- Email: [email protected]
APNOEA IN A 3-MONTH-OLD BABY PRESCRIBED COMPOUND LINCTUS CONTAINING CODEINE
1166
genital hyperammonaemia.Liver enzyme studies showed normal carbamyl phosphate synthetase activity (195 mol formedfg tissue/h, reference range 105-271) but almost absent OCT activity (95 pmiol converted/g/h, reference range 2600-10 500). Tissue
Large fat vacuole (lower left) in liver cell ; mitochondria show minor abnormalities; a few peroxisomes (dark bodies) are also shown. (Electron microscopy; x about 1000.)
phase lasted for 6 min but 30 min later he was stiff and cyanosed; he recovered after diazepam 2-55 mg i.v. Apart from dehydration no abnormal physical signs were noted, and routine investigations, including lumbar puncture, were normal. He was discharged, with a diagnosis of a febrile convulsion due to gastroenteritis, and sodium valproate 20 mg/kg per day was prescribed; after 2 weeks the dose was inadvertently increased to 33 mg/kg daily. 6 weeks later he was readmitted because of three severe episodes of vomiting and drowsiness each lasting 3-4 days. Between attacks he had been well, feeding and developing normally. He was drowsy and irritable but otherwise clinically normal. The serum valproate level was 77 mg/l; EEG showed a severe and generalised disturbance of brain function with long sweeps of 2-2 - 5 Hz delta activity; a CT brain scan was normal; laboratory studies, including liver function tests and microbiology, were normal. Sodium valproate was stopped on admission and 2 days later the patient was feeding and playing though still irritable. On day 3 he deteriorated, and during the siting of an i.v. infusion he became hypertonic with trismus and apnoea. Spontaneous respiration was re-established after diazepam 5 mg i.v. but he progressed to a clonic
decerebrate posture with apnoea and areflexia. A severe metabolic disturbance was considered likely and a high calorie glucose infusion begun. Hyperammonaemia was confirmed on day 5 (plasma ammonia 455 Mmol/1). Peritoneal dialysis was started on day 6 and the blood ammonia fell to 182 on day 7, 97 on day 8, and then remained below 80 j.tmol/1. However, though reflex movements in the legs returned over the next 14 days, brainstem responses did not. Liver biopsy was done on day 14. Mechanical ventilation was discontinued on day 24 and the child died. Plasma aminoacids showed a raised glutamine; urine orotic acid was 600 mol/mmol creatinine (reference range for age <4). Histology and electronmicroscopy (figure) showed normal liver architecture with clear vacuolated hepatocytes with central nuclei; cytoplasmic fat was mainly macrovesicular; there was little glycogen; mitochondria were swollen with fragmented cristae but were not characteristic of Reye’s syndrome ;4,5 fibrillogranular bodies were present. These appearances are consistent with con4. Schubert WK, Partin JC, Partin JS. Encephalopathy and fatty liver (Reye’s syndrome). In. Popper H, Schaffner F, eds. Progress in liver diseases, vol IV. New York: Grune and Stratton, 1972: 489-510. 5. Partin JC, Schubert WK, Partin JS. Mitochondrial ultrastructure in Reye’s syndrome N Engl J Med 1971; 285: 1339-43.
