259 these concentrations of the resins. Thus, on a weight basis, colestipol was some four times more effective. Both cholestyramine and colestipol hydrochloride are basic, high molecular weight, and insoluble anionic exchange resins. They have a strong affinity for acids and may absorb neutral substances, but they have little affinity for basic substances. Our results indicate that these anion-exchange resins bind the toxin which is now implicated in antibiotic-associated colitis, thus providing a presumptive explanation for the favourable effects previously observed with cholestyramine treatment. We have also tested the effect of anion-exchange resins on enterotoxins of Escherichia coli, Vibrio cholerce, Shigella dysenterice, and Staphylococcus aureus (type B toxin). No binding was observed, suggesting that the toxin of C. difficile is acidic or neutral while other toxins are either neutral or basic. This zoo,
study was supported by a grant Michigan.
from the
Tufts University School of Medicine, and Boston Veterans Administration Hospital, Boston, Massachusetts, U.S.A.
Upjohn Co.,
Kalama-
TE WEN CHANG ANDREW B. ONDERDONK JOHN G. BARTLETT
We are left with the conclusion that leuksmic infiltration of the testis of a microscopic type may well serve as a sanctuary from which cells reseed the marrow or central nervous system. These cells may well remain in prolonged resting phase in an environment which has been significantly altered by tissue damage. Of the series of biopsies to date there has only been one occasion where a biopsy which was considered to be equivocal was followed, approximately 8 months later by haematological relapse and, on review of all sections of that initial testicular biopsy sample, one small focus of lymphoid cells was found. Over a period of a year no other patient with a negative biopsy has yet shown hsmatological or meningeal relapse. Longer follow-up will show whether the 15% of patients with clinically normal testis but positive biopsies will be salvaged by intensive local treatment and prolonged systemic therapy. The poor prognosis for patients with overt testicular infiltration is a strong argument in favour of prophylaxis. Department of Child Life and Health,
University of Edinburgh Edinburgh EH9 1UW
O. B. EDEN
HEPATIC BRUITS IN LIVER TUMOURS TESTICULAR INFILTRATES IN CHILDHOOD LEUKÆMIA
SIR,- Your editorial and the paper by Dr Baumer and Dr Mott in the issue of July 15 raise some important points which require further clarification. Following our initial reportl to the M.R.C. Working Party on Childhood Leukaemia we have further analysed the 29 patients who presented with isolated infiltration. Their actuarial disease-free survival at 2 years is only 20%. 7 patients are alive, free of disease, at follow-ups of 13-43 months. 7 more are alive having had at least one relapse. Your editorial implied that overt testicular infiltration suggests systemic disease. Our evidence is not conclusive. Some of the 29 relapsed very early, suggesting that the disease was indeed widespread at the time that the testis was noted to be swollen. Others received further chemotherapy, which may have suppressed systemic disease, and relapsed when that therapy was discontinued. None of this, however, explains why boys fare worse than girls (there being at least 30% difference in 5-year disease-free survival). In our initial survey we found that the addition of cyclophosphamide to treatment regimens increased the risk of testicular infiltration. Morris-Jones et al.,2 in a small series, have reported histological findings consequent upon chemotherapy ; they found a relationship between cytarabine and cyclophosphamide and decreasing tubular fertility and increasing interstitial fibrosis. We have now reviewed nearly 200 routine testicular biopsies on boys just completing courses of chemotherapy and, although the analysis is preliminary, we are finding a similar increased damage effect of cyclophosphamide and possibility cytarabine.3 It is curious that a drug such as cyclophosphamide which definitely causes damage within the sensitive testis has also been implicated as leading to an increased incidence of leukaemic infiltration in that organ. Perhaps leukxmic cells initially seeded in the testis, as in other organs, survive preferentially when tissue damage occurs. The histological findings of Mathe, Sharp, Simone, and their colleagues (cited in your editorial) imply that leukaemic cells are found throughout the body even when patients are apparently in complete remission. This does not explain sex difference, though Morris-Jones et al. have demonstrated that chemotherapy does not apparently affect most boys in terms of hormonal function.
