2. SLIDES OF CONTENTS
Abt SPRM
Counting on drugs
Little intro of drugs
uses… like in EC, action on endometrium, and certain
gynaecological tumors
3. SPRM ?
A selective progesterone receptor modulator (SPRM) is an
agent that act on the progesterone receptor. A
characteristic that distinguishes such substances from
receptor full agonists (such as progesterone) and full
antagonists (such as aglepristone) is that their action
differs in different tissues (agonist in some while
antagonist in others).
4. This mixed agonist/antagonist profile of action leads to
selective stimulation or inhibition progesterone-like action in
different tissues and furthermore raises the possibility of
dissociation of desirable therapeutic effects from undesirable
side effects in synthetic progesterone receptor drug
candidates.
5. How many do we have ?..
Mifepristone (RU 486)
Ulipristal acetate (UPA)
Telapristone
Asoprisnil (ASP)
6. Mifepristone (RU 486)
Mifepristone (or RU-486) is a synthetic, steroidal antiprogestogen
and antiglucocorticoid drug.
Mifepristone is a low-efficacy partial agonist of the progesterone
receptor used as an abortifacient in the first months of pregnancy,
and in smaller doses as an emergency contraceptive.
It is also a glucocorticoid receptor antagonist to a lesser extent, and
has occasionally been used in refractory Cushing's syndrome.
7. Mifepristone was the first antiprogestin to be developed and it
has been evaluated extensively for its use as an abortifacient.
The original target for the research group was the discovery
and development of compounds with antiglucocorticoid
properties.
These antiglucocorticoid properties are of great interest in the
treatment of severe mood disorders and psychosis, although a
review of published articles was inconclusive on their efficacy,
and considered the use of these drugs in mood disorders at
'proof of concept' stage
8. Indications
1 .Medical termination of intrauterine pregnancies of up to 49
days gestation (up to 63 days gestation in Britain and Sweden)
2 .Softening and dilatation of the cervix prior to mechanical
cervical dilatation for pregnancy termination
3 . Use in combination with gemeprost for termination of
pregnancies between 13 and 24 weeks gestation
4. Labor induction in fetal death in utero
9. cont…
Mifepristone showed no detectable anti-HIV activity in
clinical trials.
Mifepristone showed initial promise in psychotic major
depression, a difficult to treat form of depression, but a
phase-III clinical trial was terminated early due to lack of
efficacy.
Mifepristone treatment produced clinical improvement in
PTSD symptoms in a small clinical trial published in 2012
10. Ulipristal Acetate (UPA)
As a SPRM, ulipristal acetate has partial agonistic as well as
antagonistic effects on the progesterone receptor. It also binds to the
glucocorticoid receptor, but has no relevant affinity to the estrogen,
androgen and mineralocorticoid receptors.
Phase II clinical trials suggest that the mechanism might consist of
blocking or delaying ovulation and of delaying the maturation of the
endometrium.
11. furthermore…
FDA Approval 13 August 2010.
Ulipristal acetate is metabolized in the liver, most
likely by CYP3A4, and to a small extent by
CYP1A2 and CYP2D6.
USE:- Emergency Contraception and Uterine
fibroids
12. Telapristone
Telapristone acetate is an investigational selective progesterone
receptor modulator (SPRM) being studied for the treatment of
certain progesterone-sensitive conditions.
It was originally developed by the National Institutes of Health
(NIH), and as of 2012, is in phase II clinical trials for the treatment
of uterine fibroids and endometriosis.
In addition to its actions as an SPRM, telapristone also has some
antiglucocorticoid activity.
13. Asoprisnil
Asoprisnil (J867) is an investigational selective
progesterone-receptor modulator.
IS tested for treatment of progesterone-sensitive
myomata.
In 2005, phase-III trials were discontinued due to
endometrial changes in patients.
14. Emergency Contraception
Emergency contraception (EC), or post-coital
contraception, refers to methods of contraception that can
be used to prevent pregnancy in the first few days after
intercourse.
