Next step in the development of mesoprogestins: the preclinical profile of EC313.

Introduction: The pharmacological target for progesterone, different progestins, and Selective Progesterone Receptor Modulators (SPRMs) is the nuclear progesterone receptor (PR). EC313 is a new member of a subgroup of SPRMs, mesoprogestins, which combine especially PR- agonistic and PR-antagonistic activities in one molecule. Methods: The suitable in vivo-model for the differentiation of SPRMs from the subgroup of mesoprogestins is the estrogen-primed juvenile rabbit endometrium assay (McPhail Assay). Remarkably, in contrast to other well-known SPRMs with no agonistic effects in this test, EC313 shows clear partial PR-agonistic effects that are higher than that of the well-known mesoprogestin Asoprisnil which already demonstrated remarkable clinical effectiveness for the treatment of uterine fibroids and endometriosis. The findings from the guinea pig studies presented here can be the impetus for further preclinical development of EC313. This model shows the same features for the termination of pregnancy by antiprogestins such as Mifepristone and Ulipristal acetate (UPA) in humans. Moreover, it is possible to distinguish between progestational and anti-progestational activities in the same experiment. Results: The EC313 treatment reveals PR dominance in the genital tract and inhibits unopposed estrogenic effects. In very high doses (30.0 mg/animal/day subcutaneously (s.c.)) given twice on pregnancy days 43 and 44, no premature labor was induced (in contrast to UPA, dosed at 10.0 and 30. mg/animal/day s.c.). The anti-ovulatory activity of EC313 exceeds that of Ulipristal acetate or Mifepristone. EC313 binds to the steroid receptors in vitro with a similar affinity as the natural ligand progesterone. At the glucocorticoid receptor (GR) EC313 acts as a weak inhibitor. Minor activities at the human androgen receptor (AR) and mineralocorticoid receptor (MR) are considered negligible. No binding to the estradiol receptor was detected. In contrast to some in vitro-receptor findings, estrogenic, anti-estrogenic, androgenic, anti-androgenic, glucocorticoid, and anti-glucocorticoid actions were absent in vivo. The tissue selectivity of EC313 was demonstrated previously by reducing the growth and proliferation of uterine fibroids in animal models (lowest effective dosage 0.1 mg/kg/day s.c.).. As shown in this article, the anti-fibroid activity of EC313 was confirmed with a 10 times lower dosage (0.01 mg/kg/day s.c.). It was also shown that EC313 reduces the growth of endometriotic lesions in a human xenograft immune-deficient (NOD-SCID) mice model with a comparatively very low dosage range. In the aforementioned EC313 activity model, UPA was tested as the reference compound, the clinical effectiveness of which has already been demonstrated. Discussion: For an explanation of these findings, the possibility is discussed that the mixed agonistic/antagonistic feature of EC313 is tissue target-specific based on its super-additive synergism characteristic for active bifunctional agents. In conclusion, the specific pharmacodynamic profile of this compound opens the possibility for the development of a drug with a distinct pharmaco-endocrinological profile against uterine fibroids, endometriosis, and other PR-dependent gynecological diseases.

Invasive ultrasound in the management of cervical ectopic pregnancy.

Invasive ultrasound management of a 6-week live cervical pregnancy in a 26-year old primipara is described. The patient was given methotrexate three times at seven-day intervals with no effect. Then 15% KCl was administered intra-amniotically via the transvaginal and transcervical route under ultrasound guidance. The procedure was successful, causing fetal death and loss of trophoblastic blood flow on Doppler examination. Over the subsequent four weeks, there was a steady decrease of serum ß-hCG concentration. After four weeks, curettage of the cervical canal and uterine cavity was performed successfully. This method of treatment enabled avoidance of invasive surgical procedures, which might have limited future fertility.

The Arabin pessary for the treatment of threatened mid-trimester miscarriage or premature labour and miscarriage: a case series.

OBJECTIVE: The Arabin pessary may be beneficial in the treatment of cervical incompetence. The aim of the study was to analyse the efficacy of the treatment method of pregnant women with cervical incompetence. METHODS: A non-randomised study performed in the obstetrical wards in Lodz, Poland utilising 54 pregnant women with cervical incompetence was developed to assess the efficiency of treatment methods of cervically incompetent women. These women were diagnosed by vaginal ultrasound examination during the course of the study. Patients with a cervical length of 15-30 mm before 28 weeks an Arabin cervical pessary were inserted, women whose cervical length was less than 15 mm were treated with cervical cerclage. The main end points of the study were preterm or term delivery. RESULTS: In the Arabin pessary group, 1.9% of women delivered before the 29th week of gestation and 83.3% of women delivered after 37 weeks of pregnancy. Eighty-seven per cent of pregnant women treated for cervical incompetence by Arabin pessary delivered by normal spontaneous labour, 1.9% delivered by forceps labour and 11.1% of patients by caesarean section. Among pregnant women treated by Arabin pessary, 3.7% of newborns were estimated as having a score of 0-4 on the Apgar scale, 13% a score of 5-7 and 83.3% a score of 8-10. CONCLUSIONS: Cervical incompetence treatment effectively prolongs the duration of gestation. Application of the Arabin pessary is an effective method of cervical incompetence treatment.

