377 increase in in-vitro P.G.E production by ovine cervical tissue at delivery, when compared with late pregnancy. 14 P.G. production by ovine cervix
(ng/g dry weight/min, means±S.E.M.
*Mann-Whitney rank-sum test (two tailed). These in-vitro data have been supported by in-vitro observaof an increase in P.G.E in cervical venous effluent during parturition (unpublished). Attempts have been made to ripen the sheep cervix with P.G.F but these have had limited success,I5 Our most recent data show that only a small fraction ofp.G. production by the cervix is P.G.F, and there is no significant change when compared with late pregnancy. We believe that P.G.s synthesised and acting locally are of major importance in the ripening process and that P.G.E rather than P.G.F is the major prostaglandin involved. Furthermore, we suggest that oestrogens may act on the cervix via local stimulation of p.G.E synthesis. These observations in sheep may well relate to the reported clinical effects of P.G.s on the cervix. P.G.E is a more potent agent than P.G.F for ripening the unfavourable human cervix,16 and this may well reflect a direct local action of P.G.E. In contrast, a recent report has suggested that high doses of P.G.F (50 mg) are as effective as P.G.E, although half the patients in this study went into labour before the proposed induction." This may well represent cervical ripening achieved indirectly via induced uterine activity. A clear distinction must be made between cervical ripening by pretreatment before induction and treatments which cause changes in cervical state by inducing labour. Finally one must consider whether or not cestrogens are involved in the normal mechanism of cervical ripening. In sheep the sharp rise in free circulating oestrogens before parturition18 correlates well with the dramatic changes in the cervix, although the exact timing of the changes in cervical compliance brought about by ripening of the tissue is not known. 19 There is no evidence that a similar "oestrogen surge" is associated with human parturition,2O although the gradual changes in the human cervix during the last trimester of pregnancy may correlate with gradually rising levels of oestrogens in the peripheral plasma. The human cervix has been shown to contain both progesterone21 and oestrogen receptors22 and it is probable that the changing steroid environment during late pregnancy and at term has a direct local action on the cervix. In summary, the mechanism by which the cervix ripens before effacement and dilatation during labour is still unknown and further research is required to provide a sound scientific basis for the drug treatments which cause cervical tions
NEW GEL FOR INTRACERVICAL APPLICATION OF PROSTAGLANDIN E2
SIR,-Local (intracervical or intravaginal) application of prostaglandin Ez (p.G,Ez) ripens the uterine cervix and/or induces labour in patients at term and has no systemic sideeffects.’-5 Local application has been made possible by mixing the prostaglandins with a viscous medium giving a gel. As viscous medium different types of cellulose (e.g., ’Tylose’ or ’Hypromellose’) are used. However, the preparation of the gel is time-consuming. Moreover, the prostaglandins are unstable and it is not known to what extent they are inactivated during preparation and storage of the gel. In clinical routine, a more simple and standardised preparation of the p.G.Ez-gel should therefore be most valuable. We have obtained promising results using the following technique. A freshly made up sterile solution of p .G.Ez (Upjohn) in 80% aqueous ethanol is aseptically added to a special powder based on a cross-linked starch polymer (Perstorp AB, Sweden). After homogenisation and lyophilisation a powder containing a predetermined amount of P.G.E, is obtained. Chemical analysis6 shows that this powder can be stored at room temperature for more
than 3 months without
a
decrease in the
amount
of un-
changed p.G.Ez. Before application, a few millilitres of saline is added to the powder. This swells within 30 s giving an easily-handled, readyto-use gel. The viscosity is easily modified by varying the volume of saline. The gel produces an effect on the cervix equal to or better than that obtained with previously used cellulose gels containing the same amount of p.G.Ez. No systemic or local sideeffects have been observed after treatment with the new gel. ULF ULMSTEN
OLOF JOHANSSON ANDERS KIRSTEIN-PEDERSEN
Department of Obstetrics and Gynæcology PÅL STENBERG University Hospital, LARS WINGERUP Malmö, Sweden
SAFETY OF INTRAVAGINAL PROSTAGLANDIN F2&agr; SIR,-In reference to Dr MacLennan and Roslyn Green’s paper of Jan. 20 (p. 117) I would remind your readers of the extreme sensitivity to this particular prostaglandin preparation found in many patients with reversible obstructive airway disease (asthma). In the general population there are many people with obstructive lung disease, both diagnosed and undiagnosed, and clinicians should be warned against using such prostaglandin preparations in the induction of labour without bearing in mind the risk of precipitating an episode of acute status asthmaticus. A careful history should be taken, and if there is even the slightest hint of an obstructive lung condition this preparation should not be used. 27301 Dequindre, Suite 104, Madison Heights, Michigan 48071, U.S.A.
BRUCE D. DUBIN
ripening. This work
was
supported by
Nuffield Department of Obstetrics and Gynæcology, and Gynæcology, Obstetrics
University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU
the Medical Research Council.
