609
adjusted for decreased creatinine clearance.2 The toxicity in this patient took 7-14 days to resolve which is longer than penicillin neurotoxicity that usually resolves in 24-72 h in patients with renal failure.3 Of note is the development of neurotoxicity at c.s.F. levels of 120 fLg/ml which is probably not a neurotoxic concentration for carbenicillin.4 Since ticarcillin assays are not widely available, patients treated with ticarcillin with renal failure must be observed for early signs of neurotox-
icity. Infectious Disease and
Nephrology
Divisions,
Department of Medicine, Genesee Hospital, and University of Rochester School of Medicine, Rochester, N.Y. 14607, U.S.A.
MICHAEL C. KALLAY HECHMATOLLAH TABECHIAN GREGORY R. RILEY LAWRENCE N. CHESSIN
MUTAGENICITY OF METRONIDAZOLE
5tx,-Jr Hartley-Asp (reb. 3, p. 2/)) draws too sweeping conclusion from too little, and in some respects, irrelevant information. From peripheral-blood lymphocyte chromosome analysis after only 7 days’ treatment with metronidazole, it can not be concluded that "for all practical purposes we can regard metronidazole as a safe drug for short-term treatment". These are the reasons: (1) Twelve patients is too few; only gross effects would have been recognised as statistically significant. (2) The first step in the transformation of a normal cell to a malignant cell is widely believed to involve a mutation. The connection between mutation, which is a permanent heritable change in D.N.A. sequence (a molecular level change), and gross changes in chromosomal anatomy is not understood. Several mutagens do not cause chromosomal aberration, so chromosomal aberration is not a sine qua non for carcinogenesis. Correlation between carcinogenesis and clastogenesis is poor compared with the high correlation between carcinogenesis and a
mutagenesis. (3) There are approximately 2200 lymphocytes per ul of peri-
POTENTIATION OF COUMARIN EFFECT BY SULFINPYRAZONE
SIR,-Combination therapy with dipyridamole and warfarin has proved useful in reducing embolic complications in patients with prosthetic heart valves,’ and trials of the combination sulfinpyrazone plus warfarin have been suggested for the same purpose,2 though evidence in favour of this combination is lacking. Potentiation of warfarin action by sulfinpyrazone was predicted3 on the basis of its ability to displace coumarins from albumin-binding sites,4 and this prediction has been borne out in one case.5 We too have seen a patient with warfarin potentiation in response to the same regimen. A 51-year-old patient who had had aortic-valve replacement and triple coronary bypass was maintained on 45 mg warfarin per week. Prothrombin-time had been stable for 3 years, ranging between 24 and 28 s (control 13 s). After two transient cerebral ischaemic attacks, sulfinpyrazone 200 mg twice a day was added. 10 days later a prolonged prothrombin-time of 58 s was found, accompanied by mild gum bleeding. Warfarin was then reduced to 30 mg per week and the prothrombin-time returned to the therapeutic range. These two cases emphasise the need for careful prothrombin-time checks in patients taking sulfinpyrazone in combination with warfarin. Department of Medicine A, Chaim Sheba Medical Centre, Tel-Hashomer, Israel
MORDECHAI WEISS
COMPARISON OF INTRAVENOUS AND SUBCUTANEOUS INSULIN INFUSIONS IN MAN
SIR,-Dr Pickup and colleagues6 compared the blood-gluresponses of the subcutaneous (s.c.) and intravenous (i.v.) continuous insulin infusion in rats. They mentioned that such studies had not been done in man. cose
pheral blood of which about 200 are short-lived with an average life-span of 6 days and about 2000 are long-lived with an average life-span of a year. In the 7-day course of treatment given by Hartley-Asp only a very small proportion of the total population of cells examined will have been exposed at the reletime. These few cells will have been diluted with
much If one wants to find effects of short exposure one must examine those cells most likely to show these effects, and for the purpose in question bone-marrow would be relevant while peri-
vant
a
larger number of mature, genetically quiescent lymphocytes.
