1602
Benign intracranial hypertension after nalidixic acid overdose in infants SIR,-In the wake of an epidemic of bacillary dysentery due to multiresistant Shigella dysenteriae type 1 in West Bengal’ the use of nalidixic acid increased significantly.2,3 Nalidixic acid is often used for the treatment of children with shigellosis in Bangladesh, Rwanda, and Sri Lanka.4 This drug has the potential to damage cartilage in weight-bearing joints in young animals5 but it has been used in paediatric practice without any major adverse effects6 and cartilage damage does not seem to be a risk. We report here twelve cases of benign intracranial hypertension after nalidixic acid therapy for acute bacillary dysentery in infants below the age of 6 months. The affected infants vomited, were irritable, and had bulging anterior fontanelles but they were afebrile and feeding well. No other neurological abnormality was found and there was no papilloedema. Questioning revealed that all these babies had inadvertently been given very high doses of nalidixic acid (100-150 mg/kg daily) for 24-48 h before the onset of symptoms. Two had generalised convulsions lasting a few minutes. All the children were immediately admitted to hospital and kept under close supervision. Laboratory tests were normal but cerebrospinal fluid pressure was increased. Nalidixic acid was withdrawn immediately and all the children were much improved within 24-48 h. The vomiting and irritability subsided and the fullness of the anterior fontanelle decreased. They were discharged on day 5. Benign intracranial hypertension is a well-known adverse effect of the quinoloneS7but nalidixic acid has been used for years for the treatment of childhood infections and this complication has only rarely been encountered in infants. The development of intracranial hypertension after overdoses of nalidixic acid should serve as a warning to anyone tempted to use this drug indiscriminately.
Dr B C Roy Memorial for Children,
Hospital
Calcutta 700 054, India, and National Institute of Cholera and Enteric Diseases, Calcutta
A. MUKHERJEE P. DUTTA M. LAHIRI S. SINHA A. K. MITRA S. K. BHATTACHARYA
1. Pal SC. Epidemic bacillary dysentry in West Bengal, India, 1984 Lancet 1984; i: 1462. 2. Bose R, Nashipuri JN, Sen PK, et al. Epidemic of dysentery in West Bengal: clinician’s enigma Lancet 1984; ii: 1160. 3. Dutta P, Dutta D, Bhattacharya SK, et al. Clinical and bacteriological profiles of shigellosis in Calcutta before and after epidemic (1984-1987) Indian J Med Res 1989; 89: 132-37. 4. Fontaine O. Antibiotics in the management of shigellosis in children what role for the quinolones? Rev Infect Dis 1989; ii: S1145-50. 5. Adam D Use of quinolones in paediatric patients. Rev Infect Dis 1989, ii. S1113-16. 6. World Health Organisation. A manual for the treatment of acute diarrhoea for use by physicians and other senior health workers (WHO/CDD/ser/80.2, rev 1). Geneva: WHO, 1984. 7. Chevais M, Reinert P, Rondeau MC, et al. Critical risk benefit analysis of perfloxacin use in children under 15 years. the problem of arthralgias. J Clin Pharmacol Ther Toxicol 1987, 25: 306-09. 8. Boreus LO, Sunderstrom B. Intracranial hypertension in a child during treatment with nalidixic acid. Br Med J 1967; ii: 744-45.
Reconstitution of interleukin 2 with albumin for infusion SIR,-Human recombinant interleukin 2 (rIL-2) for clinical use is usually supplied in a lyophilised form for ease of storage and distribution. One preparation commonly used is supplied freezedried with mannitol and sodium dodecyl sulphate. The manufacturer suggests reconstitution with water for injection and further dilution with 5% glucose when used for infusion. rIL-2 given by continuous infusion is thought to have less toxicity than bolus administration.1,2 In a trial of infused rIL-2 in advanced breast cancer we have used daily doses up to 18 million IU 1m2 reconstituted with 5% glucose, with few side-effects. No hypotension or pre-renal failure were noted and there was no need to stop treatment because of toxicity. This finding was unexpected in view of the toxic effects reported by others,3 and raised doubts about the availability of rIL-2 when given by infusion.
Percentage potency* of rIL-2 reconstituted albumin during infusion.
with and without
*Relatlve to concentration of rIL-2 at time zero with albumin Vertical bars=95% confidence interval Upper line- reconstituted with albumin and 5% glucose Lower line = reconstituted with 5% glucose alone.
