369
given, and those for which other advice is appropriate. Rigorous testing of these procedures could be achieved ral may be
by methods such as those of de Dombal and Horrocks.7 Pharmacists already have extensive knowledge about the chemical and physical properties of drugs and their formulation as medicines, pharmacological activities, and interactions, and about the underlying physiology and biochemical mechanisms. Retail pharmacists play an important community role in primary patient counselling and self-medication, and help to reduce the medical consultation load. Yet, in this respect their formal education and training is deficient; there should be more emphasis on symptom analysis and the advice and/or treatment to be given. Doctors and teachers of pharmacy must help pharmacists to become more effective health advisorsnot, it must be emphasised, to become pseudo-doctors. General Practice Wirral
Pharmacy,
G. E. DALE
Clatterbridge Hospital
R. OSBORNE HUGHES
Wirral
School of
Pharmacy, Liverpool Polytechnic
V. WALTERS
DIPROPYLACETATE AND PROPIONYL CoA CARBOXYLASE
SIR,—Hyperglycinæmia
and
and inhave been
hyperglycinuria1 2
creased concentrations of urinary propionate reported in individuals treated with antiepileptic drug sodium dipropylacetate (sodium valproate). Two of these reports suggested that the hyperglycinxmia induced by dipropylacetate may be secondary to the inhibition of propionyl CoA carboxylase (P.c.c.), perhaps by a mechanism similar to that of patients with primary P.c.c. deficiency.1 3 I have investigated the effect of dipropylacetate (courtesy of Abbott Laboratories, Chicago) on P.c.c. activity in normal human skin fibroblasts. The direct effect of dipropylacetate on P.c.c. activity was evaluated by comparing the activity in extracts of fibroblasts incubated with dipropylacetate (0.03-300 mmol/1 for 5 s to 1 h before assay (720-765 pmol of 14CO , fixed/min/mg protein) with that in extracts incubated without dipropylacetate (740 pmol/min/mg).4 The indirect effect was evaluated by comparing P.c.c. activity in extracts of confluent fibroblast cultures incubated with 0.03-300 mmol/l dipropylacetate for 3-24 h before assay (720-920 pmol/ min/mg) with that in extracts of cultures incubated without dipropylacetate (710 pmol/min/mg). There was no decrease in P.c.c. activity observed in either case. In fact, P.c.c. activity was slightly increased (16-30%) in extracts of those cultures incubated with the higher concentrations of dipropylacetate
(30-300 mmol/1). To exclude the possibility that dipropylacetate or its metabolites inhibit other enzymes in the propionate metabolic pathway, the incorporation of 14C from [1-14C] propionate into acid-precipitable material in cultured fibroblasts was studied.5 The incorporation of 14C in cultures incubated with 30 mmol/l dipropylacetate for 2 and 24 h (10.8-12.0 nanoatom 14C/mg protein) was similar to the incorporation observed in cultures incubated without dipropylacetate (10.811.5 nanoatom
tate, were performed. These investigations revealed no change in P.c.c. activity due to G.A.B.A. These studies suggest that dipropylacetate, G.A.B.A., or their metabolites do not inhibit P.c.c. activity in fibroblasts, but they do not exclude the possibility that dipropylacetate or G.A.B.A. are degraded in other organs, such as liver or brain, to metabolites not formed in fibroblasts which are capable of inhibiting P.c.c. activity in these tissues. Metabolism of dipropylacetate to propionate may easily explain the mild elevation of propionate observed in the urine of patients treated with dipropylacetate.3 Other urinary metabolites of dipropylacetate, 5-propyl-5-hydroxypentanoate and 2-propylglutarate,7 resemble the intermediates in the isoleucine degradation pathway. Perhaps these metabolites induce hyperglycinxmia in patients treated with dipropylacetate, and, similarly, the isoleucine metabolites may induce hyperglycinæmia in patients with P.c.c. deficiency. On the other hand, although the glycine concentration in the cerebrospinal fluid of two patients treated with dipropylacetate was normal,2 dipropylacetate or its metabolites may cause hyperglycinxmia by interfering with glycine metabolism by a mechanism similar to that seen in patients with non-ketotic hyperglycinaemia. Department of Human Genetics and Pediatrics, Medical College of
Virginia,
BARRY WOLF
Richmond, Virginia 23932, U.S.A.