It is intended for emergency use following unprotected
intercourse, contraceptive failure or misuse (such as
forgotten pills or torn condoms), rape or coerced sex.
15. Emergency contraception is effective only in the first few
days following intercourse before the ovum is released
from the ovary and before the sperm fertilizes the ovum.
Emergency contraceptive pills cannot interrupt an
established pregnancy or harm a developing embryo.
16. drugs in EC
WHO recommends levonorgestrel for emergency
contraceptive pill use. Ideally, this progestogen-only
method should be taken as a single dose (1.5 mg) within
five days (120 hours) of unprotected intercourse.
Alternatively, a woman can take the levonorgestrel in two
doses (0.75 mg each; 12 hours apart).
IUDs
SPRMs
17. Various trials B/W SPRM and other medication
with concern EC
A. UPA vs LNG
1696 women received either LNG (n = 852) or UPA (n = 844)
within 72 h of UI.
A total of 15 pregnancies were observed with UPA and 22 with
LNG.
With hormonal EC, being obese carries a threefold increase in the
risk of becoming pregnant; however, this risk is greater with LNG
than UPA.
18. A recently published Cochrane Systematic review indicated
that UPA was more effective within 72 h of intercourse than
LNG, but the difference was not significant (p = 0.09).
Because spermatozoa may be exposed to UPA in the female
genital tract, an in vitro experiment was carried out incubating
sperm with the SPRM; it was observed that UPA did not
modify the signal transduction of TyrP involved in sperm
capacitation and showed no agonist effect on progesterone
receptors because it did not induce the acrosomal reaction.
19. Gestrinone Vs Mifepristone
In 2010, Wu et al. conducted a randomized double blind
trial in China in which 998 women requesting EC received
a single-dose of 10 mg gestrinone (n = 499) or 10 mg MFP
(n = 499).
Failure rates were 2.4% in the gestrinone group compared
with 1.8% in the MFP group (p = 0.51).
20. They concluded that the effectiveness of 10 mg
gestrinone is not significantly different from 10 mg MFP
when used for EC.
Outside China, an open-label Thai study evaluated the
use of 10 mg MFP in 120 women, with no observed
pregnancy and good users’ satisfaction
21. According to Zhou et al. low-dose MFP significantly
increases the number of CD56(+) natural killer (NK) cells
and the percentages of CD3(-) CD56(+) CD16(-) NK cell
subset.
Then there is evidence that NK cells’ cytotoxicity and the
expression of inhibitory receptor CD94/ NKG2A on
peripheral blood NK cells are significantly increased after
being treated with MFP.
MIFEPRISTONE (MFP)
22. Finally, in vitro uterine NK cell cytotoxicity and perforin
expression were increased in a dose-dependent fashion after
treatment with MFP.
On the basis of these data, one may speculate that MFP may
negatively affect implantation by increasing the cytotoxicity of
NK cells.
The fact that cortisol is capable of attenuating or even blocking
NK cell-mediated cytotoxicity, whereas progesterone has no
effect, suggests that MFP acts as a glucocorticoid antagonist.
23. Contraception
According to Spitz, it is well-established that a daily
dose of at least 2 mg MFP is sufficient to block
ovulation, whereas the weekly administration of 25 or
50 mg does not consistently achieve this goal.
In addition, at the dose of 200 mg, MFP has a good,
although non-practical, contraceptive effect if
administered 48 h after the LH surge.
24. In spite of compliance doubts, an Indian group has now tried the
‘mid-cycle’ regimen of MFP in a prospective case-control study; 86
women were given 200-mg MFP tablets on day 16 of the cycle,
whereas 92 received combined oral contraceptive and were
followed for drug compliance, satisfaction, side effects and failure.
As it might have been expected, the study observed that the ‘mid-
cycle’ MFP regimen was significantly more acceptable by women
with a higher education (p < 0.001), with fewer side effects (p =
0.001), good satisfaction (p < 0.001) and higher compliance rate (p
= 0.05).
