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The Effect of Relcovaptan (SR 49059), an Orally Active Vasopressin V^Sub 1a^ Receptor Antagonist, on Uterine Contractions in Preterm Labor

Posted on: Thursday, 26 May 2005, 03:00 CDT

Abstract

Relcovaptan (SR 49059) is a non-peptide, orally active vasopressin V^sub 1a^ receptor inhibitor. The effect on uterine contractions in 18 women with preterm labor in pregnancy weeks 32- 36 was assessed in a double-blind investigation. The inclusion criterion was at least four regular uterine contractions over 30 min as measured by external tocodynamometry. Twelve patients received at random a single oral dose of 400 mg relcovaptan and six received placebo, and contractions were monitored up to 6 h thereafter. Rescue medication (β-adrenoceptor-stimulating drug) was allowed after 2 h. Before drug administration a mean ( SE) of 8.2 1.4 and 9.7 1.6 contractions/30 min were recorded in the relcovaptan- and placebo-treated groups, respectively. In the former group, the frequency of uterine contractions started to decrease within the first half hour, and 1.5-2 h after dosing it was steady at 3.2 0.9 contractions/30 min. Correspondingly, after placebo, 7.8 2.2 contractions/30 min were recorded, a statistically significant difference (p = 0.017). The activity in the relcovaptan-treated women remained low, whereas in the placebo group inhibited uterine contractions were observed only in women receiving 'rescue' tocolytic treatment. It is concluded that relcovaptan inhibits preterm labor.

Keywords: Preterm labor, vasopressin V^sub 1a^ receptor, oxytocin receptor, antagonist

Introduction

The initiation of uterine contractions in pregnant women, both preterm and at term, may involve oxytocin, which is released from the posterior pituitary [1] and/or locally synthesized in the uterus [2,3]. An up-regulation of uterine oxytocin receptors, on which this hormone has its predominant action, is also a possible mechanism of importance for the onset of labor contractions [4,5]. The oxytocin- related posterior pituitary hormone vasopressin is also produced by the fetus during stressful conditions such as labor [6], and this hormone has a powerful effect on the uterus via the vasopressin V^sub 1a^ receptor [5,7]. Oxytocin also binds to this receptor to some extent, as does vasopressin to the uterine oxytocin receptor of pregnant women [7]. Whether or not vasopressin contributes to the start of preterm and/or term labor is, however, unclear.

In women with preterm labor we have shown that contractions can be stopped or markedly reduced by atosiban, a peptide compound that antagonizes oxytocin and vasopressin V^sub 1a^ receptors [8], and the effect of this analog was confirmed in subsequent studies [9- 11]. Relcovaptan (SR 49059; Sanofi Synthelabo, Montpellier, France) is a non-peptide, orally active vasopressin V^sub 1a^ receptor inhibitor, which has a similar binding to the oxytocin and vasopressin V^sub 1a^ receptors to atosiban [7]. Relcovaptan inhibits vasopressin-induced uterine contractions in non-pregnant healthy volunteers [12]. It also prevents pain of primary dysmenorrhea [13], a condition in which increased vasopressin release is apparently of etiological importance [14-16]. In the present study we investigated the effect of blocking vasopressin V^sub 1a^ receptors by orally administrated relcovaptan on uterine contractions in women with preterm labor.

Materials and methods

Subjects

Nineteen pregnant women, aged 20-40 years and with a gestational age of more than 31 but less than 37 weeks, based on date of the last menstrual period and ultrasound examination between 12 and 20 weeks, were included in the study. This study was performed in the University Clinics of Sweden (Lund three patients, Malm three, Huddinge two), France (Paris two patients, Montpellier one) and Poland (Bialystok seven patients, Warsaw one). The patients all had four or more regular uterine contractions per consecutive 30 min, documented by external tocography during the 45 min preceding study medication intake. The amniotic membranes were intact and the cervical dilatation was less than 3 cm with an effacement of less than 50%. Women with clinical evidence of urinary tract infection or chorioamnionitis, signs of pre-eclampsia, abruptio placentae, fetal malformation, multiple pregnancy or those having received other tocolytic treatment within the previous 72 h were not included in the study. Use of placebo treatment was allowed in view of the short duration of treatment before rescue therapy was permitted and the relatively long pregnancy length of > 31 weeks. All patients gave their written consent to participation in the delivery room prior to their inclusion in the study. The local ethics committees in each country approved the study.

