Misoprostol : pharmacokinetics and effects on uterine contractility and cervical ripening in early pregnancy
Author: Aronsson, Annette
Date: 2007-09-07
Location: Skandiasalen, Astrid Lindgrens Barnsjukhus, Karolinska Univeristetsjukhuset, Solna
Time: 09.00
Department: Institutionen för kvinnors och barns hälsa / Department of Women's and Children's Health
View/ Open:
thesis.pdf (975.5Kb)
Abstract
Misoprostol is an orally active synthetic PGE1 analogue which has become
an important drug in obstetric and gynaecological practice because of its
uterotonic and cervical priming actions. It is safe, cheap, widely
available and stable at room temperature. Misoprostol has been found to
be useful for medical abortion, cervical priming prior to surgical
abortion, evacuation of the uterus in cases of incomplete abortion,
missed abortion and intrauterine foetal death, induction of labour and
treatment and prevention of post-partum haemorrhage. It was discovered in
clinical studies that the misoprostol tablets licensed for oral use could
be administered by other routes and that this could influence efficacy. A
better understanding of the impact of the route of administration would
thus help to further improve misoprostol regimens for several
indications. The aims of this thesis were therefore to evaluate the
effect of different administration routes and doses of conventional
misoprostol and a new slow release (SR) formulation of misoprostol,
focusing on its effects on uterine contractility and the pharmacokinetic
profile of misoprostol free acid (MPA). In addition, the effect of
misoprostol on inflammatory mediators in the cervix was investigated.
Healthy women with a normal intrauterine pregnancy in the first trimester
who requested vacuum aspiration for termination of pregnancy were
recruited for the studies.
Uterine contractility was studied after treatment with oral (400 μg), vaginal (400 μg) or sublingual misoprostol (200 or 400 μg). Regardless of the dose and route of administration, the first effect of misoprostol to be observed was a rise in tonus which was more pronounced after oral or sublingual administration. Following sublingual and vaginal administration, regular uterine contractions developed, while oral treatment had only a minor effect on uterine contractions. The response to oral treatment with 400 and 800 μg SR misoprostol was also compared to the response to 400 μg conventional oral misoprostol. SR misoprostol was found to have less effect on uterine tonus, although it was more potent in terms of inducing uterine contractions. The pharmacokinetic profile of MPA following administration of SR misoprostol compared to conventional vaginal and sublingual misoprostol revealed lower peak plasma levels but a longer lasting elevation of these plasma levels.
The effect of 400 μg oral or vaginal misoprostol on inflammatory mediators in the cervical tissue was compared with an untreated control group. Immunohistochemical analysis was performed on cervical biopsies. Treatment with misoprostol was associated with higher levels of leukocytes (CD45), and monocytes (CD68) in the cervix compared to untreated controls. A greater staining of MMP 8 and MMP 9 was found following treatment, while TIMP 1 and 2 expression did not differ between the treatment and control groups.
Taken together, the results indicate that the peak MPA serum levels seem to correlate with uterine tonus, while the duration of elevated serum levels seems to correlate with the effect on uterine contractility. A certain threshold level of MPA is needed, but once this is reached; the duration of elevated MPA over this critical threshold seems to be the most important parameter in terms of inducing contractions. The findings relating to the pharmacokinetic properties and the effect on uterine contractility of different routes of administration will enable clinicians to design optimal regimens for various clinical applications.
Uterine contractility was studied after treatment with oral (400 μg), vaginal (400 μg) or sublingual misoprostol (200 or 400 μg). Regardless of the dose and route of administration, the first effect of misoprostol to be observed was a rise in tonus which was more pronounced after oral or sublingual administration. Following sublingual and vaginal administration, regular uterine contractions developed, while oral treatment had only a minor effect on uterine contractions. The response to oral treatment with 400 and 800 μg SR misoprostol was also compared to the response to 400 μg conventional oral misoprostol. SR misoprostol was found to have less effect on uterine tonus, although it was more potent in terms of inducing uterine contractions. The pharmacokinetic profile of MPA following administration of SR misoprostol compared to conventional vaginal and sublingual misoprostol revealed lower peak plasma levels but a longer lasting elevation of these plasma levels.