DAVID A. ELLWOOD MURRAY D. MITCHELL ANNE B. M. ANDERSON A. C. TURNBULL
14 Ellwood, D. A., Mitchell, M. D., Anderson, A. B. M., Turnbull, A. C. J. Endocr (in the press). 15 Fitzpatrick, R. J. in Fetus and Birth: Ciba Fndn Symp. no. 47, p. 31. Lon-
don, 1977 16 MacKenzie, I. Z., Embrey, M. P. Br.J. Obstet. Gynæc. (in the press). 17 MacLennan, A. H, Green, R.C. Lancet, 1979, i, 117. 18 Challis, J. R. G Nature, 1971, 229, 208. 19 Fitzpatrick, R J.Ann. Rech. vet 1977, 8, 438. 20 Turnbull, A C., Flint, A. P. F., Jeremy, J. Y., Patten, P. T., Keirse, 21 22
M. J.N.C, Anderson, A.B.M. Lancet, 1974, i, 101. Sanborn, B.M., Held, B., Kuo, H S J Steroid Biochem. 1976, 7, 665. Sanborn, B. M., Held, B., Kuo, H. S. ibid. 1975, 6, 1107.
ENDOSCOPIC TREATMENT OF BILIARY-TRACT DISEASES
SIR,-Following Professor Safrany’s survey of endoscopic of biliary-tract disease your correspondentsS,jO have
treatment
1. Calder, A. A., Embrey, M. P., Tait, T. Br. J. Obstet. Gynæc 2. MacKenzie, I. Z., Embrey, M. P. Br. med. J. 1977, ii, 1381. 3. Shepherd, J., Sims, C., Craft, I. Lancet, 1976, ii, 709.
1977, 84, 264.
4. Thiery, M., Benijts, G., Derom, R., Martens, G., Amy, J. J., Van Ketz, H., De Schrijver, D. Prostaglandins, 1978, 15, 175. 5. Wingerup, L., Andersson, K.-E., Ulmsten, U. Acta obstet. gynœc. scand.
1978, 57, 403. U., Kirstein-Pedersen, A., Stenberg, P., Wingerup, press). 7. Safrany, L. Lancet, 1978, ii, 983. 8. Blumgart, L. H., Wood, C. B. ibid. p. 1249. 9. Cotton, P. B. ibid. 1979, i, 150. 10. Blumgart, L. H., Wood, C. B. ibid. p. 274. 6. Ulmsten,
L. ibid.
(in the
(ng/g dry weight/min, means±S.E.M.
*Mann-Whitney rank-sum test (two tailed). These in-vitro data have been supported by in-vitro observaof an increase in P.G.E in cervical venous effluent during parturition (unpublished). Attempts have been made to ripen the sheep cervix with P.G.F but these have had limited success,I5 Our most recent data show that only a small fraction ofp.G. production by the cervix is P.G.F, and there is no significant change when compared with late pregnancy. We believe that P.G.s synthesised and acting locally are of major importance in the ripening process and that P.G.E rather than P.G.F is the major prostaglandin involved. Furthermore, we suggest that oestrogens may act on the cervix via local stimulation of p.G.E synthesis. These observations in sheep may well relate to the reported clinical effects of P.G.s on the cervix. P.G.E is a more potent agent than P.G.F for ripening the unfavourable human cervix,16 and this may well reflect a direct local action of P.G.E. In contrast, a recent report has suggested that high doses of P.G.F (50 mg) are as effective as P.G.E, although half the patients in this study went into labour before the proposed induction." This may well represent cervical ripening achieved indirectly via induced uterine activity. A clear distinction must be made between cervical ripening by pretreatment before induction and treatments which cause changes in cervical state by inducing labour. Finally one must consider whether or not cestrogens are involved in the normal mechanism of cervical ripening. In sheep the sharp rise in free circulating oestrogens before parturition18 correlates well with the dramatic changes in the cervix, although the exact timing of the changes in cervical compliance brought about by ripening of the tissue is not known. 19 There is no evidence that a similar "oestrogen surge" is associated with human parturition,2O although the gradual changes in the human cervix during the last trimester of pregnancy may correlate with gradually rising levels of oestrogens in the peripheral plasma. The human cervix has been shown to contain both progesterone21 and oestrogen receptors22 and it is probable that the changing steroid environment during late pregnancy and at term has a direct local action on the cervix. In summary, the mechanism by which the cervix ripens before effacement and dilatation during labour is still unknown and further research is required to provide a sound scientific basis for the drug treatments which cause cervical tions
NEW GEL FOR INTRACERVICAL APPLICATION OF PROSTAGLANDIN E2
