High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16-23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrollment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy = 100%; 95% CI:12-100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

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

OBJECTIVE: To determine the effect of ONO-8815Ly on uterine contractions. DESIGN: A randomised, double-blind, placebo-controlled, dose-ascending, cross-over study. SETTING: Department of Obstetrics and Gynaecology, University Hospital of Lund, Sweden. POPULATION: Seventeen, healthy, parous and permanently sterilised women. METHODS: Intrauterine pressure was recorded on days 1-3 of bleeding of two menstruations. Subjects were intravenously treated with 4 or 8 microg/minute of ONO-8815Ly or placebo for 130 minutes. Intravenous bolus injections of oxytocin, 50 pmol/kg body weight, were given 10 minutes before, during infusion after 60 and 120 minutes and 60 minutes after completion of infusion. The plasma concentrations of ONO-8815Ly were measured in samples obtained immediately before each oxytocin injection. MAIN OUTCOME MEASURE: Area under pressure recording curve (AUC) 10 minutes before and after each oxytocin injection. RESULTS: Twelve women, six in each dose group, completed both recordings. Of these, two women of each group were not included in efficacy analysis due to non-responsiveness to oxytocin or missing baseline value. The AUC over 10 minutes before oxytocin injection after 60 minutes of infusion of ONO-8815Ly at 4 and 8 microg/minute was reduced to 21% and 37% of that before infusion, respectively. The AUC after oxytocin at that time amounted to 21% and 19%, respectively, of that before infusion. The activity and responsiveness remained low after 120 minutes but started to return to baseline 60 minutes after stopping infusion. Placebo had no effect. CONCLUSIONS: ONO-8815Ly is a potent inhibitor of spontaneous uterine contractility in non-pregnant women and it reduces the uterine response to oxytocin injections.

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. DESIGN: Receptor binding studies on transfected cell lines. In vitro contractility studies of human myometrium. SETTING: The Research Laboratory of Sanofi Recherche, Centre de Toulouse, France and the Departments of Obstetrics and Gynecology, Lund University Hospital, Sweden and Bialystok University Hospital, Poland. PARTICIPANTS: Nine women delivered by caesarean section preterm and 37 delivered at term for routine obstetric indications. INTERVENTIONS: The binding affinities of oxytocin, arginine vasopressin, atosiban (1-deamino-2-D-Tyr(OEt)-4-Thr-8-Om-oxytocin), SR 49059 and SR 121463 for the human oxytocin and different subtypes of vasopressin receptors were determined. Concentration-response curves with oxytocin and arginine vasopressin were recorded on myometrium from preterm- and term-delivered women in control experiments and in the presence of 2.5 and 10 nmol/L of SR 49059. Furthermore, using term myometrium, the influence of SR 49059 and SR 121463 in concentrations of 3, 10, 30 and 100 nmol/L on responses to the EC50 concentrations of oxytocin and vasopressin were compared. MAIN OUTCOME MEASURES: Receptor binding affinities. In vitro contractile effects and their inhibitions. RESULTS: Oxytocin had a high affinity for the oxytocin receptor (K(i) in mean = 6.8 nmol/L) and bound, to some extent, to the vasopressin V1a receptor (K(i) = 34.9 nmol/L). Vasopressin displayed higher affinities for vasopressin V1a, V1b and V2 receptors (K(i) = 1.4, 0.8 and 4.2 nmol/L, respectively) than for the oxytocin receptor (K(i) = 48 nmol/L). Atosiban and SR 49059 both had a high affinity for the vasopressin V1a receptor (K(i) = 4.7 and 7.2 nmol/L, respectively, and a moderate one for the oxytocin receptor (K(i) = 397 and 340 nmol/L, respectively). SR 121463 exerted a predominant binding to the V2 receptor (K(i) = 3.0 nmol/L). In the concentration-response experiments levels of up to 10 nmol/L of SR 49059 had no influence on the effect of oxytocin on myometrium from women preterm and at term pregnancy. However, a concentration-dependent inhibition of the responses of both these type of tissues to vasopressin was seen. The effects of EC50 concentrations of oxytocin and vasopressin on term pregnant myometrium were markedly inhibited by 10 nmol/L and higher concentrations of SR 49059, the inhibition of the response to vasopressin being more pronounced than that of the oxytocin response. SR 121463 at maximal concentration only caused slight inhibitions of the oxytocin and vasopressin responses. CONCLUSIONS: Atosiban and SR 49059 both have moderate binding affinities for the human oxytocin receptor and high binding affinities for the vasopressin V1a one. We demonstrated that SR 49059 inhibits the response of term myometrium to oxytocin and that of both preterm and term myometrium to vasopressin. These observations suggest a therapeutic potential of SR 49059 in preterm labour. The vasopressin V2 receptor is apparently not involved to any significant degree in the activation of the pregnant human uterus.

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.

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.