688 VARICOSE VEINS IN DEVELOPING COUNTRIES
SIR,—Iagree with Mr Hobbs (July 31, p. 259) that straining stool for a short while once a day, or lacking bran, perhaps only twice a week, is not very likely to play any major part in bringing about the valvular incompetence which is such a regular feature of varicose venous insufficiency. My support for Mr Hobbs’ hypothesis of some change in the supporting tissues derives from the observation throughout my surgical career of the almost consistent relationship of pes planus, often with valgus heels and acrocyanosis, with varicose veins in women. In men it does not seem to be so. If fibre lack can be thought to cause flat feet then I for one will be made happy, because, like most working surgeons, I believe we do good when we encourage patients to adopt the bran regimen, and any such collateral benefits as freedom from flat feet and varicose veins would be wonderful to achieve. at
4 Upper Harley Street, London NW1 4PN
ised and given as the average for all three dose levels. As the table shows, at 250 times the human dose (10 mg/kg) of cyproterone acetate-i.e., the dose most comparable to the highest dose of progestagens used in the C.S.M. study-no tumours occurred, and then appeared only after 1250 (50 mg/kg, and 6250 (250 mg/kg) times the human contraceptive dose. These data suggest that the increase in liver adenomas in the rat after high doses of progestagens is related to the dose level used rather than the chemical nature of the compound and that in this respect cyproterone acetate is not unique among progestagens. Department of Experimental Toxicology, Schering AG.,
J. SCHUPPLER
D-1000 Berlin 65
P. GÜNZEL
H. H. G. EASTCOTT
DIAGNOSIS OF PYOGENIC MENINGITIS
SIR,-Dr Mandal (July 17, p. 147) asks for evidence of the CYPROTERONE ACETATE a paper by Neuyou say that whereas there is no evidence that cyproterone acetate causes liver damage in man, rats injected with large doses of the drug developed hepatomas. We think this statement may give the impression that cyproterone acetate is unique in this way. We should therefore like to record the results of our evaluation of material published by the Committee on Safety of Medicines3 and our own toxicology studies in the rat. In the C.S.M. study rats were given the progestagen component of various oral contraceptives over a period of 2 yr at doses equivalent to 2-5, 30-150, and 200-400 times the human dose. In our studies 10, 50, and 250 mg/kg/day of cyproterone
SIR,—In your editorial,’ in whicn you cite
mann
and
Graf,2
given for 78 wk—equivalent to 250, 1250, and 6250 times the human oral-contraceptive dose (0-04 mg/kg) or 5, 25, and 125 times the human dose used in treatment of hypersexual states (2 mg/kg) without taking into account the fact that the compound accumulates at these dose levels in the rat. In all the studies the progestagens were mixed into the feed. The incidence of benign hepatomas is shown in the table. Unfortunately, in the C.S.M. report3 the incidence is summar-
acetate were
1. Lancet, 1976, i, 1003. 2. Neumann, F., Gräf, K. J. J. int. med. Res. 1975, 3, suppl. 4, p. 1. 3. Carcinogenicity Tests of Oral Contraceptives. Report by the Committee Safety of Medicines. H.M. Stationery Office, 1972.
superiority of countercurrent immunoelectrophoresis (c.t.E.) bacteriological culture in establishing a bacteriological diagnosis in patients with partially treated pyogenic meningitis. We have evidence to suggest that this is so.’ 10 of 129 patients with group-A meningococcal meningitis admitted to our hospital had an adequately documented history of chemotherapy before admission (long-acting sulphonamides in 5 and intramuscular penicillin in 5). Antigen was detected in the cerebrospinal fluid (c.s.F.) of 6 of these patients by C.I.E. but culture was positive in only 1. The effects of hospital treatment with full doses of penicillin (500 000 I.U./kg/24 h) or chloramphenicol (100 mg/kg/24 h) on bacteriological findings in the c.s.F. were studied in 21 patients whose c.s.F. was initially positive for group-A meningococci by culture and by C.I.E. 24 h after the start of treatment antigen was detected in the c.s.F. of 13 patients whilst culture was negative in all. 48 h after the start of treatment antigen was detected in 4 of 14 samples, but only 1 positive culture was obtained. Antigen persists in the c.s.F. of patients with pneumococcal meningitis for even longer.2 Antigen was found in the c.s.F. of 8 of 10 patients 3 days after the start of treatment with large doses of penicillin and in 4 of 8 patients 6 days after the start
over
on
Culture was not carried out on all these serial in but samples pneumococcal meningitis we have rarely found viable bacteria after 3 days of treatment. Our experience thus suggests that c.i.E. is more sensitive than culture in making a diagnosis in patients with partially
of
treatment.
1. Whittle, H. C., and others Am. J. Med. 1975, 58, 823. 2. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. Jl
Med. (in the press).
INCIDENCE OF BENIGN HEPATOMA IN PROGESTAGEN-TREATED RAT
*C.S.M.
studv.3
tested. In the C.S.M. study contraceptive dose.
