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RESPONSE TO INJURY
212
letter,s since the pattern (a) in the figure was obtained from 0-06% of a 24-hour urine sample-i.e., it is possible to use a small
of random voided specimen. To hasten the the of determination, the evaporation of the CCl4 rapidity extract can be eliminated, for satisfactory colour development is readily accomplished by adding concentrated sulphuric acid (H2SO4) to the extract; the readings are then made on the H2SO phase. By using these steps I have been able to conduct the entire test in less than six hours. The specificity of the test is also questioned, since raised levels of pregnanetriols are occasionally found in patients with adrenal carcinoma. This problem is readily solved if there is a decrease in the levels of these compounds after exogenous corticosteroid therapy for 2-3 days. I agree with Dr. Makin that pregnanetriol is not always raised in C.A.H. It is precisely for this reason that I devised a method for measuring total 17-hydroxy, 21-desoxycorticosteroids (170H, 21-D.O.C.S.),4 since, in addition to the pregnanetriols, there may be increased levels of 17-hydroxypregnanolone (5 p-pregnane-3K, 17K-diol, 20-one) and other compounds with the 17-hydroxy, 20-ketone structure which are not detected by the sulphuric-acid chromogen peak at 435 m(..t. I have been able to simplify the test for total 17-OH, 21-D.O.C.S., to be performed in 5-6 hours, as follows: amount
A urine sample (0-5-5 ml.) is incubated with &bgr;-glucuronidase at pH 4-5 for 4 hours at 38°C, and 0-5 ml. of a 20% aqueous solution of potassium borohydride (KBH4) is then added. An hour later excess KBH4 is removed by addition of 5-10 drops of glacial acetic acid. The urine is then extracted with 5 volumes of CC14, after which the CC14 extract is washed with 0-1 N sodium hydroxide and with water. To the CC14 extract is added 1-5-3-0 ml. H2SOu and the H2SO4-chromogen spectrum is determined as discussed before. Detailed studies revealed that the major effect of the KBH4 was the conversion of 17-hydroxypregnanolone to pregnanetriol, providing an increment in the peak at 435 mt over that obtained from an extract not treated with KBH,. Previous studies showed that the major C2]. compounds accumulating in patients with C.A.H. include pregnanetriol and allopregnanetriol (5o:-pregnane-3
HABEEB BACCHUS.
EFFECT OF FOOD ON ASPIRIN ABSORPTION SIR,-Dr. Spiers and Miss Malone (Feb. 25, p. 440) report that 1 hour after the administration of 1-5 g. of calcium aspirin serum-salicylate levels were significantly lower for non-fasting than for fasting subjects. Ten years ago, the late Prof. P. K. Smith of George Washington University determined, for our medical department, serum-salicylate levels on twenty-five people in a crossover study of five different commercial aspirin preparations, for both fasting and non-fasting administration. The dose in each was 650 mg. of aspirin. The accompanying table shows the average and median levels attained at 5,10, and 20 minutes, which, as discussed elsewhere,5 6 differ during the absorption period. For preparation D with fasting subjects, and for preparations A, B, and D with non-fasting subjects, half of the panel showed no perceptible level at 5 minutes. The range between the five commercial products found here is comparable to that reported elsewhere .67 Applying normal absorption kinetics to these results, it is apparent that the normal half-lives of absorption are more than Bacchus, H. Lancet, 1967, i, 514. Bacchus, H. Metabolism, 1967, 16, 153. Lieberman, S. V., Kraus, S. R., Muncy, J., Wood, J. H. J. pharm. Sci. 1964, 53, 1486. 6. Lieberman, S. V., Wood, J. H. ibid. p. 1492. 7. Levy, G. ibid. 1961, 50, 388. Wood, J. H. Pharm. Acta Helv. 1967, 42, 129.
3. 4. 5.
doubled by the non-fasting condition, and even in the fastest case will exceed 1 hour. The difference cited by Dr. Spiers and Miss Malone is therefore in line with these observations. Because of the very rapid hydrolysis of acetysalicylic to salicylic acid in the circulatory system, slower absorption results in significantly lower peak levels for the unhydrolysed, and probably more potent, drug moiety. As suggested by Dr. Spiers and Miss Malone, this factor may indeed be of significance for " optimal regimens of salicylate therapy ". Research and Development Laboratories, Bristol-Myers Products, Hillside, New Jersey 07207.