SIR,-Arterial murmurs can be heard over the abdomen in various diseases and sometimes even in normal patients with persons.’ 1 Clain et al.’ reported that in some liver diseases, such as hepatocellular carcinoma and alcoholic hepatitis, abdominal bruits were also auscultated over the liver and that they contributed to the differential diagnosis. There have been few reports on hepatic bruits in malignant liver tumours other than hepatocellular carcinoma. We have noted hepatic bruits in a case of intrahepatic cholangiocarcinoma and in a case of metastatic liver carcinoma. The murmurs were confirmed by sound recordings. A 38-year-old woman was admitted with anorexia and icterus. The liver was palpable 3.5fingerbreadths below the right costal margin. A continuous murmur with late-systolic accentuation was heard over the liver in the epigastrium. After a month the patient died. At necropsy there was an adenocarcinoma arising in the bileduct at the hepatic hilum, which infiltrated several centimetres into the liver, with multiple intrahepatic metastases of less than walnut size. A 34-year-old woman was operated on palliatively for an adenoid cystic carcinoma of the right submaxillary gland. After 3 months she was admitted with an abdominal tumour. The liver was palpable 8 fingerbreadths below the right costal margin. A late-systolic murmur was heard over the liver in the epigastrium. Laparoscopy and abdominal angiography confirmed a large liver tumour due to metastasis of the adenoid carcinoma. Tumours other than hepatocellular carcinoma should be considered when an arterial murmur is heard in the upper abdomen.
cystic
Second Department of Internal Medicine, Faculty of Medicine, Tokyo University, Tokyo 113, Japan
over the liver suggests hepatoma3-6 do not mention liver bruit as a feature series though large of this condition. This physical sign could prove especially
SIR,-A systolic bruit
even
Rivin, A. U.J. Am. med. Ass. 1972, 221, 688. Watson, W. C., Williams, P. B., Duffy, G. Ann. intern. Med. 1973, 79, 211. 3. Clain, D., Wartnaby, K., Sherlock, S. Lancet, 1966, ii, 516. 4. Mills, P. E., Jr, Calif. Med. 1967, 107, 270. 5. Shah, M. J., Agarwal, A. K., Manvi, K. N.J. Ass. Physns India, 1967, 15,
M., Peto, J. Br. med.
1. 2.
I. M., Marsden, H. B., Lendon, M., Shalet, S. M. Proc. Am. Soc. clin. Oncol. 1978, 19, 365. 3. Gowing, N. F. C., Eden, O. B., Initial Report of Testicular Tumor Panel to the M.R.C. Working Party on Childhood Leukæmia. April, 1978.
6.
1.
Eden, O, B., Hardisty, R. M, Innes, E. M., Kay, H.
2.
J. 1978, i, 334. Morris-Jones, P. H., Hann,
E.
TATSUYA MOTOKI TERUMI HAYASHI YOSHIHISA KATOH TSUGUYA SAKAMOTO TADANAO TAKEDA SATORU MURAO
483.
Tsega, E. E. Afr. med. J. 1977, 54, 281.
