343
showed IgA and C3 in dermal capillary walls and connective tissues but no fibrin/fibrinogen. Concomitant deposition of IgA and C3 in dermal vessels and in glomerular mesangium was observed in one patient with H.S.P. and in the two cases with Berger’s nephritis. Clq and C4 were either not found or were present with only slight staining intensity in the dermis or glomerular mesangium of any patient. Skin from eighteen control patients was similarly studied, including that from four normal subjects, six with systemic lupus erythematosus, one with discoid lupus erythematosus, two with lipoid nephrosis, and five with other miscellaneous conditions. None of these showed staining characteristics which resembled those found in and Berger’s nephritis. Our findings indicate that dermal immunohistochemical examination is a useful diagnostic aid in patients with H.s.P. and Berger’s nephritis. The predominance of IgA/C3 immune complexes in the absence of Clq and C4 provides indirect evidence of activation of the complement system through the alternate pathway in the dermal and glomerular lesions. These parallel findings in the two syndromes suggest that they may be related. H.s.P.
Departments of Pathology, Pediatrics, and Medicine, St. Louis University School of Medicine, 1402 South Grand, St. Louis, Missouri 63104, U.S.A.
CHENG C. TSAI
JOSEPH GIANGIACOMO JACK ZUCKNER.
One digoxin tablet (0-25 mg.’Digoxin Novum ’, Star Ltd., Tampere, Finland) or 10 ml. of digoxin standard solution (0-025 mg. per ml. World Health Organisation Centre for Chemical Reference Substances, Solna, Sweden) was given with 100 ml. of water to eight healthy volunteer female subjects during a 10-day crossover trial under laboratory supervision. Venous blood-samples were taken for radioimmunological measurement of the basal level of serum-digoxin on the 8ih, 9th, and 10th morning just before the next dose of drug. After the final dosage the samples were drawn at , 1, 2, 4, 8, and 24 hours to determine the area under the absorption curve.
During
treatment
with tablets the
mean
basal digoxin
ng. per ml. of plasma) of the concentration attained with the standard solution (0-62 ±0-04 ng. per ml, of plasma). After the final dosage of digoxin tablets the area under the absorption curve was 95-0 ±9-1% (0-18±0-03 ng. per ml. per hour) of that obtained with the standard solution (0-19 ±0-02 ng. per ml. per hour). When 12 tablets were individually dissolved according to the method in the U.S.P. (U.S.P. XVIII, sixth interim revisions effective as of Nov. 15, 1973), the mean digoxin was
95-2±10-6% (s.E.) (0-59±0-05
’
1.
2. 3.
4. 5. 6.
Our was similar to that from standard solution. results accord with those of Klink et al.,6 who found that there is not always a simple correlation between the solubility and bioavailability of digoxin tablets. The results also suggest that the solution test in the U.S.P. is an unsatisfactory method of evaluating the bioavailability of commercial digoxin tablets.
tablets
Institute of Biomedical Sciences, University of Tampere, Teiskontie 35, SF-33520, Tampere 52, Finland.
PAULI YLITALO.
Research Laboratory of Star Ltd., Pinninkatu 53, SF-33100, Tampere 10, Finland.
GUNILLA WILÉN STIG LUNDELL.
HYPOKALÆMIA AND DIGOXIN-INDUCED
DISCREPANCY BETWEEN SOLUTION AND BIOAVAILABILITY OF DIGOXIN TABLETS SIR,-Many have reported an association between the solution-rate of digoxin tablets in vitro and their biological activity.’-’ However, Klink et al. found that despite different rates of solution the bioavailability of various digoxin tablets can be identical.We have found that the solution test given in the United States Pharmacopeia (U.S.P.) is not a satisfactory method of evaluating the biological activity of digoxin tablets.