JOHN H. WOOD.
RESPONSE TO INJURY SIR,-In his excellent statement on vasoconstriction in shock, Dr. Sevitt 9 speaks of the rarity of post-traumatic bowel haemorrhage in shock in man. Ming and Levitan 10 and Freimanll have reported over seventy patients in shock, nearly all elderly, who had severe bowel haemorrhage before death." The shock was often attributable to an infection, which was unobtrusive in its clinical manifestations. In man hsemorrhagic shock becomes irreversible much less often than septic shock, so that bowel haemorrhage should be less common in this type of shock, except when therapy is too long delayed. If I understand Dr. Sevitt correctly, he doubts whether bowel haemorrhage caused by mucosal necrosis is relevant to the problem of irreversibility. I share that doubt. To me the refractory state seems to be due to something else, because prompt replacement of blood lost into the gut does not cure shock in man or in the laboratory animal. In support of the hypothesis that a bacterial toxin is involved my co-workers and I have reported12 that when we perfuse the femoral arterial blood of a dog in refractory shock for 30-60 minutes through a freshly excised donor spleen or liver intestinal bleeding stops, shock disappears, no transfusions are necessary, and full recovery follows, provided that, in addition, antibiotics are given for several days. Since the common functional denominator between spleen and liver is the reticuloendothelial system (R.E.S.), this observation seems to show that vascular integrity depends on an intact R.E.s., and that in refractory shock substitution of a competent for a weakened R.E.S. for a brief interval removes a toxin that is responsible for the intestinal bleeding as well as the persistence of shock. JACOB FINE. Boston, Massachusetts 02115. 8. 9. 10. 11. 12.
Levy, G. Anesth. Analg. curr. Res. 1965, 44, 837. Sevitt, S. Lancet, 1966, ii, 1203. Ming, Si.-C., Levitan, R. New Engl. J. Med. 1960, 263, 59. Freiman, D. G. Circulation, 1965, 32, 329. Fine, J., Palmerio, C., Rutenburg, S. Archs Surg., Chicago (in the press).
letter,s since the pattern (a) in the figure was obtained from 0-06% of a 24-hour urine sample-i.e., it is possible to use a small
of random voided specimen. To hasten the the of determination, the evaporation of the CCl4 rapidity extract can be eliminated, for satisfactory colour development is readily accomplished by adding concentrated sulphuric acid (H2SO4) to the extract; the readings are then made on the H2SO phase. By using these steps I have been able to conduct the entire test in less than six hours. The specificity of the test is also questioned, since raised levels of pregnanetriols are occasionally found in patients with adrenal carcinoma. This problem is readily solved if there is a decrease in the levels of these compounds after exogenous corticosteroid therapy for 2-3 days. I agree with Dr. Makin that pregnanetriol is not always raised in C.A.H. It is precisely for this reason that I devised a method for measuring total 17-hydroxy, 21-desoxycorticosteroids (170H, 21-D.O.C.S.),4 since, in addition to the pregnanetriols, there may be increased levels of 17-hydroxypregnanolone (5 p-pregnane-3K, 17K-diol, 20-one) and other compounds with the 17-hydroxy, 20-ketone structure which are not detected by the sulphuric-acid chromogen peak at 435 m(..t. I have been able to simplify the test for total 17-OH, 21-D.O.C.S., to be performed in 5-6 hours, as follows: amount
A urine sample (0-5-5 ml.) is incubated with &bgr;-glucuronidase at pH 4-5 for 4 hours at 38°C, and 0-5 ml. of a 20% aqueous solution of potassium borohydride (KBH4) is then added. An hour later excess KBH4 is removed by addition of 5-10 drops of glacial acetic acid. The urine is then extracted with 5 volumes of CC14, after which the CC14 extract is washed with 0-1 N sodium hydroxide and with water. To the CC14 extract is added 1-5-3-0 ml. H2SOu and the H2SO4-chromogen spectrum is determined as discussed before. Detailed studies revealed that the major effect of the KBH4 was the conversion of 17-hydroxypregnanolone to pregnanetriol, providing an increment in the peak at 435 mt over that obtained from an extract not treated with KBH,. Previous studies showed that the major C2]. compounds accumulating in patients with C.A.H. include pregnanetriol and allopregnanetriol (5o:-pregnane-3
HABEEB BACCHUS.