260 valuable in countries where laboratory services are limited. Two patients seen in Ethiopia illustrate this point. A 56-year-old Ethiopian woman was admitted to hospital with a history of right hypochondrial pain, anorexia, and weight loss for 5 months and a left-sided neck swelling for 2 months. She was cachetic with a hard round mass in the anterior triangle of the neck on the left side measuring 5 cm in diameter. The liver was 11 cm below the right costal margin, hard, and grossly nodular. The only bruit heard was loud and restricted to the chest at the right midaxillay line, seventh to eighth intercostal space. No heart murmurs were heard and chest X-ray was normal. Biopsy of the neck mass revealed carcinoma, probably from liver, and a liver biopsy confirmed
hepatoma. A 48-year-old Ethiopian man was admitted with a history of weight loss and anorexia for a month, and abdominal swelling for 10 weeks. He had slight icterus and the liver was 8 cm below the right costal margin, slightly tender, hard, and nodular. There was no bruit over the liver but one was clearly heard over the chest 7 cm above the right costal margin midclavicularly. No cardiac murmurs were heard and chest X-ray was normal. Liver biopsy revealed hepatoma. These two cases had bruits over the chest but not over the liver though in both cases the livers were nodular and grossly
enlarged. Pavlica and Samuel,’ reporting 38 cases of hepatomas from Ethiopia, described no liver bruit, while in a later report from the same country Tsega" reported 100 cases of hepatoma and 80% of these had bruits. The fortuitous discovery of a bruit over the chest in case 1 prompted careful auscultation of the chest in all cases of suspected hepatomas, and one more patient with this physical sign was found within a 6-month period. It is possible therefore that bruits in the chest in cases of hepatoma may not be uncommon and this simple physical sign may prove to be of diagnostic value. Medical Faculty, Addis Ababa University, P.O. Box 1176, Addis Ababa,
Ethiopia
*Present address: Centre for
Respiratory Investigation, Royal Infirmary,
BAYU TEKLU* Glas-
gow G4 OSF
PLASMAPHERESIS IN SEVERE ASTHMA
Sip,—Dr Gartmann and co-workers (July 1, p. 40) report apparent benefit in a patient with chronic asthma after plasmapheresis. It is clearly important to establish that measured improvement in airflow obstruction is unequivocally due to the therapy concerned, and not to extraneous factors. In the report from Switzerland, firstly, no pretreatment lung function data are presented; secondly, no details are given of concurrent medication which might have influenced the spirometric data presented; thirdly, no account is taken of the effects of diurnal rhythm of airflow obstruction on the spirometric results;and, fourthly, no details of the environmental conditions during the period of observation are recorded. This last comment is particularly important, as it may be possible to explain the slow apparent improvement in the asthma of this atopic patient, and the reported concurrent fall in serum IgE, if she was away from her usual environment. As plasmapheresis is an expensive and technically difficult form of therapy and as the measured rate of response in this case (over a period of several weeks) is slower than that reported when the same technique is used to treat other conditions2-4 we feel that further well-documented reports of the 7. Pavlica, D., Samuel, I. Br. J. Cancer, 1970, 24, 22. 1. Clark, T. J. H., Hetzel, M. R. Br. J. Dis. Chest, 1977, 2. Lockwood, C. M., and others. Lancet, 1976, i, 711. 3. Verrier Jones, J., and others. ibid. 1976, i, 709. 4. Pinching, A. J., and others. ibid. 1976, ii, 1373.
71, 87.
of plasmapheresis in chronic severe asthma should be available before a formal controlled clinical trial is set up. use
Chest Unit, Churchill Hospital,
M. F. MUERS K. D. DAWKINS
Headington, Oxford OX3 7LJ
PROSTAGLANDINS AND SULPHASALAZINE
SIR,-Mr Moore and his colleagues (July 8, p. 98) suggest that the therapeutic action of sulphasalazine in the treatment of ulcerative colitis might be by inhibition of prostaglandin (P.G.) metabolism. We too have investigated the role of P.G. biosynthesis in the pathophysiology of ulcerative colitis but our results suggest that there is a significant inhibition of synthesis
by sulphasalazine. Using a radiometric method we have demonstrated that P.G. synthetase activities are high in rectal biopsy material from patients in the acute phase of ulcerative colitis and that these activities fall after successful treatment with sulphasalazine, prednisolone enemas, and codeine phosphate.’2 With this method we have examined the effects of these drugs on homogenates of human colonic