pheral lymphocytes are not. Peripheral lymphocytes in patients on long term (1-24 months) treatment with metronidazole have shown a significant increase in chromosomal abnormalities.’I the effect of a drug is being measured against a of background naturally occurring variability, there will be a point, as the dose of the drug is reduced, at which the frequency or size of the effect will lose its statistical significance. This is not the same as the drug being without effect at this dose. A few simple statistical calculations will quickly show that if the background "noise" is loud (as it is in this case), significance is lost at quite high levels of insult. Further when the relevant population is diluted with a larger non-affected random population the frequency of the effect must rise very substantially before statistical significance can be reached.
(4) When
Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, South Australia 5000
effect of i.v. and diabetics and four diabetics.
Hypoglycaemic
Parry; M. F., Neu, H. C. ibid. 1976, 133, 46 Bloomer, H. A., Barton, L. J., Mac dock, R. K. J. Am.
med. Ass.
1967, 200,
131. 4.
in three noninsulin infusion ’
JOHN R. COULTER
Richardson, A. E., James, K. W., Spittle, C. R., Robinson, O. P. grad. Med J. 1968, 44, 844. 1. Mitelman, F., Hartley-Asp, B., Ursing, B. Lancet, 1976, ii, 802
W. Post-
Sullivan, J. M., Harken, D. E., Jorlin, R.
New Engl. J. Med. 1971, 1391. 2. Weiss, H. J. ibid. 1978, 298, 1344. 3. Koch-Weser, J., Sellers, E. M. ibid. 1971, 284, 487. 4. Seiler, K., Duckert, F. Thromb. Diath. hœmorrh. 1968, 19, 389. 5. Davis, J. M., Johns, L. E., Jr. New Engl. J. Med. 1978, 299, 955. 6. Pickup, J. C , and others. Lancet, 1978, ii, 988.
1.
2 3.
s.c.
284,
adjusted for decreased creatinine clearance.2 The toxicity in this patient took 7-14 days to resolve which is longer than penicillin neurotoxicity that usually resolves in 24-72 h in patients with renal failure.3 Of note is the development of neurotoxicity at c.s.F. levels of 120 fLg/ml which is probably not a neurotoxic concentration for carbenicillin.4 Since ticarcillin assays are not widely available, patients treated with ticarcillin with renal failure must be observed for early signs of neurotox-
icity. Infectious Disease and
Nephrology
Divisions,
Department of Medicine, Genesee Hospital, and University of Rochester School of Medicine, Rochester, N.Y. 14607, U.S.A.
MICHAEL C. KALLAY HECHMATOLLAH TABECHIAN GREGORY R. RILEY LAWRENCE N. CHESSIN
MUTAGENICITY OF METRONIDAZOLE
5tx,-Jr Hartley-Asp (reb. 3, p. 2/)) draws too sweeping conclusion from too little, and in some respects, irrelevant information. From peripheral-blood lymphocyte chromosome analysis after only 7 days’ treatment with metronidazole, it can not be concluded that "for all practical purposes we can regard metronidazole as a safe drug for short-term treatment". These are the reasons: (1) Twelve patients is too few; only gross effects would have been recognised as statistically significant. (2) The first step in the transformation of a normal cell to a malignant cell is widely believed to involve a mutation. The connection between mutation, which is a permanent heritable change in D.N.A. sequence (a molecular level change), and gross changes in chromosomal anatomy is not understood. Several mutagens do not cause chromosomal aberration, so chromosomal aberration is not a sine qua non for carcinogenesis. Correlation between carcinogenesis and clastogenesis is poor compared with the high correlation between carcinogenesis and a
mutagenesis. (3) There are approximately 2200 lymphocytes per ul of peri-
POTENTIATION OF COUMARIN EFFECT BY SULFINPYRAZONE