DRUG-ASSOCIATED ACUTE PANCREATITIS
SIR,-Bourke et al. reported an excess of diuretic prescribamong patients with acute pancreatitis in a prospective
ing
controlled study. In view of the ready accessibility of information in the patient drug file maintained by the Medicines Evaluation and Monitoring Group, I tried to determine what drugs- were taken before admission by a group of 100 patients with confirmed acute pancreatitis (identified at random retrospectively on the file) and two groups of control patients. Controls were matched for age, sex, and abdominal pain, the first group having a normal serum-amylase and the second group having an undetermined serum-amylase. The information obtained in this way is likely to be an underestimate but there is no reason to suspect a bias in the information recorded about drugs taken before admission in the three groups.
NUMBER OF DIURETICS PRESCRIBED BEFORE ADMISSION FOR
100
(Gp. I), 100 MATCHED SERUM-AMYLASE (Gp. II), AND 100
PATIENTS WITH ACUTE PANCREATITIS
CONTROLS WITH A NORMAL
MATCHED CONTROLS WITH AN UNDETERMINED SERUM-AMYLASE
(Gp. III)
14C/mg). Since dipropylacetate increases the concentration of y-aminobutyrate (G.A.B.A.) in the brain,6 similar experiments to those described above, substituting G.A.B.A. for dipropylace7. de Dombal, F. T., Horrocks, J. C. Gut, 1978, 19, 19. 1. Kamoun, P., Parvy, P., Debray-Ritzen, P. Nouv. Presse med. 2. Jaeken, J., Corbeel, L., Casaer, P., Carchon, H., Eggermant,
1977, 6, 2162. E., Eeckels, R.
Lancet, 1977, ii, 617. Schmid, R. D. Clin. chim. Acta, 1977, 74, 39. Wolf, B., Hsia, Y. E., Rosenberg, L. E. Am. J. hum. Genet. (in the press). 5. Willard, H. F., Ambam, L. M., Hart, A. C., Mahoney, M. J., Rosenberg, L. E. Hum. Genet 1976, 34, 277. 6. Similer, S., Ciesielski, L., Maitre, M., Randrianarisoa, H., Mandel, P. Biochem. Pharmac. 1973, 22, 1701.
3. 4.
The results (see table) are similar to Bourke’s in that patients with acute pancreatitis appeared to have a 2-5 times greater chance of receiving a diuretic than did a control group with acute abdominal pain and a normal serum-amylase: However, before any conclusions can be drawn, the similarity between the second control group with an undetermined serum-amylase and the test group, along with the preponderance 7. 1.
Simon, D., Penry, J. F. Epilepsia, 1975, 16, 549. Bourke, J. B., Mead, G. M., McIllmurray, M. B., Langman, M. J. 1978, i, 706.
S. Lancet,
370 of females in all groups,
must
be the
subject of further investi-
gation. Medicines Evaluation and
Monitoring Group, Royal Infirmary, Aberdeen AB9 2ZB
DOROTHY C. MOIR
DEATH FROM ACUTE PANCREATITIS
SIR The M.R.C. multicentre study’ compared glucagon and trasylol with placebo on a double-blind basis. Of 257 patients 123 received placebo, 68 were treated with glucagon, and 66 with trasylol. The mortality-rate for all patients was 10 - 7%; 11% for placebo, 12% for glucagon, and 9% for trasy-. lol. It was thus concluded that both drug treatments were ineffective. But the statistical design and the results of the M.R.C. study raise serious questions about the validity of this conclusion. Trapnell et al.2 found that trasylol reduced the mortality-rate by 70% compared with non-treated patients. To confirm these results, or even to demonstrate a reduction of mortality-rate of only 3% with trasylol, the M.R.C. study would have had to have at least 200 patients per experimental group--i.e., more than twice the number of patients. To demonstrate a mortality reduction of 5% (a clinically remarkable effect in this condition) would have demanded at least 428 patients per experimental group. This patient number would have satisfied the known relationship between the expected frequency of a result (mortality-rate) and the expected statistical difference between two patient groups. Such a study probably could not have been done since it would have lasted for years. The stringent selection of criteria for inclusion of patients in Trapnell’s study allowed for a reduction of the number of patients required for statistical evaluation. While the severity and the number of patients in the M.R.C. study raise questions about the conclusions, the data still show some support for Trapnell’s conclusion. A series of 25 severe cases were reported separately, patients who, for therapeutic or diagnostic reasons, had to have surgery. 10 of these (40%) died, a mortality-rate probably reflecting the severity of the disease.’ Classified according to therapy, the mortality-rate in each group is as follows : placebo group, 5 of 11 (45%); glucagon group, 4 of 8 (50%); trasylol group, 1 of 6 (17%). Thus, statistically, the trasylol data do not differ significantly from those obtained by Trapnell since in both studies, evaluating only severe pancreatitis cases, trasylol treatment resulted in equivalent reduction of mortality. Department of Biochemical Pharmacology, State University of New York at Buffalo, New York 14260, U.S.A.