from an acute colitic underaffected tissue from a pagoing panproctocolectomy tient undergoing partial colectomy for polyposis coli. In homogenates from both sources neither prednisolone nor codeine phosphate had any effect on P.G. production at concentrations of 5-500 fl-mol;1. Sulphasalazine did, however, inhibit P.G. biosynthesis, although not as effectively as indomethacin. The I.c’50=for sulphasalazine was 251 mol/1 while that for indomethacin was 18.2 mol/1 (I.c’50=drug concentration required to produce 50% inhibition of p.G. production). Our results are in contrast to those of Moore et al. who found little or no inhibition of animal colonic P.G. synthesis, although they used lower doses. It is not easy to relate in-vitro results to the in-vivo situation because the colonic concentration of sulphasalazine is difficult to measure and may vary according to the dosage and frequency of ingestion. Further, sulphasalazine is bound by connective tissue3 and intraluminal concentrations may not reflect tissue levels. The therapeutic effects of sulphasalazine may be due to its major metabolites 5-aminosalicylic acid (5-A.s.A.) and sulphapyridine. 5-A.s.A. inhibits P.G. biosyilthesis’as does sulphapyridine.5 Clinically 5-A.s.A. is as effective as sulphasalazine in controlling acute ulcerative colitis when administered rectally.6 This is not inconsistent with the results of Moore et al. if the parent compound is an inhibitor of both P.G. synthesis and metabolism whereas 5-A.s.A. is inhibitory to synthesis mucosa
and
on
’
only. Moore et al. state that there is no evidence to suggest a beneficial role of P.G. synthetase inhibitors in ulcerative colitis. However, P.G. synthetase inhibitors have been used successfully in the treatment of radiation-induced colitis,’’ the diarrhoea of food intolerance allergies,8 and the irritable-bowel syndrome.9 In view of the evidence that P.G. production is raised in ulcerative colitis2 410 a therapeutic role for P.G. synthetase inhibitors remains a possibility. P. R. SMITH Department of Gastroenterolgy, General D. J. DAWSON City Hospital, Stoke-on-Trent ST4 6QG C. H. J. SWAN 1. Harris, D.W., Swan, C. H. J. Lancet, 1977, ii, 196. 2. Harris, D. W., Smith, P. R., Swan, C. H. J. Gut (in the press). 3. Hanngren, A., Hansson, E., Svartz, N., Ullberg, S. Acta med. scand. 1963,
173, 391. Gould, S. R. Lancet, 1975, ii, 988. Collier, H. O. J., Francis, A. A., McDonald-Gibson, W. J., Saeed, S. A. Prostaglandins, 1976, 11, 219. 6. Azad Khan, A. K., Piris, J., Truelove, S. C. Lancet, 1977, ii, 892. 7. Mennie, A. T, Dalley, V. M., Dineen, L. C., Collier, H. O. J. ibid. 1975, ii, 942. 8. Buisseret, P D., Youlten, L. J. F, Hemzelmann, D. I., Lessor, M. H ibid 1978, i, 906. 9 Rask-Madsen, J., Bukhave, K. Gut, 1978, 19, A448 10. Gould, S. R., Brash, A. R., Connelly, M. J. Lancet, 1977, ii, 98. 4. 5.
study was supported by a grant Michigan.
from the
Tufts University School of Medicine, and Boston Veterans Administration Hospital, Boston, Massachusetts, U.S.A.
Upjohn Co.,
Kalama-
TE WEN CHANG ANDREW B. ONDERDONK JOHN G. BARTLETT
We are left with the conclusion that leuksmic infiltration of the testis of a microscopic type may well serve as a sanctuary from which cells reseed the marrow or central nervous system. These cells may well remain in prolonged resting phase in an environment which has been significantly altered by tissue damage. Of the series of biopsies to date there has only been one occasion where a biopsy which was considered to be equivocal was followed, approximately 8 months later by haematological relapse and, on review of all sections of that initial testicular biopsy sample, one small focus of lymphoid cells was found. Over a period of a year no other patient with a negative biopsy has yet shown hsmatological or meningeal relapse. Longer follow-up will show whether the 15% of patients with clinically normal testis but positive biopsies will be salvaged by intensive local treatment and prolonged systemic therapy. The poor prognosis for patients with overt testicular infiltration is a strong argument in favour of prophylaxis. Department of Child Life and Health,
University of Edinburgh Edinburgh EH9 1UW
O. B. EDEN
HEPATIC BRUITS IN LIVER TUMOURS TESTICULAR INFILTRATES IN CHILDHOOD LEUKÆMIA
