OXYQUINOUNE TOXICITY
1
709 place-i.e., to prevent admissions due to hypertension just as we do those due to anaemia and poorly controlled diabetes. If the blood pressure is unusually high in the first trimester or if the diastolic is as high as 80 mm Hg at the twentieth week then a subsequent rise in blood pressure, sometimes with proteinuria, may occur. 1 In an uncontrolled trial over the past two years at this hospital labetolol has been given to 329 patients considered to have an’ abnormally high blood pressure after allowance for age, race, and state of the pregnancy. This has been a continuing experience since the results of treating the first 60 or so cases was reported.2 No patient is admitted to hospital unless non-infective proteinuria ensues, there is significant growth retardation of the fetus (the new Cardiff fundal heights charts seem as helpful as serial scanning3), or blood pressure escapes control. A diastolic pressure of 110 mm Hg, despite an increasing dosage of labetolol, associated with fetal growth retardation, usually warrants admission. Exceptionally, labetolol may be combined with drugs such as hydralazine, bendrofluazide, and methyldopa when control of the pressure seems essential and termination inappropriate. Labetolol does not adversely affect the fetus although it may not reduce the incidence of growth retardation. Neonatal bradycardia and hypoglycaemia are insignificant, as is respiratory distress syndrome. In the puerperium the drug should be continued until the third day test the return of blood pressure to its pretreatment level alarms the inexperienced. Maybe it should be continued to the next pregnancy in a few patients. Our experience, unlike that of Rubin et al, is that in the third trimester moderate degrees of proteinuria may clear during treatment when this begins late in pregnancy. Perhaps these are not true cases of pre-eclampsia. Obstetricians are uncritically dependent on the sphygmomanometer. New Cross Hospital, Wolverhampton ALAN M. SMITH DIFFERENCE IN BIOACTIVITY BETWEEN TWO PREPARATIONS OF CYCLOPHOSPHAMIDE SIR,-There is interest in very high dose cyclophosphamide (50 mglkg daily for 4 days) for the treatment of small cell carcinoma of the bronchus4 and in allogeneic bone marrow transplantation. Haemorrhagic cystitis is a major complication at these dose levels; this can be avoided by the use of mesna.4 4 During a 4 week recent period our normal preparation of cyclophosphamide (Farmitalia Carlo Erba) was not available and instead we used ’Endoxana’ (WB Pharmaceuticals) in four patients. All these patients had haemorrhagic cystitis of mild or moderate severity while on the same dose of cyclophosphamide and mesna as used in the previous series of twenty-five patients. While the two cyclophosphamide preparations had the same nuclear magnetic resonance spectra, optical activities (by polarimetry), and gas-liquid chromatographic properties, their mass spectral properties were quantitatively different. This suggests minor structural differences between the molecules in the two preparations. In rats on doses of 50 mg/kg daily the WB . Pharmaceutical preparation was more active than the Farmitalia product, as judged by depression of spleen weights and bladder toxicity (oedema). 5 It is possible that in the chemical synthesis of the two preparations isomeric forms of cyclophosphamide may be made, or that in a sterioisomeric mixture of the drug there are different proportions of the two enantiomers. One of these enantiomers may be more bioactive than the other. Differences in the metabolic profiles of the enantiomers of cyclophosphamide have been 1 MacGillivray I. Hypertension in pregnancy. J Maternal Child Health 1977; 2: 245-52 2 Riley A, Symonds EM. The investigation of labetolol in the management of hypertension in pregnancy Amsterdam: Excerpta Medica, 1982. 3 Calvert JP, Crean EE, Newcombe RG, Pearson JF. Antenatal screening by measurement of symphysis-fundus height. Br Med J 1982; 285: 846-49 4 Souhami RL, Harper PG, Linch D, et al High dose cyclophosphamide with autologous marrow transplantation as initial treatment of small cell carcinoma of the bronchus Cancer Chemother Pharmacol 1982; 8: 31. 