98 resistance to suppression. We were not helped by the patient’s sometimes casual attitude to tablet taking and urine collection and her refusal to be admitted to hospital for longer than a week. Finally when, after a month on dexamethasone 8 mg/ day, she showed complete suppression of pregnanetriol yet no signs of Cushing’s syndrome, we reconsidered enzyme induction. We twice measured the half-life of her plasma-cortisol (3H-cortisol method) and obtained values of 41 and 43 min at a time when her plasma-primidone was 90 mol/1 and her plasma-phenobarbitone (a metabolite of primidone) was 220 jjnnol/1. We were then happy that the problem could be solved by simply increasing her steroid dose. Our relief lasted until we wondered if the metabolism of 17-hydroxyprogesterone would also be affected by the drug because, if it was, its metabolite pregnanetriol might not be a reliable marker of adrenal suppression. We gave the patient and four controls (3H-)-17-hydroxyprogesterone and examined the tritiated metabolites. Although there were differences in the patient’s metabolism2 her percentage conversion to pregnanetriol (46%) was close to that of the controls (47-52%). The interaction had a twist in its tail. Her petit mal was worse when she had a normal cycle, attacks tending to occur at the time of the menses. The primidone was therefore reinforcing its direct action on the epilepsy by enhancing steroid breakdown thereby impairing control of her C.A.H. and giving rise to amenorrhrea. Department of Obstetrics and Gynæcology
K. W. HANCOCK
and Division of Steroid Endocrinology, Department of Chemical Pathology, School of Medicine, Leeds LS2 9NG
M.
J.
LEVELL
DRUG LABELLING
SIR,-Professor Degreef and
Dr Dooms-Goosens’ have
lately drawn attention to the need for all ingredients of drugs, active and inactive, to be disclosed on the label. We have seen a case of significant loss of diabetic control due to a bulk-forming laxative preparation. A 38-year-old female with juvenileonset diabetes had been controlled on 22 units of lente insulin for several months. Diverticulitis had lately been diagnosed and the patient put on a psyllium effervescent powder (’Metamucil Instant Mix’) one packet three times daily. In the following week the patient had polyuria, and double void urine test with ’KetoDiastix’ was 4+ for glucose and "large" for ketones. Attempts to find out why diabetic control had been lost were frustrated by inadequate labelling on the package of metamucil instant mix (and metamucil) because neither stated any sugar content. The sugar content of these preparations was found in the Handbook of Nonprescription Drugs (American Pharmaceutical Association). Metamucil instant mix is stated as containing 3 calories/packet, while metamucil and other bulk laxative powders (’Hydrocil’, ’Mucilose’, ’Plova’, ’L A Formula’) all contain 50% dextrose. ’Konsyl’ is the only psyllium laxative product that does not contain any dextrose. Diabetic control returned when metamucil instant mix was discontinued. Manufacturers should list the sugar content of their products on the label and health professionals should be aware that most bulk-forming laxative products contain substantial amounts of dextrose and that a sugar-free preparation should be used in diabetic patients. Information Service, School of Pharmacy,
Drug
University of Washington, Seattle, Washington 98195, U.S.A. 2.
1.
JOSEPH CATELLANI R. J. COLLINS
Brown, T.J.M.SC. thesis, University of Leeds, 1973. Degreef, H., Dooms-Goosens, A. Lancet, 1978, i, 1201.