26. RU 486
Bagaria et al. in studying the effect of the daily
administration of 10 mg MFP on myomas in a double-blind placebo-
controlled trial, noticed that after 3 months of administration some
63% of patients had endometrial hyperplasia without atypia.
In commenting this finding, Fraser pointed out that “the
progesterone receptor modulators do not cause endometrial
hyperplasia, although they do produce endometrial appearances
that are quite unusual”.
27. Ulipristal acetate
In a preliminary study of the pharmacodynamics of 5- and 10-mg UPA
administered daily to 46 normal women recruited in a prospective, placebo-
controlled, randomized trial, amenorrhea occurred in 81.2 and 90% of cases,
respectively.
No cases of endometrial hyperplasia were detected, although estradiol levels
stayed in the physiologic follicular phase range throughout the treatment [55].
Subsequently, the same group tried to compare the effects of UPA (2.5 and 10
mg daily) with placebo in a group of 41 women. In endometrial biopsies, they
checked endometrial vascularization, fibrillar matrix and VEGF-A expression
and found that UPA does not alter any of these parameters.
28. Exposure of human endometrium to UPA causes a significant
increase in the expression of Indian Hedgehog (IHH), a protein
involved in chondrocyte differentiation, and genes involved in its
signaling (smoothened, patched-1, glioma associated oncogene
homolog 1 [GLI1] and [GLI2]).
In particular, during follicular phase there was an increased IHH
expression in all compartments except stromal cytoplasm, whereas
GLI1 was upregulated in glandular nuclei and cytoplasm,
suggesting both progestin regulation and a potential role in
endometrial differentiation and implantation.
29. At 13 weeks of treatment with different doses of UPA the mean
endometrial thicknesses were 9.4 mm in the group receiving 5
mg and 10.7 mm in the group receiving 10 mg. ‘No findings of
clinical concern’ were found, with only one case of simple
hyperplasia.
The already-mentioned specific endometrial changes were
observed in 58% of women receiving 5 mg UPA and in 59% of
those receiving 10 mg.
30. Asoprisnil
Williams et al. have also carried out a careful evaluation of endometrial effects of
asoprisnil (ASP), in a double-blind, randomized, placebo-controlled study; they found
a unique pattern of changes in the endometrium consisting of “partially developed
secretory glandular appearances and stromal changes”, accompanied by decreased
thickness, low mitotic activity in glands and stroma.
Unusually thick-walled muscular arterioles and prominent aggregations of thin-walled
vessels were present only in the stroma. They concluded that, although none of the
changes affecting glands, stroma and vessels per se were specific for ASP, together
they allowed the designation of ‘non-physiologic secretory effect’, specific of ASP.
32. MFP
In 2008, Carbonell Esteves et al. compared in an open-label trial over
a period of 3 months, doses of 10 and 5 mg MFP in 100 women with
leiomyomas and observed at 90 days a reduction in fibroid volume of
45% (p < 0.001) in the first group and a 57% (< 0.001) in the second.
This effect was accompanied by a significant reduction in the
prevalence of symptoms. At the end of treatment, some 90% of
subjects in both groups were amenorrheic.
33. Another open-label trial evaluated the effectiveness over
a 6-month period of a very low dose of 2.5 mg MFP in
17 women with a total uterine volume of > 160 cm3, or
at least one myoma of > 2.5 cm diameter.
Each of the parameters evaluated showed significant (p
< 0.001) effects: uterine volume decreased by 11%;
anemia, bleeding, pain and health status improved.
34. Another metanalysis has just been published by a Chinese group who
“identified all of the studies published before December 2012 that compared the
status of patients with leiomyoma before and after treatment with mifepristone”.