culture of the liver grew no viruses, and serology showed no evidence of recent viral infection. Studies in both parents with protein loading (0-85 glkg of protein) showed both to have normal fasting and post protein urine orotic acid: creatinine ratios for up to 8 h. Fasting and 2 h postprandial blood ammonias and plasma glutamines were also normal in the mother. The biochemical findings are diagnostic of OCT deficiency. Although affected males usually present in the neonatal period with an overwhelming illness, mild variants with later presentation have been described.b-9 In previous reports of mild variants in males enzyme levels were higher in the two patients who were neurologically normal at 6 months of age (25o6 and 14%9 of normal) though of the same order (1’ 5%*) in a child with progressive neurological signs from the age of 4 months. In an unpublished case (J. V. L.) similar levels have been recorded in a neurologically normal child presenting at the age of 17 months. Failure to demonstrate that the mother was a carrier does not invalidate the hypothesis since it is not always possible to demonstrate carrier status in obligate heterozygotes for classical OCT (M. L. Batshaw, personal communication). It is tempting to suggest that sodium valproate was directly responsible for the hyperammonaemia but patients with congenital disorders of the urea cycle are liable to develop severe hyperammonaemia unexpectedly, having previously been well. In another OCT deficient child diethyltoluamide was thought to have been responsible for precipitating hyperammonaemia.10 It seems unlikely that OCT deficiency can be implemented in all cases of acute liver failure associated with valproate therapy. Features such as jaundice and thrombocytopenia are not characteristic of OCT deficiencv, and the reported pathological findings are those of Reye’s syndrome or acute hepatocellular necrosis. Nevertheless, variants of OCT deficiency may be considerably more common than has hitherto been suspected. We agree with a Lancet editorial 1that unrecognised inborn errors of metabolism may make patients unduly susceptible to the effect of drugs. We would also caution that temporal association of life threatening illness with drug administration is only circumstantial evidence of a link between the
two events.
Royal Devon and Exeter Hospital (Wonford), Exeter EX2 5DW Institute of Child Health, London WCl Elizabeth London El
Queen
n
-
J. H. TRIPP T. HARGREAVES P. P. ANTHONY J. F. SEARLE P. MILLER
J. V. LEONARD A. D. PATRICK
Hospital for Children,
V. G. OBERHOLZER
APNOEA IN A 3-MONTH-OLD BABY PRESCRIBED COMPOUND LINCTUS CONTAINING CODEINE
SiR,-’Actifed Co’, a compound linctus containing triprolidine, pseudoephedrine hydrochloride, and codeine phosphate, is widely used as a nasal decongestant and cough suppressant in children. A near-fatal consequence of its administration to a 3-month-old baby calls into question the safety of actifed for young infants. 6. Krieger I, Snodgrass PJ, Roskamp J. Atypical clinical course of ornithine transcarbamylase deficiency due to a new mutant (comparison with Reye’sdisease) J Clin Endocrinol Metab 1979; 48: 388-92. 7. Levin B, Dobbs, RH, Burgess EA, Palmer T. Hyperammonaemia: a variant type of deficiency of liver ornithine transcarbamylase. Arch Dis Childh 1969; 44: 162-69 8. MacLeod P, MacKenzie S, Scriver CR. Partial ornithine carbamyl transferase deficiency: an inborn error of metabolism presenting as orotic aciduria in a male infant. Can Med Assoc J 1972; 107: 405-08. 9. YudkoffM, Yang W, Snodgrass PJ, Segal S. Onithine transcarbamylase deficiency in a boy with normal development. J Pediat 1980; 96: 441-43 10. Heick HMC, Shipman KT, Norman MG, James W. Reye like syndrome associated with the use of insect repellent in a presumed heterozygote for ornithine carbamyl transferase deficiency. J Pediatr 1980; 97: 471-73. 11. Editorial. Individual susceptibility. Lancet 1981; i: 368.
