- Email: [email protected]
CYCLOSPORIN AND RIFAMPICIN IN RENAL TRANSPLANTATION
980
right hand. Immediately a flare developed in the skin proximal to the injection site, and following this urticarial weals were seen in the skin of the forearm up to the elbow; these lasted roughly 4 h. There was no systemic upset such as haemodynamic changes, bronchospasm, or laryngospasm, and intubation proceeded without The operation was completed uneventfully, anaesthesia being maintained with N2O, 02, and halothane by intermittent
difficulty.
positive pressure ventilation. Intradermal testing with vecuronium bromide 0’ 04 mg produced a
weal 1
developed
cm
diameter with
a
flare 3-55 cm diameter; the latter
almost
immediately, though the weal took 10 min to reach its maximum. The pathogenesis of the reaction is unclear. IgE mediated hypersensitivity is unlikely since the patient had not previously been treated with the drug or any drug which might be cross-reactive. Vecuronium bromide could act as a non-specific histamine-releasing agent, but the mechanism involved clearly needs further study. It is important to report that reactions may occur with vecuronium bromide, albeit very infrequently, anaesthetists are not lulled into a false sense of security.
Departments of Anaesthetics and Dermatology, Royal Infirmary, Edinburgh
so
It is our policy in Oxford to prescribe antituberculous therapy of rifampicin and isoniazid to transplant recipients who have either a past history of tuberculosis or are immigrants from India or Pakistan. Nine other patients have been so treated for 9 to 12 months after transplantation, but all have been immunosuppressed with azathioprine and low-dose prednisolone. None of these grafts has been lost. In view of this experience and that presented in this case-report, we would suggest that azathioprine and prednisolone be used for immunosuppression instead of CyA if the use of rifampicin is indicated after transplantation, although one should be aware of the possible need for greater doses of prednisolone. Transplant Unit, Nuffield Department of Surgery, Oxford University, Churchill Hospital, Oxford OX3 7LJ
CYCLOSPORIN AND RIFAMPICIN IN RENAL TRANSPLANTATION SIR,-There is increasing evidence that the hepatic cytochrome P450 enzyme system is important in the metabolism of cyclosporin (CyA),1 and thus the clinical effectiveness of this immunosuppressive agent may be affected by drugs such as phenytoin that are capable of inducing these enzymes.22 We are able to confirm the findings of a report by Langhoff and Madson3of the deleterious effect on a functioning allograft of the combination of CyA and antituberculous therapy. However, in contrast to their experience, we found that antituberculous therapy was not a major problem associated with the use of azathioprine and steroids. A 60 kg, 52-year-old Pakistani male who had been a resident of the United Kingdom for 17 years was given a cadaver kidney. For the preceding 8 months he had been successfully treated for an extensively investigated pyrexia of unknown origin with rifampicin 600 mg, isoniazid 200 mg, and ethambutol 300 mg daily. In the absence of antibiotic sensitivities, this regimen was continued after transplantation. He was entered into an ongoing controlled trial of CyA versus conventional immunosuppressive therapy and was randomly allocated to oral CyA, with a starting dose of 17.55 mg/kg/day. Daily plasma samples were taken for radioimmunoassay measurement of CyA trough levels. There was initial function of the graft but, on day 7, because of clinical and histological evidence of acute rejection, he was given an intravenous bolus of0-5gg of methyl-prednisolone daily for 5 days without demonstrable response. On day 8, because no plasma CyA could be detected, the dose was increased to 30 mg/kg/day, and the antituberculous therapy was withdrawn. By day 14 he had adequate trough levels of CyA in the plasma, but since allograft function remained poor, treatment was changed to azathioprine and prednisolone. This change had no effect on allograft function and a transplant nephrectomy was performed on day 65. In our patient the effect of the antituberculous therapy resembled that of phenytoin on CyA bioavailability.2What would now be considered a high initial dose of CyA did not produced detectable levels of CyA in the plasma for 14 days, despite an increase in the CyA dose to 30 mg/kg and cessation of the antituberculous therapy on day 8. The result was the eventual loss of the renal allograft due to rejection. Of the three antituberculous drugs used, rifampicin, a lipid-soluble compound metabolised by the liver, is the most likely drug to have produced the increased clearance of CyA, the pattern of which is consistent with induction of the cytochrome P450 enzyme system. Rifampicin has recently been shown to have a similar effect on the bioavailability of prednisolone.4 Isoniazid has been shown to be a non-specific inhibitor of the cytochrome P450 system, increasing the bioavailability of phenytoin, warfarin, and primidone,5while ethambutol is a water-soluble compound predominantly excreted unchanged in the urine.