level
concentration in the test solvent corresponded to only 57’8J1’6% of the declared amount, although the recovery of digoxin in these test conditions was 98-40-7% (p < 0-0005). Although the tablets tested did not meet U.S.P. specification regarding solubility (4/12 tablets dissolved less than 55%), gastrointestinal absorption of digoxin from the
Johnson, B. F., Greer, H., McCrerie, J., Bye, C., Fowle, A. Lancet, 1973, i, 1473. Lindenbaum, J., Butler, V. P., Jr., Murphy, J. E., Cresswell, R. M. ibid. p. 1215. Wagner, J. G., Christensen, M., Sakmar, E., Blair, D., Yates, J. D., Willis, P. W., III, Sedman, A. J., Stoll, R. G. J. Am. med. Ass. 1973, 224, 199. Binnion, P. F. Clin. Pharmac. Ther. 1974, 16, 807. Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., Smith, T. W. ibid. 1974, 229, 1774. Klink, P. R., Poust, R. I., Colaizzi, J. L., McDonald, R. H., Jr. J. Pharm. Sci. 1974, 63, 1231.
ARRHYTHMIAS SIR,-One of the main reasons for giving potassium supplements to patients receiving diuretics and digitalis is to prevent possible hypokalaemia, which is considered to sensitise the patient to the arrhythmogenic effects of digitalis. We teach our medical students that digitalis
produces arrhythmias more readily in hypokalmmic patients than in patients in normal potassium balance, and this is supported by statements in major textbooks.7-9 What is the evidence that this is true ? Before 1952, the idea that potassium loss sensitises the myocardium to digitalis was based on clinical statements that increased sensitivity to digitalis occurred in patients on diuretic therapy in the presence of a normal serumpotassium level.lo Acetyl strophanthidin does produce rhythm disturbances at a lower dose after the acute reduction of serum-potassium concentration by haemodialysis in dogs."Similar results were produced by a glucose-insulin infusion which acutely reduces the plasma-potassium concentration, but this effect was not noted after chronic potassium depletion in dogs.12 Acute changes in the relationship between extracellular and intracellular potassium concentrations certainly affect the ability of the myocardium to take up circulating digoxin.13-17 Presumably for ventricular tachycardia (and other arrhythmias) to be produced by digoxin, a certain myocardial level has to be achieved,18 but at the time of a toxic digitalis-induced ventricular tachycardia in normal and acutely hypokalasmic dogs there is no difference in the myocardial concentration of digoxin.19-20 However, much of this work is concerned with the re-
8.
Bellet, S. Clinical Disorders of the Heart Beat; p. 1065. Philadelphia, 1971. Hudson, R. E. B. Cardiovascular Pathology; vol. 3, p. S238. Balti-
9.
Conn, H. L., Horwitz, O. Cardiac and Vascular Diseases; vol.
7.
more, 1970.
I,
Philadelphia, 1971. Lown, B., Levine, S. A. Current Concepts in Digitalis Therapy; chap. 5. Boston, 1954. Lown, B. et al. J. clin. Invest. 1952, 31, 648. Kleiger, R. E., Vitale, J., Lown, B. Proc. New Engl. cardiovasc. Soc. p. 553.
10. 11. 12.
1964-65, 23, 19. 13. Cohn, K. E., Kleiger, R. E., Harrison, D. C. Circulation Res. 1967, 20, 473. 14. Marcus, F. I., Kapadia, G. G., Goldsmith, C. J. Pharmac. Exp. Ther. 1969, 165, 136. 15. Morgan, L. M., Binnion, P. F. Cardiovasc. Res. 1970, 4, 235. 16. Binnion, P. F., Morgan, L. M. ibid. 1971, 5, 431. 17. Prindle, K. H., et al. Circulation Res. 1971, 28, 337. 18. Binnion, P. F. in Symposium on Digitalis; p. 254. Oslo, 1973. 19. Goldsmith, C. et al. Circulation, 1969, 39, III-92. 20. Binnion, P. F., Das Gupta, R. ibid. 1974, III-215.