Protein carriers such as albumin are commonly used to prevent the adsorption of active constituents. Our aim was to assess the availability of rIL-2 delivered over 24 h when reconstituted with glucose alone or with glucose and albumin. Proleukin (rIL-2, EuroCetus Amsterdam) was reconstituted with 1-2ml of sterile water per vial. 1 ml of this solution was then made up to 50 ml with either 5% glucose alone or 5% glucose with 2% human albumin. Solutions were made up in 50 ml syringes. Infusion sets were primed with the solution and the first ml was ejected manually (time zero). The syringes were then placed in syrmge drivers and driven at 2 ml/h. 1 ml samples were taken during the subsequent 24 h. All samples were collected in vials containing 05 ml 5% human albumin. The volume in the vial was then measured and adjusted with 1% albumin for samples reconstituted with glucose plus albumin and 5% albumin for those with glucose alone. This resulted in a two-fold dilution of the IL-2 from the infusion set and ensured that the concentration of albumin was equal in all samples. Solutions were then stored at - 20°C and assayed for IL-2 activity by bioassay with the CTLL-2 cellline.4 Cytokine-induced proliferation was assessed by 3H-thymidine incorporation into DNA.-’ Titration of the World Health Organisation first international standard for IL-2 (100 IU per ampoule) was included in the assays, which were done in triplicate with several dilutions spaced on the dose-response curve. Doseresponse relations were examined at each time interval (with and without albumin). The responses were analysed by weighted regression6 and the percentage potency for each sample was calculated relative to the concentration of rIL-2 at time zero (with
albumin). The rIL-2 preparations were highly biologically active. Formulation with albumin did not affect biological potency. During infusion the potency of rIL-2 reconstituted with albumin did not change significantly but the potency of rIL-2 diluted in 5 % glucose alone declined greatly. The potency of samples diluted with albumin was unchanged over the 24 h infusion but by 2 h the potency of rIL-2 diluted with 5% glucose alone had fallen to less than 25% and it remained low in subsequent samples (figure). Thus, with the delivery system we used, failure to reconstitute non-protein formulated rIL-2 with albumin for infusion could result in patients receiving much less than the intended dose. The low potency after 2 h and for the rest of the infusion presumably resulted from binding of the cytokine to plastic in the syringe and
giving set.
Benign intracranial hypertension after nalidixic acid overdose in infants SIR,-In the wake of an epidemic of bacillary dysentery due to multiresistant Shigella dysenteriae type 1 in West Bengal’ the use of nalidixic acid increased significantly.2,3 Nalidixic acid is often used for the treatment of children with shigellosis in Bangladesh, Rwanda, and Sri Lanka.4 This drug has the potential to damage cartilage in weight-bearing joints in young animals5 but it has been used in paediatric practice without any major adverse effects6 and cartilage damage does not seem to be a risk. We report here twelve cases of benign intracranial hypertension after nalidixic acid therapy for acute bacillary dysentery in infants below the age of 6 months. The affected infants vomited, were irritable, and had bulging anterior fontanelles but they were afebrile and feeding well. No other neurological abnormality was found and there was no papilloedema. Questioning revealed that all these babies had inadvertently been given very high doses of nalidixic acid (100-150 mg/kg daily) for 24-48 h before the onset of symptoms. Two had generalised convulsions lasting a few minutes. All the children were immediately admitted to hospital and kept under close supervision. Laboratory tests were normal but cerebrospinal fluid pressure was increased. Nalidixic acid was withdrawn immediately and all the children were much improved within 24-48 h. The vomiting and irritability subsided and the fullness of the anterior fontanelle decreased. They were discharged on day 5. Benign intracranial hypertension is a well-known adverse effect of the quinoloneS7but nalidixic acid has been used for years for the treatment of childhood infections and this complication has only rarely been encountered in infants. The development of intracranial hypertension after overdoses of nalidixic acid should serve as a warning to anyone tempted to use this drug indiscriminately.
