1118 disease was seen in one patient with melanoma limited to the skin, who received intradermal B.C.G. while manifesting a positive skin test to P.P.D. Allison and Davies 4and Taub and Gershonhave suggested that the potentiating effects of
immunological adjuvants on immune responses may require a relatively intact thymus-dependent lymphocyte Presumably this system functions poorly in system. anergic patients. We conclude that B.C.G. alone is not indicated in anergic patients with widespread melanoma, and we are limiting our trials of immunotherapy with B.C.G. to patients with localised melanoma who show intact cellular immunity. Division of Hæmatology, Department of Medicine, Toronto Western Hospital, University of Toronto, Toronto 2B, Ontario, Canada. Division of Hematology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, N.Y., U.S.A.
MICHAEL A. BAKER.
ROBERT N. TAUB.
BIOAVAILABILITY OF DIGOXIN at the international symposium in Oslo which throws further light on factors which can affect the absorption of digoxin. Although we did not measure digoxin particle size as did Jounela and Sotmnann,6 we measured other physical characteristics of the tablets tested. The method of checking bioavailability has been reportedand in this study tablets made by Ketchum produced a very low plasmadigoxin level in normal volunteers. Tablets made by Burroughs Wellcome (batch 350c), Lederle (batch 4453-203), and Ketchum (batch 1031232) were assayed for digoxin content by radioimmunoassay after being ground up and dissolved in 70% alcohol. In addition their disintegration-times and dissolution-times were measured by methods given in the U.S. Pharmacopeia and elsewhere,8 with the following results:
SiR,-We presented data
It seems that when the dissolution profile showed a small percentage of the tablet in solution after one hour and the disintegration-time was over two minutes, then the digoxin known to be present in the tablet could not be absorbed. Hence our recommendation to the symposium was that digoxin tablets should be checked by some national drug-survey agency for their physical characteristics before being permitted to be sold to the public, and those not meeting certain criteria should be withdrawn or withheld from circulation. Section of Cardiology, Pennsylvania Hospital, Philadelphia, Pennsylvania 19107, U.S.A. Lederle Laboratories, Pearl River, New York, N.Y. 10965. 4. 5. 6. 7. 8.
P. F. BINNION M. MCDERMOTT. D. LESHER.
Allison, A. C., Davies, A. J. S. Nature, 1971, 233, 330. Taub, R. N., Gershon, R. K. J. Immun. 1972, 108, 377. Jounela, A. J., Sothmann, A. Lancet, Jan. 27, 1973, p. 202. Binnion, P. F., McDermott, M. ibid. 1972, ii, 592. MacDonald, H., Burger, P. J., Dornbush, A., Pelcak, E. Drug Inf. Bull. 1969, 3, 76.
EFFECT OF PROPANTHELINE AND METOCLOPRAMIDE ON ABSORPTION OF DIGOXIN SIR,—When digoxin is given in liquid form, its absorption may be nearly complete,’but absorption of the more common tablet form is far from complete and usually surprisingly variable between different subjects and tablet formulations. 2-5 Administration of propantheline and metaclopramide changed serum levels of digoxin (Feb. 24, p. 398), an effect attributed to alterations in effective absorption time following changes in gastrointestinal motility produced by the two drugs. Dr Thompson (April 7, p. 783) argued that biliary excretion of digoxin might be changed by propantheline and metoclopramide and that could explain the altered serumdigoxin levels. Of course, this may be so, and without direct measurements the controversy cannot be settled. It seems to us, however, that the original proposal of altered gastrointestinal motility still holds. In later observations propantheline had no effect on serum-digoxin concentrations in patients given a rapidly dissolving brand of
digoxin (’Lanoxin’, Wellcome). The effects of propantheline (10 mg. three times a day for 10 days) on serum-digoxin concentrations (ng. per ml.) in 8 subjects during treatment with lanoxin or digoxin (Orion) (0-25 mg. daily) were:
The results also demonstrate propantheline-induced increases in serum-digoxin concentrations in the same subjects when treated with a more slowly dissolving brand (Orion) of digoxin. When given in equal doses, very different maintenance serum-digoxin concentrations were produced by these two brands. The trial was conducted as previously described. In another group of volunteers on maintenance digoxin therapy Orion digoxin again produced lower serum concentrations than lanoxin. During the day variations in
serum-digoxin concentrations, however, were distinctly higher when lanoxin was used. The variations in serum-digoxin concentrations (ng. per ml.11 s.D.) in 6 digitalised subjects after 0-375 mg. digoxin in tablets of the two brands were:
It is evident that the two brands of digoxin tablets are different not only in bioavailability of digoxin but also in the whole pharmacokinetics of digoxin. In a broad pharmaceutical sense digoxin tablets can be divided into slowly or rapidly dissolving ones. Rapid dissolution is associated with more complete absorption and a rapid rise in serum concentrations. Which is the best preparation for clinical use ? Slowly dissolved and absorbed tablets produce a 1. 2. 3. 4.
Doherty, J. E., Flanigan, W. J., Clark, R. L., Murphy, M. L. Circulation, 1970, 42, suppl. 3, p. 110. Huffman, D. H., Azarnoff, D. L. J. Am. med. Ass. 1972, 222, 957. Manninen, V., Melin, J., Härtel, G. Lancet, 1971, ii, 934. Lindenbaum, J., Mellow, M. H., Blackstone, M. O., Butler, V. P. New Engl. J. Med. 1971, 285, 1344. Härtel, G., Manninen, V., Melin, J., Apajalahti, A. Ann. clin. Res. 1973 (in the press).