SIR,- Your editorial and the paper by Dr Baumer and Dr Mott in the issue of July 15 raise some important points which require further clarification. Following our initial reportl to the M.R.C. Working Party on Childhood Leukaemia we have further analysed the 29 patients who presented with isolated infiltration. Their actuarial disease-free survival at 2 years is only 20%. 7 patients are alive, free of disease, at follow-ups of 13-43 months. 7 more are alive having had at least one relapse. Your editorial implied that overt testicular infiltration suggests systemic disease. Our evidence is not conclusive. Some of the 29 relapsed very early, suggesting that the disease was indeed widespread at the time that the testis was noted to be swollen. Others received further chemotherapy, which may have suppressed systemic disease, and relapsed when that therapy was discontinued. None of this, however, explains why boys fare worse than girls (there being at least 30% difference in 5-year disease-free survival). In our initial survey we found that the addition of cyclophosphamide to treatment regimens increased the risk of testicular infiltration. Morris-Jones et al.,2 in a small series, have reported histological findings consequent upon chemotherapy ; they found a relationship between cytarabine and cyclophosphamide and decreasing tubular fertility and increasing interstitial fibrosis. We have now reviewed nearly 200 routine testicular biopsies on boys just completing courses of chemotherapy and, although the analysis is preliminary, we are finding a similar increased damage effect of cyclophosphamide and possibility cytarabine.3 It is curious that a drug such as cyclophosphamide which definitely causes damage within the sensitive testis has also been implicated as leading to an increased incidence of leukaemic infiltration in that organ. Perhaps leukxmic cells initially seeded in the testis, as in other organs, survive preferentially when tissue damage occurs. The histological findings of Mathe, Sharp, Simone, and their colleagues (cited in your editorial) imply that leukaemic cells are found throughout the body even when patients are apparently in complete remission. This does not explain sex difference, though Morris-Jones et al. have demonstrated that chemotherapy does not apparently affect most boys in terms of hormonal function.
SIR,-Arterial murmurs can be heard over the abdomen in various diseases and sometimes even in normal patients with persons.’ 1 Clain et al.’ reported that in some liver diseases, such as hepatocellular carcinoma and alcoholic hepatitis, abdominal bruits were also auscultated over the liver and that they contributed to the differential diagnosis. There have been few reports on hepatic bruits in malignant liver tumours other than hepatocellular carcinoma. We have noted hepatic bruits in a case of intrahepatic cholangiocarcinoma and in a case of metastatic liver carcinoma. The murmurs were confirmed by sound recordings. A 38-year-old woman was admitted with anorexia and icterus. The liver was palpable 3.5fingerbreadths below the right costal margin. A continuous murmur with late-systolic accentuation was heard over the liver in the epigastrium. After a month the patient died. At necropsy there was an adenocarcinoma arising in the bileduct at the hepatic hilum, which infiltrated several centimetres into the liver, with multiple intrahepatic metastases of less than walnut size. A 34-year-old woman was operated on palliatively for an adenoid cystic carcinoma of the right submaxillary gland. After 3 months she was admitted with an abdominal tumour. The liver was palpable 8 fingerbreadths below the right costal margin. A late-systolic murmur was heard over the liver in the epigastrium. Laparoscopy and abdominal angiography confirmed a large liver tumour due to metastasis of the adenoid carcinoma. Tumours other than hepatocellular carcinoma should be considered when an arterial murmur is heard in the upper abdomen.
cystic
Second Department of Internal Medicine, Faculty of Medicine, Tokyo University, Tokyo 113, Japan
over the liver suggests hepatoma3-6 do not mention liver bruit as a feature series though large of this condition. This physical sign could prove especially
SIR,-A systolic bruit
even
Rivin, A. U.J. Am. med. Ass. 1972, 221, 688. Watson, W. C., Williams, P. B., Duffy, G. Ann. intern. Med. 1973, 79, 211. 3. Clain, D., Wartnaby, K., Sherlock, S. Lancet, 1966, ii, 516. 4. Mills, P. E., Jr, Calif. Med. 1967, 107, 270. 5. Shah, M. J., Agarwal, A. K., Manvi, K. N.J. Ass. Physns India, 1967, 15,
M., Peto, J. Br. med.
1. 2.
I. M., Marsden, H. B., Lendon, M., Shalet, S. M. Proc. Am. Soc. clin. Oncol. 1978, 19, 365. 3. Gowing, N. F. C., Eden, O. B., Initial Report of Testicular Tumor Panel to the M.R.C. Working Party on Childhood Leukæmia. April, 1978.
