- Email: [email protected]
OTOTOXICITY OF ERYTHROMYCIN
214
SIR,-Dr Hayler and her colleaguesl report five fatal
over-
antiarrhythmic drug disopyramide. The therapeutic plasma concentration of disopyramide lies in the range 2-4 mg/l. In three of the fatal cases the plasma concentrations of disopyramide were 25-5, 35, and 114 mg/1; in the other two the concentrations were 4.3and 8.3mg/l but the peak plasma concentrations in these two patients are not known. Hayler et doses of the
al. found that initial responses
to
concentration of 25.5 mg/l 10 h before death. Post mortem, the plasma concentration had increased to 34 mg/1. More importantly the stomach contained 2.3 g/1 disopyramide, at least 14 h after ingestion of the drug. The anticholinergic effects of disopyramide ought to have delayed stomach emptying. Hayler et al. did not mention gastric lavage. Perhaps the continued deterioration seen in their patients was, in part, due to continued absorption of disopyramide. Lavage should be attempted in all disopyramide overdoses, even if several hours have elapsed since ingestion. Urinary retention is a well-known side-effect of disopyramide, so patients taking overdoses should be catheterised to prevent renal failure secondary to obstruction. The anticholinergic activity of disopyramide may be responsible for some of the arrhythmias observed. Physostigmine, which is useful in treating tachyarrythmias secondary to tricyclic antidepressant overdosemight warrant a trial when more conventional therapy has been unsuccessful. A dose of 2 mg given by slow intravenous injection is suggested. Physostigmine will antagonise other anticholinergic symptoms should they become troublesome. We have studied three chronic hxmodialysis patients who were receiving disopyramide for ventricular arrhythmias. The first patient’s disopyramide half-life was 15.2 h without dialysis and averaged 6.41+s.D. 1.32 h during four separate dialyses. Patient 2 had half-lives of 18.6 h and 10.2 h before and during dialysis, respectively. The third patient’s disopyramide half-life was 12.1h before dialysis and 3.3h during dialysis. A Gambro Lundia parallel-flow haemodialyser was used on all patients. Ultrafiltration at 100 mm Hg was used on patient 3 and may account for the larger percentage change in half-life seen during dialysis. In addition, dialysis might be expected to have an even greater effect on disopyramide half-life at higher plasma concentrations where a lesser percent of the total plasma-disopyramide is protein bound. The treatment of disopyramide overdose should include lavage and respiratory and cardiovascular support. Antiarrhythmics should be administered as required, with consideration given to the use of physostigmine. Haemodialysis may increase the elimination of disopyramide. More experience in the treatment of disopyramide overdose will be required before definitive recommendations can be made.
opyramide plasma
DISOPYRAMIDE DIALYSABILITY
resuscitation and antiar-
rhythmic drug therapy were followed by rapid deterioration complicated by cardiac arrhythmia and loss of spontaneous respiration. Hayler et al. were unable to give any specific advice on treatment of overdoses with disopyramide. Even though disopyramide is a basic compound (pKa 8.4) which is not extensively metabolised and ’which is largely (40-60% of dose) excreted by the kidney, its elimination is not enhanced by forced acidification.2,3 One possible approach to enhance disopyramide elimination would appear to be by hxmodialysis or charcoal hasmoperfusion. The aqueous solubility of disopyramide free base at physiological pH is about 1 mg/ml, and its molecular weight is 339. The apparent volume of distribution of disopyramide in man ranges from 40 to 80 litres,3,4 and in animal stUdies5,6 extensive tissue binding of disopyramide was not apparent. The plasma protein binding of disopyramide is concentration dependent3·’ and varies from 5 to 65% as the total plasma concentration is decreased from 72 mg/1 to 0.04 mg/1. This concentration-dependent plasma protein binding may have important implications in haemodialysis. According to Gibson and Nelson,8the above physicochemical and pharmacokinetic properties would favour the effective removal of toxic concentrations of disopyramide from the body by haemodialysis. In-vitro studies have demonstrated that disopyramide is stable when incubated with human blood for 2 h at 37°C. When human blood containing an initial plasma concentration of 22 mg/1 was dialysed at 37°C in a CordisDow 4 artificial kidney at a blood-flow rate of 250 ml/min, the disopyramide plasma concentration fell to 3 mg/1 within 2 h. The terminal-phase half-life and blood clearance of disopyramide were 43 min and 33 ml/min, respectively. These in-vitro data suggest that hxmodialysis may be of potential use in enhancing the elimination of toxic concentrations of disopyramide from the body. In-vivo data, however, are needed before a general recommendation can be made for disopyramide overdose treatment.
