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DISSOLUTION OF CHOLESTEROL GALLSTONES BY URSODEOXYCHOLIC ACID

DISSOLUTION OF CHOLESTEROL GALLSTONES BY URSODEOXYCHOLIC ACID

Saturday 20 August DISSOLUTION OF CHOLESTEROL GALLSTONES BY URSODEOXYCHOLIC ACID 1977 Methods Patient Selection patients (21 men and 34 women; age...

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Saturday 20 August

DISSOLUTION OF CHOLESTEROL GALLSTONES BY URSODEOXYCHOLIC ACID

1977

Methods Patient Selection

patients (21 men and 34 women; age range 23-75 years, 46; weight 37-78 kg, mean 56) with radiolucent gallstones and radiologically visible gallbladders were included in our study. Patients with frequent attacks of biliary colic, with laboratory findings of obstructive hepatic dysfunction, or with a history of drug allergy were eluded, as well as those taking or barbiturates cholagogues Pregnant women or nursing mothers were also excluded. The only other drugs allowed during the trial were antibiotics or analgesics, if needed for an 55

mean

ISAO MAKINO

SHOICHI NAKAGAWA

Second Department of Medicine, Hokkaido

University School

of Medicine, Sapporo, Japan TAKASHI ISHIZAKI*

Department of Pharmacology, Hokkaido University School of Medicine, Sapporo, Japan ICHIRO DOHI

acute

illness.

Treatment

Centre Hospital ofJapan National Railway,

Tokyo,

Japan

There

44 patients with radiolucent gallstones in gallbladders visible on cholecystograwere phy randomly alloted to three treatment groups: ursodeoxycholic acid (600 mg/day), ursodeoxycholic acid (150 mg/day), a placebo. At the end of six months’ treatment, cholecystograms of all the patients were interpreted by radiologists who were not aware of the treatment. Dissolution of gallstones occurred in 8 (26%) of the 31 patients treated with ursodeoxycholic acid, but not in the placebo group. Ursodeoxycholic acid had no hepatotoxicity, as assessed by standard liver-function tests. These results indicate that ursodeoxycholic acid, the 7&bgr; epimer of chenodeoxycholic acid, is effective in the dissolution of cholesterol gallstones.

Introduction IN 1972 Danzinger et al.’ reported that chenodeoxycholic acid (C.D.C.A.) causes dissolution of cholesterol gallstones in man, and this effect has been confirmed.2-7 Although hepatotoxicity caused by C.D.C.A. has been reported in other primates,8-9 evidence for the safety of C.D.C.A. in man is increasing: it is now known that lithocholic acid can be converted into the sulphate by the liver and excreted. 10. 11i In 1975 we reported that ursodeoxycholic acid (U.D.C.A.), the 7p epimer of C.D.C.A., induces desaturation of bile, and in uncontrolled studies we found that gallstone dissolution can be achieved by U.D.C.A.12 We give here the results of a double-blind clinical trial of U.D.C.A.

three

groups: (1) U.D.C.A., 150 mg/day; and (3) a lactose placebo. The U.D.C.A. was synthesised by the Tokyo Tanabe Company and was more than 99% pure (assessed by gas/liquid chromatography and thin-layer chromatography). The substances used in the trial were prepacked in individual patient-coded packages containing tablets identical in colour and size. A pack containing 84 tablets was given to each patient at fortnightly intervals. Each patient had to take two tablets three times a day. Patients were instructed to swallow the tablets without tasting them, because the taste could have interfered with the double-blind nature of the trial. To assess patients’ cooperation, the number of tablets remaining in the container was were

mg/day; (2)

Summary

Groups treatment

u.D.c.A., 600

counted at each return visit. The drug code was held by one of the investigators who did not take part in the clinical assessment. The study was designed so that an individual patient could be removed from the double-blind treatment, but only if absolutely necessary. Symptoms were assessed by questioning. Of 55 patients who entered the trial, 11dropped out because they could not be followed up or would not cooperate. 44 patients (19 men and 25 women) completed at least six months’ treatment.

