981 a rise after treatment. This pattern has been Carlson et al.,5 and it could be potentially harmful. from the point of view of atherogenesis. Unlike Carlson et al., we found no rise in H.D.L. cholesterol after treatment for hypertriglyceridæmia. Six out of eight patients showed a decrease in H.D.L. cholesterol; the only one to show an increase had little reduction in serum-triglyceride. This finding is surprising in view of the reported inverse relationship between V.L.D.L. triglyceride and H.D.L. cholesterol concentrations.6 More studies are required to monitor the changes in lipoprotein composition during treatment of hypertriglyceridxmia. Treatment aimed both at reducing serum-triglyceride and at increasing H.D.L. cholesterol would seem a desirable objective.
mmol;1 showed
reported by
I thank Miss J. Wu and Ms J. Hambley for their help. This work done at Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex. St. Mary’s Hospital, London W2 1NY
R. S. ELKELES
MUTAGENICITY OF METRONIDAZOLE
lished). Coulter states that data from peripheral lymphocytes are irrelevant because the exposure time was short. Does this mean that the extensive data accumulated from acute whole-body and local radiotherapy on aberration yields in peripheral lymphocytes are also irrelevant? The fear that "only gross effects would have been recognised as statistically significant" is unwarranted : admittedly "only" 12 patients were studied but 1200 cells were analysed in each group-i.e., 3600 cells2-a population large enough for observations of statistical significance. However, the question of bone-marrow effects has not been ignored. Because bone-marrow samples are ethically unobtainable without a relevant indication, I investigated bonemarrow in mice for clastogenic activity. One advantage is that extremely high non-therapeutic doses can be given and as the background "noise"-i.e., control level in the micronucleus test-is very low, any loss of significance at low doses is eliminated. A dose range of 10-4000 mg/kg metronidazole did not have any clastogenic effect. Thus my statement, from the point of view of probability, does appear to hold water. It may be added that preliminary results from an epidemiological study in progress at the Mayo Clinic, U.S.A. on patients who received metronidazole for vaginal trichomoniasis from 1960 to 1969, do not indicate an increase in total cancer incidence over that expected for a normal population.4 Akuebolaget
Leo Research
Laboratories,
BERYL HARTLEY-ASP
5. Carlson, L A., Olsson, A. G., Ballantyne, D. Atherosclerosis, 1977, 6 Miller, G J, Miller, N. E. Lancet, 1975, i, 16. 1 Bost, R. G Metronidazole edited by S. Finegold); p. 126 1977. 2 Hartley-Asp, B. Tox. Letters (in the press). 3 Hartley-Asp, B. Mut. Res. (in the press). 4 J Am med Ass 1978, 239, 1371
SIR,-I read the report from Dr Kallay and his colleagues (March 17, p. 608) with concern since their letter implies, without evidence, that ticarcillin might be more neurotoxic than carbenicillin. Since Kallay et al. refer to our work on the
ticarcillin,1,2
human pharmacology of several comments seem to be in order. The dose of 8 g ticarcillin per day in an individual with the degree of renal failure noted was excessive since 2 g every 12 h is the recommended dose. A serum level of 850 ug/ml 12 h after a 2 g dose is also most unusual since that amount of drug usually produces concentrations below 100 ug/ml. In none of our studies could we achieve such a level except after a bolus injection of 500 mg/kg. The half-life of the drug is, at most, 15 h in the presence of renal failure, and the drug is removed by haemodialysis. Thus it is unclear what was happening in Kallay’s patient since neurotoxicity rapidly clears with withdrawal of penicillin. If a patient on thrice-weekly dialysis is receiving only 2 g ticarcillin every 8 h and does not have hepatic insufficiency, it is impossible to achieve a level of 850 µg/ml 12 h after a dose
of 2 g.