5 Shaw IC, Earl LK, McLean AEM, Souhami RL. Differences in the activity of two commercially available preparations of cyclophosphamide. Human Toxicol (in press) described.6 While these differences may be unimportant at conventional dosage, with very high doses differences in therapeutic activity and toxicity between one preparation and another may become vitally important. When prescribing high doses it is important to adhere to one commercial preparation of cyclophosphamide or to regulate the dosage of the drug and mesna according to the preparation. Cyclophosphamide appears to be one of those few examples of drugs for.which generic prescribing is not applicable. Departments of Clinical Pharmacology and Chemistry, University College London, London WC1F 6JJ; and Department of Radiotherapy and Oncology, University College Hospital, London I. C. SHAW L. K. EARL M. N. MRUZEK P. G. HARPER A. E. M. MCLEAN R. L. SOUHAMI OXYQUINOUNE TOXICITY SiR,-As stressed in your note (Nov. 27, p. 123) Ciba-Geigy’s decision gradually to phase out clioquinol containing preparations is the logical consequence of much evidence linking clioquinol with SMON (subacute myelo-optic neuropathy), mainly in Japan. The neurotoxicity of other oxyquinolines has been much less well documented.2 We have seen SMON in a patient using a combination of tilbroquinol and tiliquinol (’Intetrix’), two oxyquinolines slightly different from clioquinol. This is, to our knowledge, the first report of neurotoxicity with this compound that is prescribed worldwide. A 60-year-old man was admitted in October, 1982, for visual impairment, tiredness, and weight loss (9 kg in 5 months). He had a long history of constipation and diarrhoea, and a barium enema had demonstrated sigmoid diverticulosis, for which the patient had been taking tiliquinol and tilbroquinol continuously for four years at an average daily dose of 80 mg and 200 mg, respectively. The neurological symptoms consisted of a 2 year history of pain, dysaesthesiae, and paraesthesiae of the arms and legs inducing insomnia for 3 months; impairment of thermic sensibility in the distal parts of the legs; cerebellar ataxia; anxiety; and poor memory. He had no muscular weakness, pyramidal signs, or impairment of deep sensation. Laboratory findings in blood and CSF (including gamma-globulins) were normal. Eye symptoms appeared in July, 1982, consisting of right scotoma, asymmetric bilateral angiographic papilloedema, and colour vision disturbance. Two computed tomographic scans of the brain and a cerebral angiogram were normal. Thus, this case fulfilled the two cardinal and most of the major signs required for diagnosis by the Japanese SMON Research Commission.3 Furthermore, 3 months after withdrawal of intetrix we observed a dramatic improvement in neurological symptoms, a relief of abdominal pain, and a 9 kg weight gain; there was no change in the ophthalmological picture. We suggest that oxyquinolines other than clioquinol may cause neuro-ophthalinoldgical damage, and that the problem is not restricted to Japanese people. This is the first case of such toxicity reported with tilbrbquinol/tiliquinol, a drug combination with large sales worldwide. Furthermore the treatment was about 50 times longer than the period recommended by the manufacturers, suggesting that the neurotoxicity is a cumulative effect of this compound and the result of obvious overdosage. Physicians should restrict the prescription of all hydroxyquinolines to short-term courses. Internal Medicine and Nutrition Service and Ophthalmology Service, Hôpital de l’Hôtel-Dieu, 75181 Paris, France MICHEL SOFFER ARNAUD BASDEVANT JEAN-JACQUES SARRAGOUSSI JOCELYNE RAISON BERNARD GUY-GRAND 6. Jarman M, Milsted RAV, Smyth JF, Kinas RW, Pankiewicz K, Stec WJ. Comparative metabolism of cyclophosphamide and its enantiomers in humans. Cancer Res 1979; 39: 2726 1. SMON Research Commission. Reviews on SMON. Jap J Med Sci Biol 1975; suppl 28: 1. 2. Hansson O Toxicity of oxyquinolines Lancet 1977; i 1152. 3 Nakae K, Yamamoto SI, Igata A. Subacute myelo optic neuropathy (SMON) in Japan Lancet 1971; ii: 510-12.