Evaluation

of Efficacy Cholecystography was performed by

a

standard method

(oral or intravenous drip). A comparison was made between cholecystograms taken before the trial and after six months’ treatment. Each cholecystogram was independently interpreted by five radiologists who were not aware of the patient’s Gallstone size was recorded as the maximum diaof the largest stone seen on X-ray. The radiologists’

treatment. meter

reports were summarised as "effective", or "unchanged", or "worse". "Effective" indicated a reduction in size and/or number of the stones after treatment, "unchanged" meant no change in size and/or in number after treatment, while "worse" meant an increase in size and/or in number after treatment.

* Present address: Division of Clinical

Hospital, Tokyo, Japan

Pharmacology,

National Medical Centre

L iver-function Tests and Serum-lipids Serum G.o.T., G.P.T., alkaline phosphatase, total 8034

pro-

368 TABLE I-OBSERVER CONCORDANCE IN INTERPRETATION OF

CHOLECYSTOGRAMS

Response-rate: number of patients judged as effective (complete partial dissolution)/number of patients treated.

or

TABLE II-RELATIONSHIP BETWEEN SIX-MONTH RESPONSE ANB

Changes in lithogenic index in fasting-state bile before and after treatment with U.D.C.A.

(NUMBER OF PATIENTS SHOWING DISSOLUTION/NUMBER OF PATIENTS TREATED)

GALLSTONE SIZE

Statistical Evaluation of

Placebo Placebo

Index Before

After

treatment

treatment

150 mg

N.s.

U.D.C.A. 600 mg U.D.C.A. 150 mg v. U.D.C.A.

N.s.

v.

U.D.C.A.

v.

600 mg

N.s.

p<0 OS p<0-OS N.s.

Ranges alongside vertical scales represent means+s.D.

Statistical Analysis Statistical evaluation between

U.D.C.A.

group

(150 mg

+

600

mg)

and

placebo group; Fisher’s probability P=0-045 tein levels, and

fasting -cholesterol

and

triglyceride

con-

centrations were determined by standard methods before treatment and at monthly intervals.

Bile-lipid Analysis Bile was obtained by duodenal intubation in 15 of the 44 patients before treatment, and at least once three to six months after treatment. Gallbladder contraction was induced by duodenal instillation of 25% magnesium sulphate solution. Cholesterol’3 and bile-acid content14 were measured enzymatically, and phospholipid was determined colorimetrically." The degree of saturation of bile with cholesterol (lithogenic index) was computed by the method of Thomas and Hofmann;16 the limits of cholesterol solubility were those defined by Hegardt and Dam" and Holzbach et al.18 (an index>l is super-

saturated and < 1 unsaturated).

The comparative efficacy of the three treatments was analysed by Fisher’s probability method when indicated. The characteristics of gallstones and patients at the start of the trial were evaluated by the X2 test.

Results

Efficacy Radiologists agreed closely in their interpretation of the cholecystograms (table i). Gallstones decreased in size in 6 of the 16 patients who had 150 mg ofu.D.c.A. a day, and in 2 of the 15 patients who had 600 mg of U.D.C.A. a day (table n). No change was observed in the 13 patients given the placebo. Gallstones disappeared in 3 patients on U.D.C.A. (150 mg/day) and in 2 patients on U.D.C.A. (600 mg/day). No patients with gallstones greater than 10 mm in diameter responded (table n). There was a statistically significant difference between the U.D.C.A. (150 mg+600 mg) and placebo groups; Fisher’s probability, r=0045. ’

TABLE III-RESULTS OF LIVER-FUNCTION TESTS AND SERUM-LIPIDS BEFORE AND AFTER I

Values given are mean + standard deviation. Figures in parentheses represent no. of patients. There is no statistical difference in serum G.o.T.,serum-alkaline-phosphatase, treatment and after three and six months’ treatment.