EFFECT OF FOOD ON ASPIRIN ABSORPTION SIR,-Dr. Spiers and Miss Malone (Feb. 25, p. 440) report that 1 hour after the administration of 1-5 g. of calcium aspirin serum-salicylate levels were significantly lower for non-fasting than for fasting subjects. Ten years ago, the late Prof. P. K. Smith of George Washington University determined, for our medical department, serum-salicylate levels on twenty-five people in a crossover study of five different commercial aspirin preparations, for both fasting and non-fasting administration. The dose in each was 650 mg. of aspirin. The accompanying table shows the average and median levels attained at 5,10, and 20 minutes, which, as discussed elsewhere,5 6 differ during the absorption period. For preparation D with fasting subjects, and for preparations A, B, and D with non-fasting subjects, half of the panel showed no perceptible level at 5 minutes. The range between the five commercial products found here is comparable to that reported elsewhere .67 Applying normal absorption kinetics to these results, it is apparent that the normal half-lives of absorption are more than Bacchus, H. Lancet, 1967, i, 514. Bacchus, H. Metabolism, 1967, 16, 153. Lieberman, S. V., Kraus, S. R., Muncy, J., Wood, J. H. J. pharm. Sci. 1964, 53, 1486. 6. Lieberman, S. V., Wood, J. H. ibid. p. 1492. 7. Levy, G. ibid. 1961, 50, 388. Wood, J. H. Pharm. Acta Helv. 1967, 42, 129.
3. 4. 5.
doubled by the non-fasting condition, and even in the fastest case will exceed 1 hour. The difference cited by Dr. Spiers and Miss Malone is therefore in line with these observations. Because of the very rapid hydrolysis of acetysalicylic to salicylic acid in the circulatory system, slower absorption results in significantly lower peak levels for the unhydrolysed, and probably more potent, drug moiety. As suggested by Dr. Spiers and Miss Malone, this factor may indeed be of significance for " optimal regimens of salicylate therapy ". Research and Development Laboratories, Bristol-Myers Products, Hillside, New Jersey 07207.
JOHN H. WOOD.
RESPONSE TO INJURY SIR,-In his excellent statement on vasoconstriction in shock, Dr. Sevitt 9 speaks of the rarity of post-traumatic bowel haemorrhage in shock in man. Ming and Levitan 10 and Freimanll have reported over seventy patients in shock, nearly all elderly, who had severe bowel haemorrhage before death." The shock was often attributable to an infection, which was unobtrusive in its clinical manifestations. In man hsemorrhagic shock becomes irreversible much less often than septic shock, so that bowel haemorrhage should be less common in this type of shock, except when therapy is too long delayed. If I understand Dr. Sevitt correctly, he doubts whether bowel haemorrhage caused by mucosal necrosis is relevant to the problem of irreversibility. I share that doubt. To me the refractory state seems to be due to something else, because prompt replacement of blood lost into the gut does not cure shock in man or in the laboratory animal. In support of the hypothesis that a bacterial toxin is involved my co-workers and I have reported12 that when we perfuse the femoral arterial blood of a dog in refractory shock for 30-60 minutes through a freshly excised donor spleen or liver intestinal bleeding stops, shock disappears, no transfusions are necessary, and full recovery follows, provided that, in addition, antibiotics are given for several days. Since the common functional denominator between spleen and liver is the reticuloendothelial system (R.E.S.), this observation seems to show that vascular integrity depends on an intact R.E.s., and that in refractory shock substitution of a competent for a weakened R.E.S. for a brief interval removes a toxin that is responsible for the intestinal bleeding as well as the persistence of shock. JACOB FINE. Boston, Massachusetts 02115. 8. 9. 10. 11. 12.
Levy, G. Anesth. Analg. curr. Res. 1965, 44, 837. Sevitt, S. Lancet, 1966, ii, 1203. Ming, Si.-C., Levitan, R. New Engl. J. Med. 1960, 263, 59. Freiman, D. G. Circulation, 1965, 32, 329. Fine, J., Palmerio, C., Rutenburg, S. Archs Surg., Chicago (in the press).