Study procedure

A complete medical examination was performed within 45 min before study drug intake and after 48 h. Cardiotocography with a preset external tocodynamometry sensor and Doppler recording of fetal heart rate was performed throughout each experiment in each center (Hewlett-Packard, series 50). Blood pressure, maternal heart rate and body temperature were recorded repeatedly. Vaginal examination with classification of the cervical status according to the Bishop's score was performed at the initial examination, after 6 h, and at the end of study visit after 48 h. Samples for estimations of routine laboratory safety parameters in plasma and urine were obtained. Furthermore, urine for bacterial culture was sampled.

After the 45-min observation period the women were randomly and double-blind given capsules of 400 mg relcovaptan or placebo by the oral route with 100 ml of tap water. Twelve women received the study drug and seven received placebo. Randomization was performed by block of three and per center in order to provide more 'potentially active' drug than placebo to each center (ethical purpose). Allocation to treatment group was concealed to all participating doctors and patients. No intercurrent medication was allowed between drug intake and until 2 h. Thereafter, a rescue medication of β- adrenoceptor-stimulating drug in accordance with the routines of the respective clinics could be administered. In order to avoid any confounding influence on local release of vasopressin, no intravenous infusion or oral intake of fluid was permitted from 45 min before drug administration until 2 h thereafter.

In order to confirm administration of relcovaptan according to protocol, the plasma concentration of the drug was measured in samples obtained from an antecubital vein immediately before drug intake and after 1-3 h.

Handling of data and statistical methods

The tocodynamometry recordings were read and blindly analysed by the study co-ordinator. A primary analysis was performed for the entire 6-h measurement period with a secondary analysis excluding data obtained after administration of'rescue medication'. The primary efficacy end-point was reduction in frequency of uterine contractions in the 30-min period 1.5-2 h after intake of study drugs, i.e., the last period before 'rescue medication' was allowed. Furthermore, the frequency of uterine contractions per 30-min period up to 6 h after treatment was to be summarized, and any differences between the two subject groups were explored.

Secondary outcome parameters were maternal and fetal safety, change in cervical Bishop's score, estimated gestational age at delivery and birth weight.

The sample size calculation was to a large extent empirical. Based on published data [9-11], the placebo group could be expected to show a reduction of approximately 25% in uterine contractions, with a standard deviation of 40%. A difference between placebo and relcovaptan of 30%, i.e., a 55% reduction from baseline, was considered for this trial. With 12 patients being treated, the study would provide 80% power to detect such a difference with a one- sided test. Thus, it was expected that this first exploratory study would establish only whether or not a favorable trend existed, which would be explored more definitely in future studies.

In the event of a much larger treatment difference between placebo and relcovaptan of 50%, i.e., a 75% reduction from baseline, the study would have 85%> power to show a treatment difference at the conventional two-sided 5% significance level. In this case a more definitive result could be established. The expected 90% confidence interval for the difference from placebo was 27%.

Results

Basic obstetric data of the patients are shown in Table I. No significant differences were found between the patients treated by relcovaptan and those receiving placebo. None of the 19 patients of the study were delivered within the 48-h observation period. One subject was excluded from the analysis, since the randomization code was broken by the investigator within the first 2 h (on placebo) and she was immediately given a tocolytic drug. Analysis of activity results was therefore performed on 18 per protocol patients.

The frequency of contractions over 30-min periods in the groups treated by relcovaptan and placebo is shown in Figure 1. During the baseline pretreatment 30-min period, the mean (SEM) number of contractions in the relcovaptan group was 8.2 4.9 and in the placebo group 9.7 3.9. After treatment, the frequency of contractions in both groups tended to be reduced during the first half hour, whereafter it continued to decrease in the relcovaptan \group, but not in the placebo group. The difference in decrease at 1.5-2 h after dose (57 vs. 26%) was statistically significant (p = 0.017). During the following two consecutive intervals (2-2.5 and 2.5-3 h after dose) two patients in the relcovaptan and two in the placebo group received a 'rescue' tocolytic medication.

In the groups treated with relcovaptan, eight of the patients had their contractions stopped in two consecutive 30-min intervals, whereas this did not occur in the placebo group (significance of difference: p = 0.02). The number of patients who had decreased their contractions by at least 50% from the time of drug administration until the end of observation was seven in the relcovaptan-treated group and one in the placebo group (difference not significant). Furthermore, eight relcovaptan-treated women, but none in the placebo group, had their contractions completely stopped for two or more consecutive 30-min periods. The cervical Bishop's score before (Table I), after 6 h and at the end of the study visit after 48 h did not differ significantly within or between relcovaptan- and placebo-treated patients.

Table I. Basic obstetrics data of the study population at inclusion. Data are reported as mean ( SD).