N.T.not
ethynodiol diacetate, norgestrel, and lyncestrenol showed no increase of benign hepatomas up to 200-400 times the hum3n
SIR,—Iagree with Mr Hobbs (July 31, p. 259) that straining stool for a short while once a day, or lacking bran, perhaps only twice a week, is not very likely to play any major part in bringing about the valvular incompetence which is such a regular feature of varicose venous insufficiency. My support for Mr Hobbs’ hypothesis of some change in the supporting tissues derives from the observation throughout my surgical career of the almost consistent relationship of pes planus, often with valgus heels and acrocyanosis, with varicose veins in women. In men it does not seem to be so. If fibre lack can be thought to cause flat feet then I for one will be made happy, because, like most working surgeons, I believe we do good when we encourage patients to adopt the bran regimen, and any such collateral benefits as freedom from flat feet and varicose veins would be wonderful to achieve. at
4 Upper Harley Street, London NW1 4PN
ised and given as the average for all three dose levels. As the table shows, at 250 times the human dose (10 mg/kg) of cyproterone acetate-i.e., the dose most comparable to the highest dose of progestagens used in the C.S.M. study-no tumours occurred, and then appeared only after 1250 (50 mg/kg, and 6250 (250 mg/kg) times the human contraceptive dose. These data suggest that the increase in liver adenomas in the rat after high doses of progestagens is related to the dose level used rather than the chemical nature of the compound and that in this respect cyproterone acetate is not unique among progestagens. Department of Experimental Toxicology, Schering AG.,
J. SCHUPPLER
D-1000 Berlin 65
P. GÜNZEL
H. H. G. EASTCOTT
DIAGNOSIS OF PYOGENIC MENINGITIS
SIR,-Dr Mandal (July 17, p. 147) asks for evidence of the CYPROTERONE ACETATE a paper by Neuyou say that whereas there is no evidence that cyproterone acetate causes liver damage in man, rats injected with large doses of the drug developed hepatomas. We think this statement may give the impression that cyproterone acetate is unique in this way. We should therefore like to record the results of our evaluation of material published by the Committee on Safety of Medicines3 and our own toxicology studies in the rat. In the C.S.M. study rats were given the progestagen component of various oral contraceptives over a period of 2 yr at doses equivalent to 2-5, 30-150, and 200-400 times the human dose. In our studies 10, 50, and 250 mg/kg/day of cyproterone
SIR,—In your editorial,’ in whicn you cite
mann
and
Graf,2
given for 78 wk—equivalent to 250, 1250, and 6250 times the human oral-contraceptive dose (0-04 mg/kg) or 5, 25, and 125 times the human dose used in treatment of hypersexual states (2 mg/kg) without taking into account the fact that the compound accumulates at these dose levels in the rat. In all the studies the progestagens were mixed into the feed. The incidence of benign hepatomas is shown in the table. Unfortunately, in the C.S.M. report3 the incidence is summar-
acetate were
1. Lancet, 1976, i, 1003. 2. Neumann, F., Gräf, K. J. J. int. med. Res. 1975, 3, suppl. 4, p. 1. 3. Carcinogenicity Tests of Oral Contraceptives. Report by the Committee Safety of Medicines. H.M. Stationery Office, 1972.
superiority of countercurrent immunoelectrophoresis (c.t.E.) bacteriological culture in establishing a bacteriological diagnosis in patients with partially treated pyogenic meningitis. We have evidence to suggest that this is so.’ 10 of 129 patients with group-A meningococcal meningitis admitted to our hospital had an adequately documented history of chemotherapy before admission (long-acting sulphonamides in 5 and intramuscular penicillin in 5). Antigen was detected in the cerebrospinal fluid (c.s.F.) of 6 of these patients by C.I.E. but culture was positive in only 1. The effects of hospital treatment with full doses of penicillin (500 000 I.U./kg/24 h) or chloramphenicol (100 mg/kg/24 h) on bacteriological findings in the c.s.F. were studied in 21 patients whose c.s.F. was initially positive for group-A meningococci by culture and by C.I.E. 24 h after the start of treatment antigen was detected in the c.s.F. of 13 patients whilst culture was negative in all. 48 h after the start of treatment antigen was detected in 4 of 14 samples, but only 1 positive culture was obtained. Antigen persists in the c.s.F. of patients with pneumococcal meningitis for even longer.2 Antigen was found in the c.s.F. of 8 of 10 patients 3 days after the start of treatment with large doses of penicillin and in 4 of 8 patients 6 days after the start
over
on
Culture was not carried out on all these serial in but samples pneumococcal meningitis we have rarely found viable bacteria after 3 days of treatment. Our experience thus suggests that c.i.E. is more sensitive than culture in making a diagnosis in patients with partially
of
treatment.
1. Whittle, H. C., and others Am. J. Med. 1975, 58, 823. 2. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. Jl
Med. (in the press).
INCIDENCE OF BENIGN HEPATOMA IN PROGESTAGEN-TREATED RAT
*C.S.M.
studv.3
tested. In the C.S.M. study contraceptive dose.
N.T.not
ethynodiol diacetate, norgestrel, and lyncestrenol showed no increase of benign hepatomas up to 200-400 times the hum3n