Sonographical integrated test for detection of chromosomal aberrations.

PURPOSE: Different sonographical and biochemical methods for the detection of an elevated risk of chromosomal abnormality are used. The aim of our study was to establish a diagnostic scheme with the highest sensitivity by means of an algorithm incorporating all parameters. MATERIALS AND METHODS: In a group of 1490 pregnant women, ultrasound examination including nuchal translucency and nasal bone measurement was performed in the first trimester. Then, in the early second trimester, a second ultrasound examination combined with measuring nuchal thickness and nasal bone was carried out. RESULTS: The combination of the NT and NB measurement showed the highest sensitivity (94.7%), specificity (99.21%), PPV (85.7%) and NPV (99.73%). CONCLUSION: The proposed integrated test is characterised by a high predictive value for the detection of chromosomal abnormalities, low cost of performance and absolute safety for the foetus and could be offered to all pregnant women. The combination of two ultrasound examinations and biochemistry greatly increased the value of the test.

Ultrasound evaluation of intrauterine growth restriction therapy by a nitric oxide donor (L-arginine).

OBJECTIVE: There are numerous methods available of treating intrauterine growth restriction but their results are still not satisfactory. Currently, we are conducting a research project whose main aim is based on the use of the nitric oxide (NO) donor L-arginine in growth restriction therapy. The main aim of this study was the ultrasound evaluation of the efficacy of this therapy based on biometric measurements (the estimated fetal weight) compared with the estimated weight of newborn children. STUDY DESIGN: The investigated group comprised two randomly chosen groups of pregnant women with ultrasound-diagnosed intrauterine growth restriction (biometry < 10th centile for gestation age): 78 patients were treated by L-arginine 3 g daily orally for 20 days; and 30 patients, not treated, acted as the control group. RESULTS: The ultrasound estimation of fetal weight at the start and at the end of the treatment showed a mean increase of 642 g (SE 90 g) using the Shepard method, and 648 g (SE 94 g) using the Hadlock method, respectively. By comparison, within the control group a mean value increase of 395 g (SE 77 g) was found, using the Shepard method, and 404 g (SE 82 g) using the Hadlock method, respectively. There was a significant statistical difference when comparing the estimated fetal weight increase in both methods: p=0.008 for the Shepard calculation and p=0.012 for the Hadlock calculation. The weight of the newborn infants was also evaluated: in the treated group the mean value was 2823 g (SE 85 g) and in the untreated group the mean value was 2495 g (SE 147 g). There was a significant (p=0.027) difference, showing a positive effect of the treatment on the weight of newborns. In the treated group the percentage of growth-retarded newborns was 29% while in the untreated group it was 73%. A significant difference has been found (p < 0.01) between both of the groups of newborns. CONCLUSIONS: The ultrasound evaluation of the estimated fetal weight and the birth weight of the newborns showed an improvement: there was an acceleration of fetal development in the L-arginine-treated group of pregnant women as compared with the untreated group. The ultrasound evaluation of the estimated fetal weight is a good diagnostic tool, properly monitoring the efficacy of the L-arginine treatment of the growth-retarded fetuses.

[Pregnancy and delivery in woman after ovarian cancer treatment--case report]. / Ciaza i poród u kobiety po leczeniu raka jajnika--opis przypadku.

The course of pregnancy and delivery in women after surgical and multiagent chemotherapy of ovarian cancer was observed. The patient delivered healthy infant by cesarean section at 39 week of normal pregnancy. During the operation there were taken some of tissue excisions for histological examination. There were no clinical or macroscopic symptoms of the disease but in one of biopsy the malignant cells were present. The patient was treated by chemotherapy four weeks after delivery.

Evaluation of first trimester pregnancy in cases of threatened abortion by means of doppler sonography.

