A novel drug specific mRNA biomarker predictor for selection of patients responding to dovitinib treatment of advanced renal cell carcinoma and other solid tumors.

Purpose: Dovitinib is a receptor tyrosine kinase inhibitor of VEGFR1-3, PDGFR, FGFR1/3, c-KIT, FLT3 and topoisomerase 1 and 2. The drug response predictor (DRP) biomarker algorithm or DRP-Dovitinib is being developed as a companion diagnostic to dovitinib and was applied retrospectively.

Patients And Methods: Archival tumor samples were obtained from consenting patients in a phase 3 trial comparing dovitinib to sorafenib in renal cell carcinoma patients and the DRP-Dovitinib was applied.

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor.

Background: This phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.

Methods: E7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50-800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.

New contraceptive patch wearability assessed by investigators and participants in a randomized phase 3 study.

Objective: To evaluate skin irritation and patch adhesiveness of a new weekly low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (LNG/EE patch).

Study Design: This analysis was part of an open-label, parallel-group, multicenter, phase 3 study that randomized healthy women to the LNG/EE patch (one patch weekly for three consecutive weeks, followed by a patch-free week for 13 cycles) or to an oral contraceptive for six cycles followed by seven LNG/EE patch cycles. Participants selected patch application sites of abdomen, buttock or upper torso.

Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.

Objective: Pregnancy rates in US contraceptive clinical trials are increasing due to decreased treatment compliance. This study compared compliance with a new low-dose levonorgestrel (LNG) and ethinyl estradiol (EE) contraceptive patch (CP, Twirla™) with that of a low-dose combination oral contraceptive (COC) in a demographically diverse population.

Study Design: This analysis was part of an open-label, parallel-group, multicenter phase 3 study that randomized healthy sexually active women (17-40years) to 13cycles of LNG/EE CP or 6cycles of COC, then 7cycles of LNG/EE CP.

Safety and tolerability of a new low-dose contraceptive patch in obese and nonobese women.

Objective: The safety and tolerability of a new low-dose levonorgestrel/ethinyl estradiol (LNG/EE) contraceptive patch was compared with 2 combination oral contraceptives in 2 clinical studies in which approximately 30% of enrolled participants were obese.

Study Design: Two phase 3, open-label, randomized, parallel-group, multicenter trials compared the LNG/EE contraceptive patch (n = 1579) with combination oral contraceptives (n = 581) in healthy women 17-40 years of age. Combination oral contraceptives were LNG 100 μg per EE 20 μg (combination oral contraceptive 20; n = 375) or LNG 150 μg per EE 30 μg (combination oral contraceptive 30; n = 206).

Low-dose levonorgestrel and ethinyl estradiol patch and pill: a randomized controlled trial.

Objective: To compare a new low-dose levonorgestrel and ethinyl estradiol contraceptive patch (Patch) with a combination oral contraceptive (Pill; 100 micrograms levonorgestrel, 20 micrograms ethinyl estradiol) regarding efficacy, safety, compliance, and unscheduled uterine bleeding.

Methods: Women (17-40 years; body mass index 16-60) were randomized in a 3:1 ratio to one of two groups: Patch only (13 cycles) or Pill (six cycles) followed by Patch (seven cycles). Investigators evaluated adverse events during cycles 2, 4, 6, 9, and 13.

Therapeutically equivalent pharmacokinetic profile across three application sites for AG200-15, a novel low-estrogen dose contraceptive patch.

Background: AG200-15 Agile Patch (AP) is a novel 7-day contraceptive patch providing ethinyl estradiol (EE) exposure comparable to low-dose combination oral contraceptives. This study determined whether application of the AP to three different anatomical sites (lower abdomen, buttock and upper torso) influences the pharmacokinetic profile of EE and levonorgestrel (LNG).

Study Design: In this open-label, three-period, crossover study, 24 subjects were randomized to one of six treatment sequences; each included application of patch to abdomen, buttock and upper torso, with the AP worn on one site for 7 days.

