1427 CHILD POISONING AND TABLET CONTAINERS Gartside’s observation that a rapid increase in SIR,-Dr admissions of children for suspected poisonings in England and Wales corresponded to the change from standard screw-capped tablet bottles to bottles with easily pulled off caps (April 26, p. 886) should lead to changes in the packaging practices of pharmacists and pharmaceutical Dr Gartside’s conclusion, however, is manufacturers. unfortunate. He wrote: An investigation to determine whether suspected poisoning is associated with any particular type of container would be of great value, but it must be carried out rapidly before the picture is changed by the introduction of child-resistant containers, a ’technological advance’ which may be unnecessary." One could hardly hope for a more convincing investigation than the " cessation experiment " in the United States. As Barry observed, the number of childhood poisonings reported annually with " baby aspirin " (paEdiatric dosage tablets marketed for children in special flavours, colours, and containers) decreased dramatically after the voluntary adoption, by manufacturers, of bottles with safety closures for the dispensing of these products.l During the same time period, the annual number of reported poisonings "
striking that population-based rates and uniform definitions unnecessary in order to conclude that safety closures are advantageous. Gartside apparently doubts that safety closures are a technological advance, but he does not suggest that their use be delayed until appropriate investigations have been completed. The success of safety closures in the United States would render such a delay comparable to withholding antibiotics from a patient with meningitis pending results of culture and sensitivity studies. When the patient’s life may be at stake it is usually necessary to act on the basis of whatever information is readily available. are
Department of Psychiatry and Sciences, and Division of Forensic Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, U.S.A.
PARK ELLIOTT DIETZ.
HERPESVIRUS INFECTION AND CANCER SIR,—Dr Matas and his colleagues (June 7, p. 1277) suggest that the pathogenesis of lymphoproliferative tumours in transplant patients involves the reactivation of latent oncogenic herpesvirus. They suggest that seroepidemiological studies documenting an association of cancer and herpesvirus infections would be helpful in supporting their hypothesis. In a series of 100 patients with bronchial carcinoma we found that significantly fewer (21 out of 100) gave a history of recurrent labial herpes simplex than a control group (42 out of 100); the range of serum complement-fixing antibody titres to herpes simplex was similar in case and controls. From these findings we suggested that clinical recurrent infection might provide specific or non-specific protection against bronchial carcinoma.i These results seem to contradict the hypothesis of Dr Matas and his colleagues. However, it seems possible that, although previous recurrent herpes-simplex infection may provide some immunological protection against the development of bronchial carcinoma, the use of immunosuppressive agents in transplant patients may encourage the
oncogenic potential of latent herpesviruses. ------
Microbiology Laboratory, Ayrshire Central Hospital,
"Analgesics" England and Wales "Baby Aspirin" United States "Unspecified Aspirin" United States
"Adutt Aspirin" United States suspected poisonings among children under 5
Irvine KA12 8SS.
CONSTANCE A. C. Ross.
A
Number of of age.
PLASMA IRON AND IRON-BINDING CAPACITY Eastham SIR,— Dr (May 10, p. 1090) quotes average
years
Data from
England and Wales based on estimated hospital and data from United States based on reports to Poison Control Centers.2,3 admissions;
from unspecified types of aspirin also decreased, while that from " adult aspirin " remained stable (see accompanying
figure). Although Gartside emphasises poisonings with prescription medicines, the data he presents from England and Wales also show an increase in poisonings with analgesics (predominantly aspirin) following the change to bottles with easily pulled off caps (see figure). Assuming no important change in reporting practices or data collection, the differences between trends for aspirin poisoning in children in the United States and the trend for analgesic poisoning in children in England and Wales is sufficiently "
"
1. Barry, P. Z. Prev. Med. 1975, 4, 47. 2. U.S. Department of Health, Education and Welfare. National Clearinghouse for Poison Control Centers Bulletin, 1972, September-October. 3. Ibid. 1974. May-June.
coefficients of variation for the estimation of plasma iron and iron-binding capacities which have been taken from nationally used quality-control schemes and suggests, obtained for these estimations may therefore, that results be equivocal-i.e., " 95% of results obtained on a sample containing 300 µg. per 100 ml. (of iron-binding capacity) would fall in the range 200-400 µg. per 100 ml.". However, it is quite inappropriate to assume that, in any one department, the precision of these estimations is necessarily related to the precision obtained from results from as many as 300-400 different departments. Results obtained from a particular laboratory must always be related to the reference range of that laboratory and be interpreted in the context of the precision of the method in use. The precision obtained in many laboratories (e.g., by Dr Price and Dr Obeid) (May 17, p. 1140) is considerably better than might be inferred from Dr Eastham’s letter. Results from several laboratories which participate in a 1.
