Vilaprisan, a New Selective Progesterone Receptor Modulator in Uterine Fibroid Pharmacotherapy-Will it Really be a Breakthrough?

2020 ◽  
Vol 26 (3) ◽  
pp. 300-309 ◽  
Author(s):  
Michal Ciebiera ◽  
Salvatore G. Vitale ◽  
Simone Ferrero ◽  
George A. Vilos ◽  
Fabio Barra ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Progesterone Receptor ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Uterine Fibroids ◽  
Inhibition Of Proliferation ◽  
Receptor Modulator ◽  
Medical Regimens

Background: Vilaprisan (VPR) is a new orally available selective progesterone receptor modulator (SPRM), with anti-proliferative activity against uterine fibroids (UFs). It definitively causes suppression of ovulation and inhibition of proliferation of endometrial, myometrial and UF cells. Purpose: This review aims to summarize current knowledge on VPR from all studies, including clinical trials, conducted to date and to contextualize the potential role of VPR in future medical regimens for the treatment of UFs. Methods: We performed a literature search in PubMed US National Library of Medicine and Google Scholar databases. Both databases were extensively searched for all original and review articles/book chapters as well as congress abstracts published in English until July 2019. The use of VPR for UF therapy was identified by using the keywords: “uterine fibroids” and “vilaprisan”. Results: In phase I and II clinical trials, VPR was shown to be effective in ameliorating UF-related clinical symptoms, especially abnormal or excessive uterine bleeding and in shrinking UFs. The tolerability of VPR is roughly similar to that of ulipristal acetate (UPA) and it tends to be more favorable than that of GnRH-agonists. Conclusion: Presently, all trials examining the utility of VPR for the treatment of UF are halted; likely, due to the recently reported cases of hepato-toxicity with UPA, in addition to non reassuring toxicology results from preclinical long-term testing on rodents, carried out in parallel with late stage testing on humans. An accurate summary of robust data related to the safety of VPR is urgently needed to draw definitive conclusions on the future clinical development of this drug for UF therapy.

scholarly journals Vitamin D and Uterine Fibroids—Review of the Literature and Novel Concepts

2018 ◽  
Vol 19 (7) ◽  
pp. 2051 ◽  
Author(s):  
Michał Ciebiera ◽  
Marta Włodarczyk ◽  
Magdalena Ciebiera ◽  
Kornelia Zaręba ◽  
Krzysztof Łukaszuk ◽  
...  
Keyword(s):  
Vitamin D ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Low Cost ◽  
Uterine Fibroids ◽  
Hypovitaminosis D ◽  
Pleiotropic Effect ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

This article provides a detailed review of current knowledge on the role of vitamin D and its receptor in the biology and management of uterine fibroids (UFs). Authors present ideas for future steps in this area. A literature search was conducted in PubMed using the following key words: “uterine fibroid” and “vitamin D”. The results of the available studies, published in English from January 2002 up to April 2018, have been discussed. Vitamin D is a group of steroid compounds with a powerful impact on many parts of the human body. This vitamin is believed to regulate cell proliferation and differentiation, inhibit angiogenesis, and stimulate apoptosis. Nowadays, hypovitaminosis D is believed to be a major risk factor in the development of UFs. In many studies vitamin D appears to be a powerful factor against UFs, resulting in inhibition of tumor cell division and a significant reduction in its size, however, the exact role of this compound and its receptor in the pathophysiology of UFs is not fully understood. According to available studies, vitamin D and its analogs seem to be promising, effective, and low-cost compounds in the management of UFs and their clinical symptoms, and the anti-tumor activities of vitamin D play an important role in UF biology. The synergy between vitamin D and selected anti-UF drugs is a very interesting issue which requires further research. Further studies about the biological effect of vitamin D on UF biology are essential. Vitamin D preparations (alone or as a co-drugs) could become new tools in the fight with UFs, with the additional beneficial pleiotropic effect.

scholarly journals Role of Glucose-Lowering Medications in Erectile Dysfunction

2021 ◽  
Vol 10 (11) ◽  
pp. 2501
Author(s):  
Angelo Cignarelli ◽  
Valentina Annamaria Genchi ◽  
Rossella D’Oria ◽  
Fiorella Giordano ◽  
Irene Caruso ◽  
...  
Keyword(s):  
Erectile Dysfunction ◽  
Current Knowledge ◽  
Smooth Muscle Contractility ◽  
Glucose Lowering ◽  
Glycation End Products ◽  
Altered Metabolism

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

scholarly journals Tissue-Nonspecific Alkaline Phosphatase—A Gatekeeper of Physiological Conditions in Health and a Modulator of Biological Environments in Disease

