Ovarian hyperstimulation syndrome (OHSS) is a serious complication of assisted reproductive technology (ART). Risk factors for OHSS include female age, polycystic ovarian morphology and high ovarian reserve. The use of a gonadotrophin-releasing hormone (GnRH) agonist trigger in a freeze-all cycle is an effective strategy for reducing the risk of OHSS in suspected high responders. Various GnRH agonist trigger preparations exist but their use is subject to manufacturer availability. The national shortage of Buserelin necessitated a switch to alternative GnRH agonist trigger preparations such as Modified-Release (MR) Triptorelin resulting in a spike in OHSS cases, prompting an urgent review of our local treatment protocols and an immediate switch to Nafarelin (nasal preparation). We performed a retrospective study of freeze-all GnRH antagonist treatment cycles treated with a GnRH agonist (Triptorelin-MR, Nafarelin, and Buserelin) trigger at a London fertility clinic. The high-risk cohort consisted of patients with ≥18 follicles >12mm on ultrasonography. The diagnosis of OHSS was based on the criteria outlined by the Royal College of Obstetricians and Gynaecologists (RCOG). Relevant clinical data were extracted from medical records including female age, antral follicle count (AFC), anti-Mullerian hormone (AMH), ovarian stimulation dose (international units; IU), trigger preparation, oestradiol level on trigger day (pmol/l), oocyte yield, and the diagnosis and management of OHSS. A total of 333 patients underwent a freeze-all GnRH antagonist cycle between January 2023 and September 2024, 224 due to a high-risk of OHSS (≥18 follicles >12mm). The GnRH agonist preparations used included: Triptorelin-MR only (0.75 mg subcutaneous injection, SC; n = 69), Triptorelin-MR (0.375 mg SC) plus Menopur (150 IU SC; n = 49), Buserelin (2 mg SC; n = 69), and Nafarelin (1.6 mg nasal spray; n = 37). Forty-three patients met the RCOG diagnostic criteria for OHSS (mild n = 5, moderate n = 25 and severe n = 13). Six patients required inpatient OHSS management; none required intensive care or a chest/abdominal drain. Of those that developed severe OHSS, 92.3% (n = 12/13) had received Triptorelin-MR only or in combination with Menopur. Based on this cohort, Triptorelin-MR containing triggers are associated with a 12-fold increased risk of severe OHSS compared with other preparations and should not be used as a GnRH agonist trigger in patients at high risk of OHSS.

Several factors can affect drug release from polylactide coglycolide (PLGA)-based formulations, including polymer and drug properties, formulation components, manufacturing processes, and environmental in vitro or in vivo conditions. To achieve optimal release profiles for specific drug delivery applications, it is crucial to understand the mechanistic processes that determine drug release from PLGA-based formulations. In the current study, we developed a mechanistic model for the in vitro drug release of PLGA-based solid implants. The model accounts for all known critical quality attributes (CQAs) and considers the most important release rate processes, including water or dissolution medium influx into the porous structure of the implant, initial noncatalytic hydrolysis of PLGA, autocatalytic hydrolysis, dissolution of oligomers and monomers into the aqueous medium, the liberation of the trapped solid drug from the polymer matrix, dissolution of the solid drug into the wetted pore network, diffusion of the dissolved drug out of the implant, and distribution of the dissolved drug into the dissolution medium. The model has been validated using in vitro release data obtained from implants of four drugs (buserelin, afamelanotide, brimonidine, and nafarelin). The model presented in this manuscript provides valuable insights into the kinetics and mechanism of drug release from PLGA-based solid implants and has demonstrated the potential for optimizing formulation design. The in vitro release model, coupled with physiologically based pharmacokinetic (PBPK) modeling, can predict the in vivo performance of implants and can be used to support bioequivalence studies in a drug development program.

Dengue outbreaks persist in global tropical regions, lacking approved antivirals, necessitating critical therapeutic development against the virus. In this context, we developed the "Anti-Dengue" algorithm that predicts dengue virus inhibitors using a quantitative structure-activity relationship (QSAR) and MLTs. Using the "DrugRepV" database, we extracted chemicals (small molecules) and repurposed drugs targeting the dengue virus with their corresponding IC50 values. Then, molecular descriptors and fingerprints were computed for these molecules using PaDEL software. Further, these molecules were split into training/testing and independent validation datasets. We developed regression-based predictive models employing 10-fold cross-validation using a variety of machine learning approaches, including SVM, ANN, kNN, and RF. The best predictive model yielded a PCC of 0.71 on the training/testing dataset and 0.81 on the independent validation dataset. The created model's reliability and robustness were assessed using William's plot, scatter plot, decoy set, and chemical clustering analyses. Predictive models were utilized to identify possible drug candidates that could be repurposed. We identified goserelin, gonadorelin, and nafarelin as potential repurposed drugs with high pIC50 values. "Anti-Dengue" may be beneficial in accelerating antiviral drug development against the dengue virus.

The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina's capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of -8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson-Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (-46.97 to -118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility.

