A Novel Intrauterine Device for the Spatio-Temporal Release of Norethindrone Acetate as a Counter-Estrogenic Intervention in the Genitourinary Syndrome of Menopause.

The genitourinary syndrome of menopause (GSM) is a widely occurring condition affecting millions of women worldwide. The current treatment of GSM involves the use of orally or vaginally administered estrogens, often with the risk of endometrial hyperplasia. The utilization of progestogens offers a means to counteract the effects of estrogen on the endometrial tissue, decreasing unwanted side effects and improving therapeutic outcomes. In this study, a norethindrone acetate (NETA)-loaded, hollow, cylindrical, and sustained release platform has been designed, fabricated, and optimized for implantation in the uterine cavity as a counter-estrogenic intervention in the treatment of GSM. The developed system, which comprises ethyl cellulose (EC) and polycaprolactone (PCL), has been statistically optimized using a two-factor, two-level factorial design, with the mechanical properties, degradation, swelling, and in vitro drug release of NETA from the device evaluated. The morphological characteristics of the platform were further investigated through scanning electron microscopy in addition to cytocompatibility studies using NIH/3T3 cells. Results from the statistical design highlighted the platform with the highest NETA load and the EC-to-PCL ratio that exhibited favorable release and weight loss profiles. The drug release data for the optimal formulation were best fitted with the Peppas-Sahlin model, implicating both diffusion and polymer relaxation in the release mechanism, with cell viability results noting that the prepared platform demonstrated favorable cytocompatibility. The significant findings of this study firmly establish the developed platform as a promising candidate for the sustained release of NETA within the uterine cavity. This functionality serves as a counter-estrogenic intervention in the treatment of GSM, with the platform holding potential for further advanced biomedical applications.

Intravaginal Drug Delivery Systems to Treat the Genitourinary Syndrome of Menopause: Towards the Design of Safe and Efficacious Estrogen-loaded Prototypes.

Estrogens locally delivered to the vagina by tablets, capsules, rings, pessaries, and creams are the most common and highly recommended platforms to treat the genitourinary syndrome of menopause (GSM). Estradiol, an essential estrogen, is routinely administered alone, or in combination with progestins, to effectively alleviate the symptoms associated with moderate to severe menopause when non-pharmacological interventions are not indicated. Since the risk and side effects of estradiol use depends on the administered amount and duration of use, the lowest effective dose of estradiol is recommended when long-term treatment is required. Although there is a wealth of data and literature comparing vaginally administered estrogen-containing products, there is a lack of information revealing the effect of the delivery system used and formulation constituent's attributes on the efficacy, safety, and patient acceptability of these dosage forms. This review therefore aims to classify and compare various designs of commercially available and non-commercial vaginal 17ß-estradiol formulations and analyze their performance in terms of systemic absorption, efficacy, safety, and patient satisfaction and acceptance. The vaginal estrogenic platforms included in this review are the currently marketed and investigational 17ß-estradiol tablets, softgel capsules, creams, and rings for the treatment of GSM, based on their different design specifications, estradiol loads, and materials used in their preparation. Additionally, the mechanisms of the effects of estradiol on GSM have been discussed, as well as their potential impact on treatment efficacy and patient compliance.

Adding colchicine to tocilizumab in hospitalized patients with severe COVID-19 pneumonia: An open-label randomized controlled trial.

INTRODUCTION: Colchicine acts upstream in the cytokines cascade by inhibiting the nod-like receptor protein 3 (NLRP3) inflammasome while interleukin 6 (IL-6) receptor antagonists, such as tocilizumab, block the end result of the cytokines cascade. Hence, adding colchicine to tocilizumab with the aim of blocking the early and end products of the cytokines cascade, might reduce the risk of developing cytokine storm. METHODS AND ANALYSIS: We aim to conduct an open-label randomized controlled trial to evaluate the efficacy and safety of adding colchicine to tocilizumab among patients with severe COVID-19 pneumonia to reduce the rate of invasive mechanical ventilation and mortality. We will include patients with severe COVID-19 pneumonia who received tocilizumab according to our local guidelines. Enrolled patients will be then randomized in 1:1 to colchicine versus no colchicine. Patients will be followed up for 30 days. The primary outcome is the rate of invasive mechanical ventilation and will be determined using Cox proportional hazard model. DISCUSSION: Given colchicine's ease of use, low cost, good safety profile, and having different anti-inflammatory mechanism of action than other IL-6 blockade, colchicine might serve as a potential anti-inflammatory agent among patients with severe COVID-19 pneumonia. This study will provide valuable insights on the use of colchicine in severe COVID-19 when added to IL-6 antagonists. ETHICS AND DISSEMINATION: The Medical Research Center and Institutional Review Board at Hamad Medical Corporation in Qatar approved the study protocol (MRC-01-21-299). Results of the analysis will be submitted for publication in a peer-reviewed journal.