A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea.

STUDY QUESTION: What is the safe and pharmacodynamically active dose range for PDC31 (prostaglandin F2α receptor inhibitor) in patients with primary dysmenorrhea (PD)? SUMMARY ANSWER: The 1 mg/kg/h dose of PDC31 appears to be safe and potentially effective in reducing intrauterine pressure (IUP) and pain associated with excessive uterine contractility when given as a 3-h infusion in patients with PD. WHAT IS KNOWN ALREADY: PDC31 has previously been shown to reduce the duration and strength of PGF2α-induced contractions in human uterine myometrial strip models and to delay delivery in animal models of preterm labor. STUDY DESIGN, SIZE, DURATION: This was a prospective, multi-center, dose-escalating first-in-human Phase I study conducted from March 2011 to June 2012. A total of 24 women with PD were enrolled and treated with one of five doses (0.01, 0.05, 0.15, 0.3, 0.5 and 1 mg/kg/h) of PDC31 given as a 3-h infusion. Patients were observed for a further 24 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was conducted at four hospitals in Europe in non-pregnant, menstruating women with PD. Women with PD (n = 24) received PDC31 infused over 3 h within 8-10 h of the onset of menstruation. IUP and pain monitoring through the visual analog scale (VAS) was assessed prior to, during and following the infusion. Patients were observed for dose-limiting toxicities and other adverse events. Pharmacokinetic samples were also taken to profile the drug. MAIN RESULTS AND THE ROLE OF CHANCE: A 3-h infusion of PDC31 was safe up to and including doses of 1 mg/kg/h. Most adverse events were mild (n = 15; 83.3%) and not considered associated with PDC31 (n = 14; 77.8%). PDC31 infusion decreased uterine activity based on IUP and pain (VAS) scores. IUP was decreased by 23% over all dose levels, reaching a minimum at 135-150 min. There appeared to be a dose-dependent effect on IUP, with the high dose group (1 mg/kg/h) showing the largest decrease in IUP. There was a statistically significant linear dose-effect and concentration-effect relationship for several IUP parameters over the evaluation period of 60-180 min. A dose differentiating effect on pain was seen with the two highest doses. PDC31 demonstrated uncomplicated, linear pharmacokinetics with a terminal half-life of ∼2 h. LIMITATIONS, REASONS FOR CAUTION: This was a first-in-human study and exposure to PDC31 was limited for safety reasons. As such, pharmacodynamic parameters were assessed at a two-sided Type I error of 20%, an appropriate level for the exploratory nature of this study without a placebo control arm. This limited the chance of false positive findings to one in five. WIDER IMPLICATIONS OF THE FINDINGS: Like PD, preterm labor is associated with prostaglandin-mediated uterine contractions; therefore, the findings of this study support further development of PDC31 as a treatment for both PD and preterm labor. STUDY FUNDING/COMPETING INTERESTS: This work was funded by PDC Biotech GmbH, Vienna, Austria. B.B., R.M.L., L.W., R.J.S., K.J.B. and C.F.S. received reimbursement for the conduct of this study from PDC Biotech GmbH. W.H., M.S. and R.P.S. are paid consultants for PDC Biotech GmbH. P.G. is a paid consultant and shareholder of PDC Biotech GmbH. TRIAL REGISTRATION NUMBER: NCT01250587 at www.clinicaltrials.gov.

Concentrations of inhibins and activin in women undergoing stimulation with recombinant follicle-stimulating hormone for in vitro fertilization treatment.

OBJECTIVE: To investigate the influence of human recombinant follicle-stimulating hormone (FSH) on circulating serum concentrations of the ovarian proteohormones inhibin A, inhibin B, pro alpha-C, and activin A and serum levels of estradiol after down-regulation with GnRH analogue. DESIGN: Serum concentrations of ovarian proteohormones and estradiol. SETTING: Academic clinical practice. PATIENT(S): 30 women who underwent assisted reproductive techniques. INTERVENTION(S): Blood samples were analyzed for inhibin A, inhibin B, pro alpha-C, activin A, and estradiol during IVF treatment at points coinciding with pituitary down-regulation, stimulation with recombinant FSH, ovulatory triggering, and the luteal phase of the cycle. RESULT(S): Activin A levels did not change with recombinant FSH stimulation. In women with a sonographically detected leading follicle >17 mm in diameter, levels of inhibin A, pro alpha-C, and estradiol increased significantly (P<.05). The increase in inhibin B level was not statistically significant. In patients without adequate follicle development during FSH stimulation, serum levels of inhibins remained low and did not significantly deviate from values measured before stimulation. CONCLUSION(S): Inhibin A and pro alpha-C are effective markers of follicular development and may be effective additions to estradiol as a marker.

Inverse correlation between baseline inhibin B and FSH after stimulation with GnRH: a study of serum levels of inhibin A and B, pro alpha-C and activin A in women with ovulatory disturbances before and after stimulation with GnRH.

