- Email: [email protected]
TREATMENT OF CHRONIC PROCTOSIGMOIDITIS WITH CYCLOSPORIN ENEMAS
97
reported in women who conceive while taking ACE inhibitors but stop the drug when pregnancy is diagnosed. In our case liquor volume improved from "virtually no liquor" to "normal liquor volume" when the ACE inhibitor was replaced by labetalol. After delivery anuria was not a problem, but severe respiratory failure with hypoplastic lungs was. The fact that oligohydramnios/neonatal anuria has been reported only when the mother was taking an ACE inhibitor at the time of fetal death or delivery may be paralleled by study of Robillard et al of the harmful effects of captopril on fetal and neonatal renal function in animals.6 This complication is not inevitable but it has appeared in a proportion of reports on ACE inhibitor therapy in mid-pregnancy. This is not evidence of causality, but it would appear prudent to avoid the use of these agents in pregnancy. Department of Obstetrics and Gynaecology, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH
F. BROUGHTON PIPKIN P. N. BAKER E. M. SYMONDS
Guignard JP, Burgener F, Calame A. Persistent anuria in a neonate: a side-effect of captopnl? Int J Pediatr Nephrol 1981; 2: 133. 2. Boutroy M-J, Vert P, Hurault de Ligny B, Milton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984; ii: 935-36. 3. Plouin PE, Tchobroutsky C. Inhibition de l’enzyme de conversion de l’angiotensine au 1.
de la grossesse humaine. Presse Méd 1985; 14: 2175-78. 4. Knott PD, Thorpe SS, Lamont CAR. Congential renal dysgenesis possibly due to captopril. Lancet 1989; i: 451. 5. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215-16. 6. Robillard JE, Nakamura K, Matherne P, et al. Renal hemodynamics and functional adjustments to postnatal life. Sem Perinatol 1988; 12: 143-50. cours
TREATMENT OF CHRONIC PROCTOSIGMOIDITIS WITH CYCLOSPORIN ENEMAS
SIR,-Our fmdings are similar to those of Dr Brynskov and colleagues (April 1, p 721) who used cyclosporin retention enemas successfully in eight patients with refractory distal ulcerative colitis. We have used topical cyclosporin in six patients with chronically active idiopathic proctosigmoiditis unresponsive to conventional therapy. 6-10 months previously three of them had had an ileostomy and subtotal colectomy, sigmoidorectal remnant being brought to the surface to form a mucous fistula, because of severe ulcerative colitis requiring emergency surgery (to be followed, if possible, by ileorectal anastomosis). Active disease of the rectosigmoid stump persisted despite topical treatment with betamethasone 2 mg and/or mesalazine (5-aminosalicylic acid) 1 -5 g in 100 ml water twice a day. The other three patients had chronic active proctosigmoiditis despite treatment for more than 6 months with oral sulphasalazine 3 g/daily and topical corticosteroids and/or mesalazine as above. In all the patients the disease was severe on endoscopic and histological criteria. All six patients continued the previous treatment for a further month except that cyclosporin was added to the enemas. In three patients cyclosporin (Sandoz oral solution) was added to the enemas at doses of 2-5 mg/kg, and the mixture vigorously shaken; in the other three patients intravenous solution was added at doses of 0-75 routine blood tests (including
mg/kg. Clinical assessment, drug blood levels), and
sigmoidoscopy with rectal biopsy were done before treatment and after 10, 20, and 30 days of treatment. One
patient with
intravenous solution
a
rectosigmoid stump (treated with the enemas) and two not previously
as
colectomised (one given the intravenous and the other the oral cyclosporin solution as enemas) progressively improved clinically at endoscopy, and histologically at the end of treatment were in complete remission. In the first patient ileorectal anastomosis could be done as planned. All three patients suspended topical treatment and are still in remission after 5, 5, and 6 months. No changes were seen in the other three patients. As in Brynskov’s patients, cyclosporin blood levels (Sandoz radioimmunoassay) were less than 60 ng/ml, with one exception (100 ng/ml). No side-effects were noted. The fact that three of six patients with proctosigmoiditis of more than 6 months’ duration unresponsive to full-dose conventional
therapy
achieved complete and persistent remission after topical cydosporin was added for a month, strongly suggests that topical
cyclosporin has a role in the management of such patients. The efficacy, absorption, and tolerability of cyclosporin enemas that we observed are similar to the experiences of Brynskov et al, even though the enema composition was different and the doses were much smaller and administered twice daily. TULLIO RANZI MARIA CRISTINA CAMPANINI PIETRO VELIO Department of Special Medical Pathology III, FILIPPO QUARTO DI PALO of University Milan, PAOLO BIANCHI 20122 Milan, Italy
ORAL CONTRACEPTIVES AND BREAST CANCER
SIR,-From the UK Case-Control Study Group’s data (May 6, p 973) it would seem that a combined oral contraceptive (OC) with 50 Ilg ethinyl oestradiol (or equivalent) will increase the incidence of breast cancer in young women in proportion to the length of exposure. This could be a consequence of accelerated promotion of
already initiated cancers and therefore would not affect the overall long-term incidence. From various national cancer registration data there is no evidence of an overall increase in breast cancer incidence in relation to OC use, despite many millions of women having been
exposed to OCs since
1964.