showed IgA and C3 in dermal capillary walls and connective tissues but no fibrin/fibrinogen. Concomitant deposition of IgA and C3 in dermal vessels and in glomerular mesangium was observed in one patient with H.S.P. and in the two cases with Berger’s nephritis. Clq and C4 were either not found or were present with only slight staining intensity in the dermis or glomerular mesangium of any patient. Skin from eighteen control patients was similarly studied, including that from four normal subjects, six with systemic lupus erythematosus, one with discoid lupus erythematosus, two with lipoid nephrosis, and five with other miscellaneous conditions. None of these showed staining characteristics which resembled those found in and Berger’s nephritis. Our findings indicate that dermal immunohistochemical examination is a useful diagnostic aid in patients with H.s.P. and Berger’s nephritis. The predominance of IgA/C3 immune complexes in the absence of Clq and C4 provides indirect evidence of activation of the complement system through the alternate pathway in the dermal and glomerular lesions. These parallel findings in the two syndromes suggest that they may be related. H.s.P.
Departments of Pathology, Pediatrics, and Medicine, St. Louis University School of Medicine, 1402 South Grand, St. Louis, Missouri 63104, U.S.A.
CHENG C. TSAI
JOSEPH GIANGIACOMO JACK ZUCKNER.
One digoxin tablet (0-25 mg.’Digoxin Novum ’, Star Ltd., Tampere, Finland) or 10 ml. of digoxin standard solution (0-025 mg. per ml. World Health Organisation Centre for Chemical Reference Substances, Solna, Sweden) was given with 100 ml. of water to eight healthy volunteer female subjects during a 10-day crossover trial under laboratory supervision. Venous blood-samples were taken for radioimmunological measurement of the basal level of serum-digoxin on the 8ih, 9th, and 10th morning just before the next dose of drug. After the final dosage the samples were drawn at , 1, 2, 4, 8, and 24 hours to determine the area under the absorption curve.
During
treatment
with tablets the
mean
basal digoxin
ng. per ml. of plasma) of the concentration attained with the standard solution (0-62 ±0-04 ng. per ml, of plasma). After the final dosage of digoxin tablets the area under the absorption curve was 95-0 ±9-1% (0-18±0-03 ng. per ml. per hour) of that obtained with the standard solution (0-19 ±0-02 ng. per ml. per hour). When 12 tablets were individually dissolved according to the method in the U.S.P. (U.S.P. XVIII, sixth interim revisions effective as of Nov. 15, 1973), the mean digoxin was
95-2±10-6% (s.E.) (0-59±0-05
’
1.
2. 3.
4. 5. 6.
Our was similar to that from standard solution. results accord with those of Klink et al.,6 who found that there is not always a simple correlation between the solubility and bioavailability of digoxin tablets. The results also suggest that the solution test in the U.S.P. is an unsatisfactory method of evaluating the bioavailability of commercial digoxin tablets.
tablets
Institute of Biomedical Sciences, University of Tampere, Teiskontie 35, SF-33520, Tampere 52, Finland.
PAULI YLITALO.
Research Laboratory of Star Ltd., Pinninkatu 53, SF-33100, Tampere 10, Finland.
GUNILLA WILÉN STIG LUNDELL.
HYPOKALÆMIA AND DIGOXIN-INDUCED
DISCREPANCY BETWEEN SOLUTION AND BIOAVAILABILITY OF DIGOXIN TABLETS SIR,-Many have reported an association between the solution-rate of digoxin tablets in vitro and their biological activity.’-’ However, Klink et al. found that despite different rates of solution the bioavailability of various digoxin tablets can be identical.We have found that the solution test given in the United States Pharmacopeia (U.S.P.) is not a satisfactory method of evaluating the biological activity of digoxin tablets.