NATHAN BACK
INTRAUTERINE HYPOTHYROIDISM DUE TO ANTITHYROID-DRUG THERAPY FOR THYROTOXICOSIS DURING PREGNANCY
SIR,-Antithyroid drugs can cross the placenta and impair thyroid function in fetus, leading to goitre formation with or without hypothyroidism.3 Neonatal goitres in infants born to mothers who have taken antithyroid drugs during pregnancy for thyrotoxicosis probably result from increased secretion of fetal thyroid-stimulating hormone (T.S.H.) in response
the
the depressed fetal thyroid-hormone output induced by the placental transfer of these drugs. Increased T.S.H. levels in the cord blood have been reported in infants who have druginduced goitres.4 However, little is known about thyroid hormone or T.s.H. levels in the neonatal period in infants who are to
.
1. M.R.C. Multicentre Trial. Lancet, 1977, ii, 632. 2. Trapnell, J. E., Rigby, C. C., Talbot, C. H., Duncan, E. H. L.
1974, 61, 177. 3. Burrow, G. N.J. clin. Endocr. Metab. 1965, 25, 403. 4. Refetoff, S., and others. J. Pediat. 1974, 85, 240.
DAYS POST-PARTUM
Thyroid biochemistry post partum. to antithyroid drugs in utero and who have no goitre clinical evidence of hypothyroidism.s We have information on two such infants during the first three weeks of life. Both infants were delivered spontaneously at term and appeared clinically euthyroid and without thyroid enlargement. The mother of baby A was thyrotoxic and taking 40 mg carbimazole and 80 µg triiodothyronine daily when she first came to our clinic at 24 weeks’ gestation. The drugs were stopped but had to be restarted at 34 weeks because of recurrence of symptoms, and carbimazole 30 mg/day with 60 µg of triiodothyronine was continued until delivery. The mother of baby M received carbimazole alone 15-30 mg/day throughout pregnancy, and she was on 30 mg at the time of delivery. The thyroid biochemistry of the mothers at the time of delivery was:
exposed
or
Mother of A Mother of M Normal range (in non-pregnant patients)
T4
T3
Binding capacity
(nmol//)
(nmol/l)
(%)
175 4-7 140 1.9 55-144
0.9-2.8
133 129 ..
The serum thyroxine (T4), triiodothyronine (T3), and T.S.H. in the neonatal period of these two infants are shown in the figure. The serum-T.S.H. was high in cord blood and at 6 h and 24 h but it returned to near normal within 72 h after delivery. High cord-blood T.S.H. can be caused by extreme parturition stress and hypoxia6 but in their absence the likely cause of the raised T.S.H. levels in these two infants is maternal antithyroid drug therapy. The rise in T4 at about 24 h after delivery induced by the surge of T.S.H. secretion shortly after birth’ was not observed in these two infants. The effect of placentally transferred antithyroid drugs on the fetal pituitary-thyroid axis seems transient, with recovery within 72 h after withdrawal of exposure. These data are consistent with a state of relative hypothyroidism, and presumably this existed in utero throughout the time the mother was receiving antithyroid drugs during her pregnancy. The first case (A) shows that this state is not prevented by simultaneous administration of amounts of triiodothyronine sufficient to raise the circulating maternal level. Can relative hypothy-
Br. J. Surg. 5. 6. 7.