I

3 AND 6 MONTHS OF

TREATMENT WITH U.D.C.A, I

serum-cholesterol,and serum-triglyceride between the values before

369

When the dose of U.D.C.A. was calculated as mg/kg body-weight, it was 1.9-4.1 mg/kg/day in the 150 mg/day group (2.9±0.6), and 9.0-12.2 mg/kg/day in the 600 mg/day group (10.2±1.0). The minimum dose in those reported as "effective" was 2.8 mg/kg/day.

Cholesterol Saturation of Bile (Lithogenic Index)

Changes in the lithogenic index in 15 of the 44 patients are shown in the accompanying figure. Bile samples in 11 of the 15 patients were supersaturated with cholesterol before treatment, and the index was 1.38±0.43 in the 150 mg/day group, 1-31±0-51 in the 600 mg/day group, and 1.17±0.36 in the placebo group. The lithogenic index after treatment remained unchanged in patients given the placebo (1-14±0.38), but all bile samples from both groups treated with U.D.C.A. became unsaturated (0-55±0.08 in 150 mg group and 0.66±0.13 in 600 mg group). However, there was no statistically significant difference between the two groups. Patient and Stone Characteristics at Entry The characteristics of patients and the type of stone in each group were analysed at the end of the trial. There was no difference regarding sex, body-weight, presence of other diseases, or the use of other drugs. Patients receiving U.D.C.A. were older than those in the placebo group. However, 12 of the 16 patients given 150 mg/day had stones less than 10 mm in diameter, compared with only 6 of the 15patients given 600 mg/day

(table n). Side-effects There was no increase in the levels of serum-enzymes in the patients receiving U.D.C.A. Blood levels of cholesterol remained unchanged; but the decrease in the mean value of serum-triglyceride levels after six months treatment was 20-9% and 21.0% in U.D.C.A. 150 mg group and 600 mg group respectively. This difference was not statistically significant, but the numbers of patients were small (table ill). No patient had diarrhoea. Discussion Complete partial gallstone dissolution occurred in 8 (26%) of the 31 patients treated with U.D.C.A. ; there was no dissolution in patients receiving the placebo. Thus u.D.c.A. is effective for dissolution of cholesterol gallstones in man. However, unlike the results with C.D.C.A., those obtained with U.D.C.A. did not depend on the dose, since the response was not greater in the high dose group, probably because this group had more patients with large, single stones and such stones are or

known to be resistant to treatment. to previous reports, 3. the effective dose of for the dissolution of gallstones was 14-15 mg/kg/day. In our study, the dose in the 6 patients with good results in the 150 mg group ranged from 2.8 to 4.11 mg/kg/day (3-3±0-5), a quarter of the effective dose of C.D.C.A. This suggests that u.D.c.A. could be used in smaller doses than C.D.C.A. in the treatment of gall-

According

C.D.C.A.

stones.

The

amount of U.D.C.A. needed to expand the pool of bile acids is achieved with a dose of 150 mg/day or that the maximum decrease in hepatic secretion of cholesterol is reached with this dose, and that no further response occurs even if the dose is increased. However, more extensive studies with larger numbers of patients are needed before this matter is resolved. Salen et al.19 reported the formation of u.D.c.A. in patients during treatment with C.D.C.A., and they showed that there might be interconversion between C.D.C.A. and U.D.C.A. in man.20 It would be interesting to know if the decrease of biliary cholesterol was caused by U.D.C.A. or by C.D.C.A., produced by conversion of U.D.C.A. In our study, U.D.C.A. appears to be more potent in the dissolution of gallstones in low doses, and bile became unsaturated in all the patients receiving V.D.C:A. 150 mg/day. Therefore, it seems that u.D.c.A. itself could contribute to the reduced hepatic secretion of cholesterol. As chemical dissolution of gallstones may require the administration of bile acids for two years, the drug used must be safe. We observed no side-effects with U.D.C.A. It has been widely used as a cholagogue in Japan in a dose of 150-300 mg/day with no known side-effects, other than mild diarrhoea. There are differences in the pharmacological properties of the two drugs: C.D.C.A. induces epithelial cells loss, fluid and electrolyte secretion, and increased mucosal permeability when perfused into the human colon; these actions were not observed with