SIR,--Dr Coulter (March 17, p. 609) criticises my conclusion that "for all practical purposes we can regard metronidazole as a safe drug for short-term treatment" (Feb. 3, p. 275) on the grounds that it was based only on the findings in human peripheral lymphocytes after a 7-day treatment. This is not the case, as is apparent from my letter. The statement is based upon data from experiments in vivo in animals and in human cells in vitro covering mutagenic, D.N.A. repair, and clastogenic effects. The dominant lethal test in mice and rats was negative (ref. 1 and L. John and others, unpublished), no increase in unscheduled D.N.A. repair was found either in human lymphocytes or fibroblasts (ref. 1 and B. Lambert, unpublished) nor was any increase found in the level of sister chromatid exchanges or chromosomal aberrations on in vitro treatment with metronidazole and its metabolites (Lambert, unpub-
S-251 00 Helsingborg, Sweden
NEUROTOXICITY OF TICARCILLIN
26, 603.
particular issue with the statement that patients should be watched for early signs of neuroticarcillin receiving toxicity. We have treated seven patients with ticarcillin who had combined renal and hepatic failure and we have never encountered neurotoxicity. All penicillins should be used with caution in a patient with renal failure since we have encountered neurotoxicity even with oxacillin, a highly protein-bound agent. I take
Division of Infectious
Diseases, Department of Medicine, College of Physicians and Surgeons of Columbia University, York, N.Y. 10032, U S A.
HAROLD C. NEU
New
AMIODARONE, METOCLOPRAMIDE, AND RENAL FAILURE
SIR,-Like Dr Bateman and Dr Davies (Jan. 20, p. 166) we have observed an increased incidence of extrapyramidal problems in patients with severe chronic renal failure who were taking metoclopramide. Dr Caralps (March 10, p. 554) reports the disappearance of the extrapyramidal response to metoclopramide after successful renal transplantation in a patient who had reacted to this drug when in chronic renal failure. This case supports the conclusion that the extrapyramidal sideeffects are related to the accumulation of the drug in patients in chronic renal failure who are sensitive to metoclopramide. A uraemic patient under our care had an extrapyramidal syndrome of dystonic type after administration of metoclopramide for her vomiting (glomerular filtration-rate around 10 ml/min). She responded in the same way to amiodarone given for angina pectoris several months later, the glomerular filtration-rate remaining stable. fhe syndrome was reproducible and its intensity was proportional to dosage. The extrapyramidal manifestations were reproduced a second and third time after low doses of amiodarone (100 mg/day), developing on day 5 and day 6, respectively. The syndrome had gone completely 24--48 h after discontinuation of treatment. You comment in your editorial of March 11 *)92) on corneal deposits as a possible complication of amiodarone therapy. Other side-effects, such as bradycardia, arthralgia, allergic reactions, have also been described,3 but extrapyramidal symptoms have not previously been recorded. Since this drug is often given to urxmic patients with cardiac disturbances, we 1 Parry, M. F., Neu, H C.J infect Dis 1976, 134, 476 2 Parry, M.F., Neu, H C ibid 1976, 133, 46 3 Wade, A editor The Extra Pharmacopœia, p 1641. London, 1977
mmol;1 showed
reported by
I thank Miss J. Wu and Ms J. Hambley for their help. This work done at Northwick Park Hospital and Clinical Research Centre, Harrow, Middlesex. St. Mary’s Hospital, London W2 1NY
R. S. ELKELES
MUTAGENICITY OF METRONIDAZOLE
lished). Coulter states that data from peripheral lymphocytes are irrelevant because the exposure time was short. Does this mean that the extensive data accumulated from acute whole-body and local radiotherapy on aberration yields in peripheral lymphocytes are also irrelevant? The fear that "only gross effects would have been recognised as statistically significant" is unwarranted : admittedly "only" 12 patients were studied but 1200 cells were analysed in each group-i.e., 3600 cells2-a population large enough for observations of statistical significance. However, the question of bone-marrow effects has not been ignored. Because bone-marrow samples are ethically unobtainable without a relevant indication, I investigated bonemarrow in mice for clastogenic activity. One advantage is that extremely high non-therapeutic doses can be given and as the background "noise"-i.e., control level in the micronucleus test-is very low, any loss of significance at low doses is eliminated. A dose range of 10-4000 mg/kg metronidazole did not have any clastogenic effect. Thus my statement, from the point of view of probability, does appear to hold water. It may be added that preliminary results from an epidemiological study in progress at the Mayo Clinic, U.S.A. on patients who received metronidazole for vaginal trichomoniasis from 1960 to 1969, do not indicate an increase in total cancer incidence over that expected for a normal population.4 Akuebolaget
Leo Research
Laboratories,
BERYL HARTLEY-ASP
5. Carlson, L A., Olsson, A. G., Ballantyne, D. Atherosclerosis, 1977, 6 Miller, G J, Miller, N. E. Lancet, 1975, i, 16. 1 Bost, R. G Metronidazole edited by S. Finegold); p. 126 1977. 2 Hartley-Asp, B. Tox. Letters (in the press). 3 Hartley-Asp, B. Mut. Res. (in the press). 4 J Am med Ass 1978, 239, 1371
SIR,-I read the report from Dr Kallay and his colleagues (March 17, p. 608) with concern since their letter implies, without evidence, that ticarcillin might be more neurotoxic than carbenicillin. Since Kallay et al. refer to our work on the
ticarcillin,1,2
human pharmacology of several comments seem to be in order. The dose of 8 g ticarcillin per day in an individual with the degree of renal failure noted was excessive since 2 g every 12 h is the recommended dose. A serum level of 850 ug/ml 12 h after a 2 g dose is also most unusual since that amount of drug usually produces concentrations below 100 ug/ml. In none of our studies could we achieve such a level except after a bolus injection of 500 mg/kg. The half-life of the drug is, at most, 15 h in the presence of renal failure, and the drug is removed by haemodialysis. Thus it is unclear what was happening in Kallay’s patient since neurotoxicity rapidly clears with withdrawal of penicillin. If a patient on thrice-weekly dialysis is receiving only 2 g ticarcillin every 8 h and does not have hepatic insufficiency, it is impossible to achieve a level of 850 µg/ml 12 h after a dose
of 2 g.