.
Virginia Mason Medical Center, Seattle, Washington 98101, U.S.A.
JOHN R. HORN M. LEO HUGHES
Department of Drug Metabolism and Radiochemistry, G. D. Searle & Co. Research and Development, Chicago, Illinois 60682, U.S.A.
SIR,-Dr Hayler and her colleagues suggest that methods which would enhance the clearance of disopyramide might be useful in treating disopyramide overdoses. The terminal event in four of the five cases seems to have been left heart-failure
resulting in rapidly progressive pulmonary oeriema. It would prudent to treat disopyramide overdosage with supportive therapy, including ventilatory assistance, intravenous morphine, diuretics, and antiarrhythmic agents. The seemingly paradoxical initial response to resuscitation with subsequent deterioration may be explained by the anticholinergic activity of disopyramide. Hayler’s case 4 had a disseem
1. 2. 3.
Hayler, A. M., Holt, D. W., Volans, G. N. Lancet, 1978, i, 908. Ankier, S. I., Kaye, C. M. Br.J. clin. Pharmac. 1976, 3, 672. Cunningham, J. L., Shen, D. D., Shudo, I., Azarnoff, D. L. Clin. Pharmacokin. 1977, 2, 373. 4. Karim, A. Angiology, 1975, 26, suppl. 1,85. 5. Karim, A., Kook, C., Campion, J., Doherty, M., Arch int. Pharmacodyn de Ther. 1977, 228, 222. 6. Karim, A., Kook, C., Novotney, R. L., Zagarella, J., Campion, J. Drug Metab. Dispos. 1978, 6, 338. 7. Hinderling, P. H., Bres, J., Garrett, E. R. J. pharm. Sci. 1974, 63, 168. 2. 8.
Gibson, T. P., Nelson, H. A. Clin Pharmacokin. 1977, 2, 403.
OTOTOXICITY OF ERYTHROMYCIN
AZIZ KARIM
SIR,-Dr Quinnan and Dr McCabe4 report ototoxicity associated with erythromycin in two patients with impaired renal function, and cite three other cases.5)6 We have seen two patients on chronic intermittent dialysis with audiographically documented bilateral perceptive hearing loss during administration of oral erythromycin. A 17-year-old girl who had been on hsmodialysis three times weekly since December, 1975, because of chronic pyelonephritis of her single kidney, and who had had a normal audiogram 6 months earlier and no previous complaints of hearing loss, took oral erythromycin stearate 500 mg twice daily for 6 weeks followed by 500 mg four times daily for 2 weeks because of infected skin lesions. During the lower dosage period there was no hearing loss, but after 13 days at the higher dose she complained of poor hearing, which had started 7 days earlier. The audiogram disclosed a perceptive hearing Heel, R. C., Brogden, T. M., Avery, G. S. Drugs, 1978, 15, 331. Burk, J. S., Walker, J. E., Rumack, B. H., Ott, J. E.J. Am. med. Ass. 1974, 230, 1405. 3 Hinderling, P. H., Bres, J., Garrett, E. R. J. pharm. Sci. 1974, 63, 1684. 4. Quinnan, G. V., Jr, McCabe, W. R. Lancet, 1978, i, 1161. 5. Mintz, U., Amir, J., Pinkhas, J., de Vries, A. J. Am. med. Ass. 1971, 225, 1. 2.
1122. 6.
Eckman, M., Johnson. Tl., Tiess, R. New Engl.J. Med. 1975, 292, 649.