interested in the possible protective effect of OCs against breast cancer. There is evidence to indicate that oestrogen is a promoter of initiated breast cancers’-3 and that this mechanism may be opposed by progestins, the basis of the "opposed oestrogen" hypothesis.4,5 The study group’s results seem to support this hypothesis. They find a high frequency of breast carcinoma for women on high oestrogen OCs, a modest or no increase for combined low oestrogen OCs (eg, relative risk of 1-04 for 30 289 women-months on 30 Itg ethinyl oestradiol combined with levonorgestrel), and significant protection for those on progesterone-only pills, which is described as "unexpected". This raises the interesting idea that it would be possible to design an OC to prevent breast cancer and hence provide valid data on OCs and breast cancer in randomised trials. In the meantime it would seem likely that OCs with a low dose of ethinyl oestradiol combined with levonorgestrel (’Eugynon 30’, ’Ovran 30’, ’Microgynon 30’, ’Ovranette’) carry little or no risk of promotion of breast cancer and women on these OCs should continue to take them. I
am more
Division of Medicine, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
TREVOR J. POWLES
1. Millar AB, Bulbrook RD. The epidemiology and etiology of breast cancers. N Engl J Med 1980; 303: 1246-48. 2. Jordan VC. Comparative anti-oestrogen action in experimental breast cancers. Adv Exp Med Biol 1981; 138: 165-78. 3. Cusick J, Wang DY, Bulbrook RD. The prevention of breast cancers. Lancet 1986; i: 83-86. 4. Mauvais-Jarvis P, Sitruk-Ware R, Kuttenn F. Luteal phase defect and breast cancer genesis. Breast Cancer Res Treat 1982; 2: 139-50. 5. Mauvais-Jarvis P, Kutterin F, Gompel A. Anti-oestrogen action of progesterone in breast tissue. Breast Cancer Res Treat 1986; 8: 179-87.