Ross, C. A. C., Tyrrell, W. F. Lancet, 1974, i, 871.
1428
quality-control scheme give the following ranges for coefficient of variation: plasma-iron 0.9%—7.7% (from 19 laboratories, 17 gave results of less than 4%); plasmairon-binding capacity 2.1%—6.6% (from 12 laboratories). With careful organisation of existing resources it is unlikely that in many departments the inclusion of plasma iron and iron-binding capacity estimations will require extra staff or sophisticated equipment. Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 2XU.
SHIRLEY M. STEIN.
but after 3 months the plasma-urea remains at 60 mg. per 100 ml. with a creatinine clearance of 14 ml. per minute and the plasma-bicarbonate is 12 meq. per litre. It is clearly important that patients should not be restarted on rifampicin therapy after a lapse without careful consideration. Although renal side-effects have so far only been described with intermittent therapy, there should perhaps be an awareness of the possibility of these complications occurring with continuous treatment.
anuria,
M. COCHRAN P. J. MOORHEAD M. PLATTS.
Renal Unit,
Royal Hospital, Sheffield S1 3SR.
PERMANENT RENAL DAMAGE WITH RIFAMPICIN
SIR,-Acute renal failure has been associated with intermittent rifampicin therapy, or re-introduction of the drug.1-4 In two cases 1,2 circulating antibodies to rifampicin were found. These patients had an attack of vomiting, diarrhoea, malaise, and rigors 1-4 hours after ingestion of the drug. Anuria then followed and maintenance dialysis was usually required, but full recovery was the rule. Renal biopsies 2-4 showed acute tubular necrosis with normal vasculature and glomeruli and there was no evidence of immune complex deposition. We report here two further cases, one with permanent renal damage. A 59-year-old woman was receiving P.A.s., isoniazid, and rifampicin 3 days per week for abdominal tuberculosis. After 9 months the patient developed nausea and occasional diarrhoea. The drugs were stopped but were given again 1 month later. 2 hours after taking rifampicin the patient had mid-abdominal pain, vomiting, rigors, and malaise. After 5 days she became anuric. On admission to hospital there was palmar erythema and upper abdominal tenderness but no other abnormalities. Plasma-urea was 242 mg. per 100 ml. Liver enzymes were slightly raised; a liver biopsy was normal. Renal biopsy showed acute tubular necrosis with C’3 identifiable in the region of the necrotic cells. No bound immunoglobulin or fibrin was seen. There was no direct fluorescence attributable to rifampicin. Plasma-C’3was reduced (43 mg. per 100 ml.). No circulating antibodies to rifampicin were found using the indirect antiglobulin technique. The patient was managed on hxmodialysis until diuresis after 10 days, and full recovery followed. At follow-up, the plasma-urea was 28 mg. per 100 ml. A 42-year-old woman was receiving isoniazid and rifampicin for pulmonary tuberculosis. She took the drugs irregularly. Nonetheless her health improved and X-ray appearances resolved. Her plasma-urea was 9 mg. per 100 ml. After taking no drugs for about 9 months, oral therapy was again prescribed. 30 minutes after ingestion of rifampicin she developed mid-abdominal pain and vomited. She later passed three loose stools. There was severe malaise but no rigors. 4 hours after taking the drug there was pain and slight swelling of the left ankle, with discoloration of the skin. On admission to hospital, there was mild jaundice, oral herpes, and an area of cutaneous vasculitis over the left ankle. She was anuric. Plasmaurea was 128 mg. per 100 ml., bilirubin 53 mg. per 100 ml. with all liver enzymes raised. A test for hepatitis-B antigen There was no evidence of disseminated was negative. intravascular coagulation. Liver biopsy was normal. Two renal biopsies showed severe cortical necrosis. Circulating rifampicin antibodies could not be detected. Plasma C/g 3 and C’ levels were normal. Management by peritoneal dialysis was followed by production of urine after 3 weeks’ Poole, G., Stradling, P., Worlledge, S. Br. med. J. 1970, iii, 343. Kleinknecht, D., Homberg, J. C., Decroix, G. Lancet, 1972, i, 1238. 3. Cordonnier, D., Muller, J. M. ibid. 1972, ii, 1364. 4. Ramgopal, V., Leonard, C., Bhathena, D. ibid. 1973, i, 1195. 1. 2.