215 loss of at least 40 dB at all tested frequencies. 2 days after cessation of erythromycin, both subjective hearing and the audiogram improved. An audiogram made a month later disclosed no abnormalities. The second patient, a 58-year-old man on chronic intermittent dialysis twice weekly since January, 1975, because of bilateral cortical necrosis, was treated with oral erythromycin stearate 500 mg four times daily for 19 days because of infection of a bovine graft and suspected allergy to penicillin. A progressive perceptive hearing loss of 60 dB developed 8 days after the erythromycin therapy was started. 2 days after withdrawal of the erythromycin, subjective hearing and the audiogram improved and became normal within 25 days. Like the patients described by Eckman et al. our patients received oral erythromycin, whereas those described by Mintz et al. and Quinnan and McCabe were treated parenterally. All reported patients received erythromycin in a dose of at least 4 g daily. Our two patients received only 2 g daily, but since they had almost no residual kidney function their serum concentrations were probably high.’ Whether ototoxicity is due to erythromycin itself or a metabolite is not known. From our findings it is unlikely that the toxic agent is removed by hxmodialysis. Departments of Infectious Diseases and Nephrology, University Hospital, Leaden, Netherlands
W. F. VAN MARION J. W. M. VAN DER MEER M. W. KALFF S. M. SCHICHT
CONVULSIONS IN A BREAST-FED INFANT AFTER MATERNAL INDOMETHACIN woman complained of severe from symphyseolysis during the last month of pregnancy. There was an uneventful delivery of a normal boy in the 41st week. Breast-feeding began on the third day. Because of the pain from the symphyseolysis the mother was given indomethacin, from the fourth day, in doses increasing to 200 mg daily which, from the sixth day, corresponded to 3 mg indomethacin/kg (normal adult dose 1-2 mg/kg). The next day she complained of a severe headache and indomethacin was discontinued. On the same day she was discharged from hospital with her healthy child. 2 h after returning home the child was found with general seizures lasting about 5 min. He was admitted to a children’s hospital. The next day the child had another general seizure episode lasting about 2 min. Examination revealed a normal boy with a normal neurological state. There was no evidence for sepsis, or hypoglycaemia, hypocalcsemia, or other metabolic disorder. The cerebrospinal fluid was normal as was the metabolic screening.
SIR,-A 29-year-old healthy
pain
Transillumination,
two E.E.G.S, echoencephalography, and all normal. The child was sent home healthy after 2 days continuing breast feeding. No serum or urine was collected from the mother or the child, or breast milk from the mother. Extrapolation via a simulated pharmacokinetic computer 1 program based on pharmacokinetic data for indomethacin’ that the maternal concentration was 1-4 plasma suggested jig/ml (see figure). Hardly anything is known about the passage of indomethacin from plasma into breast milk, but a casereport made available to us from the files of a drug company indicates concentrations similar to those of plasma during the steady state. On this assumption, and with a breast-milk volume of 500 ml/day, this child would have received 0.5-2.0 mg indomethacin/24 h (0-1-0-55 mg/kg). Glucuronidation is an important mechanism for the eliE.c.G. were
Wilson, J. T., van Boxtel, J. in Antibiotics and Chemotherapy: vol. xxv (pharmacokinetics) (edited by H. Schönfeld). Bask, 1978. 1. Alván, G., Orme, M., Bertilsson, L., Ekstrand, R., Palmér, L. Clin. Pharmac. Ther. 1975, 18, 364. 7.