OBJECTIVE: Interest has focused recently on the influences of the polypeptide factors inhibin and activin on the selective regulation of the pituitary secretion of gonadotropins. DESIGN: Measurement of the concentrations of inhibin-related proteins in relation to the changes in pituitary gonadotropin (FSH, LH) parameters, after GnRH stimulation with a bolus injection of 100 microg gonadorelin, in 19 women with ovulatory disturbances. METHODS: Serum levels of inhibin A and B, activin A, and pro alpha-C were measured using sensitive ELISA kits. RESULTS: Within 60 min after GnRH stimulation, FSH values doubled from 5 to 10 mU/ml (P < 0.001). LH increased 12-fold from 2 to 24 mU/ml (P < 0.001). Activin A showed a significant decrease from 0.47 to 0.36 ng/ml (P < 0.001), whereas pro alpha-C increased from 127 to 156 pg/ml (P = 0.039). The median inhibin A concentration did not show a significant change between baseline and the 60 min value, whereas inhibin B was characterized by a minor, but not significant, increase in the median from 168 to 179 pg/ml (P = 0.408). A significant inverse correlation (P = 0.014) with a mean coefficient of correlation of 0.5516 was found, demonstrating a strong relationship between high inhibin B baseline levels and a small increase of FSH after 60 min. CONCLUSION: Our results show an interesting correlation between the baseline inhibin B and the change in FSH before and after GnRH stimulation. A high baseline inhibin B implies only a minor increase of FSH after 60 min.

Urinary excretion of 2,3-dinor-6-keto-PGF1 alpha and 11-dehydro-TXB2 by the gravid spontaneously hypertensive rat.

Little is known about the pathophysiological processes leading to superimposed preeclampsia. We present an animal model where the uteroplacental blood flow in spontaneously hypertensive rats (SHR) was reduced by a silver clip. Thus, a superimposed preeclampsia-like syndrome could be studied under defined conditions. Urinary excretion of 2,3-dinor-6-keto PGF1 alpha and 11-dehydro-TxB2 were measured by enzyme immunoassays at day 16 and 20 of pregnancy. In gravid, sham-operated animals excretion of 2,3-dinor-6-keto-PGF1 alpha was largely elevated compared to non gravid control animals (day 16: 1259 vs. 258 ng/kg 24h; day 20: 471 vs. 269 ng/kg.24h). However, in the gravid rats with reduced uteroplacental blood flow urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased to non gravid levels (day 16: 335 ng/kg.24h; day 20: 238 ng/kg.24h). By antihypertensive therapy with dihydralazin this effect was largely abolished. Only minor alterations were found in the excretion of 11-dehydro-TxB2. Our findings suggest, that a reduction of uteroplacental blood flow in the spontaneously hypertensive rat decreases the systemic prostacyclin synthesis.

Atrial natriuretic peptide (ANP) in preeclampsia-like syndrome in a rat model.

The pathophysiology of preeclampsia has not been fully clarified. A variety of factors have been implicated with this disease including vasoactive peptides and hormones during the last 20 years. Inadequate generation of atrial natriuretic peptide (ANP) has been one of the mechanisms discussed as to possibly contribute to the development of hypertension. In human pregnancy multiple studies of ANP-plasma-concentration in normal or hypertensive pregnancies showed conflicting results. The complexity of the clinical findings of hypertension in pregnancy makes it very difficult to carry out comparative clinical and biochemical studies in humans. In an animal experience genetic as environmental influences could be excluded. Therefore, the present study shows an experimental preeclampsia-like syndrome in the rat by reduction of the utero-placental flow. We observed a significant increase of plasma ANP in pregnant rats with experimentally induced hypertension. Furthermore, our results suggest that the ventricles could be an important source of ANP gene expression.

Risk weighing in twin pregnancy.

Multiple pregnancies are more often associated with complications than singleton pregnancies. In our retrospective study of 613 twin pregnancies the most important risk factors in twin pregnancies were premature labour before the 37th week of gestation and the premature rupture of the membrane. The increase of perinatal mortality and morbidity for twins might be primary the result of premature delivery.

[Value of prostaglandins in a pre-eclampsia-equivalent animal model]. / Stellenwert der Prostaglandine in einem Präeklampsie-äquivalenten Tiermodell.

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Urinary excretion of 6-keto-PGF1 alpha TxB2 and PGE2 in a rat animal model for preeclampsia-like syndrome.

The etiology of pregnancy induced hypertension (PIH) is still unknown. The pathophysiology must be clarified. In this paper we present an animal model where hypertension in pregnant and non-pregnant rats was induced by an experimental reduction of uteroplacental blood flow. Thus, a preeclampsia-like syndrome could be studied under defined conditions. The eicosanoid system was investigated for pathophysiological alterations of the kidney by measuring urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE2 with radioimmunoassay at day 18 of pregnancy. First, in gravid control animals concentrations of all three prostaglandins were significantly elevated compared to non-gravid controls. However, in hypertensive gravid rats urinary concentrations of these prostaglandins fell even below the levels of non-gravid controls. The observed decrease was more pronounced for the vasodilatory 6-keto-PGF1 alpha and PGE2 than for the vasoconstrictive TxB2. Our results demonstrate that an experimental reduction of uteroplacental blood flow in the rat culminates in symptoms which clinically (hypertension, proteinuria) and pathophysiologically (eicosanoid system) resemble to preeclampsia.

[Breast cancer grading by automated image processing]. / Mammakarzinomgrading durch automatisierte Bildverarbeitung.

Individual oncological therapy of carcinoma of the breast depends on information on the individual prognosis and malignancy. Image processing and analysis of the digital structure of the cellular nucleus adds new prognostic data to standard morphological and biochemical parameters and should be used for further individualisation of oncological therapy.