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1648
Author(s):  
Daniel Liedtke ◽  
Christine Hofmann ◽  
Franz Jakob ◽  
Eva Klopocki ◽  
Stephanie Graser
Keyword(s):  
Alkaline Phosphatase ◽  
Clinical Symptoms ◽  
Current Knowledge ◽  
Systemic Disease ◽  
Loss Of Function ◽  
Inorganic Pyrophosphate ◽  
Wide Range ◽  
Mineralization Processes ◽  
Tissue Nonspecific Alkaline Phosphatase

Tissue-nonspecific alkaline phosphatase (TNAP) is a ubiquitously expressed enzyme that is best known for its role during mineralization processes in bones and skeleton. The enzyme metabolizes phosphate compounds like inorganic pyrophosphate and pyridoxal-5′-phosphate to provide, among others, inorganic phosphate for the mineralization and transportable vitamin B6 molecules. Patients with inherited loss of function mutations in the ALPL gene and consequently altered TNAP activity are suffering from the rare metabolic disease hypophosphatasia (HPP). This systemic disease is mainly characterized by impaired bone and dental mineralization but may also be accompanied by neurological symptoms, like anxiety disorders, seizures, and depression. HPP characteristically affects all ages and shows a wide range of clinical symptoms and disease severity, which results in the classification into different clinical subtypes. This review describes the molecular function of TNAP during the mineralization of bones and teeth, further discusses the current knowledge on the enzyme’s role in the nervous system and in sensory perception. An additional focus is set on the molecular role of TNAP in health and on functional observations reported in common laboratory vertebrate disease models, like rodents and zebrafish.

Cytokines and Adhesion Molecules in Allergic Rhinitis

1998 ◽  
Vol 12 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Claus Bachert ◽  
Martin Wagenmann ◽  
Gabriele Holtappels
Keyword(s):  
T Cells ◽  
Allergic Rhinitis ◽  
Adhesion Molecules ◽  
Current Knowledge ◽  
Allergic Inflammation ◽  
Allergen Challenge ◽  
Activated T Cells ◽  
Viral Rhinitis

This review summarizes our current knowledge of nasal allergic inflammation based on studies of cytokines, chemokines, and adhesion molecules in allergic rhinitis. The article also includes some aspects of viral rhinitis. Due to artificial or natural allergen exposure, an increase in the number of eosinophils and basophils, mast cells, IgE-positive cells, macrophages, monocyte-like cells, Langerhans cells, and activated T-cells can be observed within the mucosa and on the mucosal surface. Mediators are known to be released in response to allergens, but do not seem to be adequate to initiate the cell recruitment. After antigen challenge, the release of proinflammatory and regulatory cytokines could be demonstrated, and TH2-type cytokine mRNA upregulation in allergic mucosa has been shown. Proinflammatory cytokines initiate an adhesion cascade and activate T-cells that create an “atopic” cytokine environment within the tissue, which also may be linked to the long-term selective recruitment of eosinophils. However, the acute selective migration of eosinophils after allergen challenge is not fully understood, nor is the role of chemokines in allergic and viral rhinitis. Allergic rhinitis clearly represents an inflammatory reaction.

scholarly journals Predictive Factors of Response to Selective Progesterone Receptor Modulator (Ulipristal Acetate) in the Pharmacological Treatment of Uterine Fibroids

2020 ◽  
Vol 17 (3) ◽  
pp. 798
Author(s):  
Iwona Szydłowska ◽  
Aleksandra Marciniak ◽  
Jolanta Nawrocka-Rutkowska ◽  
Aleksandra Rył ◽  
Andrzej Starczewski
Keyword(s):  
Blood Flow ◽  
Progesterone Receptor ◽  
Predictive Factors ◽  
Uterine Fibroids ◽  
Volume Number ◽  
Ulipristal Acetate ◽  
Uterine Arteries ◽  
Receptor Modulator ◽  
Estradiol Concentration ◽  
Status Of Women