1167
gestation, weighing 133 kg. The complicated by hyaline membrane disease which required ventilation, but he was discharged home in good The baby was born at 30 weeks’
neonatal period
the age of 4 weeks. 8 weeks later he had an upper tract infection for which actifed compound was prescribed in a dose of 5 ml four times a day. Within 24 hours, and after only two doses, his mother noted he was sleepy, breathing heavily, and had small pupils. A general practitioner (M.F.D.) was called and diagnosed narcotic intoxication. Immediate transfer to hospital by ambulance was arranged, the baby being accompanied by the general practitioner who needed to give mouth-to-mouth breathing for apnoea. On arrival in the casualty department the baby was collapsed, cold, and semi-comatose with pin-point pupils and Cheyne-Stokes breathing. His weight was 3 - 0 kg. He was treated with intravenous naloxone with dramatic effect. 2 days later he was discharged home and has been well since. Actifed compound contains 10 mg codeine phosphate in 5 ml.i Although only two of the four prescribed 5 ml doses had been given, the amount would have provided a codeine intake of about 666 mg/kg, well above the advised dosage2(1-2 mg/kg), and almost certainly caused the near-fatal apnoea and collapse. Even had the recommended dose of actifed compound for a 3-month-old baby been administered (2 -5 ml three times a day) the codeine intake would have been a dangerously high. There is clearly an urgent need to revise the dose recommendations for this product as they apply to young infants. The youngest recommended age for prescribing actifed, either alone or in combination with codeine phosphate, is 3 months.’ This baby was 3 months old but, allowing for 10 weeks’ prematurity, his post-conceptional age was equivalent only to that of a term infant. Because preterm babies are, as a general rule, less able to metabolise and excrete drugs than babies born at term,3 it would seem sensible, in the first 6 months or so after birth, to take into account any premature delivery before administering drugs whose advised dosage is based on age rather than weight as with actifed. This is especially so now that preterm babies can be sent home4 from neonatal units much earlier than previously recommended.4 The new British National Formulary deprecates the use of cough suppressant and sympathomimetic drug combinations.5 If indicated, the components should be prescribed separately and dosage adjusted independently. This case report is a timely reminder of this important therapeutic principle.
health
PROTHROMBIN TIMES BEFORE AND AFTER SUBCUTANEOUS
INJECTION OF HEPARIN ANALOGUE (SSHA) AND HEPARIN
was
at
respiratory
Neonatal Unit, Leicester Royal
Infirmary Maternity Hospital,
Leicester LE1 5W
Countesthorpe, Leicester
T. C. R. WILKES D. P. DAVIES M. F. DAR
SIR,-While heparin is very effective in preventing
had a higher anti-Xa specific activity than heparin following either subcutaneous or intravenous injection.6,7 Furthermore, it has also been shown that SSHA releases anti-Xa clotting activity, lipoprotein lipase activity, and platelet factor 4 antigen after parenteral injection.8A second injection of the drug after 90 min or an increase in dose does not increase the level of induced anti-Xa clotting activity.8 Possible mechamisms of action include the release by SSHA of endogenous glycosaminoglycans (possibly heparan sulphate) and interference, by released lipase, of a modulator of anti-Xa activity.8 Our studies in healthy volunteers indicate that SSHA, unlike heparin, may also modify the extrinsic pathway of activation of intravascular coagulation when used in small doses. Five healthy volunteers, aged between 21 and 28 years, received, with 1 week between injections, three doses of SSHA (75 mg in 0 - 2 ml, 55 mg in 0 -15 ml, and 35 mg in 0-11 ml) and 50 mg of calcium heparin in 0 -2ml subcutaneously; blood was sampled before and 1, 3, 5, and 7 h after injection. Prothrombin clotting time was measured as follows. To 0’1ml of test plasma were added 0 -1ml of brain thromboplastin (Ortho Diagnostics) and 0 -1ml of 005 mol/1 calcium chloride. The clotting time at 37°C was measured using a Burkard coagulometer. The thromboplastin was diluted with distilled water to give a normal prothrombin time of approximately 32 s with normal plasma, and the diluted solution was kept on ice until used. The results are shown in the table. There was a significant increase in prothrombin time, in a dose related manner, in the volunteers who received SSHA. Similar changes were not observed when heparin was administered. The mechanism by which SSHA prolongs the prothrombin time remains to be determined. V. V. KAKKAR B. DJAZAERI M. SCULLY K. WEERASINGHE
venous
its main drawback is the risk of haemorrhage. Comparisons6-8 of the low-molecular-weight semisynthetic heparin analogue SSHA-73025 with commercial heparins show that, while the analogue was virtually inactive in vnro in anti-factor Xa and kaolin cephalin clotting time assays, it
complications,
1 Anon Data sheet compendium 1980-81. London:
tailed) at 0-5% level or better.