This letter has been shown to Mrs Chilvers and colleagues, reply, on behalf of the Study Group to it and to previous correspondence, follows.-ED. L. SIR,-In the group of letters (June 3, pp 1257-58) in reply to our report, Dr Stadel and his colleagues regret that our study was limited to breast cancer diagnosed before age 36. We chose that limit to explore the hypothesis that an increased risk of breast cancer is associated with oral contraceptive (OC) use either at young ages or before first full-term pregnancy. Only women under 36 would have had the opportunity to use OCs when very young. Earlier studies had shown that use of OCs during the middle reproductive years alone does not increase the risk of breast cancer. The important issue is whether the increased risk that we observe persists as the cohort ages. Our current study of women aged 36-45 should help to answer this question. Stadel et al argue that future studies should include women aged up to age 64 years. Their table in suggests otherwise. Only 13% of control women aged 45-54 had used OCs for 8 or more years and in the UK the number might be smaller due to the slightly later introduction of OCs here. Women older than 55 whose
reported in women who conceive while taking ACE inhibitors but stop the drug when pregnancy is diagnosed. In our case liquor volume improved from "virtually no liquor" to "normal liquor volume" when the ACE inhibitor was replaced by labetalol. After delivery anuria was not a problem, but severe respiratory failure with hypoplastic lungs was. The fact that oligohydramnios/neonatal anuria has been reported only when the mother was taking an ACE inhibitor at the time of fetal death or delivery may be paralleled by study of Robillard et al of the harmful effects of captopril on fetal and neonatal renal function in animals.6 This complication is not inevitable but it has appeared in a proportion of reports on ACE inhibitor therapy in mid-pregnancy. This is not evidence of causality, but it would appear prudent to avoid the use of these agents in pregnancy. Department of Obstetrics and Gynaecology, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH
F. BROUGHTON PIPKIN P. N. BAKER E. M. SYMONDS
Guignard JP, Burgener F, Calame A. Persistent anuria in a neonate: a side-effect of captopnl? Int J Pediatr Nephrol 1981; 2: 133. 2. Boutroy M-J, Vert P, Hurault de Ligny B, Milton A. Captopril administration in pregnancy impairs fetal angiotensin converting enzyme activity and neonatal adaptation. Lancet 1984; ii: 935-36. 3. Plouin PE, Tchobroutsky C. Inhibition de l’enzyme de conversion de l’angiotensine au 1.
de la grossesse humaine. Presse Méd 1985; 14: 2175-78. 4. Knott PD, Thorpe SS, Lamont CAR. Congential renal dysgenesis possibly due to captopril. Lancet 1989; i: 451. 5. Schubiger G, Flury G, Nussberger J. Enalapril for pregnancy-induced hypertension: acute renal failure in a neonate. Ann Intern Med 1988; 108: 215-16. 6. Robillard JE, Nakamura K, Matherne P, et al. Renal hemodynamics and functional adjustments to postnatal life. Sem Perinatol 1988; 12: 143-50. cours
TREATMENT OF CHRONIC PROCTOSIGMOIDITIS WITH CYCLOSPORIN ENEMAS
SIR,-Our fmdings are similar to those of Dr Brynskov and colleagues (April 1, p 721) who used cyclosporin retention enemas successfully in eight patients with refractory distal ulcerative colitis. We have used topical cyclosporin in six patients with chronically active idiopathic proctosigmoiditis unresponsive to conventional therapy. 6-10 months previously three of them had had an ileostomy and subtotal colectomy, sigmoidorectal remnant being brought to the surface to form a mucous fistula, because of severe ulcerative colitis requiring emergency surgery (to be followed, if possible, by ileorectal anastomosis). Active disease of the rectosigmoid stump persisted despite topical treatment with betamethasone 2 mg and/or mesalazine (5-aminosalicylic acid) 1 -5 g in 100 ml water twice a day. The other three patients had chronic active proctosigmoiditis despite treatment for more than 6 months with oral sulphasalazine 3 g/daily and topical corticosteroids and/or mesalazine as above. In all the patients the disease was severe on endoscopic and histological criteria. All six patients continued the previous treatment for a further month except that cyclosporin was added to the enemas. In three patients cyclosporin (Sandoz oral solution) was added to the enemas at doses of 2-5 mg/kg, and the mixture vigorously shaken; in the other three patients intravenous solution was added at doses of 0-75 routine blood tests (including
mg/kg. Clinical assessment, drug blood levels), and
sigmoidoscopy with rectal biopsy were done before treatment and after 10, 20, and 30 days of treatment. One
patient with
intravenous solution
a
rectosigmoid stump (treated with the enemas) and two not previously
as
colectomised (one given the intravenous and the other the oral cyclosporin solution as enemas) progressively improved clinically at endoscopy, and histologically at the end of treatment were in complete remission. In the first patient ileorectal anastomosis could be done as planned. All three patients suspended topical treatment and are still in remission after 5, 5, and 6 months. No changes were seen in the other three patients. As in Brynskov’s patients, cyclosporin blood levels (Sandoz radioimmunoassay) were less than 60 ng/ml, with one exception (100 ng/ml). No side-effects were noted. The fact that three of six patients with proctosigmoiditis of more than 6 months’ duration unresponsive to full-dose conventional
therapy
achieved complete and persistent remission after topical cydosporin was added for a month, strongly suggests that topical
cyclosporin has a role in the management of such patients. The efficacy, absorption, and tolerability of cyclosporin enemas that we observed are similar to the experiences of Brynskov et al, even though the enema composition was different and the doses were much smaller and administered twice daily. TULLIO RANZI MARIA CRISTINA CAMPANINI PIETRO VELIO Department of Special Medical Pathology III, FILIPPO QUARTO DI PALO of University Milan, PAOLO BIANCHI 20122 Milan, Italy
ORAL CONTRACEPTIVES AND BREAST CANCER
SIR,-From the UK Case-Control Study Group’s data (May 6, p 973) it would seem that a combined oral contraceptive (OC) with 50 Ilg ethinyl oestradiol (or equivalent) will increase the incidence of breast cancer in young women in proportion to the length of exposure. This could be a consequence of accelerated promotion of
already initiated cancers and therefore would not affect the overall long-term incidence. From various national cancer registration data there is no evidence of an overall increase in breast cancer incidence in relation to OC use, despite many millions of women having been
exposed to OCs since
1964.