SIR,-Combination therapy with dipyridamole and warfarin has proved useful in reducing embolic complications in patients with prosthetic heart valves,’ and trials of the combination sulfinpyrazone plus warfarin have been suggested for the same purpose,2 though evidence in favour of this combination is lacking. Potentiation of warfarin action by sulfinpyrazone was predicted3 on the basis of its ability to displace coumarins from albumin-binding sites,4 and this prediction has been borne out in one case.5 We too have seen a patient with warfarin potentiation in response to the same regimen. A 51-year-old patient who had had aortic-valve replacement and triple coronary bypass was maintained on 45 mg warfarin per week. Prothrombin-time had been stable for 3 years, ranging between 24 and 28 s (control 13 s). After two transient cerebral ischaemic attacks, sulfinpyrazone 200 mg twice a day was added. 10 days later a prolonged prothrombin-time of 58 s was found, accompanied by mild gum bleeding. Warfarin was then reduced to 30 mg per week and the prothrombin-time returned to the therapeutic range. These two cases emphasise the need for careful prothrombin-time checks in patients taking sulfinpyrazone in combination with warfarin. Department of Medicine A, Chaim Sheba Medical Centre, Tel-Hashomer, Israel
MORDECHAI WEISS
COMPARISON OF INTRAVENOUS AND SUBCUTANEOUS INSULIN INFUSIONS IN MAN
SIR,-Dr Pickup and colleagues6 compared the blood-gluresponses of the subcutaneous (s.c.) and intravenous (i.v.) continuous insulin infusion in rats. They mentioned that such studies had not been done in man. cose
pheral blood of which about 200 are short-lived with an average life-span of 6 days and about 2000 are long-lived with an average life-span of a year. In the 7-day course of treatment given by Hartley-Asp only a very small proportion of the total population of cells examined will have been exposed at the reletime. These few cells will have been diluted with
much If one wants to find effects of short exposure one must examine those cells most likely to show these effects, and for the purpose in question bone-marrow would be relevant while peri-
vant
a
larger number of mature, genetically quiescent lymphocytes.
pheral lymphocytes are not. Peripheral lymphocytes in patients on long term (1-24 months) treatment with metronidazole have shown a significant increase in chromosomal abnormalities.’I the effect of a drug is being measured against a of background naturally occurring variability, there will be a point, as the dose of the drug is reduced, at which the frequency or size of the effect will lose its statistical significance. This is not the same as the drug being without effect at this dose. A few simple statistical calculations will quickly show that if the background "noise" is loud (as it is in this case), significance is lost at quite high levels of insult. Further when the relevant population is diluted with a larger non-affected random population the frequency of the effect must rise very substantially before statistical significance can be reached.
(4) When
Division of Tissue Pathology, Institute of Medical and Veterinary Science, Adelaide, South Australia 5000
effect of i.v. and diabetics and four diabetics.
Hypoglycaemic
Parry; M. F., Neu, H. C. ibid. 1976, 133, 46 Bloomer, H. A., Barton, L. J., Mac dock, R. K. J. Am.
med. Ass.
1967, 200,
131. 4.
in three noninsulin infusion ’
JOHN R. COULTER
Richardson, A. E., James, K. W., Spittle, C. R., Robinson, O. P. grad. Med J. 1968, 44, 844. 1. Mitelman, F., Hartley-Asp, B., Ursing, B. Lancet, 1976, ii, 802
W. Post-
Sullivan, J. M., Harken, D. E., Jorlin, R.
New Engl. J. Med. 1971, 1391. 2. Weiss, H. J. ibid. 1978, 298, 1344. 3. Koch-Weser, J., Sellers, E. M. ibid. 1971, 284, 487. 4. Seiler, K., Duckert, F. Thromb. Diath. hœmorrh. 1968, 19, 389. 5. Davis, J. M., Johns, L. E., Jr. New Engl. J. Med. 1978, 299, 955. 6. Pickup, J. C , and others. Lancet, 1978, ii, 988.
1.
2 3.
s.c.
284,