OBJECTIVE: Threatened abortion is one of the major problems in Obstetrics and applies to (1/3) of all pregnancies. The aim of this study was to establish normal ranges for Doppler indices of the flow velocity waveforms in uterine arteries (S/D, RI, PI) and ss-hCG serum concentrations in a control group in the first trimester of pregnancy. The obtained values were compared with those obtained in pregnancies threatened by abortion (6 - 11 weeks). METHODS: Investigated groups: 55 controls and 47 with symptoms of threatened abortion, 27 of them aborted. Ultrasound examinations were carried out by means of an endovaginal probe. Serum ss-hCG was determined by immunoenzymatic method. The standards for measured values were established based on means from measurements obtained in the control group in the corresponding week of pregnancy. RESULTS: We observed negative correlation between gestational age and RI and negative tendencies for S/D and PI indices in the control group. Positive correlation (p < 0.05) was found between ss-hCG serum concentration and gestational age (up to 9(th) week) and significant differences in ss-hCG concentrations between both examined groups. There were also statistical differences for S/D, RI and PI indices in both analyzed groups for each week of pregnancy. CONCLUSION: We conclude that measurement of the quality parameters of the flow velocity waveforms in uterine arteries and calculation of beta-hCG concentration in serum are useful methods in diagnosis of threatened abortion in the first trimester of pregnancy.

[Ultrasonographic assessment of pregnancy development after endometriosis treatment]. / Ultrasonograficzna ocena rozwoju ciazy u kobiet leczonych z powodu endometriozy.

Investigated group comprised pregnant women after sterility treatment, which underwent obstetrical care in Institute of Obstetrics and Gynaecology Medical Academy of Lódz in years 1998-2000. In the first group were 25 pregnant women after endometriosis treatment, the second one 23 healthy pregnant women. At term were performed ultrasound examinations (biometry and estimated fetal weight) than were assessed neonatal weight in both groups. There were found the similar mean age in both groups, but in the group after treatment more women in age over 30 years were observed (not significant). The higher weights were observed in the group of healthy pregnant women in ultrasound fetal estimation before delivery (about 343.5 g) and neonatal weight after delivery (about 407 g) but without significance. There is possibility of the better vascular development in the feto-maternal circulation in the course of pregnancy in healthy women than after endometriosis treatment, but for the correct conclusions should be made further research on larger collectives. Ultrasound assessment is a useful method in prenatal diagnostic with possibility of precise analysis of the fetal development.

[Pregnancy and delivery in women after endometriosis treatment]. / Ciaza i poród u kobiet po leczeniu nieplodnosci spowodowanej endometrioza.

The study was done in Clinic of Pathology Pregnancy in A.M. in Lódz in 1998-2000 y. The first group consist of women after endometriosis treatment--30, the second--30 healthy pregnant women. The course of pregnancy and delivery was observed. High rate of: women over 35 years old, preterm delivery, cervical insufficiency treated surgically, caesarean sections rate were observed in group of women after endometriosis treatment. There was no difference at neonatal state between groups.

[Evaluation of the effectiveness of a low-dose aspirin in the treatment of intrauterine growth retardation (IUGR)]. / Ocena skutecznosci leczenia hipotrofii plodu przy uzyciu malych dawek kwasu acetylosalicylowego.

OBJECTIVE: To evaluate the benefits of IUGR treatment by low doses of acetylsalicylic acid (ASA) (1.5 mg/kg) compared to the standard method. The study was based on the reports that aspirin at low doses shifts prostacyclin/tromboxan A2 balance to the dominance of prostacyclin by inhibiting cyclooxygenase activity in platelets, which results in the improvement of the utero-placental circulation. MATERIAL AND METHOD: 31 pregnant women with diagnosed fetal IUGR were randomly assigned to two groups, receiving either low-dose ASA (n = 22) or the standard treatment (Sadamin, Partusisten, glucose i.v., amino acids i.v.) for 10 days. Ultrasound examination of the biometric parameters of the fetus (BPD, AC, FL) was performed and estimated fetal weight (EFW) calculated before and after treatment. The birthweight of infants in the two examined groups was compared. RESULTS: The mean increase in EFW was higher in the aspirin-treated group compared to that receiving standard treatment (478 g vs 246 g, p < 0.05). In all the biometric parameters under study a higher increase was noted in the group with aspirin treatment; however, the difference was not statistically significant. The mean birthweight was found to be higher in the ASA group as well (2856 g vs 2511 g). The frequency of small-for-gestational-age (SGA) infants (birth weight below 10th percentile) was lower in the ASA group than in the controls (27% vs 55%). The low-dose aspirin therapy did not produce any adverse side-effects either among mothers of infants. CONCLUSION: The treatment with low doses of aspirin reduces the proportion of SGA babies and increases birthweight in the case of a diagnosed fetal growth retardation. Since the number of subjects in this study was relatively small, further clinical trials are necessary to evaluate the effectiveness of IUGR treatment by low-dose aspirin.