CR, Keown PA Cyclosporine therapy in perspective In Morris PJ, Tilney N, eds. Progress in transplantation, 1. Edinburgh: Churchill Livingstone, 1984: 11-45. Keown PA, Laupacis A, Carruthers G, et al. Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation 1984; 38: 304-06. Langhoff E, Madson S. Rapid metabolism of cycloporin and prednisolone in kidney transplant patient receiving tuberculostatic treatment. Lancet 1983; ii: 1031 McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br MedJ 1983; 286: 923-25. Muakkassah SF, Bidlock WR, Yang WC. Mechanism of the inhibitory action of isoniazid on microsomal drug metabolism. Biochem Pharmacol 1981; 30: 1651-58.
1. Stiller
that
A. G. SPENCE R. STC. BARNETSON
R. D. M. ALLEN A. G. HUNNISETT P. J. MORRIS
2 3. 4. 5.
ACUTE VINCRISTINE NEUROTOXICITY
SIR,-Dr Arnold and colleagues’ letter (Feb 9, p 346) on unusually neurotoxic effects of vincristine in their patients with breast carcinoma was published at the time that we were contacting the Eli Lilly medical consultants about some unusually severe side-effects that we had noticed in our patients. Several had severe constipation, abdominal pain of unusually severe intensity and long duration, obstinate constipation, and severe peripheral neuropathy. The events that made us suspect undue toxicity occurred in a 10-year-old female with a malignant ovarian teratoma being treated with vincristine, cyclophosphamide, and actinomycin D. She had severe abdominal pain, constipation, generalised seizures, and the syndrome of inappropriate antidiuretic hormone secretion, for which she required a long hospital stay, extensive neurological work-up, and anticonvulsant treatment. We are now reviewing all the cases who received vincristine from the time our pharmacy switched to the ready-to-use form, since Arnold and colleagues have drawn attention to the change in the manufacturing technique as a possible reason for the increase in frequency of acute neurotoxocity. severe
Children’s Hospital of New Orleans, Louisiana State University Medical Center, New Orleans, Louisiana, USA
R. P. WARRIER RAFAEL DUCOS
NOCTURNAL ENURESIS ASSOCIATED WITH SODIUM VALPROATE
SIR,-I wish to report on nocturnal enuresis as a dose-related adverse effect of sodium valproate in 2 out of 150 Greek children, treated for seizures. This unwanted effect has not been previously reported and might be overlooked as resulting from the seizures themselves. Case 1.-This 6-year-old girl had 10-20 absence seizures daily, with clonic movements and automatism. She was moderately hyperkinetic, possibly because of prematurity (32 weeks, 1400 g). Otherwise her development was normal. Sphincter control was complete at 3 years of age. Treatment with sodium valproate 200 mg three times daily resulted in a striking remission in seizures but improvement was accompanied by enuresis every night from the second day of treatment. Early morning plasma levels of sodium valproate were 52 - 2 g/ml before and 1 h after the morning dose. An immediate remission of the nocturnal enuresis was achieved, without seizure relapse, by reducing the valproate dose to 200 mg twice daily and by giving the last daily dose after an early dinner (early morning levels reduced to 33 !-tg/ml before ingestion of the drug). 8 years later (aged 14), she is well adjusted, with occasional myoclonic jerking, and is taking sodium valproate 500 mg twice
daily.