THEOPHYLLINE PHARMACOKINETICS IN RESPIRATORY VIRAL ILLNESS
SiR,-Dr Chang and colleagues’ suggest that certain upperrespiratory-tract viral infections may affect theophylline metabolism, and they state that there is a marked decrease in this drug’s elimination half-life in the month after infection. This observation would be of great importance if it could be confirmed for other drugs. The elimination half-life of theophylline one month after infection was approximately 60% of that during infection (range 23-101%). We question both the
and
the conclusions methods used to derive these results drawn. The Schack and Waxler (1949)2 spectrophotometric method for assaying theophylline is recognised to be non-specific and fails adequately to discriminate between theophylline, its metabolites, and dietary xanthines. Duplicate control estimations may show the method to be reproducible, but this does not necessarily mean that it is specific. Many specific chromatographic procedures are now available. Sampling for a period as short as 5 h after drug administration is too short to define accurately the elimination kinetics of a drug such as theophylline.3 The possibility of inadequate duration of sampling is illustrated by the results from patients 1 and 2. For these two patients, the theophylline half-lives a month after illness are given as 2.09 h and 1-37 h, respectively. These values are, to our knowledge, without precedent, and it is difficult not to conclude either that there was some error in the assay or that there were too few data points for calculation of the elimination line to permit the elimination half-life to be determined precisely. The use of a one-tailed Student’st test for statistical comparisons suggests that Chang et al. had prejudged the results. Finally, to generalise, on the basis of the results for one patient (no. 6), that influenza B does not cause this change while influenza A does, seems speculative in the extreme. -
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
JOHN G. KELLY KEVIN O’MALLEY
PROSTAGLANDINS AND MECHANISM OF ACTION OF SULPHASALAZINE IN ULCERATIVE COLITIS use in the long-term treatment of ulcerathan 30 years, the mechanism of action of sulphasalazine remains obscure. Gould has suggested that sulphasalazine or its metabolites inhibit prostaglandin (P.G.) synthesis.’’ This may benefit ulcerative colitis by reducing diarrhooea, since prostaglandins cause diarrhoea,3.6 probably by stimulating intestinal motility and reducing epithelial water transport. There is also evidence that in patients with active ulcerative colitis P.G. synthesis is increased in colonic mucosaand levels of the major urinary p.G.F metabolite are increased.8 Yet there is no evidence to suggest that powerful inhibitors of P.G. synthesis (e.g., the aspirin-like drugs) have any beneficial effect in ulcerative colitis-indeed, aspirin-like drugs cause gastric and duodenal ulceration both in laboratory animals and in man. Since certain types of ulcers are thought to be caused by P.G. deficiency,3. and, noting that sulphasalazine is used prophylactically for the prevention of relapses in the patient who has
SIR,-Despite
tive colitis for
1. 2. 3. 4. 5.
6. 7. 8. 9.
its
more
Chang, K. C., Bell, T. D., Laver, B. A., Chai, H. Lancet, 1978, i, 1132. Schack, J., Waxler, S. I. J. Pharmac. exp. Ther. 1949, 97, 283. Gibaldi, M., Weintraub, H. J. pharm. Sci. 1971, 60, 624. Gould, S. R. Lancet, 1975, ii, 988. Robert, A. in Advances in Prostaglandin and Thromboxane Research (edited by B. Samuelsson and R. Paoletti); p. 507. New York, 1976. Misiewicz, J. J., Waller, S. L., Kiley, N., Horton, E, W. Lancet, 1969, i, 648. Gould, S. R. Prostaglandins, 1976, 11, 489. Gould, S. R., Brash, A. R., Conolly, M. E. Lancet, 1977, ii, 98. Hinsdale, J. C., Engel, J. J., Wilson, D. E. Prostaglandins, 1974, 6, 495.
K. W. HANCOCK
and Division of Steroid Endocrinology, Department of Chemical Pathology, School of Medicine, Leeds LS2 9NG
M.
J.
LEVELL
DRUG LABELLING
SIR,-Professor Degreef and
Dr Dooms-Goosens’ have
lately drawn attention to the need for all ingredients of drugs, active and inactive, to be disclosed on the label. We have seen a case of significant loss of diabetic control due to a bulk-forming laxative preparation. A 38-year-old female with juvenileonset diabetes had been controlled on 22 units of lente insulin for several months. Diverticulitis had lately been diagnosed and the patient put on a psyllium effervescent powder (’Metamucil Instant Mix’) one packet three times daily. In the following week the patient had polyuria, and double void urine test with ’KetoDiastix’ was 4+ for glucose and "large" for ketones. Attempts to find out why diabetic control had been lost were frustrated by inadequate labelling on the package of metamucil instant mix (and metamucil) because neither stated any sugar content. The sugar content of these preparations was found in the Handbook of Nonprescription Drugs (American Pharmaceutical Association). Metamucil instant mix is stated as containing 3 calories/packet, while metamucil and other bulk laxative powders (’Hydrocil’, ’Mucilose’, ’Plova’, ’L A Formula’) all contain 50% dextrose. ’Konsyl’ is the only psyllium laxative product that does not contain any dextrose. Diabetic control returned when metamucil instant mix was discontinued. Manufacturers should list the sugar content of their products on the label and health professionals should be aware that most bulk-forming laxative products contain substantial amounts of dextrose and that a sugar-free preparation should be used in diabetic patients. Information Service, School of Pharmacy,
Drug
University of Washington, Seattle, Washington 98195, U.S.A. 2.