SIR,-Local (intracervical or intravaginal) application of prostaglandin Ez (p.G,Ez) ripens the uterine cervix and/or induces labour in patients at term and has no systemic sideeffects.’-5 Local application has been made possible by mixing the prostaglandins with a viscous medium giving a gel. As viscous medium different types of cellulose (e.g., ’Tylose’ or ’Hypromellose’) are used. However, the preparation of the gel is time-consuming. Moreover, the prostaglandins are unstable and it is not known to what extent they are inactivated during preparation and storage of the gel. In clinical routine, a more simple and standardised preparation of the p.G.Ez-gel should therefore be most valuable. We have obtained promising results using the following technique. A freshly made up sterile solution of p .G.Ez (Upjohn) in 80% aqueous ethanol is aseptically added to a special powder based on a cross-linked starch polymer (Perstorp AB, Sweden). After homogenisation and lyophilisation a powder containing a predetermined amount of P.G.E, is obtained. Chemical analysis6 shows that this powder can be stored at room temperature for more
than 3 months without
a
decrease in the
amount
of un-
changed p.G.Ez. Before application, a few millilitres of saline is added to the powder. This swells within 30 s giving an easily-handled, readyto-use gel. The viscosity is easily modified by varying the volume of saline. The gel produces an effect on the cervix equal to or better than that obtained with previously used cellulose gels containing the same amount of p.G.Ez. No systemic or local sideeffects have been observed after treatment with the new gel. ULF ULMSTEN
OLOF JOHANSSON ANDERS KIRSTEIN-PEDERSEN
Department of Obstetrics and Gynæcology PÅL STENBERG University Hospital, LARS WINGERUP Malmö, Sweden
SAFETY OF INTRAVAGINAL PROSTAGLANDIN F2&agr; SIR,-In reference to Dr MacLennan and Roslyn Green’s paper of Jan. 20 (p. 117) I would remind your readers of the extreme sensitivity to this particular prostaglandin preparation found in many patients with reversible obstructive airway disease (asthma). In the general population there are many people with obstructive lung disease, both diagnosed and undiagnosed, and clinicians should be warned against using such prostaglandin preparations in the induction of labour without bearing in mind the risk of precipitating an episode of acute status asthmaticus. A careful history should be taken, and if there is even the slightest hint of an obstructive lung condition this preparation should not be used. 27301 Dequindre, Suite 104, Madison Heights, Michigan 48071, U.S.A.
BRUCE D. DUBIN
ripening. This work
was
supported by
Nuffield Department of Obstetrics and Gynæcology, and Gynæcology, Obstetrics
University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU
the Medical Research Council.
DAVID A. ELLWOOD MURRAY D. MITCHELL ANNE B. M. ANDERSON A. C. TURNBULL
14 Ellwood, D. A., Mitchell, M. D., Anderson, A. B. M., Turnbull, A. C. J. Endocr (in the press). 15 Fitzpatrick, R. J. in Fetus and Birth: Ciba Fndn Symp. no. 47, p. 31. Lon-
don, 1977 16 MacKenzie, I. Z., Embrey, M. P. Br.J. Obstet. Gynæc. (in the press). 17 MacLennan, A. H, Green, R.C. Lancet, 1979, i, 117. 18 Challis, J. R. G Nature, 1971, 229, 208. 19 Fitzpatrick, R J.Ann. Rech. vet 1977, 8, 438. 20 Turnbull, A C., Flint, A. P. F., Jeremy, J. Y., Patten, P. T., Keirse, 21 22
M. J.N.C, Anderson, A.B.M. Lancet, 1974, i, 101. Sanborn, B.M., Held, B., Kuo, H S J Steroid Biochem. 1976, 7, 665. Sanborn, B. M., Held, B., Kuo, H. S. ibid. 1975, 6, 1107.
ENDOSCOPIC TREATMENT OF BILIARY-TRACT DISEASES
SIR,-Following Professor Safrany’s survey of endoscopic of biliary-tract disease your correspondentsS,jO have
treatment
1. Calder, A. A., Embrey, M. P., Tait, T. Br. J. Obstet. Gynæc 2. MacKenzie, I. Z., Embrey, M. P. Br. med. J. 1977, ii, 1381. 3. Shepherd, J., Sims, C., Craft, I. Lancet, 1976, ii, 709.
1977, 84, 264.
4. Thiery, M., Benijts, G., Derom, R., Martens, G., Amy, J. J., Van Ketz, H., De Schrijver, D. Prostaglandins, 1978, 15, 175. 5. Wingerup, L., Andersson, K.-E., Ulmsten, U. Acta obstet. gynœc. scand.
1978, 57, 403. U., Kirstein-Pedersen, A., Stenberg, P., Wingerup, press). 7. Safrany, L. Lancet, 1978, ii, 983. 8. Blumgart, L. H., Wood, C. B. ibid. p. 1249. 9. Cotton, P. B. ibid. 1979, i, 150. 10. Blumgart, L. H., Wood, C. B. ibid. p. 274. 6. Ulmsten,
L. ibid.
(in the
