.C.T.H. secretion cannot be determined from these experi- and one and a half hours. The time at which the maximum ments, though the response of Case 4, whose pituitary response was seen varied from 20 to 60 minutes after the A.C.T.H. secretion had been acutely suppressed by dexa- drug had been given. In one of the female patients the test methasone, makes it more likely that it is due to a direct was repeated after she had been treated with carbenoxolone action on the adrenal cortex. This conclusion is supported by for one week, with similar results. The responses of the four the studies of Khan and Sullivan (1968), who found that the female subjects to 100 mg. of carbenoxolone are illustrated in anti-inflammatory action of carbenoxolone in rats was greatly Fig. 1, and the responses of the three male subjects to the reduced by bilateral adrenalectomy but not by hypophysec- same dose are shown in Fig. 2. The response to 50 mg. of tomy. carbenoxolone is included here for comparison, indicating The analytical method used here measures the total uncon- that the rise is similar but of shorter duration than with the jugated 11-hydroxycorticoids in the plasma, and a change of bigger dose. The basal plasma 11-OHCS levels in these concentration of this magnitude could occur only as a result patients were all within the normal morning range of 6 to 24 of either increased production or reduction in the rate of ,ug./100 ml., and the mean rise was 11-9 ug./100 ml. In women removal from the blood stream. Carbenoxolone is conjugated it ranged from 8.4 to 18.0 ,ug./100 ml., with a mean of 12.0 ,ug./ with glucuronic acid in the liver, and one possible way in 100 ml., and in males it ranged from 11-4 to 12.0 ,ug./100 ml., which this drug might affect normal adrenal function is by with a mean of 11.7 ,ug./100 ml. the inhibition of steroid inactivation in the liver, which has The lack of response to carbenoxolone sodium in patients been shown to occur in vitro (Atherden, 1958). If this were so, with Addison's disease and secondary adrenal atrophy is also the half-life of cortisol and other steroids in the circulation shown in Figs.

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