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Controlled-release prostaglandin E2 pessary and cervical ripening
562
LETTERS to the EDITOR Controlled-release prostaglandin and cervical ripening
E2 pessary
Sm,—The controlled-release prostaglandin E2 (PGE2) polymer pessary ’Propess’ was developed to produce a predictable controlled release of prostaglandins when used vaginally to ripen the cervix in labour induction. Initial in-vivo studies with the pessary indicated that the release of prostaglandins as assessed by changes in PGE metabolite concentrations in the peripheral circulation was much slower than that observed with wax pessaries and viscous gels.’ The release of prostaglandins in vivo seems to be similar to that expected from in-vitro studies (figure).2 Dr Kouzam and Dr Ledward’s (July
14, p 119) report is disturbing. However, evidence from kinetic sutdies indicates that "dose dumping" is not the explanation for their experience. In a prospective randomised trial comparing the controlled release pessary with a ’Witepsol’ pessary (Dynamit Nobel, UK) in 190 women with favourable cervical features, no primiparous and 2 multiparous women delivered within three hours of pessary insertion. We have, however, treated 2 patients with the controlledrelease pessary in whom uterine overstimulation arose 4 h after treatment in 1, and 4-5 h after treatment in the other. In these 2 patients, the total release of PGE2 was 5-3 mg and 4-3 mg over that time, as calculated from the amount of PGE2 that was recovered from the pessaries on removal. This was about the amount predicted from the release characteristics of the pessary. Over the past 15 years we have managed patients who have begun labour rapidly after vaginal prostaglandins in various formulations to ripen the cervix or induce labour, and the labours have proved short and uncomfortable. Such labours were infrequent and have generally been confined to multiparae with a favourable cervix at the time of treatment. In over 400 patients treated with the controlledrelease pessary, labour was completed within an hour. In neither of Kouzam and Ledward’s 2 cases of very rapid labour was the cervical score provided, and both patients were multiparous; their third case seems to be irrelevant since they make no mention of labour having started. Careful cervical assessment is essential before treatment with prostaglandins in any form, and is probably best avoided when the cervix is ripe (Bishop score 9 or more). It is therefore essential that those using prostaglandins should be experienced in assessment of the cervix. The pessary has been promoted as a vehicle that can be removed in the event of uterine overstimulation. The difficulties of pessary recovery described by Dr Bex (July 14, p 119), Dr Baravilala (Aug
18, p 437), and their colleagues has also been observed by others. We did
not have this difficulty during the development stages of the pessary, although we have subsequently done so. It has, however, been our experience that increased experience of pessary use generally improves the ease of removal. Although there is no
evidence that long-term retention of the polymer pessary may be a hazard, as Bex et al say, we have a policy in our hospital of ensuring that removal of the pessary is recorded by whoever extracts it from the vagina.
Prostaglandins when given vaginally in any carrier vehicle should be treated with care, and appropriate maternal and fetal observations made following administration. The nonbiodegradable pessary allows removal once labour is established and the management of overstimulation by removal of the pessary or immediate administration of a tocolytic agent. We therefore hope that a reliable retrieval mechanism will soon be developed and that the efficacy of the pessary will be established by clinical trials. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
I. Z. MACKENZIE A. V. G. TAYLOR
IZ, Castle B, Mountford L, Ferguson J, Brennecke S, Embrey MP. Prostaglandin release from preparations used vaginally for the induction of labour. Prostaglandins 1987; 34: 939-46. 2. Taylor AVG, Boland J, MacKenzie IZ. The concurrent in vitro and in vivo release of PGE2 from a controlled release hydrogel polymer pessary for cervical ripening. Prostaglandins 1990; 40: 89-98. 3. MacKenzie IZ, Annan B, Jackson C, Hurley P, Hey F, Newman M. A randomised trial comparing a non-biodegradable polymer PGE2 pessary with a glyceride PGE2 pessary for labour induction. Book of Abstracts for the XII World Congress of Gynecology and Obstetrics. Rio de Janiero, October 1988. Pp 199-200. 1. MacKenzie
SiR,—Dr Khouzam and Dr Ledward report adverse reactions to the controlled release of a prostaglandin E2 pessary (’Propess’, Roussel). They conclude that in-vivo dose dumping is frequent. This statement is not supported by any analytical evidence and disturbs me. The materials from which the propess delivery system was made were developed over thirteen years from polymer chemistry research with which I have been continuously associated. The system was designed from the outset with safety in mind and it is impossible to dump the dose. The pessary is a continuous crosslinked matrix from which the maximum rate of drug diffusion is defmed by physical laws. In the vagina, because of variable water availability, release might be obtained at less than the in vitro maximum attainable rate, but neither higher rates nor dose dumping could be achieved. Low rates are not a safety issue. The issues raised by Khouzam and Ledward, and by Dr Bex and Dr Baravialala and their colleagues, clearly need to be addressed. A mechanism for easy withdrawal of the device, allowing guaranteed termination of a prostaglandin E2 delivery at the judgment of the supervising clinician, is being developed. Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow G1 1XL, UK
N. B. GRAHAM
Screening for uterine neoplasms PGE2 release from 10 mg propess pessary after removal in 24 patients. Rateofre!easeofPGEis09mg/h (95% confidence intervals,6-1 2).