The effect of 400 μg oral or vaginal misoprostol on inflammatory mediators in the cervical tissue was compared with an untreated control group. Immunohistochemical analysis was performed on cervical biopsies. Treatment with misoprostol was associated with higher levels of leukocytes (CD45), and monocytes (CD68) in the cervix compared to untreated controls. A greater staining of MMP 8 and MMP 9 was found following treatment, while TIMP 1 and 2 expression did not differ between the treatment and control groups.
Taken together, the results indicate that the peak MPA serum levels seem to correlate with uterine tonus, while the duration of elevated serum levels seems to correlate with the effect on uterine contractility. A certain threshold level of MPA is needed, but once this is reached; the duration of elevated MPA over this critical threshold seems to be the most important parameter in terms of inducing contractions. The findings relating to the pharmacokinetic properties and the effect on uterine contractility of different routes of administration will enable clinicians to design optimal regimens for various clinical applications.
List of papers:
I. Aronsson A, Bygdeman M, Gemzell-Danielsson K (2004). "Effects of misoprostol on uterine contractility following different routes of administration." Hum Reprod 19(1): 81-4
Pubmed
II. Aronsson A, Ulfgren AK, Ståbi B, Stavreus-Evers A, Gemzell-Danielsson K (2005). "The effect of orally and vaginally administered misoprostol on inflammatory mediators and cervical ripening during early pregnancy." Contraception 72(1): 33-9
Pubmed
III. Fiala C, Aronsson A, Stephansson O, Gemzell-Danielsson K (2005). "Effects of slow release misoprostol on uterine contractility in early pregnancy." Hum Reprod 20(9): 2648-52. Epub 2005 May 26
Pubmed
IV. Aronsson A, Fiala C, Stephansson O, Granath F, Watzer B, Schweer H, Gemzell-Danielsson K (2007). "Pharmacokinetic profiles up to 12 h after administration of vaginal, sublingual and slow-release oral misoprostol." Hum Reprod 22(7): 1912-8. Epub 2007 May 8
Pubmed
I. Aronsson A, Bygdeman M, Gemzell-Danielsson K (2004). "Effects of misoprostol on uterine contractility following different routes of administration." Hum Reprod 19(1): 81-4
Pubmed
II. Aronsson A, Ulfgren AK, Ståbi B, Stavreus-Evers A, Gemzell-Danielsson K (2005). "The effect of orally and vaginally administered misoprostol on inflammatory mediators and cervical ripening during early pregnancy." Contraception 72(1): 33-9
Pubmed
III. Fiala C, Aronsson A, Stephansson O, Gemzell-Danielsson K (2005). "Effects of slow release misoprostol on uterine contractility in early pregnancy." Hum Reprod 20(9): 2648-52. Epub 2005 May 26
Pubmed
IV. Aronsson A, Fiala C, Stephansson O, Granath F, Watzer B, Schweer H, Gemzell-Danielsson K (2007). "Pharmacokinetic profiles up to 12 h after administration of vaginal, sublingual and slow-release oral misoprostol." Hum Reprod 22(7): 1912-8. Epub 2007 May 8
Pubmed
Issue date: 2007-08-17
Rights:
Publication year: 2007
ISBN: 978-91-7357-293-4
Statistics
Total Visits
Views | |
---|---|
Misoprostol ...(legacy) | 927 |
Misoprostol ... | 199 |
Total Visits Per Month
September 2023 | October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | |
---|---|---|---|---|---|---|---|
Misoprostol ... | 0 | 2 | 1 | 1 | 1 | 1 | 0 |
File Visits
Views | |
---|---|
thesis.pdf | 1570 |
thesis.pdf(legacy) | 611 |
thesis.pdf.txt(legacy) | 2 |
Top country views
Views | |
---|---|
United States | 384 |
China | 86 |
Sweden | 67 |
Germany | 57 |
Egypt | 39 |
South Korea | 37 |
India | 25 |
United Kingdom | 18 |
Russia | 18 |
Finland | 15 |
Top cities views
Views | |
---|---|
Seoul | 30 |
Beijing | 29 |
Sunnyvale | 25 |
Romeo | 22 |
Kiez | 20 |
Stockholm | 15 |
Ballerup | 12 |
Cairo | 12 |
Ashburn | 10 |
Helsinki | 9 |