Transcript of OXYQUINOUNE TOXICITY
709
place-i.e., to prevent admissions due to hypertension just as we dothose due to anaemia and poorly controlled diabetes. If the bloodpressure is unusually high in the first trimester or if the diastolic isas high as 80 mm Hg at the twentieth week then a subsequent rise inblood pressure, sometimes with proteinuria, may occur.
1
In an uncontrolled trial over the past two years at this hospitallabetolol has been given to 329 patients considered to have an’abnormally high blood pressure after allowance for age, race, andstate of the pregnancy. This has been a continuing experience sincethe results of treating the first 60 or so cases was reported.2 Nopatient is admitted to hospital unless non-infective proteinuriaensues, there is significant growth retardation of the fetus (the newCardiff fundal heights charts seem as helpful as serial scanning3), orblood pressure escapes control. A diastolic pressure of 110 mm Hg,despite an increasing dosage of labetolol, associated with fetalgrowth retardation, usually warrants admission. Exceptionally,labetolol may be combined with drugs such as hydralazine,bendrofluazide, and methyldopa when control of the pressure seemsessential and termination inappropriate. Labetolol does not
adversely affect the fetus although it may not reduce the incidence ofgrowth retardation. Neonatal bradycardia and hypoglycaemia areinsignificant, as is respiratory distress syndrome.In the puerperium the drug should be continued until the third
day test the return of blood pressure to its pretreatment level alarmsthe inexperienced. Maybe it should be continued to the next
pregnancy in a few patients.Our experience, unlike that of Rubin et al, is that in the third
trimester moderate degrees of proteinuria may clear duringtreatment when this begins late in pregnancy. Perhaps these are nottrue cases of pre-eclampsia. Obstetricians are uncriticallydependent on the sphygmomanometer.New Cross Hospital,Wolverhampton ALAN M. SMITH
DIFFERENCE IN BIOACTIVITY BETWEEN TWOPREPARATIONS OF CYCLOPHOSPHAMIDE
SIR,-There is interest in very high dose cyclophosphamide (50mglkg daily for 4 days) for the treatment of small cell carcinoma ofthe bronchus4 and in allogeneic bone marrow transplantation.Haemorrhagic cystitis is a major complication at these dose levels;this can be avoided by the use of mesna.4
4
During a 4 week recent period our normal preparation ofcyclophosphamide (Farmitalia Carlo Erba) was not available andinstead we used ’Endoxana’ (WB Pharmaceuticals) in four patients.All these patients had haemorrhagic cystitis of mild or moderateseverity while on the same dose of cyclophosphamide and mesna asused in the previous series of twenty-five patients.While the two cyclophosphamide preparations had the same
nuclear magnetic resonance spectra, optical activities (bypolarimetry), and gas-liquid chromatographic properties, their
mass spectral properties were quantitatively different. This
suggests minor structural differences between the molecules in thetwo preparations. In rats on doses of 50 mg/kg daily the WB .Pharmaceutical preparation was more active than the Farmitaliaproduct, as judged by depression of spleen weights and bladdertoxicity (oedema). 5
It is possible that in the chemical synthesis of the two preparationsisomeric forms of cyclophosphamide may be made, or that in asterioisomeric mixture of the drug there are different
proportions of the two enantiomers. One of these enantiomers maybe more bioactive than the other. Differences in the metabolic
profiles of the enantiomers of cyclophosphamide have been
1 MacGillivray I. Hypertension in pregnancy. J Maternal Child Health 1977; 2: 245-522 Riley A, Symonds EM. The investigation of labetolol in the management of
hypertension in pregnancy Amsterdam: Excerpta Medica, 1982.3 Calvert JP, Crean EE, Newcombe RG, Pearson JF. Antenatal screening by
measurement of symphysis-fundus height. Br Med J 1982; 285: 846-494 Souhami RL, Harper PG, Linch D, et al High dose cyclophosphamide with
autologous marrow transplantation as initial treatment of small cell carcinoma of thebronchus Cancer Chemother Pharmacol 1982; 8: 31.
