Publications by authors named "Adriana Bastidas"

10 Publications

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Effects of an oral contraceptive containing estetrol and drospirenone on ovarian function.

Contraception 2021 Mar 6. Epub 2021 Mar 6.

Estetra SRL, an affiliate's company of Mithra Pharmaceuticals, Liège, Belgium; University of Liège, Liège, Belgium.

Objective: To evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function.

Study Design: Single-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n = 41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n = 41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every 3 days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study.

Results: None of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than EE/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated.

Conclusions: E4 15 mg/DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP.

Implications Statement: Treatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.
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March 2021

Endocrine and metabolic effects of an oral contraceptive containing estetrol and drospirenone.

Contraception 2021 Apr 9;103(4):213-221. Epub 2021 Jan 9.

Estetra SRL, An Affiliate's Company of Mithra Pharmaceuticals, Liège, Belgium; University of Liège, Liège, Belgium.

Objectives: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP).

Study Design: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n = 38), or ethinylestradiol (EE) 30 µg/levonorgestrel (LNG) 150 µg (n = 29), or EE 20 µg/DRSP 3 mg (n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism.

Results: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] +30.5%, luteinizing hormone [LH] -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and cortisol binding globulin ([CBG] (+40.0%) were less compared to EE/LNG (cortisol +109.0%, CBG +152.0%) and EE/DRSP (cortisol +107.0%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for sex hormone binding globulin ([SHBG] +55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism.

Conclusions: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products.

Implications Statement: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
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April 2021

Immunogenicity of the adjuvanted recombinant zoster vaccine: persistence and anamnestic response to additional doses administered 10 years after primary vaccination.

J Infect Dis 2020 Jun 5. Epub 2020 Jun 5.

GSK, Rockville, Maryland, United States.

Background: The adjuvanted recombinant zoster vaccine (RZV) is highly immunogenic and efficacious in adults ≥50 years (Y) of age (YOA). We evaluated (1) long-term immunogenicity of an initial 2-dose RZV schedule by following-up adults vaccinated at ≥60 YOA and by modeling, and (2) immunogenicity of 2 additional doses administered 10Y post-initial vaccination.

Methods: Persistence of humoral and cell-mediated immune (CMI) responses to 2 initial RZV doses was assessed through 10Y post-initial vaccination, and modeled through 20Y using a Piecewise, Power law and Fraser model. Immunogenicity and safety of 2 additional RZV doses were also evaluated (NCT02735915).

Results: Seventy adults were enrolled. Ten years post-initial vaccination, humoral and CMI responses were ~6-fold and ~3.5-fold above pre-initial vaccination levels, respectively. Predicted immune persistence through 20Y post-initial vaccination was similar across the 3 models. Sixty-two participants (82.6±4.4 YOA) received at least 1 additional RZV dose. Strong anamnestic humoral and CMI responses were elicited by 1 additional dose, without further increases after a second additional dose.

Conclusions: Immune responses to an initial 2-dose RZV course persisted for many years in older adults. Strong anamnestic immune responses can be induced by additional dosing 10Y after the initial 2-dose course.
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June 2020

Recombinant Zoster Vaccine Significantly Reduces the Impact on Quality of Life Caused by Herpes Zoster in Adult Autologous Hematopoietic Stem Cell Transplant Recipients: A Randomized Placebo-Controlled Trial (ZOE-HSCT).

Biol Blood Marrow Transplant 2019 12 5;25(12):2474-2481. Epub 2019 Aug 5.

Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Herpes zoster (HZ) can have a substantial impact on quality of life (QoL). The vaccine efficacy (VE) of a recombinant zoster vaccine (RZV) was 68.2% (95% confidence interval [CI], 55.6% to 77.5%) in a phase 3 study in adult autologous hematopoietic stem cell transplant (HSCT) recipients (NCT01610414). Herein, we report the impact of RZV on patients' QoL. Autologous HSCT recipients were randomized 1:1 to receive 2 doses of RZV or placebo, given 1 to 2 months apart. QoL was measured by the Short Form Survey-36 and Euro-QoL-5 Dimension at baseline, 1 month, and 1 year postdose 2 and during suspected HZ episodes with the Zoster Brief Pain Inventory (ZBPI). The RZV impact on ZBPI burden of illness and burden of interference scores was estimated. The 2 scores were calculated from the area under the curve (days 0 to 182) of the ZBPI worst pain and ZBPI activities of daily living scores, respectively, assuming a score of 0 for patients not having a confirmed HZ episode. The ZBPI maximum worst pain score was significantly lower in the RZV than placebo group (mean: 5.8 versus 7.1, P = .011). Consequently, the VE estimates for HZ burden of illness (82.5%; 95% CI, 73.6 to 91.4) and burden of interference (82.8%; 95% CI, 73.3 to 92.3) were higher than the HZ VE estimate (ie, 68.2%). RZV showed significantly better QoL scores than placebo 1 week following rash onset among patients with confirmed HZ. In addition to reducing the risk of HZ and its complications, RZV significantly reduced the impact of HZ on patients' QoL in those who developed breakthrough disease.
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December 2019

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

JAMA 2019 07;322(2):123-133

Duke University Medical Center, Durham, North Carolina.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster.

Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.

Design, Setting, And Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.

Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.

Main Outcomes And Measures: The primary end point was occurrence of confirmed herpes zoster cases.

Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.

Conclusions And Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.

Trial Registration: Identifier: NCT01610414.
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July 2019

Persistence of immune response to an adjuvanted varicella-zoster virus subunit vaccine for up to year nine in older adults.

Hum Vaccin Immunother 2018 06 21;14(6):1370-1377. Epub 2018 Mar 21.

b Clinical R&D, GSK , Wavre , Belgium.

Background: In adults aged ≥60 years, two doses of the herpes zoster subunit vaccine (HZ/su; 50 µg varicella-zoster virus glycoprotein E [gE] and AS01 Adjuvant System) elicited humoral and cell-mediated immune responses persisting for at least six years. We assessed immunogenicity nine years post-initial vaccination.

Methods: This open extension study (NCT02735915) followed 70 participants who received two HZ/su doses in the initial trial (NCT00434577). Blood samples to assess the cellular (intracellular cytokine staining) and humoral (ELISA) immunity were taken at year nine post-initial vaccination.

Results: Participants' mean age at dose 1 was 72.3 years. The fold increases over pre-vaccination in the mean frequency of gE-specific CD4+ T-cells expressing ≥2 activation markers plateaued from year four post-dose 1 until year nine. Anti-gE antibody geometric mean concentrations plateaued and remained above pre-vaccination levels from year four onwards. Immunogenicity at year nine was similar across age strata (60-69, ≥70 years) and confirmed statistical prediction model results using data for up to year six. Further modeling using all data up to year nine predicted immune responses would remain above the pre-vaccination level up to year 15.

Conclusion: In adults aged ≥60 years, HZ/su-induced immunogenicity remained above pre-vaccination levels for at least nine years post-initial vaccination.

Summary: After vaccination with HZ/su, both cell mediated and humoral immunity remained above pre-vaccination levels up to year 9 regardless of age group. Immune responses are predicted to remain above baseline up to 15 years post initial vaccination.
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June 2018

Effect of upper abdomen tissue manipulation on adhesion formation between injured areas in a laparoscopic mouse model.

J Minim Invasive Gynecol 2009 May-Jun;16(3):307-12. Epub 2009 Mar 14.

Department of Obstetrics and Gynecology at the University Hospital Gasthuisberg, Leuven, Belgium.

Study Objective: These experiments were designed to examine the effect of manipulation during surgery as a cofactor in adhesion formation at trauma sites.

Design: Randomized, controlled trial. Canadian Task Force Classification-class 1.

Setting: University laboratory research center.

Subjects: A standardized laparoscopic mouse model (Balb\c mice 9-10 weeks old) for adhesion formation after opposing bipolar lesions and 60 minutes of carbon-dioxide pneumoperitoneum. In this model adhesions are known to decrease after the addition of 3% of oxygen, dexamethasone, or both. In addition, adhesions decrease with experience (i.e., with a decreasing amount of manipulation during the learning curve).

Interventions: A factorial design was used to evaluate the effects of dexamethasone and of adding 3% of oxygen on manipulation-enhanced adhesion formation during a learning curve. Blocks of 4 animals were thus randomized as controls (carbon-dioxide pneumoperitoneum only) or received an additional 3% of oxygen, dexamethasone, or both. In a second experiment, the effects of manipulation on adhesion formation were quantified. In a third experiment we evaluated whether dexamethasone had a specific effect on manipulation-enhanced adhesion formation.

Measurements And Main Results: Qualitative and quantitative adhesion scoring 7 days after the intervention. The first experiment confirmed that adhesion formation decreased during the learning curve (p <.0001) and after the addition of dexamethasone whether assessed as the total adhesion score (p <.0001 and p =.0009, respectively) or a quantitative score (p <.0001 and p <.0001, respectively). The second experiment showed that adhesion formation increased by standardized touching and grasping of omentum and bowels (proportion score p =.0059 and p =.0003, respectively) and this effect increased with duration of touching (p =.0301). In the third experiment, dexamethasone was confirmed to decreased adhesion formation (p =.0001) but this effect was not specific for manipulation-enhanced adhesion formation.

Conclusion: Manipulation of intraperitoneal organs in the upper abdomen enhances adhesion formation at trauma sites, confirming that the peritoneal cavity is a cofactor in adhesion formation. Dexamethasone decreases adhesion formation but the effect is not specific for manipulation-enhanced adhesion formation.
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August 2009

Intercoat gel (oxiplex): efficacy, safety, and tissue response in a laparoscopic mouse model.

J Minim Invasive Gynecol 2009 Mar-Apr;16(2):188-94

Departments of Obstetrics and Gynecology at University Hospital Leuven, Belgium.

Study Objective: To study the efficacy and safety of Intercoat gel in a laparoscopic mouse model with pneumoperitoneum-enhanced adhesion formation.

