Margareta Steinwall

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Receptor binding of oxytocin and vasopressin antagonists and inhibitory effects on isolated myometrium from preterm and term pregnant women

Objective To test binding affinities for, and inhibitory effects on, myometrium of some oxytocin and vasopressin antagonists with respect to their therapeutic potential.

FE 200 440: a selective oxytocin antagonist on the term-pregnant human uterus

Objective To compare a newly developed oxytocin antagonist, FE 200 440, with atosiban and ANTAG III, as to potency and selectivity of inhibitory effects on oxytocin‐ and vasopressin‐induced myometrial responses. FE 200 440 has high affinity for the human cloned oxytocin receptor, approximately 300‐fold that for the vasopressin V1a receptor, whereas atosiban binds well to both receptors.

The effect of relcovaptan (SR 49059), an orally active vasopressin V1a receptor antagonist, on uterine contractions in preterm labor

Relcovaptan (SR 49059) is a non-peptide, orally active vasopressin V1a 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.

Inhibitory effects of SR 49059 on oxytocin- and vasopressin-induced uterine contractions in non-pregnant women

Background.  Compounds that block uterine oxytocin and vasopressin V1a receptors have a therapeutic potential in preterm labor and primary dysmenorrhoea. The orally active vasopressin V1a receptor antagonist, SR49059, inhibits the effect of vasopressin on human uterine activity in vivo, but the influence on the response to oxytocin is unknown.

Effects of the vasopressin V1a receptor antagonist, SR 49059, on the response of human uterine arteries to vasopressin and other vasoactive substances

BACKGROUND Arginine vasopressin (AVP) activates the uterus via V1a receptors and is apparently an important factor for the myometrial hyperactivity, uterine ischemia and pain of primary dysmenorrhea. The orally active and selective, non-peptide AVP1a receptor antagonist, SR 49059, has been shown to inhibit the myometrial action of AVP, but the specific influence of this substance on the effects of AVP and other vasoactive agents on human uterine arteries is unknown. METHODS Concentration-responses of AVP on isolated medium-sized human uterine arteries were studied after incubation with only vehicle (DMSO, 0.1%) and with SR 49059 in concentrations of 0.5, 2.5 and 10 nmol/L. Furthermore, the concentration-responses of AVP were investigated without and with SR 49059 (2 and 10 nmol/L) on small and medium-sized arteries. Finally, the influence of 2.5 nmol/L of SR 49059 on concentration-responses of endothelin-1, noradrenaline and prostaglandin F2 alpha was studied. RESULTS The EC50 for AVP on medium-sized arteries was 0.53 +/- 13 nmol/L. SR 49059 caused a competitive, dose-dependent inhibition of AVP-responses, the highest concentration giving an EC50 of 460 nmol/L. The pA2 value was 9.84. The responses of the small artery preparations to AVP, both without and with the antagonist, were more pronounced than those of the medium-sized ones. The vasoconstrictive effects of endothelin-1, noradrenaline and prostaglandin F2 alpha were less pronounced than those of AVP and unaffected by pre-exposure to SR 49059. CONCLUSIONS The high potency of AVP on human uterine arteries, particularly those of small size, supports an involvement of the peptide in the regulation of uterine blood flow in both physiological and pathophysiological condition. SR 49059 is a potent and selective AVP V1a receptor antagonist in the smooth muscle of human uterine arteries.

Oxytocin mRNA content in the endometrium of non-pregnant women.

Objective  To study oxytocin mRNA in the human endometrium at different phases of the menstrual cycle.

ONO‐8815Ly, an EP2 agonist that markedly inhibits uterine contractions in women

Objective  To determine the effect of ONO‐8815Ly on uterine contractions.

Osmotically-induced release of vasopressin and oxytocin in non-pregnant women - influence of estrogen and progesterone

BACKGROUND Circulating vasopressin and oxytocin are influenced by ovarian steroid blood levels, but the effect of estrogen and progestogen treatment on induced release of the posterior pituitary hormones is not clear. METHODS Eight postmenopausal women who had not been on hormonal replacement therapy for at least two months were included in the study. The women were treated for four weeks with transdermal administration of estradiol-17beta in a daily dose of 100 microg with the addition of 5 mg tablets of medoxyprogesterone twice daily for the last two weeks. A 25 minute intravenous infusion of hypertonic saline (0.06 mg/kg/min) was given before hormonal treatment, and after two and four weeks with serial plasma sampling for assay of vasopressin and oxytocin. RESULTS The mean basal concentration of vasopressin, which was 0.83+/-0.13 (SE) pmol/L before hormonal treatment, increased to a statistically significant degree after estradiol alone to 1.18+/-0.11 pmol/L and decreased after combined estrogen/progestogen treatment to 0.31+/-0.02 pmol/L. Sodium concentration and osmolality increased in a similar way during all three infusions, but the resultant increase in vasopressin concentration was significantly smaller and slower after treatment with estradiol alone than in the first experiment without pretreatment. The areas under the concentration curve for the second and third infusion were significantly smaller than when no hormone treatment was given. The induced hyperosmolality also caused a rise in oxytocin levels, but no influence of ovarian hormone treatment was observed. CONCLUSIONS Ovarian hormone administration influences vasopressin secretion, affecting both the basal levels in plasma and the responses to an increase in plasma osmolality. The influence of ovarian hormones on oxytocin secretion is minimal.