SIR,--Dr Coulter (March 17, p. 609) criticises my conclusion that "for all practical purposes we can regard metronidazole as a safe drug for short-term treatment" (Feb. 3, p. 275) on the grounds that it was based only on the findings in human peripheral lymphocytes after a 7-day treatment. This is not the case, as is apparent from my letter. The statement is based upon data from experiments in vivo in animals and in human cells in vitro covering mutagenic, D.N.A. repair, and clastogenic effects. The dominant lethal test in mice and rats was negative (ref. 1 and L. John and others, unpublished), no increase in unscheduled D.N.A. repair was found either in human lymphocytes or fibroblasts (ref. 1 and B. Lambert, unpublished) nor was any increase found in the level of sister chromatid exchanges or chromosomal aberrations on in vitro treatment with metronidazole and its metabolites (Lambert, unpub-
S-251 00 Helsingborg, Sweden
NEUROTOXICITY OF TICARCILLIN
26, 603.
particular issue with the statement that patients should be watched for early signs of neuroticarcillin receiving toxicity. We have treated seven patients with ticarcillin who had combined renal and hepatic failure and we have never encountered neurotoxicity. All penicillins should be used with caution in a patient with renal failure since we have encountered neurotoxicity even with oxacillin, a highly protein-bound agent. I take
Division of Infectious
Diseases, Department of Medicine, College of Physicians and Surgeons of Columbia University, York, N.Y. 10032, U S A.
HAROLD C. NEU
New
AMIODARONE, METOCLOPRAMIDE, AND RENAL FAILURE
SIR,-Like Dr Bateman and Dr Davies (Jan. 20, p. 166) we have observed an increased incidence of extrapyramidal problems in patients with severe chronic renal failure who were taking metoclopramide. Dr Caralps (March 10, p. 554) reports the disappearance of the extrapyramidal response to metoclopramide after successful renal transplantation in a patient who had reacted to this drug when in chronic renal failure. This case supports the conclusion that the extrapyramidal sideeffects are related to the accumulation of the drug in patients in chronic renal failure who are sensitive to metoclopramide. A uraemic patient under our care had an extrapyramidal syndrome of dystonic type after administration of metoclopramide for her vomiting (glomerular filtration-rate around 10 ml/min). She responded in the same way to amiodarone given for angina pectoris several months later, the glomerular filtration-rate remaining stable. fhe syndrome was reproducible and its intensity was proportional to dosage. The extrapyramidal manifestations were reproduced a second and third time after low doses of amiodarone (100 mg/day), developing on day 5 and day 6, respectively. The syndrome had gone completely 24--48 h after discontinuation of treatment. You comment in your editorial of March 11 *)92) on corneal deposits as a possible complication of amiodarone therapy. Other side-effects, such as bradycardia, arthralgia, allergic reactions, have also been described,3 but extrapyramidal symptoms have not previously been recorded. Since this drug is often given to urxmic patients with cardiac disturbances, we 1 Parry, M. F., Neu, H C.J infect Dis 1976, 134, 476 2 Parry, M.F., Neu, H C ibid 1976, 133, 46 3 Wade, A editor The Extra Pharmacopœia, p 1641. London, 1977