Design: Randomized controlled trial. Evidence obtained from a properly designed, randomized, controlled trial (Canadian Task Force classification I).

Setting: University laboratory research center.

Subjects: Balb\c female mice 9 to 10 weeks old.

Interventions: Two laparoscopic mouse models for adhesion formation were used. In the first model, adhesions following bipolar opposing lesions in the pelvis were enhanced by 60 minutes of carbon-dioxide pneumoperitoneum. In the second model, adhesions were further enhanced by bowel manipulation. The first experiment evaluated the efficacy of Intercoat in both models. The second experiment evaluated the efficacy of Intercoat in the first model, when applied immediately on the lesion, when applied at the end of the pneumoperitoneum, and when applied in the upper abdomen. Biopsy specimens were taken after 7 days and were evaluated after hematoxylin-eosin and CD45 staining.

Measurements And Main Results: Qualitative and quantitative adhesion scoring. Morphology was evaluated by standard light microscopy. In both models, Intercoat decreased adhesion formation whether applied immediately on the lesion or at the end of the pneumoperitoneum (qualitative and quantitative scoring p <.0001 and p <.0001, respectively). Intercoat application is associated with tissue redness, vascular congestion, and cellular edema but without an inflammatory reaction. Applied in the upper abdomen, Intercoat does not increase adhesions, but decreases adhesions at higher doses (p =.0024). Intercoat in high doses had a toxic effect (p =.0058).

Conclusion: Intercoat is an effective antiadhesion product. It is associated with tissue edema and vasodilatation as observed after 7 days both macroscopically and by histology.
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August 2009

Efficacy of barriers and hypoxia-inducible factor inhibitors to prevent CO(2) pneumoperitoneum-enhanced adhesions in a laparoscopic mouse model.

J Minim Invasive Gynecol 2007 Sep-Oct;14(5):591-9

Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium.

Study Objective: To investigate the effects of hypoxia-inducible factor (HIF) inhibitors, flotation agents, barriers, and a surfactant on pneumoperitoneum-enhanced adhesions in a laparoscopic mouse model.

Design: Prospective randomized trial (Canadian Task Force classification I).

Setting: Department of Obstetrics and Gynecology, University Hospital Gasthuisberg, Catholic University of Leuven.

Subjects: One hundred fourteen female BALB/c mice.

Interventions: Adhesions were induced during laparoscopy in BALB/c female mice. Pneumoperitoneum was maintained for 60 minutes with humidified CO(2). In 3 experiments the effects of HIF inhibitors such as 17-allylamino 17-demethoxygeldanamycin, radicicol, rapamycin, and wortmanin, flotation agents such as Hyskon and carboxymethylcellulose, barriers such as Hyalobarrier gel and SprayGel, and surfactant such as phospholipids were evaluated.

Measurements And Main Results: Adhesions were scored after 7 days during laparotomy. Adhesion formation decreased with the administration of wortmannin (p <.01), phospholipids (p <.01), Hyalobarrier Gel (p <.01), and SprayGel (p <.01).

Conclusions: These experiments confirm the efficacy of barriers and phospholipids to separate or lubricate damaged surfaces. They also confirm the role of mesothelial hypoxia in this model by the efficacy of the HIF inhibitor wortmannin.
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December 2007

Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors.

Int J Cancer 2005 Mar;114(2):202-8

Center for Human Genetics, University of Leuven, Leuven, Belgium.

Desmoid tumors (aggressive fibromatosis) are locally invasive soft tissue tumors in which beta-catenin/TCF3 mediated Wnt signaling is activated. More than 80% of desmoid tumors contain activating mutations in beta-catenin. It has been shown that the Wnt signaling pathway interacts with Wilms' tumor gene 1 (WT1) in normal kidney development and plays a role in the genesis of some Wilms' tumors. About 15% of Wilms' tumors contain WT1 mutations and of these, about 50% contain beta-catenin mutations. This overlap in mutation pattern of WT1 and beta-catenin in Wilms' tumor suggests that these 2 genes may collaborate in the genesis of a subset of Wilms' tumors. To investigate whether this hypothesis could be extended to other Wnt-dependent tumor types, we searched for WT1 mutations and studied WT1 expression in beta-catenin mutant desmoid tumors. We investigated the expression of WT1 mRNA and protein in desmoid tumors. Medium to high abundant levels of WT1 mRNA were detected by TaqMan quantitative PCR in all tested desmoid cells, whereas adjacent normal fibroblasts showed less expression of WT1. Western blot analysis and immunohistochemistry confirmed this overexpression at the protein level. A mutational screen of the WT1 zinc-finger region by sequence analysis did not identify any mutations. Finally, we investigated a possible role of beta-catenin on WT1 regulation and vice versa. Overexpression of different beta-catenin mutants in the HEK293T cell line did not modulate WT1 promoter activity and WT1 did not affect beta-catenin /TCF transcriptional activity in this cell line. These results show that the wild-type WT1 gene is strongly overexpressed in beta-catenin mutant desmoid tumors and may play a role in tumorigenesis of desmoid tumors, similar to what has been suggested in some epithelial malignancies.
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March 2005