6.
1.
Eden, O, B., Hardisty, R. M, Innes, E. M., Kay, H.
2.
J. 1978, i, 334. Morris-Jones, P. H., Hann,
E.
TATSUYA MOTOKI TERUMI HAYASHI YOSHIHISA KATOH TSUGUYA SAKAMOTO TADANAO TAKEDA SATORU MURAO
483.
Tsega, E. E. Afr. med. J. 1977, 54, 281.
260 valuable in countries where laboratory services are limited. Two patients seen in Ethiopia illustrate this point. A 56-year-old Ethiopian woman was admitted to hospital with a history of right hypochondrial pain, anorexia, and weight loss for 5 months and a left-sided neck swelling for 2 months. She was cachetic with a hard round mass in the anterior triangle of the neck on the left side measuring 5 cm in diameter. The liver was 11 cm below the right costal margin, hard, and grossly nodular. The only bruit heard was loud and restricted to the chest at the right midaxillay line, seventh to eighth intercostal space. No heart murmurs were heard and chest X-ray was normal. Biopsy of the neck mass revealed carcinoma, probably from liver, and a liver biopsy confirmed
hepatoma. A 48-year-old Ethiopian man was admitted with a history of weight loss and anorexia for a month, and abdominal swelling for 10 weeks. He had slight icterus and the liver was 8 cm below the right costal margin, slightly tender, hard, and nodular. There was no bruit over the liver but one was clearly heard over the chest 7 cm above the right costal margin midclavicularly. No cardiac murmurs were heard and chest X-ray was normal. Liver biopsy revealed hepatoma. These two cases had bruits over the chest but not over the liver though in both cases the livers were nodular and grossly
enlarged. Pavlica and Samuel,’ reporting 38 cases of hepatomas from Ethiopia, described no liver bruit, while in a later report from the same country Tsega" reported 100 cases of hepatoma and 80% of these had bruits. The fortuitous discovery of a bruit over the chest in case 1 prompted careful auscultation of the chest in all cases of suspected hepatomas, and one more patient with this physical sign was found within a 6-month period. It is possible therefore that bruits in the chest in cases of hepatoma may not be uncommon and this simple physical sign may prove to be of diagnostic value. Medical Faculty, Addis Ababa University, P.O. Box 1176, Addis Ababa,
Ethiopia
*Present address: Centre for
Respiratory Investigation, Royal Infirmary,
BAYU TEKLU* Glas-
gow G4 OSF
PLASMAPHERESIS IN SEVERE ASTHMA
Sip,—Dr Gartmann and co-workers (July 1, p. 40) report apparent benefit in a patient with chronic asthma after plasmapheresis. It is clearly important to establish that measured improvement in airflow obstruction is unequivocally due to the therapy concerned, and not to extraneous factors. In the report from Switzerland, firstly, no pretreatment lung function data are presented; secondly, no details are given of concurrent medication which might have influenced the spirometric data presented; thirdly, no account is taken of the effects of diurnal rhythm of airflow obstruction on the spirometric results;and, fourthly, no details of the environmental conditions during the period of observation are recorded. This last comment is particularly important, as it may be possible to explain the slow apparent improvement in the asthma of this atopic patient, and the reported concurrent fall in serum IgE, if she was away from her usual environment. As plasmapheresis is an expensive and technically difficult form of therapy and as the measured rate of response in this case (over a period of several weeks) is slower than that reported when the same technique is used to treat other conditions2-4 we feel that further well-documented reports of the 7. Pavlica, D., Samuel, I. Br. J. Cancer, 1970, 24, 22. 1. Clark, T. J. H., Hetzel, M. R. Br. J. Dis. Chest, 1977, 2. Lockwood, C. M., and others. Lancet, 1976, i, 711. 3. Verrier Jones, J., and others. ibid. 1976, i, 709. 4. Pinching, A. J., and others. ibid. 1976, ii, 1373.