Dr B C Roy Memorial for Children,
Hospital
Calcutta 700 054, India, and National Institute of Cholera and Enteric Diseases, Calcutta
A. MUKHERJEE P. DUTTA M. LAHIRI S. SINHA A. K. MITRA S. K. BHATTACHARYA
1. Pal SC. Epidemic bacillary dysentry in West Bengal, India, 1984 Lancet 1984; i: 1462. 2. Bose R, Nashipuri JN, Sen PK, et al. Epidemic of dysentery in West Bengal: clinician’s enigma Lancet 1984; ii: 1160. 3. Dutta P, Dutta D, Bhattacharya SK, et al. Clinical and bacteriological profiles of shigellosis in Calcutta before and after epidemic (1984-1987) Indian J Med Res 1989; 89: 132-37. 4. Fontaine O. Antibiotics in the management of shigellosis in children what role for the quinolones? Rev Infect Dis 1989; ii: S1145-50. 5. Adam D Use of quinolones in paediatric patients. Rev Infect Dis 1989, ii. S1113-16. 6. World Health Organisation. A manual for the treatment of acute diarrhoea for use by physicians and other senior health workers (WHO/CDD/ser/80.2, rev 1). Geneva: WHO, 1984. 7. Chevais M, Reinert P, Rondeau MC, et al. Critical risk benefit analysis of perfloxacin use in children under 15 years. the problem of arthralgias. J Clin Pharmacol Ther Toxicol 1987, 25: 306-09. 8. Boreus LO, Sunderstrom B. Intracranial hypertension in a child during treatment with nalidixic acid. Br Med J 1967; ii: 744-45.
Reconstitution of interleukin 2 with albumin for infusion SIR,-Human recombinant interleukin 2 (rIL-2) for clinical use is usually supplied in a lyophilised form for ease of storage and distribution. One preparation commonly used is supplied freezedried with mannitol and sodium dodecyl sulphate. The manufacturer suggests reconstitution with water for injection and further dilution with 5% glucose when used for infusion. rIL-2 given by continuous infusion is thought to have less toxicity than bolus administration.1,2 In a trial of infused rIL-2 in advanced breast cancer we have used daily doses up to 18 million IU 1m2 reconstituted with 5% glucose, with few side-effects. No hypotension or pre-renal failure were noted and there was no need to stop treatment because of toxicity. This finding was unexpected in view of the toxic effects reported by others,3 and raised doubts about the availability of rIL-2 when given by infusion.
Percentage potency* of rIL-2 reconstituted albumin during infusion.
with and without
*Relatlve to concentration of rIL-2 at time zero with albumin Vertical bars=95% confidence interval Upper line- reconstituted with albumin and 5% glucose Lower line = reconstituted with 5% glucose alone.
Protein carriers such as albumin are commonly used to prevent the adsorption of active constituents. Our aim was to assess the availability of rIL-2 delivered over 24 h when reconstituted with glucose alone or with glucose and albumin. Proleukin (rIL-2, EuroCetus Amsterdam) was reconstituted with 1-2ml of sterile water per vial. 1 ml of this solution was then made up to 50 ml with either 5% glucose alone or 5% glucose with 2% human albumin. Solutions were made up in 50 ml syringes. Infusion sets were primed with the solution and the first ml was ejected manually (time zero). The syringes were then placed in syrmge drivers and driven at 2 ml/h. 1 ml samples were taken during the subsequent 24 h. All samples were collected in vials containing 05 ml 5% human albumin. The volume in the vial was then measured and adjusted with 1% albumin for samples reconstituted with glucose plus albumin and 5% albumin for those with glucose alone. This resulted in a two-fold dilution of the IL-2 from the infusion set and ensured that the concentration of albumin was equal in all samples. Solutions were then stored at - 20°C and assayed for IL-2 activity by bioassay with the CTLL-2 cellline.4 Cytokine-induced proliferation was assessed by 3H-thymidine incorporation into DNA.-’ Titration of the World Health Organisation first international standard for IL-2 (100 IU per ampoule) was included in the assays, which were done in triplicate with several dilutions spaced on the dose-response curve. Doseresponse relations were examined at each time interval (with and without albumin). The responses were analysed by weighted regression6 and the percentage potency for each sample was calculated relative to the concentration of rIL-2 at time zero (with
albumin). The rIL-2 preparations were highly biologically active. Formulation with albumin did not affect biological potency. During infusion the potency of rIL-2 reconstituted with albumin did not change significantly but the potency of rIL-2 diluted in 5 % glucose alone declined greatly. The potency of samples diluted with albumin was unchanged over the 24 h infusion but by 2 h the potency of rIL-2 diluted with 5% glucose alone had fallen to less than 25% and it remained low in subsequent samples (figure). Thus, with the delivery system we used, failure to reconstitute non-protein formulated rIL-2 with albumin for infusion could result in patients receiving much less than the intended dose. The low potency after 2 h and for the rest of the infusion presumably resulted from binding of the cytokine to plastic in the syringe and
giving set.