Computer-calculated plasma levels attained after indomethacin given according to the time schedule in the case. A new 50 mg dose was administered each time of the slope of the curve after each peak.
at
the lowest
point
mination of indomethacin, and, since this capacity in a child 1 week old is limited, the drug could accumulate. Indomethacin lowers the convulsive threshold; this might be harmful in the newborn who already have an increased tendency to convulsions. We conclude that indomethacin therapy given to the mother and the excretion of the drug in breast milk probably caused the seizures in this otherwise healthy infant. The boy is now 1 year old. Mental and motor development have been normal and seizures have not recurred. There is a strong case for warning against the use of indomethacin as an analgesic drug in nursing mothers. ORVAR EEG-OLOFSSON INGEMAR MALMROS
Pædiatric Clinic,
Linköping University Drug Information Centre, Department of Clinical Pharmacology, Huddinge University Hospital,
CARL-ERIC ELWIN BENGT STÉEN
S-141 86 Stockholm, Sweden
ALTERED WARFARIN METABOLISM IN IRON-DEFICIENT PATIENT
SIR,-We have investigated a patient with iron-deficiency anxmia who eliminated the anticoagulant warfarin unusually
slowly, leading to a prolonged hypoprothrombinasmic response. A 24-year-old female was admitted to the Tameside General Hospital with an iliac-vein thrombosis. She was profoundly iron-deficient (Hb 7.6 g/dl), probably due to intermittent bleeding from a hiatus hernia related to marked kyphoscoliosis. Renal function was normal, and bromsulphophthalein retention was treated with a
3-2%
at
45 min. Her
venous
thrombosis
was
single dose of 30 mg oral warfarin sodium (0.7 mg/kg body-weight). She was given no further warfarin, but her prothrombin ratio rose to a peak at 9.0 on day 5, and was still high at 1.4 on day 30, despite 20 mg of vitamin Kl intravenously on day 24. Plasma-warfarin levels’ were 2.4 fJ.g/ml on day 8 and 0.65 p.g/ml on day 22. After 3 months on oral iron supplements, her haemoglobin had risen to 14.4 g/dl, and her plasma antipyrine half-life was 6.4 h, the normal for young females being 10·3±2.1 h2. Warfarin plasma elimination half-life was pro1. 2.
Hewick,
D. S., McEwen, J.J. Pharm. Pharmac. 1973, 25, 458. O’Malley, K., Crooks, J., Duke, E., Stevenson, I. H. Br. med. J. 1971, iii,
3.
Shepherd, A. M. M., Hewick, D. S., Moreland, J. clin. Pharmac. 1977, iv, 315.
607. T.
A., Stevenson, I. H. Br.
SIR,-Dr Hayler and her colleaguesl report five fatal
over-
antiarrhythmic drug disopyramide. The therapeutic plasma concentration of disopyramide lies in the range 2-4 mg/l. In three of the fatal cases the plasma concentrations of disopyramide were 25-5, 35, and 114 mg/1; in the other two the concentrations were 4.3and 8.3mg/l but the peak plasma concentrations in these two patients are not known. Hayler et doses of the
al. found that initial responses
to
concentration of 25.5 mg/l 10 h before death. Post mortem, the plasma concentration had increased to 34 mg/1. More importantly the stomach contained 2.3 g/1 disopyramide, at least 14 h after ingestion of the drug. The anticholinergic effects of disopyramide ought to have delayed stomach emptying. Hayler et al. did not mention gastric lavage. Perhaps the continued deterioration seen in their patients was, in part, due to continued absorption of disopyramide. Lavage should be attempted in all disopyramide overdoses, even if several hours have elapsed since ingestion. Urinary retention is a well-known side-effect of disopyramide, so patients taking overdoses should be catheterised to prevent renal failure secondary to obstruction. The anticholinergic activity of disopyramide may be responsible for some of the arrhythmias observed. Physostigmine, which is useful in treating tachyarrythmias secondary to tricyclic antidepressant overdosemight warrant a trial when more conventional therapy has been unsuccessful. A dose of 2 mg given by slow intravenous injection is suggested. Physostigmine will antagonise other anticholinergic symptoms should they become troublesome. We have studied three chronic hxmodialysis patients who were receiving disopyramide for ventricular arrhythmias. The first patient’s disopyramide half-life was 15.2 h without dialysis and averaged 6.41+s.D. 1.32 h during four separate dialyses. Patient 2 had half-lives of 18.6 h and 10.2 h before and during dialysis, respectively. The third patient’s disopyramide half-life was 12.1h before dialysis and 3.3h during dialysis. A Gambro Lundia parallel-flow haemodialyser was used on all patients. Ultrafiltration at 100 mm Hg was used on patient 3 and may account for the larger percentage change in half-life seen during dialysis. In addition, dialysis might be expected to have an even greater effect on disopyramide half-life at higher plasma concentrations where a lesser percent of the total plasma-disopyramide is protein bound. The treatment of disopyramide overdose should include lavage and respiratory and cardiovascular support. Antiarrhythmics should be administered as required, with consideration given to the use of physostigmine. Haemodialysis may increase the elimination of disopyramide. More experience in the treatment of disopyramide overdose will be required before definitive recommendations can be made.