Thrombosis Research Unit, Department of Surgery, King’s College Hospital Medical School, London SE5 8RX
SYNTHETIC HEPARIN ANALOGUE AND PROTHROMBIN TIME
thromboembolic
*Significantly different from pre-injection means (by Student’s paired t test, two
Datapharm Publications,
1981:
1164-65
2 Forfar, JO, Arneil GC. Textbook of paediatrics, 2 edit. Edinburgh: Churchill Livingstone, 1978: 1747. 3 Shirkey HC, In: Shirkey HC, ed. Pediatric therapy, 4 edit. St Louis: C V Mosby, 1974: 32-46.
4 Davies DP, Haxby V, Herbert S, McNeish AS. When should preterm babies be
sent
home from neonatal units Lancet 1979; i: 914-16. 5 British National Formulary 1981 no 1. London: British Medical Association and Pharmaceutical Press; 1981: 95-96 6 Thomas DP, Michalski R, Lane DA, Johnson EA, Kakkar VV. A heparin analogue with specific action on antithrombin III. Lancet 1977; i: 120-22. 7 Lane DA, Michalski R, VanRoss ME, Kakkar VV. Comparison of heparin and a semisynthetic heparin analogue, A73025 I. Kinetics of elimination from the circulation of man following intravenous injection Br J Haematol 1977; 37: 247-56. 8 Thomas DP, Barrowcliffe TW, Merton RE, Stocks J, Dawes J, Pepper DS. In vivo release of anti-Xa clotting activity by a heparin analogue Thromb Res 1980; 17: 831-40
Obituary JOHN WILLIAM FIELD C.M.G., M.D. Birm., hon. D.Sc. Malaya Dr Jack Field, formerly director of the Institute for Medical Research, Federation of Malaysia, died on April 15. Born in Birmingham in 1899, he served in the 1914-18 war and sustained a leg wound which left him with a slight limp. After ualifying in medicine at Birmingham, he joined the Malayan Medical Service in 1925 and served as medical officer in various districts. He was appointed malaria research officer at the Institute for Medical Research, Kuala Lumpur, in 1931, and embarked on the work which was to bring him international recognition. His work displayed originality, high technical ability, and a rare capacity for analysing his results. The procedures he developed in the malaria research division of the Institute formed valuable guidelines for his successors, and permitted comparability of findings with different drugs over many years.
genital hyperammonaemia.Liver enzyme studies showed normal carbamyl phosphate synthetase activity (195 mol formedfg tissue/h, reference range 105-271) but almost absent OCT activity (95 pmiol converted/g/h, reference range 2600-10 500). Tissue
Large fat vacuole (lower left) in liver cell ; mitochondria show minor abnormalities; a few peroxisomes (dark bodies) are also shown. (Electron microscopy; x about 1000.)
phase lasted for 6 min but 30 min later he was stiff and cyanosed; he recovered after diazepam 2-55 mg i.v. Apart from dehydration no abnormal physical signs were noted, and routine investigations, including lumbar puncture, were normal. He was discharged, with a diagnosis of a febrile convulsion due to gastroenteritis, and sodium valproate 20 mg/kg per day was prescribed; after 2 weeks the dose was inadvertently increased to 33 mg/kg daily. 6 weeks later he was readmitted because of three severe episodes of vomiting and drowsiness each lasting 3-4 days. Between attacks he had been well, feeding and developing normally. He was drowsy and irritable but otherwise clinically normal. The serum valproate level was 77 mg/l; EEG showed a severe and generalised disturbance of brain function with long sweeps of 2-2 - 5 Hz delta activity; a CT brain scan was normal; laboratory studies, including liver function tests and microbiology, were normal. Sodium valproate was stopped on admission and 2 days later the patient was feeding and playing though still irritable. On day 3 he deteriorated, and during the siting of an i.v. infusion he became hypertonic with trismus and apnoea. Spontaneous respiration was re-established after diazepam 5 mg i.v. but he progressed to a clonic
decerebrate posture with apnoea and areflexia. A severe metabolic disturbance was considered likely and a high calorie glucose infusion begun. Hyperammonaemia was confirmed on day 5 (plasma ammonia 455 Mmol/1). Peritoneal dialysis was started on day 6 and the blood ammonia fell to 182 on day 7, 97 on day 8, and then remained below 80 j.tmol/1. However, though reflex movements in the legs returned over the next 14 days, brainstem responses did not. Liver biopsy was done on day 14. Mechanical ventilation was discontinued on day 24 and the child died. Plasma aminoacids showed a raised glutamine; urine orotic acid was 600 mol/mmol creatinine (reference range for age <4). Histology and electronmicroscopy (figure) showed normal liver architecture with clear vacuolated hepatocytes with central nuclei; cytoplasmic fat was mainly macrovesicular; there was little glycogen; mitochondria were swollen with fragmented cristae but were not characteristic of Reye’s syndrome ;4,5 fibrillogranular bodies were present. These appearances are consistent with con4. Schubert WK, Partin JC, Partin JS. Encephalopathy and fatty liver (Reye’s syndrome). In. Popper H, Schaffner F, eds. Progress in liver diseases, vol IV. New York: Grune and Stratton, 1972: 489-510. 5. Partin JC, Schubert WK, Partin JS. Mitochondrial ultrastructure in Reye’s syndrome N Engl J Med 1971; 285: 1339-43.