BREAST CANCER ASSOCIATED WITH ADMINISTRATION OF SPIRONOLACTONE
SIR,-We have become concerned by the observation practice of 5 women in whom breast carcinoma developed during or after the prolonged administration of spironolactone. While we recognise, of course, the likelihood that this association may be purely coincidental, we feel it imperative to report the observation.
in a medical
Case 1.—An 81-year-old woman with arteriosclerotic heartdisease and nephropathy receivedAldactazide’ (25 mg.
spironolactone plus 25 mg. hydrochlorothiazide) three times daily for four months. She was later givenDyazide’ (50 mg. She had triamterene plus 25 mg. hydrochlorothiazide). received no oestrogen therapy. Digoxin had been given for a long period, but it was stopped before the administration of aldactazide. One year later, she was found to have an inflammatory carcinoma of the left breast, which was resected. Histological examination showed an infiltrating duct carcinoma with fibrosis, extensive lymphatic invasion, and metastases to most of the axillary nodes. Extensive metastases of the pleura and thoracic wall and an inflammatory carcinoma of the right breast later developed. Case 2.-A 65-year-old White female Government worker had taken aldactazide for two years for hypertension and chronic leg cedema. She had previously received oestrogens (’ Premarin’) which had been discontinued sixteen months before the appearance of a bloody nipple discharge. Biopsy and subsequent breast resection established a diagnosis of well-differentiated, infiltrating, duct carcinoma with skin and lymphatic invasion, and metastases to 4 of 11 axillary nodes. Case 3.-A 47-year-old White housewife with a history of thyrotoxicosis had received aldactazide three times weekly for sixteen months because of idiopathic cedema. She was found to have a left breast mass and underwent radical mastectomy, which disclosed two in-situ lobular carcinomas. Biopsy of the " " right breast, several months later, showed florid sclerosing focal lobular with duct adenosis, papillomatosis, hyperplasia, and microscopical fibroadenomas. Case 4.-A 49-year-old Government employee with multi-
nodular, multicystic thyroid enlargement was given thyroid substance (’ Thyrolar ’, sodium L-thyroxine plus sodium tri-
iodothyronine) and the thyroid nodularity decreased. She was given aldactazide one daily for one to two weeks premenstrually, because of premenstrual headaches and cedema, with improvement in these symptoms. After twenty-three months of this regimen, she was found on routine physical examination to have bilateral breast masses. At operation she had bilateral multifocal, lobular, infiltrating carcinomas, with extensive metastases, including one in the ovary. Case 5.-A 62-year-old retired Government employee had received aldactazide (plus reserpine and allopurinol) for thirteen months as treatment for hypertension. She was found to have a breast mass, which proved to be an infiltrating duct carcinoma with positive axillary nodes. She died of metastatic disease. Our concern that spironolactone may play a role in the initiation of breast carcinoma or in the stimulation of an unrecognised preexisting carcinoma is heightened by the
following facts. Gynsecomastia is
a
complication
of
spironolactone
striking that population-based rates and uniform definitions unnecessary in order to conclude that safety closures are advantageous. Gartside apparently doubts that safety closures are a technological advance, but he does not suggest that their use be delayed until appropriate investigations have been completed. The success of safety closures in the United States would render such a delay comparable to withholding antibiotics from a patient with meningitis pending results of culture and sensitivity studies. When the patient’s life may be at stake it is usually necessary to act on the basis of whatever information is readily available. are
Department of Psychiatry and Sciences, and Division of Forensic Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, U.S.A.
PARK ELLIOTT DIETZ.
HERPESVIRUS INFECTION AND CANCER SIR,—Dr Matas and his colleagues (June 7, p. 1277) suggest that the pathogenesis of lymphoproliferative tumours in transplant patients involves the reactivation of latent oncogenic herpesvirus. They suggest that seroepidemiological studies documenting an association of cancer and herpesvirus infections would be helpful in supporting their hypothesis. In a series of 100 patients with bronchial carcinoma we found that significantly fewer (21 out of 100) gave a history of recurrent labial herpes simplex than a control group (42 out of 100); the range of serum complement-fixing antibody titres to herpes simplex was similar in case and controls. From these findings we suggested that clinical recurrent infection might provide specific or non-specific protection against bronchial carcinoma.i These results seem to contradict the hypothesis of Dr Matas and his colleagues. However, it seems possible that, although previous recurrent herpes-simplex infection may provide some immunological protection against the development of bronchial carcinoma, the use of immunosuppressive agents in transplant patients may encourage the
oncogenic potential of latent herpesviruses. ------
Microbiology Laboratory, Ayrshire Central Hospital,
"Analgesics" England and Wales "Baby Aspirin" United States "Unspecified Aspirin" United States
"Adutt Aspirin" United States suspected poisonings among children under 5
Irvine KA12 8SS.