opyramide plasma
DISOPYRAMIDE DIALYSABILITY
resuscitation and antiar-
rhythmic drug therapy were followed by rapid deterioration complicated by cardiac arrhythmia and loss of spontaneous respiration. Hayler et al. were unable to give any specific advice on treatment of overdoses with disopyramide. Even though disopyramide is a basic compound (pKa 8.4) which is not extensively metabolised and ’which is largely (40-60% of dose) excreted by the kidney, its elimination is not enhanced by forced acidification.2,3 One possible approach to enhance disopyramide elimination would appear to be by hxmodialysis or charcoal hasmoperfusion. The aqueous solubility of disopyramide free base at physiological pH is about 1 mg/ml, and its molecular weight is 339. The apparent volume of distribution of disopyramide in man ranges from 40 to 80 litres,3,4 and in animal stUdies5,6 extensive tissue binding of disopyramide was not apparent. The plasma protein binding of disopyramide is concentration dependent3·’ and varies from 5 to 65% as the total plasma concentration is decreased from 72 mg/1 to 0.04 mg/1. This concentration-dependent plasma protein binding may have important implications in haemodialysis. According to Gibson and Nelson,8the above physicochemical and pharmacokinetic properties would favour the effective removal of toxic concentrations of disopyramide from the body by haemodialysis. In-vitro studies have demonstrated that disopyramide is stable when incubated with human blood for 2 h at 37°C. When human blood containing an initial plasma concentration of 22 mg/1 was dialysed at 37°C in a CordisDow 4 artificial kidney at a blood-flow rate of 250 ml/min, the disopyramide plasma concentration fell to 3 mg/1 within 2 h. The terminal-phase half-life and blood clearance of disopyramide were 43 min and 33 ml/min, respectively. These in-vitro data suggest that hxmodialysis may be of potential use in enhancing the elimination of toxic concentrations of disopyramide from the body. In-vivo data, however, are needed before a general recommendation can be made for disopyramide overdose treatment.
.
Virginia Mason Medical Center, Seattle, Washington 98101, U.S.A.
JOHN R. HORN M. LEO HUGHES
Department of Drug Metabolism and Radiochemistry, G. D. Searle & Co. Research and Development, Chicago, Illinois 60682, U.S.A.
SIR,-Dr Hayler and her colleagues suggest that methods which would enhance the clearance of disopyramide might be useful in treating disopyramide overdoses. The terminal event in four of the five cases seems to have been left heart-failure
resulting in rapidly progressive pulmonary oeriema. It would prudent to treat disopyramide overdosage with supportive therapy, including ventilatory assistance, intravenous morphine, diuretics, and antiarrhythmic agents. The seemingly paradoxical initial response to resuscitation with subsequent deterioration may be explained by the anticholinergic activity of disopyramide. Hayler’s case 4 had a disseem
1. 2. 3.
Hayler, A. M., Holt, D. W., Volans, G. N. Lancet, 1978, i, 908. Ankier, S. I., Kaye, C. M. Br.J. clin. Pharmac. 1976, 3, 672. Cunningham, J. L., Shen, D. D., Shudo, I., Azarnoff, D. L. Clin. Pharmacokin. 1977, 2, 373. 4. Karim, A. Angiology, 1975, 26, suppl. 1,85. 5. Karim, A., Kook, C., Campion, J., Doherty, M., Arch int. Pharmacodyn de Ther. 1977, 228, 222. 6. Karim, A., Kook, C., Novotney, R. L., Zagarella, J., Campion, J. Drug Metab. Dispos. 1978, 6, 338. 7. Hinderling, P. H., Bres, J., Garrett, E. R. J. pharm. Sci. 1974, 63, 168. 2. 8.