Figure 1. Frequency of uterine contractions over a 30-min period (toco-dynamometry) before and 6 h after treatment with relcovaptan (n = 12) and placebo (H = 6) in all women including those receiving 'rescue medication' from 2 h and onwards (ten patients on relcovaptan and four on placebo). Means and SEM are indicated. The frequency of uterine contractions over 30 min in the period 1.5-2 h after dose was significantly lower in the relcovaptan- than in the placebo-treated women (p = 0.017).

No serious adverse events occurred during the study period and no side-effect related to study drug administration was observed. The routine safety plasma urine parameters, including bacterial culture in urine, were all found to be normal. The blood pressure in the relcovaptan-treated patients after drug administration tended to be lower and the supine heart rate higher than in the placebo-treated subjects, but not to any statistically significant degree (Figure 2).

After this study women were treated by their obstetrician in various ways according to local routines, but the gestational age at delivery in the two groups did not differ: mean 241 days in the group treated by relcovaptan and 242 days in the placebo group. The birth weights in the two groups were also similar: mean 3448 and 3360 g, respectively.

Figure 2. Supine blood pressure and heart rate (beats per minute, bpm) of women with preterm labor before and after treatment with relcovaptan (n- 12) and placebo (w = 6). Observations after treating women with 'rescue medications' are not included (n= 14 after 2 h). Means and SEM are indicated.

The relcovaptan concentration in plasma in the samples that were obtained 1-3 h after actual drug intake, fell in the range of 84- 931 ng/ml.

Discussion

The results of this study have given the first evidence of an inhibitory action of an orally active vasopressin antagonist on preterm labor contractions. The frequency of contractions was significantly reduced in the group treated by relcovaptan in comparison with that in the women who received placebo. A full inhibitory effect after relcovaptan appeared in the period 1.5-2 h after dose. This observation is in agreement with our findings in a previous study with oral relcovaptan administration and repeated intravenous vasopressin injections for uterine challenge in healthy volunteers [12]. The plasma concentration of relcovaptan 1-3 h after drug intake in the present women was also well above that causing inhibition of vasopressin effects in healthy volunteers [12]. The inhibition of contractions in the present relcovaptantreated patients lasted for the remainder of the 6-h observation period after drug intake.

Although relcovaptan is principally a vasopressin V^sub 1a^ receptor antagonist [7], an action via the oxytocin receptor might to some extent have contributed to the effect. The binding of relcovaptan to the oxytocin receptor is considerably lower than that to the vasopressin V^sub 1a^ receptor, K^sub i's^ in a recent study being 340 and 7.2 nmol/1, respectively [7]. A similar relation in binding to these two receptors was demonstrated for atosiban [7]. It may be that a lower dose would have been more discriminative, having no action on the oxytocin receptor. In fact, in nonpregnant volunteers we recently demonstrated an inhibitory effect of relcovaptan in doses up to 200 mg on the response in uterine activity to 10 pmol/kg body weight of vasopressin, but not on that to 50 pmol/kg body weight of oxytocin [17]. The relative importance of the two receptors in preterm labor can probably not be fully delineated until different receptor-specific analogs have been developed and tested in the human, but vasopressin may play a prominent part.

An interesting finding of this study was the limited placebo response, as compared to that found in the only placebo-controlled investigation performed previously with this type of drug, atosiban [9]. In that study, the decrease in frequency of contractions was 57% in the women treated by drug and 27% in the placebo group. The small response in the placebotreated women of the present study (14%) maybe due to the fact that, in contrast to the previous study, hydration, which influences vasopressin release, was prohibited. It is well known that hydration has a clinical effect on the condition, and intravenous saline infusion is routinely administered to women with preterm labor in many countries [9]. This lack of placebo effect in the absence of hydration supports the importance of vasopressin in the etiology of preterm labor.

No significant effect of relcovaptan on blood pressure and heart rate was observed in the present study, although the blood pressure tended to be lower and supine heart rate higher in relcovaptan- treated patients than in the placebo subjects. This tendency would suggest a mild vasodilatory effect of relcovaptan in accordance with previous findings in a study in hypertensive patients [18]. A possible mechanism of such an effect could be antagonism by relcovaptan of the effects of the endogenous vasopressin on vessel walls. It has been reported that 5-10 mmHg of the normal arterial blood pressure is maintained by the natural secretion of vasopressin [19]. The vasodilatory effect of relcovaptan, if existent, is certainly much less pronounced than that for other tocolytic treatments such as ritodrine and nifedipine [20].

The observed inhibition of uterine contractions in the present study suggests a therapeutic value of the vasopressin V1 a antagonist in the treatment of preterm labor. Since completion of the present study, the development of relcovaptan has been put on hold by the sponsor. However, an orally active vasopressin Vi3 receptor antagonist might be the compound valuable in the maintenance therapy of out-patients with a history of preterm labor.