71, 87.
of plasmapheresis in chronic severe asthma should be available before a formal controlled clinical trial is set up. use
Chest Unit, Churchill Hospital,
M. F. MUERS K. D. DAWKINS
Headington, Oxford OX3 7LJ
PROSTAGLANDINS AND SULPHASALAZINE
SIR,-Mr Moore and his colleagues (July 8, p. 98) suggest that the therapeutic action of sulphasalazine in the treatment of ulcerative colitis might be by inhibition of prostaglandin (P.G.) metabolism. We too have investigated the role of P.G. biosynthesis in the pathophysiology of ulcerative colitis but our results suggest that there is a significant inhibition of synthesis
by sulphasalazine. Using a radiometric method we have demonstrated that P.G. synthetase activities are high in rectal biopsy material from patients in the acute phase of ulcerative colitis and that these activities fall after successful treatment with sulphasalazine, prednisolone enemas, and codeine phosphate.’2 With this method we have examined the effects of these drugs on homogenates of human colonic
from an acute colitic underaffected tissue from a pagoing panproctocolectomy tient undergoing partial colectomy for polyposis coli. In homogenates from both sources neither prednisolone nor codeine phosphate had any effect on P.G. production at concentrations of 5-500 fl-mol;1. Sulphasalazine did, however, inhibit P.G. biosynthesis, although not as effectively as indomethacin. The I.c’50=for sulphasalazine was 251 mol/1 while that for indomethacin was 18.2 mol/1 (I.c’50=drug concentration required to produce 50% inhibition of p.G. production). Our results are in contrast to those of Moore et al. who found little or no inhibition of animal colonic P.G. synthesis, although they used lower doses. It is not easy to relate in-vitro results to the in-vivo situation because the colonic concentration of sulphasalazine is difficult to measure and may vary according to the dosage and frequency of ingestion. Further, sulphasalazine is bound by connective tissue3 and intraluminal concentrations may not reflect tissue levels. The therapeutic effects of sulphasalazine may be due to its major metabolites 5-aminosalicylic acid (5-A.s.A.) and sulphapyridine. 5-A.s.A. inhibits P.G. biosyilthesis’as does sulphapyridine.5 Clinically 5-A.s.A. is as effective as sulphasalazine in controlling acute ulcerative colitis when administered rectally.6 This is not inconsistent with the results of Moore et al. if the parent compound is an inhibitor of both P.G. synthesis and metabolism whereas 5-A.s.A. is inhibitory to synthesis mucosa
and
on
’
only. Moore et al. state that there is no evidence to suggest a beneficial role of P.G. synthetase inhibitors in ulcerative colitis. However, P.G. synthetase inhibitors have been used successfully in the treatment of radiation-induced colitis,’’ the diarrhoea of food intolerance allergies,8 and the irritable-bowel syndrome.9 In view of the evidence that P.G. production is raised in ulcerative colitis2 410 a therapeutic role for P.G. synthetase inhibitors remains a possibility. P. R. SMITH Department of Gastroenterolgy, General D. J. DAWSON City Hospital, Stoke-on-Trent ST4 6QG C. H. J. SWAN 1. Harris, D.W., Swan, C. H. J. Lancet, 1977, ii, 196. 2. Harris, D. W., Smith, P. R., Swan, C. H. J. Gut (in the press). 3. Hanngren, A., Hansson, E., Svartz, N., Ullberg, S. Acta med. scand. 1963,
173, 391. Gould, S. R. Lancet, 1975, ii, 988. Collier, H. O. J., Francis, A. A., McDonald-Gibson, W. J., Saeed, S. A. Prostaglandins, 1976, 11, 219. 6. Azad Khan, A. K., Piris, J., Truelove, S. C. Lancet, 1977, ii, 892. 7. Mennie, A. T, Dalley, V. M., Dineen, L. C., Collier, H. O. J. ibid. 1975, ii, 942. 8. Buisseret, P D., Youlten, L. J. F, Hemzelmann, D. I., Lessor, M. H ibid 1978, i, 906. 9 Rask-Madsen, J., Bukhave, K. Gut, 1978, 19, A448 10. Gould, S. R., Brash, A. R., Connelly, M. J. Lancet, 1977, ii, 98. 4. 5.