the

Dosage

index was calculated in only 14 patients, but even so it was surprising to find a high level of desaturation in all the patients treated with 150 mg of U.D.C.A., and less desaturation in patients treated with a high dose (see figure). Possible explanations are that

lithogenic

&mid ot;

U.D.C.A.21

findings indicate that u.D.c.A. is potent and apparently safe in the dissolution of gallstones. Further investigations are needed to compare U.D.C.A. with C.D.C.A. and to assess the best dose and its safety and efficacy. Our

We thank Prof. Alan F. Hofmann, of the Mayo Clinic Foundation, Rochester, Minnesota, for his valuable advice.

Requests for reprints should be addressed

to

1. M.

REFERENCES 1.

Danzinger, R. G., Hofmann, A. F., Schoenfield, L. J., Thistle, J. L. New Engl. J. Med. 1972, 286,1. 2. Bell, G. D., Whitney, B., Dowling, R. H. Lancet, 1972, ii, 1213. 3. Iser, J. H., Dowling, R. H., Mok, H. Y. I., Bell, G. D. New Engl. J. Med. 1975, 293, 398. 4. Fromm, H., Eschler, A., Töllner, D., Canzler, H., Schmidt, F. W. Dt. med. Wschr. 1975, 100, 1619. 5. Thistle, J. L., Hofmann, A. F. New Engl. J. Med. 1973, 289, 655. 6. Hofmann, A. F., Paumgartner, G. (editors) Chenodeoxycholic Acid Therapy of Gallstones: Stuttgart, 1974. 7. Hofmann, A. F., Paumgartner, G. (editors): Progress Report 1975: Stutt-

gart, 1975. Dryska, H., Salen, G., Zaki, F. G., Chen, T., Mosbach, E. H. Gastroenterology, 1976, 70, 93. 9. McSherry, C. K., Momssey, K. P., Swarm, R. L., May, P. S., Niemann, W. H., Glenn, F. Ann. Surg. 1976, 184, 490. 10. Cowen, A. E., Korman, M. G., Hofmann, A. F., Cass, O. W. Gastroenterology, 1975, 69, 59. 11. Allan, R. N., Thistle, J. L., Hofmann, A. F., Carter, J. A., Yu, P. Y. S. Gut, 1976, 17, 405. 12. Makino, I., Shinozaki, K., Yoshino, K., Nakagawa, S. Jap. J. Gastroent. 1975, 72, 690. 13. Allain, C. C., Poon, L. S., Chan, C. S. G., Richimond, W., Fu, P. C. Clin. Chem. 1974, 20, 470. 14. Iwata, T., Yamazaki, K. J. Biochem. Tokyo, 1964, 56, 426. 15. Hoefimayr, J., Fried, R. Med. Ernährung, 1966, 7, 9. 16. Thomas, P. J., Hofmann, A. F. Gastroenterology, 1973, 65, 698. 17. Hegardt, F. G., Dam, H. Z. Ernaehrungswiss, 1971, 10, 1043. 18. Holzbach, R. T., Marsh, M., Olszewski, M., Holan, K. J. clin. Invest. 1973, 8.

52, 1467. 19.

Salen, G., Tint, G. S., Eliav, B., Deering, N., Mosbach, E. H. ibid. 1976,

53, 612. 20. Salen, G., Fedorowski,

T., Colalillo, A., Mosbach, E. H. Gastroenterology, 1976, 70, 992. 21. Chadwick, V. S., Gadinella, T. S., Dobongnie, J. C., Phillips, S. F., Hofmann, A. F.

Gastroenterology (in the press).