1156
potentiation of warfarin activity (see acompanying figure). All of these patients, whose ages varied from 43 to 72 years,
CONTENT OF AROMATIC COMPOUNDS IN MAIN BRANDS OF PETROL IN BELGIUM
received days for
two tablets of co-trimoxazole twice daily for 3 to 12 respiratory or urinary-tract infections. Tltey were not taking any other drugs likely to affect anticoagulant control with warfarin, and in no case was there an obvious alternative explanation from the clinical history to account for the increased prothrombin ratios. In each patient the prothrombin
ratio became elevated some time between the second and the sixth day of combined threapy. In patient 6 the increased prothrombin ratio necessitated the intravenous administration of 5 mg vitamin KI following gastrointestinal haemorrhage. In patient 1 the increase was corrected by reducing warfarin dosage, whereas in patients 2 and 6 it was necessary to withdraw the anticoagulant for several days. Following cessation of co-trimoxazole a prothrombin ratio of between 2 and 3 was achieved in all patients with doses of 1.5to 7.5mg warfarin
Belgium, during the postwar period, benzene was added petrol to save foreign currency. Since both patients had been using a minor-brand petrol, we suspected that some small firms added cheap aromatic compounds during the recent petrol crisis. The results of gas chromatography and infra-red spectrophotometry of the incriminated petrol (brands 2 and 9) and samples of the main brands sold in Belgium are shown in In
daily. In the only other clinical report of potentiation-that of a single patient described by Barnett and Hancock ’-elevation of plasma-warfarin was observed suggesting inhibition of metabolism of the anticoagulant by co-trimoxazole. Our own observations, however, have shown a slight fall in plasma-warfarin levels in one patient and a marked fall in another.2 Hansen et al. have reported increased half-lives of phenytoin in 6 patients receiving co-trimoxazole; and other sulphonamides are known to inhibit drug metabolism in liver microsomes-for example, sulphaphenazole inhibits the metabolism of tolbutamideand phenytoin,S while sulphamethizole
inhibits the biotransformation of these two and also that of warfarin.6 Perhaps the same mechanism partly accounts for the interaction described above. Although we are unable at this stage to estimate the likely incidence, it is apparent that, whatever the mechanism, in some patients the concurrent administration of co-trimoxazole potentiates the effect of warfarin. We should like to thank our clinical colleagues for report details of patients under their care.
Departments of Pharmacy and Hæmatology, Queen Elizabeth Hospital, Birmingham B15 2TH.
allowing
to
the table. We wish
draw attention to the danger of the use of petrol since it contains appreciable amounts of benzene solvent, and up to 20% aromatic compounds. A similar risk may exist in other countries. Laboratory
J.
for
Hæmatology,
Department of Medical Research, Akademisch Ziekenhuis St Rafaël, 35, Capucijnenvoer, 3000 Leuven, Belgium and Section of Occupational Health, Department of Social Medicine, University of Leuven.
C. HASSALL C. L. FEETAM R. H. LFACH M.
to
as a
R. L. VERWILGHEN A. VAN DORPE H. VEULEMANS
us to
MEYNELL
DANGERS OF PETROL USED AS SOLVENT
SIR,-The hmmatological toxicity of benzene
is well known the reason for legislation proscribing its use as a solvent. The Belgian Factory Acts allow only products containing less than 0.25% benzene and 1% toluene and xylene to be used in industry. These regulations do not, however, apply to motor-car petrol. Lately we have seen two patients who appeared to have developed hæmatological symptoms after the use of petrol as a solvent.
and
the leucocyte count was increased (110 000/ mm), with a marked shift to the left. After some days, however, bone-marrow hypoplasia occurred and resulted in anasmia (8-8 gldl) and granulocytopema (700/mm’). The haematotogical picture reverted to normal within 4 weeks, without specific treatment.