Gibson, T. P., Nelson, H. A. Clin Pharmacokin. 1977, 2, 403.
OTOTOXICITY OF ERYTHROMYCIN
AZIZ KARIM
SIR,-Dr Quinnan and Dr McCabe4 report ototoxicity associated with erythromycin in two patients with impaired renal function, and cite three other cases.5)6 We have seen two patients on chronic intermittent dialysis with audiographically documented bilateral perceptive hearing loss during administration of oral erythromycin. A 17-year-old girl who had been on hsmodialysis three times weekly since December, 1975, because of chronic pyelonephritis of her single kidney, and who had had a normal audiogram 6 months earlier and no previous complaints of hearing loss, took oral erythromycin stearate 500 mg twice daily for 6 weeks followed by 500 mg four times daily for 2 weeks because of infected skin lesions. During the lower dosage period there was no hearing loss, but after 13 days at the higher dose she complained of poor hearing, which had started 7 days earlier. The audiogram disclosed a perceptive hearing Heel, R. C., Brogden, T. M., Avery, G. S. Drugs, 1978, 15, 331. Burk, J. S., Walker, J. E., Rumack, B. H., Ott, J. E.J. Am. med. Ass. 1974, 230, 1405. 3 Hinderling, P. H., Bres, J., Garrett, E. R. J. pharm. Sci. 1974, 63, 1684. 4. Quinnan, G. V., Jr, McCabe, W. R. Lancet, 1978, i, 1161. 5. Mintz, U., Amir, J., Pinkhas, J., de Vries, A. J. Am. med. Ass. 1971, 225, 1. 2.
1122. 6.
Eckman, M., Johnson. Tl., Tiess, R. New Engl.J. Med. 1975, 292, 649.
215 loss of at least 40 dB at all tested frequencies. 2 days after cessation of erythromycin, both subjective hearing and the audiogram improved. An audiogram made a month later disclosed no abnormalities. The second patient, a 58-year-old man on chronic intermittent dialysis twice weekly since January, 1975, because of bilateral cortical necrosis, was treated with oral erythromycin stearate 500 mg four times daily for 19 days because of infection of a bovine graft and suspected allergy to penicillin. A progressive perceptive hearing loss of 60 dB developed 8 days after the erythromycin therapy was started. 2 days after withdrawal of the erythromycin, subjective hearing and the audiogram improved and became normal within 25 days. Like the patients described by Eckman et al. our patients received oral erythromycin, whereas those described by Mintz et al. and Quinnan and McCabe were treated parenterally. All reported patients received erythromycin in a dose of at least 4 g daily. Our two patients received only 2 g daily, but since they had almost no residual kidney function their serum concentrations were probably high.’ Whether ototoxicity is due to erythromycin itself or a metabolite is not known. From our findings it is unlikely that the toxic agent is removed by hxmodialysis. Departments of Infectious Diseases and Nephrology, University Hospital, Leaden, Netherlands
W. F. VAN MARION J. W. M. VAN DER MEER M. W. KALFF S. M. SCHICHT
CONVULSIONS IN A BREAST-FED INFANT AFTER MATERNAL INDOMETHACIN woman complained of severe from symphyseolysis during the last month of pregnancy. There was an uneventful delivery of a normal boy in the 41st week. Breast-feeding began on the third day. Because of the pain from the symphyseolysis the mother was given indomethacin, from the fourth day, in doses increasing to 200 mg daily which, from the sixth day, corresponded to 3 mg indomethacin/kg (normal adult dose 1-2 mg/kg). The next day she complained of a severe headache and indomethacin was discontinued. On the same day she was discharged from hospital with her healthy child. 2 h after returning home the child was found with general seizures lasting about 5 min. He was admitted to a children’s hospital. The next day the child had another general seizure episode lasting about 2 min. Examination revealed a normal boy with a normal neurological state. There was no evidence for sepsis, or hypoglycaemia, hypocalcsemia, or other metabolic disorder. The cerebrospinal fluid was normal as was the metabolic screening.