culture of the liver grew no viruses, and serology showed no evidence of recent viral infection. Studies in both parents with protein loading (0-85 glkg of protein) showed both to have normal fasting and post protein urine orotic acid: creatinine ratios for up to 8 h. Fasting and 2 h postprandial blood ammonias and plasma glutamines were also normal in the mother. The biochemical findings are diagnostic of OCT deficiency. Although affected males usually present in the neonatal period with an overwhelming illness, mild variants with later presentation have been described.b-9 In previous reports of mild variants in males enzyme levels were higher in the two patients who were neurologically normal at 6 months of age (25o6 and 14%9 of normal) though of the same order (1’ 5%*) in a child with progressive neurological signs from the age of 4 months. In an unpublished case (J. V. L.) similar levels have been recorded in a neurologically normal child presenting at the age of 17 months. Failure to demonstrate that the mother was a carrier does not invalidate the hypothesis since it is not always possible to demonstrate carrier status in obligate heterozygotes for classical OCT (M. L. Batshaw, personal communication). It is tempting to suggest that sodium valproate was directly responsible for the hyperammonaemia but patients with congenital disorders of the urea cycle are liable to develop severe hyperammonaemia unexpectedly, having previously been well. In another OCT deficient child diethyltoluamide was thought to have been responsible for precipitating hyperammonaemia.10 It seems unlikely that OCT deficiency can be implemented in all cases of acute liver failure associated with valproate therapy. Features such as jaundice and thrombocytopenia are not characteristic of OCT deficiencv, and the reported pathological findings are those of Reye’s syndrome or acute hepatocellular necrosis. Nevertheless, variants of OCT deficiency may be considerably more common than has hitherto been suspected. We agree with a Lancet editorial 1that unrecognised inborn errors of metabolism may make patients unduly susceptible to the effect of drugs. We would also caution that temporal association of life threatening illness with drug administration is only circumstantial evidence of a link between the
two events.
Royal Devon and Exeter Hospital (Wonford), Exeter EX2 5DW Institute of Child Health, London WCl Elizabeth London El
Queen
n
-
J. H. TRIPP T. HARGREAVES P. P. ANTHONY J. F. SEARLE P. MILLER
J. V. LEONARD A. D. PATRICK
Hospital for Children,
V. G. OBERHOLZER
APNOEA IN A 3-MONTH-OLD BABY PRESCRIBED COMPOUND LINCTUS CONTAINING CODEINE
SiR,-’Actifed Co’, a compound linctus containing triprolidine, pseudoephedrine hydrochloride, and codeine phosphate, is widely used as a nasal decongestant and cough suppressant in children. A near-fatal consequence of its administration to a 3-month-old baby calls into question the safety of actifed for young infants. 6. Krieger I, Snodgrass PJ, Roskamp J. Atypical clinical course of ornithine transcarbamylase deficiency due to a new mutant (comparison with Reye’sdisease) J Clin Endocrinol Metab 1979; 48: 388-92. 7. Levin B, Dobbs, RH, Burgess EA, Palmer T. Hyperammonaemia: a variant type of deficiency of liver ornithine transcarbamylase. Arch Dis Childh 1969; 44: 162-69 8. MacLeod P, MacKenzie S, Scriver CR. Partial ornithine carbamyl transferase deficiency: an inborn error of metabolism presenting as orotic aciduria in a male infant. Can Med Assoc J 1972; 107: 405-08. 9. YudkoffM, Yang W, Snodgrass PJ, Segal S. Onithine transcarbamylase deficiency in a boy with normal development. J Pediat 1980; 96: 441-43 10. Heick HMC, Shipman KT, Norman MG, James W. Reye like syndrome associated with the use of insect repellent in a presumed heterozygote for ornithine carbamyl transferase deficiency. J Pediatr 1980; 97: 471-73. 11. Editorial. Individual susceptibility. Lancet 1981; i: 368.