CONSTANCE A. C. Ross.
A
Number of of age.
PLASMA IRON AND IRON-BINDING CAPACITY Eastham SIR,— Dr (May 10, p. 1090) quotes average
years
Data from
England and Wales based on estimated hospital and data from United States based on reports to Poison Control Centers.2,3 admissions;
from unspecified types of aspirin also decreased, while that from " adult aspirin " remained stable (see accompanying
figure). Although Gartside emphasises poisonings with prescription medicines, the data he presents from England and Wales also show an increase in poisonings with analgesics (predominantly aspirin) following the change to bottles with easily pulled off caps (see figure). Assuming no important change in reporting practices or data collection, the differences between trends for aspirin poisoning in children in the United States and the trend for analgesic poisoning in children in England and Wales is sufficiently "
"
1. Barry, P. Z. Prev. Med. 1975, 4, 47. 2. U.S. Department of Health, Education and Welfare. National Clearinghouse for Poison Control Centers Bulletin, 1972, September-October. 3. Ibid. 1974. May-June.
coefficients of variation for the estimation of plasma iron and iron-binding capacities which have been taken from nationally used quality-control schemes and suggests, obtained for these estimations may therefore, that results be equivocal-i.e., " 95% of results obtained on a sample containing 300 µg. per 100 ml. (of iron-binding capacity) would fall in the range 200-400 µg. per 100 ml.". However, it is quite inappropriate to assume that, in any one department, the precision of these estimations is necessarily related to the precision obtained from results from as many as 300-400 different departments. Results obtained from a particular laboratory must always be related to the reference range of that laboratory and be interpreted in the context of the precision of the method in use. The precision obtained in many laboratories (e.g., by Dr Price and Dr Obeid) (May 17, p. 1140) is considerably better than might be inferred from Dr Eastham’s letter. Results from several laboratories which participate in a 1.
Ross, C. A. C., Tyrrell, W. F. Lancet, 1974, i, 871.
1428
quality-control scheme give the following ranges for coefficient of variation: plasma-iron 0.9%—7.7% (from 19 laboratories, 17 gave results of less than 4%); plasmairon-binding capacity 2.1%—6.6% (from 12 laboratories). With careful organisation of existing resources it is unlikely that in many departments the inclusion of plasma iron and iron-binding capacity estimations will require extra staff or sophisticated equipment. Department of Clinical Chemistry, Western General Hospital, Edinburgh EH4 2XU.
SHIRLEY M. STEIN.
but after 3 months the plasma-urea remains at 60 mg. per 100 ml. with a creatinine clearance of 14 ml. per minute and the plasma-bicarbonate is 12 meq. per litre. It is clearly important that patients should not be restarted on rifampicin therapy after a lapse without careful consideration. Although renal side-effects have so far only been described with intermittent therapy, there should perhaps be an awareness of the possibility of these complications occurring with continuous treatment.
anuria,
M. COCHRAN P. J. MOORHEAD M. PLATTS.
Renal Unit,
Royal Hospital, Sheffield S1 3SR.
PERMANENT RENAL DAMAGE WITH RIFAMPICIN
SIR,-Acute renal failure has been associated with intermittent rifampicin therapy, or re-introduction of the drug.1-4 In two cases 1,2 circulating antibodies to rifampicin were found. These patients had an attack of vomiting, diarrhoea, malaise, and rigors 1-4 hours after ingestion of the drug. Anuria then followed and maintenance dialysis was usually required, but full recovery was the rule. Renal biopsies 2-4 showed acute tubular necrosis with normal vasculature and glomeruli and there was no evidence of immune complex deposition. We report here two further cases, one with permanent renal damage. A 59-year-old woman was receiving P.A.s., isoniazid, and rifampicin 3 days per week for abdominal tuberculosis. After 9 months the patient developed nausea and occasional diarrhoea. The drugs were stopped but were given again 1 month later. 2 hours after taking rifampicin the patient had mid-abdominal pain, vomiting, rigors, and malaise. After 5 days she became anuric. On admission to hospital there was palmar erythema and upper abdominal tenderness but no other abnormalities. Plasma-urea was 242 mg. per 100 ml. Liver enzymes were slightly raised; a liver biopsy was normal. Renal biopsy showed acute tubular necrosis with C’3 identifiable in the region of the necrotic cells. No bound immunoglobulin or fibrin was seen. There was no direct fluorescence attributable to rifampicin. Plasma-C’3was reduced (43 mg. per 100 ml.). No circulating antibodies to rifampicin were found using the indirect antiglobulin technique. The patient was managed on hxmodialysis until diuresis after 10 days, and full recovery followed. At follow-up, the plasma-urea was 28 mg. per 100 ml. A 42-year-old woman was receiving isoniazid and rifampicin for pulmonary tuberculosis. She took the drugs irregularly. Nonetheless her health improved and X-ray appearances resolved. Her plasma-urea was 9 mg. per 100 ml. After taking no drugs for about 9 months, oral therapy was again prescribed. 