level
concentration in the test solvent corresponded to only 57’8J1’6% of the declared amount, although the recovery of digoxin in these test conditions was 98-40-7% (p < 0-0005). Although the tablets tested did not meet U.S.P. specification regarding solubility (4/12 tablets dissolved less than 55%), gastrointestinal absorption of digoxin from the
Johnson, B. F., Greer, H., McCrerie, J., Bye, C., Fowle, A. Lancet, 1973, i, 1473. Lindenbaum, J., Butler, V. P., Jr., Murphy, J. E., Cresswell, R. M. ibid. p. 1215. Wagner, J. G., Christensen, M., Sakmar, E., Blair, D., Yates, J. D., Willis, P. W., III, Sedman, A. J., Stoll, R. G. J. Am. med. Ass. 1973, 224, 199. Binnion, P. F. Clin. Pharmac. Ther. 1974, 16, 807. Greenblatt, D. J., Duhme, D. W., Koch-Weser, J., Smith, T. W. ibid. 1974, 229, 1774. Klink, P. R., Poust, R. I., Colaizzi, J. L., McDonald, R. H., Jr. J. Pharm. Sci. 1974, 63, 1231.
ARRHYTHMIAS SIR,-One of the main reasons for giving potassium supplements to patients receiving diuretics and digitalis is to prevent possible hypokalaemia, which is considered to sensitise the patient to the arrhythmogenic effects of digitalis. We teach our medical students that digitalis
produces arrhythmias more readily in hypokalmmic patients than in patients in normal potassium balance, and this is supported by statements in major textbooks.7-9 What is the evidence that this is true ? Before 1952, the idea that potassium loss sensitises the myocardium to digitalis was based on clinical statements that increased sensitivity to digitalis occurred in patients on diuretic therapy in the presence of a normal serumpotassium level.lo Acetyl strophanthidin does produce rhythm disturbances at a lower dose after the acute reduction of serum-potassium concentration by haemodialysis in dogs."Similar results were produced by a glucose-insulin infusion which acutely reduces the plasma-potassium concentration, but this effect was not noted after chronic potassium depletion in dogs.12 Acute changes in the relationship between extracellular and intracellular potassium concentrations certainly affect the ability of the myocardium to take up circulating digoxin.13-17 Presumably for ventricular tachycardia (and other arrhythmias) to be produced by digoxin, a certain myocardial level has to be achieved,18 but at the time of a toxic digitalis-induced ventricular tachycardia in normal and acutely hypokalasmic dogs there is no difference in the myocardial concentration of digoxin.19-20 However, much of this work is concerned with the re-
8.
Bellet, S. Clinical Disorders of the Heart Beat; p. 1065. Philadelphia, 1971. Hudson, R. E. B. Cardiovascular Pathology; vol. 3, p. S238. Balti-
9.
Conn, H. L., Horwitz, O. Cardiac and Vascular Diseases; vol.
7.
more, 1970.
I,
Philadelphia, 1971. Lown, B., Levine, S. A. Current Concepts in Digitalis Therapy; chap. 5. Boston, 1954. Lown, B. et al. J. clin. Invest. 1952, 31, 648. Kleiger, R. E., Vitale, J., Lown, B. Proc. New Engl. cardiovasc. Soc. p. 553.
10. 11. 12.
1964-65, 23, 19. 13. Cohn, K. E., Kleiger, R. E., Harrison, D. C. Circulation Res. 1967, 20, 473. 14. Marcus, F. I., Kapadia, G. G., Goldsmith, C. J. Pharmac. Exp. Ther. 1969, 165, 136. 15. Morgan, L. M., Binnion, P. F. Cardiovasc. Res. 1970, 4, 235. 16. Binnion, P. F., Morgan, L. M. ibid. 1971, 5, 431. 17. Prindle, K. H., et al. Circulation Res. 1971, 28, 337. 18. Binnion, P. F. in Symposium on Digitalis; p. 254. Oslo, 1973. 19. Goldsmith, C. et al. Circulation, 1969, 39, III-92. 20. Binnion, P. F., Das Gupta, R. ibid. 1974, III-215.