interested in the possible protective effect of OCs against breast cancer. There is evidence to indicate that oestrogen is a promoter of initiated breast cancers’-3 and that this mechanism may be opposed by progestins, the basis of the "opposed oestrogen" hypothesis.4,5 The study group’s results seem to support this hypothesis. They find a high frequency of breast carcinoma for women on high oestrogen OCs, a modest or no increase for combined low oestrogen OCs (eg, relative risk of 1-04 for 30 289 women-months on 30 Itg ethinyl oestradiol combined with levonorgestrel), and significant protection for those on progesterone-only pills, which is described as "unexpected". This raises the interesting idea that it would be possible to design an OC to prevent breast cancer and hence provide valid data on OCs and breast cancer in randomised trials. In the meantime it would seem likely that OCs with a low dose of ethinyl oestradiol combined with levonorgestrel (’Eugynon 30’, ’Ovran 30’, ’Microgynon 30’, ’Ovranette’) carry little or no risk of promotion of breast cancer and women on these OCs should continue to take them. I
am more
Division of Medicine, Royal Marsden Hospital, Sutton, Surrey SM2 5PT
TREVOR J. POWLES
1. Millar AB, Bulbrook RD. The epidemiology and etiology of breast cancers. N Engl J Med 1980; 303: 1246-48. 2. Jordan VC. Comparative anti-oestrogen action in experimental breast cancers. Adv Exp Med Biol 1981; 138: 165-78. 3. Cusick J, Wang DY, Bulbrook RD. The prevention of breast cancers. Lancet 1986; i: 83-86. 4. Mauvais-Jarvis P, Sitruk-Ware R, Kuttenn F. Luteal phase defect and breast cancer genesis. Breast Cancer Res Treat 1982; 2: 139-50. 5. Mauvais-Jarvis P, Kutterin F, Gompel A. Anti-oestrogen action of progesterone in breast tissue. Breast Cancer Res Treat 1986; 8: 179-87.
This letter has been shown to Mrs Chilvers and colleagues, reply, on behalf of the Study Group to it and to previous correspondence, follows.-ED. L. SIR,-In the group of letters (June 3, pp 1257-58) in reply to our report, Dr Stadel and his colleagues regret that our study was limited to breast cancer diagnosed before age 36. We chose that limit to explore the hypothesis that an increased risk of breast cancer is associated with oral contraceptive (OC) use either at young ages or before first full-term pregnancy. Only women under 36 would have had the opportunity to use OCs when very young. Earlier studies had shown that use of OCs during the middle reproductive years alone does not increase the risk of breast cancer. The important issue is whether the increased risk that we observe persists as the cohort ages. Our current study of women aged 36-45 should help to answer this question. Stadel et al argue that future studies should include women aged up to age 64 years. Their table in suggests otherwise. Only 13% of control women aged 45-54 had used OCs for 8 or more years and in the UK the number might be smaller due to the slightly later introduction of OCs here. Women older than 55 whose