30 minutes after ingestion of rifampicin she developed mid-abdominal pain and vomited. She later passed three loose stools. There was severe malaise but no rigors. 4 hours after taking the drug there was pain and slight swelling of the left ankle, with discoloration of the skin. On admission to hospital, there was mild jaundice, oral herpes, and an area of cutaneous vasculitis over the left ankle. She was anuric. Plasmaurea was 128 mg. per 100 ml., bilirubin 53 mg. per 100 ml. with all liver enzymes raised. A test for hepatitis-B antigen There was no evidence of disseminated was negative. intravascular coagulation. Liver biopsy was normal. Two renal biopsies showed severe cortical necrosis. Circulating rifampicin antibodies could not be detected. Plasma C/g 3 and C’ levels were normal. Management by peritoneal dialysis was followed by production of urine after 3 weeks’ Poole, G., Stradling, P., Worlledge, S. Br. med. J. 1970, iii, 343. Kleinknecht, D., Homberg, J. C., Decroix, G. Lancet, 1972, i, 1238. 3. Cordonnier, D., Muller, J. M. ibid. 1972, ii, 1364. 4. Ramgopal, V., Leonard, C., Bhathena, D. ibid. 1973, i, 1195. 1. 2.
BREAST CANCER ASSOCIATED WITH ADMINISTRATION OF SPIRONOLACTONE
SIR,-We have become concerned by the observation practice of 5 women in whom breast carcinoma developed during or after the prolonged administration of spironolactone. While we recognise, of course, the likelihood that this association may be purely coincidental, we feel it imperative to report the observation.
in a medical
Case 1.—An 81-year-old woman with arteriosclerotic heartdisease and nephropathy receivedAldactazide’ (25 mg.
spironolactone plus 25 mg. hydrochlorothiazide) three times daily for four months. She was later givenDyazide’ (50 mg. She had triamterene plus 25 mg. hydrochlorothiazide). received no oestrogen therapy. Digoxin had been given for a long period, but it was stopped before the administration of aldactazide. One year later, she was found to have an inflammatory carcinoma of the left breast, which was resected. Histological examination showed an infiltrating duct carcinoma with fibrosis, extensive lymphatic invasion, and metastases to most of the axillary nodes. Extensive metastases of the pleura and thoracic wall and an inflammatory carcinoma of the right breast later developed. Case 2.-A 65-year-old White female Government worker had taken aldactazide for two years for hypertension and chronic leg cedema. She had previously received oestrogens (’ Premarin’) which had been discontinued sixteen months before the appearance of a bloody nipple discharge. Biopsy and subsequent breast resection established a diagnosis of well-differentiated, infiltrating, duct carcinoma with skin and lymphatic invasion, and metastases to 4 of 11 axillary nodes. Case 3.-A 47-year-old White housewife with a history of thyrotoxicosis had received aldactazide three times weekly for sixteen months because of idiopathic cedema. She was found to have a left breast mass and underwent radical mastectomy, which disclosed two in-situ lobular carcinomas. Biopsy of the " " right breast, several months later, showed florid sclerosing focal lobular with duct adenosis, papillomatosis, hyperplasia, and microscopical fibroadenomas. Case 4.-A 49-year-old Government employee with multi-
nodular, multicystic thyroid enlargement was given thyroid substance (’ Thyrolar ’, sodium L-thyroxine plus sodium tri-
iodothyronine) and the thyroid nodularity decreased. She was given aldactazide one daily for one to two weeks premenstrually, because of premenstrual headaches and cedema, with improvement in these symptoms. After twenty-three months of this regimen, she was found on routine physical examination to have bilateral breast masses. At operation she had bilateral multifocal, lobular, infiltrating carcinomas, with extensive metastases, including one in the ovary. Case 5.-A 62-year-old retired Government employee had received aldactazide (plus reserpine and allopurinol) for thirteen months as treatment for hypertension. She was found to have a breast mass, which proved to be an infiltrating duct carcinoma with positive axillary nodes. She died of metastatic disease. Our concern that spironolactone may play a role in the initiation of breast carcinoma or in the stimulation of an unrecognised preexisting carcinoma is heightened by the
following facts. Gynsecomastia is
a
complication
of
spironolactone