1167
gestation, weighing 133 kg. The complicated by hyaline membrane disease which required ventilation, but he was discharged home in good The baby was born at 30 weeks’
neonatal period
the age of 4 weeks. 8 weeks later he had an upper tract infection for which actifed compound was prescribed in a dose of 5 ml four times a day. Within 24 hours, and after only two doses, his mother noted he was sleepy, breathing heavily, and had small pupils. A general practitioner (M.F.D.) was called and diagnosed narcotic intoxication. Immediate transfer to hospital by ambulance was arranged, the baby being accompanied by the general practitioner who needed to give mouth-to-mouth breathing for apnoea. On arrival in the casualty department the baby was collapsed, cold, and semi-comatose with pin-point pupils and Cheyne-Stokes breathing. His weight was 3 - 0 kg. He was treated with intravenous naloxone with dramatic effect. 2 days later he was discharged home and has been well since. Actifed compound contains 10 mg codeine phosphate in 5 ml.i Although only two of the four prescribed 5 ml doses had been given, the amount would have provided a codeine intake of about 666 mg/kg, well above the advised dosage2(1-2 mg/kg), and almost certainly caused the near-fatal apnoea and collapse. Even had the recommended dose of actifed compound for a 3-month-old baby been administered (2 -5 ml three times a day) the codeine intake would have been a dangerously high. There is clearly an urgent need to revise the dose recommendations for this product as they apply to young infants. The youngest recommended age for prescribing actifed, either alone or in combination with codeine phosphate, is 3 months.’ This baby was 3 months old but, allowing for 10 weeks’ prematurity, his post-conceptional age was equivalent only to that of a term infant. Because preterm babies are, as a general rule, less able to metabolise and excrete drugs than babies born at term,3 it would seem sensible, in the first 6 months or so after birth, to take into account any premature delivery before administering drugs whose advised dosage is based on age rather than weight as with actifed. This is especially so now that preterm babies can be sent home4 from neonatal units much earlier than previously recommended.4 The new British National Formulary deprecates the use of cough suppressant and sympathomimetic drug combinations.5 If indicated, the components should be prescribed separately and dosage adjusted independently. This case report is a timely reminder of this important therapeutic principle.