5 Shaw IC, Earl LK, McLean AEM, Souhami RL. Differences in the activity of twocommercially available preparations of cyclophosphamide. Human Toxicol (inpress)
described.6 While these differences may be unimportant at
conventional dosage, with very high doses differences in
therapeutic activity and toxicity between one preparation andanother may become vitally important.When prescribing high doses it is important to adhere to one
commercial preparation of cyclophosphamide or to regulate thedosage of the drug and mesna according to the preparation.Cyclophosphamide appears to be one of those few examples of drugsfor.which generic prescribing is not applicable.Departments of Clinical Pharmacologyand Chemistry,
University College London,London WC1F 6JJ;and Department of Radiotherapyand Oncology,
University College Hospital, London
I. C. SHAWL. K. EARLM. N. MRUZEKP. G. HARPERA. E. M. MCLEANR. L. SOUHAMI
OXYQUINOUNE TOXICITY
SiR,-As stressed in your note (Nov. 27, p. 123) Ciba-Geigy’sdecision gradually to phase out clioquinol containing preparationsis the logical consequence of much evidence linking clioquinol withSMON (subacute myelo-optic neuropathy), mainly in Japan. Theneurotoxicity of other oxyquinolines has been much less welldocumented.2 We have seen SMON in a patient using a combinationof tilbroquinol and tiliquinol (’Intetrix’), two oxyquinolines slightlydifferent from clioquinol. This is, to our knowledge, the first reportof neurotoxicity with this compound that is prescribed worldwide.A 60-year-old man was admitted in October, 1982, for visual
impairment, tiredness, and weight loss (9 kg in 5 months). He had along history of constipation and diarrhoea, and a barium enema haddemonstrated sigmoid diverticulosis, for which the patient had beentaking tiliquinol and tilbroquinol continuously for four years at anaverage daily dose of 80 mg and 200 mg, respectively.The neurological symptoms consisted of a 2 year history of pain,
dysaesthesiae, and paraesthesiae of the arms and legs inducinginsomnia for 3 months; impairment of thermic sensibility in thedistal parts of the legs; cerebellar ataxia; anxiety; and poor memory.He had no muscular weakness, pyramidal signs, or impairmentof deep sensation. Laboratory findings in blood and CSF (includinggamma-globulins) were normal. Eye symptoms appeared in July,1982, consisting of right scotoma, asymmetric bilateral
angiographic papilloedema, and colour vision disturbance. Twocomputed tomographic scans of the brain and a cerebral
angiogram were normal.Thus, this case fulfilled the two cardinal and most of the major
signs required for diagnosis by the Japanese SMON ResearchCommission.3 Furthermore, 3 months after withdrawal of intetrixwe observed a dramatic improvement in neurological symptoms, arelief of abdominal pain, and a 9 kg weight gain; there was no changein the ophthalmological picture.We suggest that oxyquinolines other than clioquinol may cause
neuro-ophthalinoldgical damage, and that the problem is not
restricted to Japanese people. This is the first case of such toxicityreported with tilbrbquinol/tiliquinol, a drug combination with largesales worldwide. Furthermore the treatment was about 50 timeslonger than the period recommended by the manufacturers,suggesting that the neurotoxicity is a cumulative effect of thiscompound and the result of obvious overdosage. Physicians shouldrestrict the prescription of all hydroxyquinolines to short-termcourses.
Internal Medicine and Nutrition Service
and Ophthalmology Service,Hôpital de l’Hôtel-Dieu,75181 Paris, France
MICHEL SOFFERARNAUD BASDEVANT
JEAN-JACQUES SARRAGOUSSIJOCELYNE RAISONBERNARD GUY-GRAND
6. Jarman M, Milsted RAV, Smyth JF, Kinas RW, Pankiewicz K, Stec WJ. Comparativemetabolism of cyclophosphamide and its enantiomers in humans. Cancer Res 1979;39: 2726
1. SMON Research Commission. Reviews on SMON. Jap J Med Sci Biol 1975; suppl 28:1.
2. Hansson O Toxicity of oxyquinolines Lancet 1977; i 1152.3 Nakae K, Yamamoto SI, Igata A. Subacute myelo optic neuropathy (SMON) in Japan
Lancet 1971; ii: 510-12.