Acknowledgements

We are grateful to Kent Bergfors and Regis Pignol for excellent monitoring of this study. The study was financially supported by Sanofi-Synthelabo. Drs Rmi Brouard and Gerard Le-Fur are employees of Sanofi-Synthelabo.

References

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5. Bossmar T, kerlund M, Fantoni G, Szamatowicz J, Melin P, Maggi M. Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human myometrium. Effects of the antagonist Atosiban. Am J Obstet Gynecol 1994;171:1634-1642.

6. Chard T, Hudson CN, Edwards CRW, Boyd NHR. Release of oxytocin and vasopressin by the human foetus during labour. Nature 1971;234:352-354.

7. kerlund M, Brouard R, Bossmar T, et al. Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women. Br J Obstet Gynaecol 1999;106:1047-1053.

8. kerlund M, Strmberg P, Hauksson A, et al. Inhibition of uterine contractions of premature labour with an oxytocin analogue. Results from a pilot study. Br J Obstet Gynaecol 1987;94:1040-1044.

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10. Romero R, Sibai BM, Sanchez-Ramos L, et al. An oxytocin receptor antagonist (Atosiban) in the treatment of preterm labor: A randomized, double-blind, placebo-controlled trial with tocolytic rescue. Am J Obstet Gynecol 2000; 182:1173-1183.

11. Worldwide Atosiban versus β-Agonist Study Group. An analysis of the pooled data from three randomised doubleblind controlled trials of the oxytocin antagonist atosiban versus the β-adrenergic agonists ritodrine, terbutaline and salbutamol in the treatment of preterm labour. Br J Obstet Gynaecol 2001;108:133- 142.

12. Bossmar T, Brouard R, Doberl A, kerlund M. Effects of SR 49059, an orally active vasopressin V^sub 1a^ receptor antagonist on vasopressin-induced uterine contractions in women. Br J Obstet Gynaecol 1997;104:471-477.

13. Brouard R, Bossmar T, Fourni-Lloret D, Chassard D, kerlund M. Effect of SR 49059, an orally active vasopressin V^sub 1a^ receptor an\tagonist, in the prevention of dysmenorrhoea. Br J Obstet Gynaecol 2000;107:614-618.

14. kerlund M, Andersson K-E, Ingemarsson I. Effects of terbutaline on myometrial activity, endometrial blood-flow, and lower abdominal pain in women with primary dysmenorrhoea. Br J Obstet Gynaecol 1976;83:673-678.

15. kerlund M, Strmberg P, Forsling M-L. Primary dysmenorrhoea and vasopressin. Br J Obstet Gynaecol 1979;86: 484-487.

16. Ekstrm P, Laudanski T, Mrugacz G, Forsling M, Kindahl H, kerlund M. Stimulation of vasopressin release in women with primary dysmenorrhoea and after oral contraceptive treatment - effect on uterine contractility. Br J Obstet Gynaecol 1992;99:680-684.

17. Steinwall M, Bossmar T, Gaud C, kerlund M. Inhibitory effect of SR 49059 on oxytocin- and vasopressin-induced uterine contractions in non-pregnant women. Acta Obstet Gynecol Scand 2003;82:1-7.

18. Thibonnier M, Kilani A, Rahman M, et al. Effects of the nonpeptide V (1) vasopressin receptor antagonist, SR 49059, in hypertensive patients. Hypertension 1999;34:1293-1300.

19. Cowley AW Jr, Switzer SJ5 Guinn MM. Evidence and quantification of the vasopressin arterial pressure control system in the dog. Circ Res 1980;46:58-67.

20. McCombs J. Update on tocolytic therapy. Ann Pharmacother 1995,29:515-522.

MARGARETA STEINWALL1, THOMAS BOSSMAR1, RMI BROUARD5, TADEUSZ LAUDANSKI2, PER OLOFSSON3, REMIGIUSZ URBAN2, ICERSTIN WOLFF4, GRARD LEFUR5, & MATS KERLUND1

1 Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden, 2 Department of Obstetrics and Gynecology, University Hospital, Bialystok, Poland, 3 Department of Obstetrics and Gynecology, University Hospital, Malm, Sweden, 4 Department of Obstetrics and Gynecology, Hospital of Huddinge, Sweden, and 5 Sanofi-Synthelabo Recherche, Paris, France

Correspondence: M. kerlund, Department of Obstetrics and Gynecology, University Hospital, S-221 85 Lund, Sweden. Tel: +46 46 17 25 20. Fax: + 46 46 15 78 68. E-mail: mats.akerlund@gyn.lu.se

Copyright CRC Press Feb 2005

Source: Gynecological Endocrinology

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