SiR,—Dr Osmers and colleagues (June 30, p 1569) claim that vaginosonography is a suitable screening procedure for the early diagnosis of endometrial cancer, and they have introduced this screening test into routine clinical practice. The current trend towards introduction of screening tests in gynaecological oncology
LETTERS to the EDITOR Controlled-release prostaglandin and cervical ripening
E2 pessary
Sm,—The controlled-release prostaglandin E2 (PGE2) polymer pessary ’Propess’ was developed to produce a predictable controlled release of prostaglandins when used vaginally to ripen the cervix in labour induction. Initial in-vivo studies with the pessary indicated that the release of prostaglandins as assessed by changes in PGE metabolite concentrations in the peripheral circulation was much slower than that observed with wax pessaries and viscous gels.’ The release of prostaglandins in vivo seems to be similar to that expected from in-vitro studies (figure).2 Dr Kouzam and Dr Ledward’s (July
14, p 119) report is disturbing. However, evidence from kinetic sutdies indicates that "dose dumping" is not the explanation for their experience. In a prospective randomised trial comparing the controlled release pessary with a ’Witepsol’ pessary (Dynamit Nobel, UK) in 190 women with favourable cervical features, no primiparous and 2 multiparous women delivered within three hours of pessary insertion. We have, however, treated 2 patients with the controlledrelease pessary in whom uterine overstimulation arose 4 h after treatment in 1, and 4-5 h after treatment in the other. In these 2 patients, the total release of PGE2 was 5-3 mg and 4-3 mg over that time, as calculated from the amount of PGE2 that was recovered from the pessaries on removal. This was about the amount predicted from the release characteristics of the pessary. Over the past 15 years we have managed patients who have begun labour rapidly after vaginal prostaglandins in various formulations to ripen the cervix or induce labour, and the labours have proved short and uncomfortable. Such labours were infrequent and have generally been confined to multiparae with a favourable cervix at the time of treatment. In over 400 patients treated with the controlledrelease pessary, labour was completed within an hour. In neither of Kouzam and Ledward’s 2 cases of very rapid labour was the cervical score provided, and both patients were multiparous; their third case seems to be irrelevant since they make no mention of labour having started. Careful cervical assessment is essential before treatment with prostaglandins in any form, and is probably best avoided when the cervix is ripe (Bishop score 9 or more). It is therefore essential that those using prostaglandins should be experienced in assessment of the cervix. The pessary has been promoted as a vehicle that can be removed in the event of uterine overstimulation. The difficulties of pessary recovery described by Dr Bex (July 14, p 119), Dr Baravilala (Aug
18, p 437), and their colleagues has also been observed by others. We did
not have this difficulty during the development stages of the pessary, although we have subsequently done so. It has, however, been our experience that increased experience of pessary use generally improves the ease of removal. Although there is no
evidence that long-term retention of the polymer pessary may be a hazard, as Bex et al say, we have a policy in our hospital of ensuring that removal of the pessary is recorded by whoever extracts it from the vagina.
Prostaglandins when given vaginally in any carrier vehicle should be treated with care, and appropriate maternal and fetal observations made following administration. The nonbiodegradable pessary allows removal once labour is established and the management of overstimulation by removal of the pessary or immediate administration of a tocolytic agent. We therefore hope that a reliable retrieval mechanism will soon be developed and that the efficacy of the pessary will be established by clinical trials. Nuffield Department of Obstetrics and Gynaecology, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK
I. Z. MACKENZIE A. V. G. TAYLOR
IZ, Castle B, Mountford L, Ferguson J, Brennecke S, Embrey MP. Prostaglandin release from preparations used vaginally for the induction of labour. Prostaglandins 1987; 34: 939-46. 2. Taylor AVG, Boland J, MacKenzie IZ. The concurrent in vitro and in vivo release of PGE2 from a controlled release hydrogel polymer pessary for cervical ripening. Prostaglandins 1990; 40: 89-98. 3. MacKenzie IZ, Annan B, Jackson C, Hurley P, Hey F, Newman M. A randomised trial comparing a non-biodegradable polymer PGE2 pessary with a glyceride PGE2 pessary for labour induction. Book of Abstracts for the XII World Congress of Gynecology and Obstetrics. Rio de Janiero, October 1988. Pp 199-200. 1. MacKenzie
SiR,—Dr Khouzam and Dr Ledward report adverse reactions to the controlled release of a prostaglandin E2 pessary (’Propess’, Roussel). They conclude that in-vivo dose dumping is frequent. This statement is not supported by any analytical evidence and disturbs me. The materials from which the propess delivery system was made were developed over thirteen years from polymer chemistry research with which I have been continuously associated. The system was designed from the outset with safety in mind and it is impossible to dump the dose. The pessary is a continuous crosslinked matrix from which the maximum rate of drug diffusion is defmed by physical laws. In the vagina, because of variable water availability, release might be obtained at less than the in vitro maximum attainable rate, but neither higher rates nor dose dumping could be achieved. Low rates are not a safety issue. The issues raised by Khouzam and Ledward, and by Dr Bex and Dr Baravialala and their colleagues, clearly need to be addressed. A mechanism for easy withdrawal of the device, allowing guaranteed termination of a prostaglandin E2 delivery at the judgment of the supervising clinician, is being developed. Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, Glasgow G1 1XL, UK
N. B. GRAHAM
Screening for uterine neoplasms PGE2 release from 10 mg propess pessary after removal in 24 patients. Rateofre!easeofPGEis09mg/h (95% confidence intervals,6-1 2).
SiR,—Dr Osmers and colleagues (June 30, p 1569) claim that vaginosonography is a suitable screening procedure for the early diagnosis of endometrial cancer, and they have introduced this screening test into routine clinical practice. The current trend towards introduction of screening tests in gynaecological oncology