health
PROTHROMBIN TIMES BEFORE AND AFTER SUBCUTANEOUS
INJECTION OF HEPARIN ANALOGUE (SSHA) AND HEPARIN
was
at
respiratory
Neonatal Unit, Leicester Royal
Infirmary Maternity Hospital,
Leicester LE1 5W
Countesthorpe, Leicester
T. C. R. WILKES D. P. DAVIES M. F. DAR
SIR,-While heparin is very effective in preventing
had a higher anti-Xa specific activity than heparin following either subcutaneous or intravenous injection.6,7 Furthermore, it has also been shown that SSHA releases anti-Xa clotting activity, lipoprotein lipase activity, and platelet factor 4 antigen after parenteral injection.8A second injection of the drug after 90 min or an increase in dose does not increase the level of induced anti-Xa clotting activity.8 Possible mechamisms of action include the release by SSHA of endogenous glycosaminoglycans (possibly heparan sulphate) and interference, by released lipase, of a modulator of anti-Xa activity.8 Our studies in healthy volunteers indicate that SSHA, unlike heparin, may also modify the extrinsic pathway of activation of intravascular coagulation when used in small doses. Five healthy volunteers, aged between 21 and 28 years, received, with 1 week between injections, three doses of SSHA (75 mg in 0 - 2 ml, 55 mg in 0 -15 ml, and 35 mg in 0-11 ml) and 50 mg of calcium heparin in 0 -2ml subcutaneously; blood was sampled before and 1, 3, 5, and 7 h after injection. Prothrombin clotting time was measured as follows. To 0’1ml of test plasma were added 0 -1ml of brain thromboplastin (Ortho Diagnostics) and 0 -1ml of 005 mol/1 calcium chloride. The clotting time at 37°C was measured using a Burkard coagulometer. The thromboplastin was diluted with distilled water to give a normal prothrombin time of approximately 32 s with normal plasma, and the diluted solution was kept on ice until used. The results are shown in the table. There was a significant increase in prothrombin time, in a dose related manner, in the volunteers who received SSHA. Similar changes were not observed when heparin was administered. The mechanism by which SSHA prolongs the prothrombin time remains to be determined. V. V. KAKKAR B. DJAZAERI M. SCULLY K. WEERASINGHE
venous
its main drawback is the risk of haemorrhage. Comparisons6-8 of the low-molecular-weight semisynthetic heparin analogue SSHA-73025 with commercial heparins show that, while the analogue was virtually inactive in vnro in anti-factor Xa and kaolin cephalin clotting time assays, it
complications,
1 Anon Data sheet compendium 1980-81. London:
tailed) at 0-5% level or better.
Thrombosis Research Unit, Department of Surgery, King’s College Hospital Medical School, London SE5 8RX
SYNTHETIC HEPARIN ANALOGUE AND PROTHROMBIN TIME
thromboembolic
*Significantly different from pre-injection means (by Student’s paired t test, two
Datapharm Publications,
1981:
1164-65
2 Forfar, JO, Arneil GC. Textbook of paediatrics, 2 edit. Edinburgh: Churchill Livingstone, 1978: 1747. 3 Shirkey HC, In: Shirkey HC, ed. Pediatric therapy, 4 edit. St Louis: C V Mosby, 1974: 32-46.
4 Davies DP, Haxby V, Herbert S, McNeish AS. When should preterm babies be
sent
home from neonatal units Lancet 1979; i: 914-16. 5 British National Formulary 1981 no 1. London: British Medical Association and Pharmaceutical Press; 1981: 95-96 6 Thomas DP, Michalski R, Lane DA, Johnson EA, Kakkar VV. A heparin analogue with specific action on antithrombin III. Lancet 1977; i: 120-22. 7 Lane DA, Michalski R, VanRoss ME, Kakkar VV. Comparison of heparin and a semisynthetic heparin analogue, A73025 I. Kinetics of elimination from the circulation of man following intravenous injection Br J Haematol 1977; 37: 247-56. 8 Thomas DP, Barrowcliffe TW, Merton RE, Stocks J, Dawes J, Pepper DS. In vivo release of anti-Xa clotting activity by a heparin analogue Thromb Res 1980; 17: 831-40
Obituary JOHN WILLIAM FIELD C.M.G., M.D. Birm., hon. D.Sc. Malaya Dr Jack Field, formerly director of the Institute for Medical Research, Federation of Malaysia, died on April 15. Born in Birmingham in 1899, he served in the 1914-18 war and sustained a leg wound which left him with a slight limp. After ualifying in medicine at Birmingham, he joined the Malayan Medical Service in 1925 and served as medical officer in various districts. He was appointed malaria research officer at the Institute for Medical Research, Kuala Lumpur, in 1931, and embarked on the work which was to bring him international recognition. His work displayed originality, high technical ability, and a rare capacity for analysing his results. The procedures he developed in the malaria research division of the Institute formed valuable guidelines for his successors, and permitted comparability of findings with different drugs over many years.