Pharmacokinetics and adhesion of the Agile transdermal contraceptive patch (AG200-15) during daily exposure to external conditions of heat, humidity and exercise.

Background: This study compares the pharmacokinetic profile, adhesion and safety of the AG200-15 Agile Patch (AP), a novel contraceptive patch releasing low-dose ethinyl estradiol (EE) and levonorgestrel (LNG), during wear under external conditions of heat, humidity and exercise versus normal activities.

Study Design: This open-label, three-period, five-treatment, crossover study randomized 24 healthy women to one of six external condition sequences. Each sequence included one normal wear and two external conditions periods.

Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel.

Background: The effect of obesity on ovarian follicular suppression in women using low-estrogen dose contraceptive patches has not been determined.

Study Design: A Phase II, parallel-group, multicenter, three-cycle study evaluated three patches containing different ethinyl estradiol (EE) and levonorgestrel (LNG) doses. Serum levels of EE, LNG, sex hormone-binding globulin and progesterone were compared in 41 obese [body mass index (BMI) ≥30] and 75 nonobese (BMI <30) women.

Ethinyl estradiol and levonorgestrel pharmacokinetics with a low-dose transdermal contraceptive delivery system, AG200-15: a randomized controlled trial.

Background: This study evaluated the ethinyl estradiol (EE) and levonorgestrel (LNG) pharmacokinetic profiles of AG200-15, a transdermal contraceptive delivery system, compared with a combination oral contraceptive (COC) containing EE 35 mcg and norgestimate 250 mcg.

Study Design: A Phase 1, open-label, single-center study in 36 healthy women was conducted over three cycles with a randomized crossover design. After a run-in cycle of 21 days on and 7 days off with AG200-15, participants were randomized to receive one of two treatments: a 21/7-day cycle of AG200-15 either followed or preceded by one cycle of the COC.

Pharmacokinetics, tolerability and cycle control of three transdermal contraceptive delivery systems containing different doses of ethinylestradiol and levonorgestrel.

Background: The only available contraceptive patch, Ortho Evra®, delivers a relatively high dose of estrogen.

Materials And Methods: Three transdermal contraceptive delivery systems (TCDS) containing low doses of ethinylestradiol (EE) and levonorgestrel (LNG) were evaluated in two open-label randomized trials. In a phase 1, two-period, cross-over trial, AG200-12.

Risk of hyperkalemia in women taking ethinylestradiol/drospirenone and other oral contraceptives.

Background: The oral contraceptive ethinyl estradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) contains a progestin component that possesses potassium-sparing diuretic activity similar to spironolactone. We sought to determine whether EE/DRSP use might lead to adverse effects possibly attributable to hyperkalemia.

Long-term safety of drospirenone-estradiol for hormone therapy: a randomized, double-blind, multicenter trial.

Objective: The purpose of this multicenter, double-blind, randomized, parallel-group study was to determine the effect of thirteen 28-day cycles of drospirenone combined with estradiol, compared with estradiol alone, on the endometrium of postmenopausal women.

Design: Postmenopausal women not on hormone therapy but with an intact uterus were enrolled (N = 1,147); 1,142 were evaluated. Participants were randomly assigned to treatment with 1.

Efficacy of a new low-dose oral contraceptive with drospirenone in premenstrual dysphoric disorder.

Objective: To compare the efficacy of a new low-dose oral contraceptive pill (OCP) formulation with placebo in reducing symptoms of premenstrual dysphoric disorder.

Methods: This multicenter, double-blind, randomized clinical trial consisted of 2 run-in and 3 treatment cycles with daily symptom charting; 450 women with symptoms of premenstrual dysphoric disorder were randomized to either placebo or an OCP formulation containing drospirenone 3 mg and ethinyl estradiol 20 microg. Hormones were administered for 24 days, followed by 4 days of inactive pills (24/4).

Short-term angiopeptin therapy and the incidence of graft vessel disease after heart transplantation.