Hayek, A., Brooks, M. ibid. 1975,87,446. Walfish, P. G. Lancet, 1976,i, 1208. Erenberg, A., and others. Pediatrics, 1974, 53, 211.
given, and those for which other advice is appropriate. Rigorous testing of these procedures could be achieved ral may be
by methods such as those of de Dombal and Horrocks.7 Pharmacists already have extensive knowledge about the chemical and physical properties of drugs and their formulation as medicines, pharmacological activities, and interactions, and about the underlying physiology and biochemical mechanisms. Retail pharmacists play an important community role in primary patient counselling and self-medication, and help to reduce the medical consultation load. Yet, in this respect their formal education and training is deficient; there should be more emphasis on symptom analysis and the advice and/or treatment to be given. Doctors and teachers of pharmacy must help pharmacists to become more effective health advisorsnot, it must be emphasised, to become pseudo-doctors. General Practice Wirral
Pharmacy,
G. E. DALE
Clatterbridge Hospital
R. OSBORNE HUGHES
Wirral
School of
Pharmacy, Liverpool Polytechnic
V. WALTERS
DIPROPYLACETATE AND PROPIONYL CoA CARBOXYLASE
SIR,—Hyperglycinæmia
and
and inhave been
hyperglycinuria1 2
creased concentrations of urinary propionate reported in individuals treated with antiepileptic drug sodium dipropylacetate (sodium valproate). Two of these reports suggested that the hyperglycinxmia induced by dipropylacetate may be secondary to the inhibition of propionyl CoA carboxylase (P.c.c.), perhaps by a mechanism similar to that of patients with primary P.c.c. deficiency.1 3 I have investigated the effect of dipropylacetate (courtesy of Abbott Laboratories, Chicago) on P.c.c. activity in normal human skin fibroblasts. The direct effect of dipropylacetate on P.c.c. activity was evaluated by comparing the activity in extracts of fibroblasts incubated with dipropylacetate (0.03-300 mmol/1 for 5 s to 1 h before assay (720-765 pmol of 14CO , fixed/min/mg protein) with that in extracts incubated without dipropylacetate (740 pmol/min/mg).4 The indirect effect was evaluated by comparing P.c.c. activity in extracts of confluent fibroblast cultures incubated with 0.03-300 mmol/l dipropylacetate for 3-24 h before assay (720-920 pmol/ min/mg) with that in extracts of cultures incubated without dipropylacetate (710 pmol/min/mg). There was no decrease in P.c.c. activity observed in either case. In fact, P.c.c. activity was slightly increased (16-30%) in extracts of those cultures incubated with the higher concentrations of dipropylacetate
(30-300 mmol/1). To exclude the possibility that dipropylacetate or its metabolites inhibit other enzymes in the propionate metabolic pathway, the incorporation of 14C from [1-14C] propionate into acid-precipitable material in cultured fibroblasts was studied.5 The incorporation of 14C in cultures incubated with 30 mmol/l dipropylacetate for 2 and 24 h (10.8-12.0 nanoatom 14C/mg protein) was similar to the incorporation observed in cultures incubated without dipropylacetate (10.811.5 nanoatom
tate, were performed. These investigations revealed no change in P.c.c. activity due to G.A.B.A. These studies suggest that dipropylacetate, G.A.B.A., or their metabolites do not inhibit P.c.c. activity in fibroblasts, but they do not exclude the possibility that dipropylacetate or G.A.B.A. are degraded in other organs, such as liver or brain, to metabolites not formed in fibroblasts which are capable of inhibiting P.c.c. activity in these tissues. Metabolism of dipropylacetate to propionate may easily explain the mild elevation of propionate observed in the urine of patients treated with dipropylacetate.3 Other urinary metabolites of dipropylacetate, 5-propyl-5-hydroxypentanoate and 2-propylglutarate,7 resemble the intermediates in the isoleucine degradation pathway. Perhaps these metabolites induce hyperglycinxmia in patients treated with dipropylacetate, and, similarly, the isoleucine metabolites may induce hyperglycinæmia in patients with P.c.c. deficiency. On the other hand, although the glycine concentration in the cerebrospinal fluid of two patients treated with dipropylacetate was normal,2 dipropylacetate or its metabolites may cause hyperglycinxmia by interfering with glycine metabolism by a mechanism similar to that seen in patients with non-ketotic hyperglycinaemia. Department of Human Genetics and Pediatrics, Medical College of
Virginia,
BARRY WOLF
Richmond, Virginia 23932, U.S.A.