right hand. Immediately a flare developed in the skin proximal to the injection site, and following this urticarial weals were seen in the skin of the forearm up to the elbow; these lasted roughly 4 h. There was no systemic upset such as haemodynamic changes, bronchospasm, or laryngospasm, and intubation proceeded without The operation was completed uneventfully, anaesthesia being maintained with N2O, 02, and halothane by intermittent
difficulty.
positive pressure ventilation. Intradermal testing with vecuronium bromide 0’ 04 mg produced a
weal 1
developed
cm
diameter with
a
flare 3-55 cm diameter; the latter
almost
immediately, though the weal took 10 min to reach its maximum. The pathogenesis of the reaction is unclear. IgE mediated hypersensitivity is unlikely since the patient had not previously been treated with the drug or any drug which might be cross-reactive. Vecuronium bromide could act as a non-specific histamine-releasing agent, but the mechanism involved clearly needs further study. It is important to report that reactions may occur with vecuronium bromide, albeit very infrequently, anaesthetists are not lulled into a false sense of security.
Departments of Anaesthetics and Dermatology, Royal Infirmary, Edinburgh
so
It is our policy in Oxford to prescribe antituberculous therapy of rifampicin and isoniazid to transplant recipients who have either a past history of tuberculosis or are immigrants from India or Pakistan. Nine other patients have been so treated for 9 to 12 months after transplantation, but all have been immunosuppressed with azathioprine and low-dose prednisolone. None of these grafts has been lost. In view of this experience and that presented in this case-report, we would suggest that azathioprine and prednisolone be used for immunosuppression instead of CyA if the use of rifampicin is indicated after transplantation, although one should be aware of the possible need for greater doses of prednisolone. Transplant Unit, Nuffield Department of Surgery, Oxford University, Churchill Hospital, Oxford OX3 7LJ
CYCLOSPORIN AND RIFAMPICIN IN RENAL TRANSPLANTATION SIR,-There is increasing evidence that the hepatic cytochrome P450 enzyme system is important in the metabolism of cyclosporin (CyA),1 and thus the clinical effectiveness of this immunosuppressive agent may be affected by drugs such as phenytoin that are capable of inducing these enzymes.22 We are able to confirm the findings of a report by Langhoff and Madson3of the deleterious effect on a functioning allograft of the combination of CyA and antituberculous therapy. However, in contrast to their experience, we found that antituberculous therapy was not a major problem associated with the use of azathioprine and steroids. A 60 kg, 52-year-old Pakistani male who had been a resident of the United Kingdom for 17 years was given a cadaver kidney. For the preceding 8 months he had been successfully treated for an extensively investigated pyrexia of unknown origin with rifampicin 600 mg, isoniazid 200 mg, and ethambutol 300 mg daily. In the absence of antibiotic sensitivities, this regimen was continued after transplantation. He was entered into an ongoing controlled trial of CyA versus conventional immunosuppressive therapy and was randomly allocated to oral CyA, with a starting dose of 17.55 mg/kg/day. Daily plasma samples were taken for radioimmunoassay measurement of CyA trough levels. There was initial function of the graft but, on day 7, because of clinical and histological evidence of acute rejection, he was given an intravenous bolus of0-5gg of methyl-prednisolone daily for 5 days without demonstrable response. On day 8, because no plasma CyA could be detected, the dose was increased to 30 mg/kg/day, and the antituberculous therapy was withdrawn. By day 14 he had adequate trough levels of CyA in the plasma, but since allograft function remained poor, treatment was changed to azathioprine and prednisolone. This change had no effect on allograft function and a transplant nephrectomy was performed on day 65. In our patient the effect of the antituberculous therapy resembled that of phenytoin on CyA bioavailability.2What would now be considered a high initial dose of CyA did not produced detectable levels of CyA in the plasma for 14 days, despite an increase in the CyA dose to 30 mg/kg and cessation of the antituberculous therapy on day 8. The result was the eventual loss of the renal allograft due to rejection. Of the three antituberculous drugs used, rifampicin, a lipid-soluble compound metabolised by the liver, is the most likely drug to have produced the increased clearance of CyA, the pattern of which is consistent with induction of the cytochrome P450 enzyme system. Rifampicin has recently been shown to have a similar effect on the bioavailability of prednisolone.4 Isoniazid has been shown to be a non-specific inhibitor of the cytochrome P450 system, increasing the bioavailability of phenytoin, warfarin, and primidone,5while ethambutol is a water-soluble compound predominantly excreted unchanged in the urine.