This analysis included 11 randomized controlled trials of MFP at doses between
2.5 and 25 mg/day for 3 -- 6 months, involving 780 women with symptomatic
uterine leiomyomas and concluded that MFP “could effectively reduce uterine
and leiomyoma volume and alleviate leiomyoma symptoms, including
hypermenorrhea, the mean menstrual blood loss, pelvic pain, pelvic pressure,
anaemia, and dysmenorrhoea”.
They also stated that no significant differences could be observed in the rate of
‘atypical endometrial hyperplasia’ between the MFP-treated groups and
controls.
35. Finally, at the beginning of 2014, a report appeared on an
open-label trial in 33 women using the vaginal route for
the administration of 10 mg/day MFP.
Treatment significantly reduced the volume of fibroids
from 135.3 ± 22.9 cm3 to 101.2 ± 22.4 cm3 at 3 months. It
seems therefore that the vaginal route can be usefully
employed when treating uterine leiomyomas.
36. Ulipristal acetate
Over the last decade, the effect of ulipristal on uterine
leiomyomas has been systematically investigated following the
discovery that UPA inhibits proliferation and stimulates
apoptosis, inhibits vascular endothelial growth factor and
adrenomedullin expression in leiomyoma cells, without
affecting normal myometrial cells
37. In 2011, the same group published further results of their randomized, placebo-
controlled double-blind clinical trial aimed at evaluating the efficacy and
tolerability of UPA in 28 women harboring uterine leiomyomas. Again, two
dosages (20 and 10 mg/day) were utilized; all patients were treated for 3
months and a second 3-month course was offered.
Whereas over the 3 months the total volume of fibroids increased by 7% in
controls, it decreased by 24 and 17%, respectively, in the two treatment groups.
In patients who continued for a second 3-month period, fibroid volume further
decreased by 11%. Amenorrhea occurred in 20/26 treated women and in none
of the controls. Of importance the fact that in both treatment groups
haemoglobin concentration improved together with the subjects’ quality of life.
38. Human experimental data now positively show that treatment with
UPA induces apoptosis in uterine fibroid cells. Horak et al. have
treated two groups of 6 and 5 subjects harboring leiomyomas with 5
and 10 mg UPA daily for 3 months and one group of 17 women with
a superagonist GnRH analog.
Ten patients with no hormonal treatment were used as controls.
Following myomectomy or hysterectomy, they found that apoptosis
was present in a significantly higher proportion of patients treated
with UPA compared to the GnRH analog and was absent in
controls.
39. Asoprisnil
In 2007, Chwalisz et al. published the results of a prospective, randomized,
double-blind, placebo-controlled study in 129 subjects with leiomyomas, given
ASP at doses of 5, 10 or 25 mg, or placebo daily for 12 weeks.
They found that this SPRM produces amenorrhea in a dose-dependent
fashion (28, 64 and 83%, respectively) and reduces fibroid and total uterine
volumes.
The decrease was statistically significantly greater in the 25 mg than in the
placebo group, with a reduction at 3 months of 36%.
40. Conclusion
MFP at doses of 10, 12.5 and 25 mg and UPA at the dose of 30 mg have
shown to be effective for up to 120 h after UI.
Data indicate that UPA is more efficacious than LNG during the first 72 h. MFP
is currently marketed as an EC in a few countries, whereas UPA has recently
been approved for EC in 25 countries of Europe and North America.
Important developments have occurred in the field of preoperative treatment of
uterine leiomyomas. Three different SPRM (ASP, MFP and UPA) have been
investigated for this indication with promising results and one (UPA) is now
marketed in Europe and North America for this indication.
41. A recent metanalysis of the use of MFP has identified all
studies published before December 2012 and concluded that
MFP can effectively reduce uterine and leiomyoma volume and
alleviate leiomyoma symptoms, including hypermenorrhea,
menstrual blood loss, pelvic pain, pelvic pressure, anemia and
dysmenorrhea.
With regard to UPA, at daily doses of 20 and 10 mg over 90
days can significantly reduce fibroid volume; treatment also
substantially decreases or eliminates menstrual bleeding and
inhibits ovulation.