was
The first patient, a welder, used petrol to clean the surface of trucks before repair. The petrol was bought daily from a nearby petrol station in a ierry-can. The patient developed a severe haemorrhagic syndrome due to profound thrombocytopenia. After treatment with corticosteroids the blood returned to normal within 3 weeks, and there was no recurrence of symptoms when the patient changed his occupation. The second patient is a drawer on steelplate. He used petrol, obtained from a local petrol station, to clean the iron sheets, His workbench was put in a small and poorly ventilated shed. Lately he had complained of vomiting, attributed to inhalation of the petrol fumes. On admission to hospital, chronic myeloid leukaemia was suspected: 1. Barnett, D. B., Hancock, B. W. Br med.J 1975, i, 608. 2. Hassall, C., Feetam, C. L., Leach, R. H., Meynell, M. J. ibid 1975, ii, 684 3 Hansen, J. M., Siersbaek-Nielsen, K., Skovsted, L., Kampmann, J P, Lumholtz, B. ibid. p. 684. 4. Christensen, L. K., Hansen, J. M., Kristensen, M. Lancet, 1963, ii, 1298. 5. Hansen, J. M., Kristensen, M., Skovsted, L., Christensen, I. K ibid. 1966,
ii, 265 6. Lumholtz, B., Siersbaek-Nielsen, K., Skovsted, L., Kampmann, J P., Hansen, J. M. Clin. Pharmac. Ther. 1975, 17, 731
ZINC AND
DIODOQUIN IN ACRODERMATITIS ENTEROPATHICA
SIR,—Dr Delves and his colleagues (Nov. 8, p. 9291 described the absorption and retention of zinc and other trace metals in a case of acrodermatitis enteropathica (A.E.) treated with ’Diodoquin’. Their suggestion that diodoquin might be acting as a zinc-transport agent by virtue of its metal-binding properties has already been made by us.’ Other workers have speculated that lack of zinc absorption might be the underlying defect in A.E.2 3However, the evidence offered by Dr Delves and his colleagues does not prove that intestinal zinc absorption is impaired, since no measurements were made in the untreated state. Comparison with mean values for absorption in healthy controls is not informative without a measure of the degree of scatter of these values. Available data suggest that the absorption of zinc from the intestines is highly variable.’-’ Using neutron-activation analysis in a case of A.F. we found that skin and hair samples taken before zinc therapy had normal zinc levels, yet serum-zinc levels were extremely low.’ In another untreated case of A.E. in this hospital, normal zinc levels were found in skin and hair as well as in serum.’ These findings indicate that the demonstration of low concentration of tissue zinc and/or subnormal serum-zinc levels is neither an absolute nor a diagnostic feature ofA.F. and should 1. 2 3
Portnoy, B., Molokhia, M. Br. J. Derm. 1974, 91, 701. E. J. Lancet, 1974, ii, 399. Lombeck, I , Schnippering, H. G., Ritzl, F., Fainendegen, I F. Bremer. II J ibid. 1975, i, 855. 4. Henkm, R. I., ibid. p. 1379. 5. Alexander, F. W., Clayton, B. E., Delves, H. T. Q. Jl. Med 1974, 43, 89 6. Portnoy, B , Molokhia, M., Br.J. Derm. (in the press). 7 Garretts, M., Molokhia, M Unpublished.
Moynahan,
potentiation of warfarin activity (see acompanying figure). All of these patients, whose ages varied from 43 to 72 years,
CONTENT OF AROMATIC COMPOUNDS IN MAIN BRANDS OF PETROL IN BELGIUM
received days for
two tablets of co-trimoxazole twice daily for 3 to 12 respiratory or urinary-tract infections. Tltey were not taking any other drugs likely to affect anticoagulant control with warfarin, and in no case was there an obvious alternative explanation from the clinical history to account for the increased prothrombin ratios. In each patient the prothrombin
ratio became elevated some time between the second and the sixth day of combined threapy. In patient 6 the increased prothrombin ratio necessitated the intravenous administration of 5 mg vitamin KI following gastrointestinal haemorrhage. In patient 1 the increase was corrected by reducing warfarin dosage, whereas in patients 2 and 6 it was necessary to withdraw the anticoagulant for several days. Following cessation of co-trimoxazole a prothrombin ratio of between 2 and 3 was achieved in all patients with doses of 1.5to 7.5mg warfarin
Belgium, during the postwar period, benzene was added petrol to save foreign currency. Since both patients had been using a minor-brand petrol, we suspected that some small firms added cheap aromatic compounds during the recent petrol crisis. The results of gas chromatography and infra-red spectrophotometry of the incriminated petrol (brands 2 and 9) and samples of the main brands sold in Belgium are shown in In
daily. In the only other clinical report of potentiation-that of a single patient described by Barnett and Hancock ’-elevation of plasma-warfarin was observed suggesting inhibition of metabolism of the anticoagulant by co-trimoxazole. Our own observations, however, have shown a slight fall in plasma-warfarin levels in one patient and a marked fall in another.2 Hansen et al. have reported increased half-lives of phenytoin in 6 patients receiving co-trimoxazole; and other sulphonamides are known to inhibit drug metabolism in liver microsomes-for example, sulphaphenazole inhibits the metabolism of tolbutamideand phenytoin,S while sulphamethizole
inhibits the biotransformation of these two and also that of warfarin.6 Perhaps the same mechanism partly accounts for the interaction described above. Although we are unable at this stage to estimate the likely incidence, it is apparent that, whatever the mechanism, in some patients the concurrent administration of co-trimoxazole potentiates the effect of warfarin. We should like to thank our clinical colleagues for report details of patients under their care.