Background: Graft vessel disease, the major limitation for long-term success after heart transplantation, is triggered by injury to the graft vessel endothelium, resulting in the expression of adhesion molecules, the migration of leukocytes into the graft, and the release of growth factors. Angiopeptin, a stable analog of somatostatin, is a growth-hormone inhibitor with additional anti-proliferative effects. We evaluated angiopeptin for prevention of graft vasculopathy after cardiac transplantation in the first prospective, randomized, double-blind, clinical trial.

Evaluation of a unique oral contraceptive in the treatment of premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is a severe form of premenstrual syndrome (PMS). This is the first trial of a unique oral contraceptive containing a combination of drospirenone (DRSP, 3 mg) and ethinyl estradiol (EE, 30 microg) for the treatment of PMDD. DRSP is a spironolactone-like progestin with antiandrogenic and antimineralocorticoid activity.

Effects of estrogen on nitric oxide synthase expression in rat aorta allograft and smooth muscle cells.

Background: We find that chronic estradiol treatment inhibits the development of transplant arteriosclerosis (TA). The mechanism of this inhibition remains unclear. The objective of this study is to investigate in a non-cyclosporin-requiring TA model whether estradiol-17beta treatment modulates the expression of both endothelial nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) in the early phase following transplantation.

Oestrogen and transplant vascular disease.

1. The aetiology of chronic rejection is clearly multifactorial and relates to both immunological and non-immunological factors. 2.

Expression of IGF-1, IGF-1 receptor and TGF-beta following balloon angioplasty in atherosclerotic and normal rabbit iliac arteries: an immunocytochemical study.

Growth factors have been implicated in the pathogenesis of restenosis (myointimal hyperplasia after coronary interventions). In this study, we examined the expression of insulin-like growth factor-I (IGF-1), IGF-1 receptor, and transforming growth factor-beta (TGF-beta) in atherosclerotic and normal rabbit iliac arteries following overstretch balloon angioplasty of the iliac arteries to create a vascular lesion. Animals were sacrificed at 0, 3, 7, 15 and 42 days post angioplasty.

Estradiol inhibits allograft-inducible major histocompatibility complex class II antigen expression and transplant arteriosclerosis in the absence of immunosuppression.

Background: The etiology of transplant arteriosclerosis is unknown, but current data point to the alloimmune response. Previously, we found that estradiol-17beta (E2) with immunosuppressant cyclosporine abolishes major histocompatibility complex (MHC) class II expression in the allograft. This study determines the effect of E2 on MHC class II antigen expression in the allograft, in the absence of immunosuppression.

Upregulation of estrogen receptor-alpha expression in rabbit cardiac allograft.

Estrogen receptor (ER) expression has been detected in different tissues, and estradiol-17beta treatment protects against experimental transplant arteriosclerosis. In this study, ER-alpha expression in the rabbit hearts and attached aortas before and after cardiac-aorta allograft transplantation was examined. Ten male New Zealand White rabbits were transplanted with cardiac-aorta allografts from male Dutch Belted rabbits.

Estradiol 17-beta represses insulin-like growth factor I receptor expression in smooth muscle cells from rabbit cardiac recipients.

Background: A crucial step in cell cycle progression is the activation of the insulin-like growth factor I (IGF-I) receptor (IGF-IR) by its ligand. Earlier, we found estradiol 17-beta treatment of cardiac allograft recipients attenuates transplant arteriosclerosis; this was associated with inhibition of vascular cell proliferation induced by IGF-I. The current study demonstrates regulation of IGF-IR by estradiol 17-beta in vivo and in vitro in recipient native and allograft aorta and in aorta smooth muscle cells (SMCs).

Exposure of vascular allografts to insulin-like growth factor-I (IGF-I) increases vascular expression of IGF-I ligand and receptor protein and accelerates arteriosclerosis in rats.

Background: Accelerated arteriosclerosis limits the survival of transplanted hearts. We hypothesized that insulin-like growth factor-I (IGF-I) is crucial in accelerating transplant arteriosclerosis. Recently, we reported that exposure to IGF-I prior to transplantation accelerates transplant arteriosclerosis in the rat aorta allograft model.