Background: Selective progesterone receptor modulator ulipristal acetate (UPA) is a drug used in management of symptomatic myomas. It was observed that the response to UPA treatment in uterine myomas varied amongst patients. An attempt was thus made at establishing predictive factors conducive to better reaction to treatment with UPA. The aim of this study was to assess the efficacy of UPA treatment in women with myomas, depending on pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Materials and methods: The study included patients with one to four myomas. The UPA treatment was a preparation stage for surgical treatment in all patients. The study group was divided into the subgroups according to pretreatment myomas’ volume, number of myomas, age of patients, estrogenic status of women, and pretreatment blood flow in uterine arteries. Results: A better effect of reduction in size of myomas after UPA treatment was noted when pretreatment myomas’ volume was lower than 30 cm3. A significant reduction in fibroids’ size was observed after UPA therapy independently of the number of myomas and age of patients. A good response after the UPA therapy was observed when pretreatment estradiol concentration was below 50 pg/mL and when uterine artery resistance index (RI) was above 0.8. Conclusions: Our research demonstrates that treatment with ulipristal acetate is an efficient method in preoperative preparation of patients with uterine fibroids. The most important factor of positive response to UPA therapy is myoma volume. The number of myomas and patient’s age do not interfere with effects of UPA therapy. Pretreatment estradiol concentration is significant, yet secondary for the effects of therapy. The UPA therapy has no impact on blood flow in the uterine arteries and no adverse influence on estradiol concentrations.

scholarly journals The Role of Simulation Modeling in Planning Long-Term Clinical Trials in Type 2 Diabetes

2013 ◽  
Vol 16 (7) ◽  
pp. A587-A588
Author(s):  
V. Foos ◽  
D. Grant ◽  
J.L. Palmer ◽  
M. Lamotte ◽  
P. McEwan
Keyword(s):  
Type 2 Diabetes ◽  
Clinical Trials ◽  
Simulation Modeling

scholarly journals Long-term macrolide antibiotics in asthma therapy

2011 ◽  
Vol 2 (4) ◽  
pp. 243-258
Author(s):  
Daisuke Takekoshi ◽  
Patrick Belvitch ◽  
Israel Rubinstein
Keyword(s):  
Clinical Trials ◽  
Antimicrobial Properties ◽  
Inflammatory Cells ◽  
Macrolide Antibiotics ◽  
Oxygen Species ◽  
Immunomodulatory Effects ◽  
Diffuse Panbronchiolitis ◽  
Heterogeneous Nature

Macrolide antibiotics drew worldwide attention when their use was dramatically successful in the treatment of diffuse panbronchiolitis in 1980s. The success was attributed to their immunomodulatory effects, rather than their antimicrobial properties. Since then, studies have shown that macrolides exert their immunomodulatory effects through several mechanisms, including suppression of proinflammatory cytokines, promoting apoptosis of inflammatory cells, improving phagocytic function, ameliorating airway hypersecretion, and inhibiting production of reactive oxygen species. Macrolides have also been studied in the treatment of asthma. This review highlights the role of macrolides in the treatment of asthma, presenting an overview of the main clinical trials. Despite favourable preclinical data and reports of anecdotal successes, the results of clinical trials are conflicting. This may be due to the heterogeneous nature of asthma. Further studies are needed to identify particular subgroup of asthma that will respond to macrolides.

scholarly journals Markers of Inflammation and Vascular Parameters in Selective Progesterone Receptor Modulator (Ulipristal Acetate)-Treated Uterine Fibroids

2021 ◽  
Vol 10 (16) ◽  
pp. 3721
Author(s):  
Iwona Szydłowska ◽  
Marta Grabowska ◽  
Jolanta Nawrocka-Rutkowska ◽  
Andrzej Kram ◽  
Małgorzata Piasecka ◽  
...  
Keyword(s):  
Progesterone Receptor ◽  
Inflammatory Markers ◽  
Uterine Fibroids ◽  
Response To Treatment ◽  
Control Group ◽  
Ulipristal Acetate ◽  
Weak Response ◽  
Receptor Modulator ◽  
Markers Of Inflammation ◽  
Response Group

The exact mechanism of selective progesterone receptor modulator action in leiomyoma still challenges researchers. The aim of the study was to assess the effects of ulipristal acetate (UPA) on immunoexpression of inflammatory markers and vascularization in fibroids. UPA-treated patients were divided into three groups: (1) good response (≥25% reduction in volume of fibroid), (2) weak response (insignificant volume reduction), (3) and no response to treatment (no decrease or increase in fibroid volume). The percentage of TGFβ, IL6, IL10, CD117, and CD68-positive cells were significantly lower in the group with a good response to treatment vs. the control group. Moreover, the percentage of IL10 and CD68-positive cells in the group with a good response to treatment were also significantly lower compared to the no response group. Additionally, a significant decrease in the percentage of IL10-positive cells was found in the good response group vs. the weak response group. There were no statistical differences in the percentage of TNFα-positive cells and vessel parameters between all compared groups. The results of the study indicate that a good response to UPA treatment may be associated with a decrease of inflammatory markers, but it does not influence myoma vascularization.

Sign in / Sign up

Export Citation Format

Share Document