CR, Keown PA Cyclosporine therapy in perspective In Morris PJ, Tilney N, eds. Progress in transplantation, 1. Edinburgh: Churchill Livingstone, 1984: 11-45. Keown PA, Laupacis A, Carruthers G, et al. Interaction between phenytoin and cyclosporine following organ transplantation. Transplantation 1984; 38: 304-06. Langhoff E, Madson S. Rapid metabolism of cycloporin and prednisolone in kidney transplant patient receiving tuberculostatic treatment. Lancet 1983; ii: 1031 McAllister WA, Thompson PJ, Al-Habet SM, Rogers HJ. Rifampicin reduces effectiveness and bioavailability of prednisolone. Br MedJ 1983; 286: 923-25. Muakkassah SF, Bidlock WR, Yang WC. Mechanism of the inhibitory action of isoniazid on microsomal drug metabolism. Biochem Pharmacol 1981; 30: 1651-58.
1. Stiller
that
A. G. SPENCE R. STC. BARNETSON
R. D. M. ALLEN A. G. HUNNISETT P. J. MORRIS
2 3. 4. 5.
ACUTE VINCRISTINE NEUROTOXICITY
SIR,-Dr Arnold and colleagues’ letter (Feb 9, p 346) on unusually neurotoxic effects of vincristine in their patients with breast carcinoma was published at the time that we were contacting the Eli Lilly medical consultants about some unusually severe side-effects that we had noticed in our patients. Several had severe constipation, abdominal pain of unusually severe intensity and long duration, obstinate constipation, and severe peripheral neuropathy. The events that made us suspect undue toxicity occurred in a 10-year-old female with a malignant ovarian teratoma being treated with vincristine, cyclophosphamide, and actinomycin D. She had severe abdominal pain, constipation, generalised seizures, and the syndrome of inappropriate antidiuretic hormone secretion, for which she required a long hospital stay, extensive neurological work-up, and anticonvulsant treatment. We are now reviewing all the cases who received vincristine from the time our pharmacy switched to the ready-to-use form, since Arnold and colleagues have drawn attention to the change in the manufacturing technique as a possible reason for the increase in frequency of acute neurotoxocity. severe
Children’s Hospital of New Orleans, Louisiana State University Medical Center, New Orleans, Louisiana, USA
R. P. WARRIER RAFAEL DUCOS
NOCTURNAL ENURESIS ASSOCIATED WITH SODIUM VALPROATE
SIR,-I wish to report on nocturnal enuresis as a dose-related adverse effect of sodium valproate in 2 out of 150 Greek children, treated for seizures. This unwanted effect has not been previously reported and might be overlooked as resulting from the seizures themselves. Case 1.-This 6-year-old girl had 10-20 absence seizures daily, with clonic movements and automatism. She was moderately hyperkinetic, possibly because of prematurity (32 weeks, 1400 g). Otherwise her development was normal. Sphincter control was complete at 3 years of age. Treatment with sodium valproate 200 mg three times daily resulted in a striking remission in seizures but improvement was accompanied by enuresis every night from the second day of treatment. Early morning plasma levels of sodium valproate were 52 - 2 g/ml before and 1 h after the morning dose. An immediate remission of the nocturnal enuresis was achieved, without seizure relapse, by reducing the valproate dose to 200 mg twice daily and by giving the last daily dose after an early dinner (early morning levels reduced to 33 !-tg/ml before ingestion of the drug). 8 years later (aged 14), she is well adjusted, with occasional myoclonic jerking, and is taking sodium valproate 500 mg twice
daily.