DRUG-ASSOCIATED ACUTE PANCREATITIS
SIR,-Bourke et al. reported an excess of diuretic prescribamong patients with acute pancreatitis in a prospective
ing
controlled study. In view of the ready accessibility of information in the patient drug file maintained by the Medicines Evaluation and Monitoring Group, I tried to determine what drugs- were taken before admission by a group of 100 patients with confirmed acute pancreatitis (identified at random retrospectively on the file) and two groups of control patients. Controls were matched for age, sex, and abdominal pain, the first group having a normal serum-amylase and the second group having an undetermined serum-amylase. The information obtained in this way is likely to be an underestimate but there is no reason to suspect a bias in the information recorded about drugs taken before admission in the three groups.
NUMBER OF DIURETICS PRESCRIBED BEFORE ADMISSION FOR
100
(Gp. I), 100 MATCHED SERUM-AMYLASE (Gp. II), AND 100
PATIENTS WITH ACUTE PANCREATITIS
CONTROLS WITH A NORMAL
MATCHED CONTROLS WITH AN UNDETERMINED SERUM-AMYLASE
(Gp. III)
14C/mg). Since dipropylacetate increases the concentration of y-aminobutyrate (G.A.B.A.) in the brain,6 similar experiments to those described above, substituting G.A.B.A. for dipropylace7. de Dombal, F. T., Horrocks, J. C. Gut, 1978, 19, 19. 1. Kamoun, P., Parvy, P., Debray-Ritzen, P. Nouv. Presse med. 2. Jaeken, J., Corbeel, L., Casaer, P., Carchon, H., Eggermant,
1977, 6, 2162. E., Eeckels, R.
Lancet, 1977, ii, 617. Schmid, R. D. Clin. chim. Acta, 1977, 74, 39. Wolf, B., Hsia, Y. E., Rosenberg, L. E. Am. J. hum. Genet. (in the press). 5. Willard, H. F., Ambam, L. M., Hart, A. C., Mahoney, M. J., Rosenberg, L. E. Hum. Genet 1976, 34, 277. 6. Similer, S., Ciesielski, L., Maitre, M., Randrianarisoa, H., Mandel, P. Biochem. Pharmac. 1973, 22, 1701.
3. 4.
The results (see table) are similar to Bourke’s in that patients with acute pancreatitis appeared to have a 2-5 times greater chance of receiving a diuretic than did a control group with acute abdominal pain and a normal serum-amylase: However, before any conclusions can be drawn, the similarity between the second control group with an undetermined serum-amylase and the test group, along with the preponderance 7. 1.
Simon, D., Penry, J. F. Epilepsia, 1975, 16, 549. Bourke, J. B., Mead, G. M., McIllmurray, M. B., Langman, M. J. 1978, i, 706.
S. Lancet,
370 of females in all groups,
must
be the
subject of further investi-
gation. Medicines Evaluation and
Monitoring Group, Royal Infirmary, Aberdeen AB9 2ZB
DOROTHY C. MOIR
DEATH FROM ACUTE PANCREATITIS
SIR The M.R.C. multicentre study’ compared glucagon and trasylol with placebo on a double-blind basis. Of 257 patients 123 received placebo, 68 were treated with glucagon, and 66 with trasylol. The mortality-rate for all patients was 10 - 7%; 11% for placebo, 12% for glucagon, and 9% for trasy-. lol. It was thus concluded that both drug treatments were ineffective. But the statistical design and the results of the M.R.C. study raise serious questions about the validity of this conclusion. Trapnell et al.2 found that trasylol reduced the mortality-rate by 70% compared with non-treated patients. To confirm these results, or even to demonstrate a reduction of mortality-rate of only 3% with trasylol, the M.R.C. study would have had to have at least 200 patients per experimental group--i.e., more than twice the number of patients. To demonstrate a mortality reduction of 5% (a clinically remarkable effect in this condition) would have demanded at least 428 patients per experimental group. This patient number would have satisfied the known relationship between the expected frequency of a result (mortality-rate) and the expected statistical difference between two patient groups. Such a study probably could not have been done since it would have lasted for years. The stringent selection of criteria for inclusion of patients in Trapnell’s study allowed for a reduction of the number of patients required for statistical evaluation. While the severity and the number of patients in the M.R.C. study raise questions about the conclusions, the data still show some support for Trapnell’s conclusion. A series of 25 severe cases were reported separately, patients who, for therapeutic or diagnostic reasons, had to have surgery. 10 of these (40%) died, a mortality-rate probably reflecting the severity of the disease.’ Classified according to therapy, the mortality-rate in each group is as follows : placebo group, 5 of 11 (45%); glucagon group, 4 of 8 (50%); trasylol group, 1 of 6 (17%). Thus, statistically, the trasylol data do not differ significantly from those obtained by Trapnell since in both studies, evaluating only severe pancreatitis cases, trasylol treatment resulted in equivalent reduction of mortality. Department of Biochemical Pharmacology, State University of New York at Buffalo, New York 14260, U.S.A.