SIR,-A 29-year-old healthy
pain
Transillumination,
two E.E.G.S, echoencephalography, and all normal. The child was sent home healthy after 2 days continuing breast feeding. No serum or urine was collected from the mother or the child, or breast milk from the mother. Extrapolation via a simulated pharmacokinetic computer 1 program based on pharmacokinetic data for indomethacin’ that the maternal concentration was 1-4 plasma suggested jig/ml (see figure). Hardly anything is known about the passage of indomethacin from plasma into breast milk, but a casereport made available to us from the files of a drug company indicates concentrations similar to those of plasma during the steady state. On this assumption, and with a breast-milk volume of 500 ml/day, this child would have received 0.5-2.0 mg indomethacin/24 h (0-1-0-55 mg/kg). Glucuronidation is an important mechanism for the eliE.c.G. were
Wilson, J. T., van Boxtel, J. in Antibiotics and Chemotherapy: vol. xxv (pharmacokinetics) (edited by H. Schönfeld). Bask, 1978. 1. Alván, G., Orme, M., Bertilsson, L., Ekstrand, R., Palmér, L. Clin. Pharmac. Ther. 1975, 18, 364. 7.
Computer-calculated plasma levels attained after indomethacin given according to the time schedule in the case. A new 50 mg dose was administered each time of the slope of the curve after each peak.
at
the lowest
point
mination of indomethacin, and, since this capacity in a child 1 week old is limited, the drug could accumulate. Indomethacin lowers the convulsive threshold; this might be harmful in the newborn who already have an increased tendency to convulsions. We conclude that indomethacin therapy given to the mother and the excretion of the drug in breast milk probably caused the seizures in this otherwise healthy infant. The boy is now 1 year old. Mental and motor development have been normal and seizures have not recurred. There is a strong case for warning against the use of indomethacin as an analgesic drug in nursing mothers. ORVAR EEG-OLOFSSON INGEMAR MALMROS
Pædiatric Clinic,
Linköping University Drug Information Centre, Department of Clinical Pharmacology, Huddinge University Hospital,
CARL-ERIC ELWIN BENGT STÉEN
S-141 86 Stockholm, Sweden
ALTERED WARFARIN METABOLISM IN IRON-DEFICIENT PATIENT
SIR,-We have investigated a patient with iron-deficiency anxmia who eliminated the anticoagulant warfarin unusually
slowly, leading to a prolonged hypoprothrombinasmic response. A 24-year-old female was admitted to the Tameside General Hospital with an iliac-vein thrombosis. She was profoundly iron-deficient (Hb 7.6 g/dl), probably due to intermittent bleeding from a hiatus hernia related to marked kyphoscoliosis. Renal function was normal, and bromsulphophthalein retention was treated with a
3-2%
at
45 min. Her
venous
thrombosis
was
single dose of 30 mg oral warfarin sodium (0.7 mg/kg body-weight). She was given no further warfarin, but her prothrombin ratio rose to a peak at 9.0 on day 5, and was still high at 1.4 on day 30, despite 20 mg of vitamin Kl intravenously on day 24. Plasma-warfarin levels’ were 2.4 fJ.g/ml on day 8 and 0.65 p.g/ml on day 22. After 3 months on oral iron supplements, her haemoglobin had risen to 14.4 g/dl, and her plasma antipyrine half-life was 6.4 h, the normal for young females being 10·3±2.1 h2. Warfarin plasma elimination half-life was pro1. 2.
Hewick,
D. S., McEwen, J.J. Pharm. Pharmac. 1973, 25, 458. O’Malley, K., Crooks, J., Duke, E., Stevenson, I. H. Br. med. J. 1971, iii,
3.
Shepherd, A. M. M., Hewick, D. S., Moreland, J. clin. Pharmac. 1977, iv, 315.
607. T.
A., Stevenson, I. H. Br.