Departments of Pharmacy and Hæmatology, Queen Elizabeth Hospital, Birmingham B15 2TH.
allowing
to
the table. We wish
draw attention to the danger of the use of petrol since it contains appreciable amounts of benzene solvent, and up to 20% aromatic compounds. A similar risk may exist in other countries. Laboratory
J.
for
Hæmatology,
Department of Medical Research, Akademisch Ziekenhuis St Rafaël, 35, Capucijnenvoer, 3000 Leuven, Belgium and Section of Occupational Health, Department of Social Medicine, University of Leuven.
C. HASSALL C. L. FEETAM R. H. LFACH M.
to
as a
R. L. VERWILGHEN A. VAN DORPE H. VEULEMANS
us to
MEYNELL
DANGERS OF PETROL USED AS SOLVENT
SIR,-The hmmatological toxicity of benzene
is well known the reason for legislation proscribing its use as a solvent. The Belgian Factory Acts allow only products containing less than 0.25% benzene and 1% toluene and xylene to be used in industry. These regulations do not, however, apply to motor-car petrol. Lately we have seen two patients who appeared to have developed hæmatological symptoms after the use of petrol as a solvent.
and
the leucocyte count was increased (110 000/ mm), with a marked shift to the left. After some days, however, bone-marrow hypoplasia occurred and resulted in anasmia (8-8 gldl) and granulocytopema (700/mm’). The haematotogical picture reverted to normal within 4 weeks, without specific treatment.
was
The first patient, a welder, used petrol to clean the surface of trucks before repair. The petrol was bought daily from a nearby petrol station in a ierry-can. The patient developed a severe haemorrhagic syndrome due to profound thrombocytopenia. After treatment with corticosteroids the blood returned to normal within 3 weeks, and there was no recurrence of symptoms when the patient changed his occupation. The second patient is a drawer on steelplate. He used petrol, obtained from a local petrol station, to clean the iron sheets, His workbench was put in a small and poorly ventilated shed. Lately he had complained of vomiting, attributed to inhalation of the petrol fumes. On admission to hospital, chronic myeloid leukaemia was suspected: 1. Barnett, D. B., Hancock, B. W. Br med.J 1975, i, 608. 2. Hassall, C., Feetam, C. L., Leach, R. H., Meynell, M. J. ibid 1975, ii, 684 3 Hansen, J. M., Siersbaek-Nielsen, K., Skovsted, L., Kampmann, J P, Lumholtz, B. ibid. p. 684. 4. Christensen, L. K., Hansen, J. M., Kristensen, M. Lancet, 1963, ii, 1298. 5. Hansen, J. M., Kristensen, M., Skovsted, L., Christensen, I. K ibid. 1966,
ii, 265 6. Lumholtz, B., Siersbaek-Nielsen, K., Skovsted, L., Kampmann, J P., Hansen, J. M. Clin. Pharmac. Ther. 1975, 17, 731
ZINC AND
DIODOQUIN IN ACRODERMATITIS ENTEROPATHICA
SIR,—Dr Delves and his colleagues (Nov. 8, p. 9291 described the absorption and retention of zinc and other trace metals in a case of acrodermatitis enteropathica (A.E.) treated with ’Diodoquin’. Their suggestion that diodoquin might be acting as a zinc-transport agent by virtue of its metal-binding properties has already been made by us.’ Other workers have speculated that lack of zinc absorption might be the underlying defect in A.E.2 3However, the evidence offered by Dr Delves and his colleagues does not prove that intestinal zinc absorption is impaired, since no measurements were made in the untreated state. Comparison with mean values for absorption in healthy controls is not informative without a measure of the degree of scatter of these values. Available data suggest that the absorption of zinc from the intestines is highly variable.’-’ Using neutron-activation analysis in a case of A.F. we found that skin and hair samples taken before zinc therapy had normal zinc levels, yet serum-zinc levels were extremely low.’ In another untreated case of A.E. in this hospital, normal zinc levels were found in skin and hair as well as in serum.’ These findings indicate that the demonstration of low concentration of tissue zinc and/or subnormal serum-zinc levels is neither an absolute nor a diagnostic feature ofA.F. and should 1. 2 3
Portnoy, B., Molokhia, M. Br. J. Derm. 1974, 91, 701. E. J. Lancet, 1974, ii, 399. Lombeck, I , Schnippering, H. G., Ritzl, F., Fainendegen, I F. Bremer. II J ibid. 1975, i, 855. 4. Henkm, R. I., ibid. p. 1379. 5. Alexander, F. W., Clayton, B. E., Delves, H. T. Q. Jl. Med 1974, 43, 89 6. Portnoy, B , Molokhia, M., Br.J. Derm. (in the press). 7 Garretts, M., Molokhia, M Unpublished.
Moynahan,