NATHAN BACK
INTRAUTERINE HYPOTHYROIDISM DUE TO ANTITHYROID-DRUG THERAPY FOR THYROTOXICOSIS DURING PREGNANCY
SIR,-Antithyroid drugs can cross the placenta and impair thyroid function in fetus, leading to goitre formation with or without hypothyroidism.3 Neonatal goitres in infants born to mothers who have taken antithyroid drugs during pregnancy for thyrotoxicosis probably result from increased secretion of fetal thyroid-stimulating hormone (T.S.H.) in response
the
the depressed fetal thyroid-hormone output induced by the placental transfer of these drugs. Increased T.S.H. levels in the cord blood have been reported in infants who have druginduced goitres.4 However, little is known about thyroid hormone or T.s.H. levels in the neonatal period in infants who are to
.
1. M.R.C. Multicentre Trial. Lancet, 1977, ii, 632. 2. Trapnell, J. E., Rigby, C. C., Talbot, C. H., Duncan, E. H. L.
1974, 61, 177. 3. Burrow, G. N.J. clin. Endocr. Metab. 1965, 25, 403. 4. Refetoff, S., and others. J. Pediat. 1974, 85, 240.
DAYS POST-PARTUM
Thyroid biochemistry post partum. to antithyroid drugs in utero and who have no goitre clinical evidence of hypothyroidism.s We have information on two such infants during the first three weeks of life. Both infants were delivered spontaneously at term and appeared clinically euthyroid and without thyroid enlargement. The mother of baby A was thyrotoxic and taking 40 mg carbimazole and 80 µg triiodothyronine daily when she first came to our clinic at 24 weeks’ gestation. The drugs were stopped but had to be restarted at 34 weeks because of recurrence of symptoms, and carbimazole 30 mg/day with 60 µg of triiodothyronine was continued until delivery. The mother of baby M received carbimazole alone 15-30 mg/day throughout pregnancy, and she was on 30 mg at the time of delivery. The thyroid biochemistry of the mothers at the time of delivery was:
exposed
or
Mother of A Mother of M Normal range (in non-pregnant patients)
T4
T3
Binding capacity
(nmol//)
(nmol/l)
(%)
175 4-7 140 1.9 55-144
0.9-2.8
133 129 ..
The serum thyroxine (T4), triiodothyronine (T3), and T.S.H. in the neonatal period of these two infants are shown in the figure. The serum-T.S.H. was high in cord blood and at 6 h and 24 h but it returned to near normal within 72 h after delivery. High cord-blood T.S.H. can be caused by extreme parturition stress and hypoxia6 but in their absence the likely cause of the raised T.S.H. levels in these two infants is maternal antithyroid drug therapy. The rise in T4 at about 24 h after delivery induced by the surge of T.S.H. secretion shortly after birth’ was not observed in these two infants. The effect of placentally transferred antithyroid drugs on the fetal pituitary-thyroid axis seems transient, with recovery within 72 h after withdrawal of exposure. These data are consistent with a state of relative hypothyroidism, and presumably this existed in utero throughout the time the mother was receiving antithyroid drugs during her pregnancy. The first case (A) shows that this state is not prevented by simultaneous administration of amounts of triiodothyronine sufficient to raise the circulating maternal level. Can relative hypothy-
Br. J. Surg. 5. 6. 7.
Hayek, A., Brooks, M. ibid. 1975,87,446. Walfish, P. G. Lancet, 1976,i, 1208. Erenberg, A., and others. Pediatrics, 1974, 53, 211.
![[Acute pancreatitis].](/assets/img/hold.png)