1.
JOSEPH CATELLANI R. J. COLLINS
Brown, T.J.M.SC. thesis, University of Leeds, 1973. Degreef, H., Dooms-Goosens, A. Lancet, 1978, i, 1201.
THEOPHYLLINE PHARMACOKINETICS IN RESPIRATORY VIRAL ILLNESS
SiR,-Dr Chang and colleagues’ suggest that certain upperrespiratory-tract viral infections may affect theophylline metabolism, and they state that there is a marked decrease in this drug’s elimination half-life in the month after infection. This observation would be of great importance if it could be confirmed for other drugs. The elimination half-life of theophylline one month after infection was approximately 60% of that during infection (range 23-101%). We question both the
and
the conclusions methods used to derive these results drawn. The Schack and Waxler (1949)2 spectrophotometric method for assaying theophylline is recognised to be non-specific and fails adequately to discriminate between theophylline, its metabolites, and dietary xanthines. Duplicate control estimations may show the method to be reproducible, but this does not necessarily mean that it is specific. Many specific chromatographic procedures are now available. Sampling for a period as short as 5 h after drug administration is too short to define accurately the elimination kinetics of a drug such as theophylline.3 The possibility of inadequate duration of sampling is illustrated by the results from patients 1 and 2. For these two patients, the theophylline half-lives a month after illness are given as 2.09 h and 1-37 h, respectively. These values are, to our knowledge, without precedent, and it is difficult not to conclude either that there was some error in the assay or that there were too few data points for calculation of the elimination line to permit the elimination half-life to be determined precisely. The use of a one-tailed Student’st test for statistical comparisons suggests that Chang et al. had prejudged the results. Finally, to generalise, on the basis of the results for one patient (no. 6), that influenza B does not cause this change while influenza A does, seems speculative in the extreme. -
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
JOHN G. KELLY KEVIN O’MALLEY
PROSTAGLANDINS AND MECHANISM OF ACTION OF SULPHASALAZINE IN ULCERATIVE COLITIS use in the long-term treatment of ulcerathan 30 years, the mechanism of action of sulphasalazine remains obscure. Gould has suggested that sulphasalazine or its metabolites inhibit prostaglandin (P.G.) synthesis.’’ This may benefit ulcerative colitis by reducing diarrhooea, since prostaglandins cause diarrhoea,3.6 probably by stimulating intestinal motility and reducing epithelial water transport. There is also evidence that in patients with active ulcerative colitis P.G. synthesis is increased in colonic mucosaand levels of the major urinary p.G.F metabolite are increased.8 Yet there is no evidence to suggest that powerful inhibitors of P.G. synthesis (e.g., the aspirin-like drugs) have any beneficial effect in ulcerative colitis-indeed, aspirin-like drugs cause gastric and duodenal ulceration both in laboratory animals and in man. Since certain types of ulcers are thought to be caused by P.G. deficiency,3. and, noting that sulphasalazine is used prophylactically for the prevention of relapses in the patient who has
SIR,-Despite
tive colitis for
1. 2. 3. 4. 5.
6. 7. 8. 9.
its
more
Chang, K. C., Bell, T. D., Laver, B. A., Chai, H. Lancet, 1978, i, 1132. Schack, J., Waxler, S. I. J. Pharmac. exp. Ther. 1949, 97, 283. Gibaldi, M., Weintraub, H. J. pharm. Sci. 1971, 60, 624. Gould, S. R. Lancet, 1975, ii, 988. Robert, A. in Advances in Prostaglandin and Thromboxane Research (edited by B. Samuelsson and R. Paoletti); p. 507. New York, 1976. Misiewicz, J. J., Waller, S. L., Kiley, N., Horton, E, W. Lancet, 1969, i, 648. Gould, S. R. Prostaglandins, 1976, 11, 489. Gould, S. R., Brash, A. R., Conolly, M. E. Lancet, 1977, ii, 98. Hinsdale, J. C., Engel, J. J., Wilson, D. E. Prostaglandins, 1974, 6, 495.