At present, only surgical sterilization is available for veterinarians and pet owners seeking suppression of fertility in male dogs, in most countries. An alternative contraceptive alternative approach is GnRH releasing implants that desensitize the pituitary to the stimulatory effects of GnRH and thereby block testicular function (testosterone and sperm production). Two GnRH agonists (deslorelin and azagly-nafarelin) have been researched in controlled release formulations for this purpose. A deslorelin-releasing biodegradable implant, marketed under the name Suprelorin®, has been available in Australia and New Zealand since 2007, the European Union (EU) since 2008, and received regulatory approval in China and Mexico in late 2019. Two versions of the implant are available, one labeled for a minimum of 6 months of fertility suppression in male dogs, and the other for a minimum of 12 months in male dogs. Another GnRH agonist (azagly-nafarelin) was also included in a solid implant (Gonazon®). Research results showed it delivered 6-months to 1 year of suppressed fertility; however, it is not commercialized. This review paper summarizes research on the mechanism of action for these technologies and compiles and interprets the research on efficacy and safety. New findings on usage of the deslorelin releasing implant in countries where veterinarians and pet owners have this option is shared. Research on off-label use of the product in male dogs is also reviewed. This review aims to aid in the evaluation of the deslorelin releasing implant as an adjunct or alternative for surgical sterilization of male dogs.

This study describes a novel nonlinear variant of the well-known Yalkowsky general solubility equation (GSE). The modified equation can be trained with small molecules, mostly from the Lipinski Rule of 5 (Ro5) chemical space, to predict the intrinsic aqueous solubility, S0, of large molecules (MW > 800 Da) from beyond the rule of 5 (bRo5) space, to an accuracy almost equal to that of a recently described random forest regression (RFR) machine learning analysis. The new approach replaces the GSE constant factors in the intercept (0.5), the octanol-water log P (-1.0), and melting point, mp (-0.01) terms with simple exponential functions incorporating the sum descriptor, Φ+B (Kier Φ molecular flexibility and Abraham H-bond acceptor potential). The constants in the modified three-variable (log P, mp, Φ+B) equation were determined by partial least-squares (PLS) refinement using a small-molecule log S0 training set (n = 6541) of mostly druglike molecules. In this "flexible-acceptor" GSE(Φ,B) model, the coefficient of log P (normally fixed at -1.0) varies smoothly from -1.1 for rigid nonionizable molecules (Φ+B = 0) to -0.39 for typically flexible (Φ ∼ 20, B ∼ 6) large molecules. The intercept (traditionally fixed at +0.5) varies smoothly from +1.9 for completely inflexible small molecules to -2.2 for typically flexible large molecules. The mp coefficient (-0.007) remains practically constant, near the traditional value (-0.01) for most molecules, which suggests that the small-to-large molecule continuum is mainly solvation responsive, apparently with only minor changes in the crystal lattice contributions. For a test set of 32 large molecules (e.g., cyclosporine A, gramicidin A, leuprolide, nafarelin, oxytocin, vancomycin, and mostly natural-product-derived therapeutics used in infectious/viral diseases, in immunosuppression, and in oncology) the modified equation predicted the intrinsic solubility with a root-mean-square error of 1.10 log unit, compared to 3.0 by the traditional GSE, and 1.07 by RFR.

We aimed to explore whether ovulation induced by a GnRH analogue (GnRHa), followed by daily GnRHa luteal support provides an efficient platform for natural cycle frozen embryo transfer (NC-FET). In this cohort study, included were normo-ovulatory women who underwent NC-FET cycles, under the age of 40, with an antral follicle count > eight. Ovulation was triggered with triptorelin (0.2 mg Decapeptyl; Ferring), and luteal support was initiated two days later, using a Nafarelin inhaler (Synarel, Pfizer), 200 μg twice daily. Main outcome measures were luteal estradiol and progesterone levels (three to five days following ovulation), implantation rate, ongoing pregnancy rate, early pregnancy loss rate, and live birth rate. Fifty-one patients treated between 2017 and 2018 were included. Mid luteal progesterone levels among study patients, were non-significantly different between patients who achieved pregnancy and those who did not, but differed significantly on day 14 following ovulation (86.0 ± 31.3 vs. 9.8 ± 9.5 nmol/L, respectively, p < 0.001). Twenty-three patients achieved a clinical pregnancy (45.1 %); interestingly, there were no chemical pregnancies. Three pregnancies ended in an early abortion at 6-7 weeks gestation, and 20 pregnancies continued as ongoing pregnancies (39.2 %). One patient had a late abortion at 16 weeks gestation, and 14 had a live birth. In conclusion, in this proof of concept study, inducing ovulation with a bolus of GnRHa in NC-FET, followed by repeated daily GnRHa administration, resulted in satisfactory luteal phase steroid levels and high ongoing pregnancy and live birth rates.

The recent outbreak of the 2019 novel coronavirus disease (COVID-19) has been proved as a global threat. No particular drug or vaccine has not yet been discovered which may act specifically against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and causes COVID-19. For this highly infectious virus, 3CL-like main protease (3CLpro) plays a key role in the virus life cycle and can be considered as a pivotal drug target. Structure-based virtual screening of DrugBank database resulted in 20 hits against 3CLpro. Atomistic 100 ns molecular dynamics of five top hits and binding energy calculation analyses were performed for main protease-hit complexes. Among the top five hits, Nafarelin and Icatibant affirmed the binding energy (g_MMPBSA) of -712.94 kJ/mol and -851.74 kJ/mol, respectively. Based on binding energy and stability of protein-ligand complex; the present work reports these two drug-like hits against SARS-CoV-2 main protease.Communicated by Ramaswamy H. Sarma.

The use of bioactive peptides as a doping agent in both human and animal sports has become increasingly popular in recent years. As such, methods to control the misuse of bioactive peptides in equine sports have received attention. This paper describes a sensitive accurate mass method for the detection of 40 bioactive peptides and two non-peptide growth hormone secretagogues (< 2 kDa) at low pg/mL levels in horse urine using ultra-high performance liquid chromatography-high resolution mass spectrometry (UHPLC/HRMS). A simple mixed-mode cation exchange solid-phase extraction (SPE) cartridge was employed for the extraction of 42 targets and/or their in vitro metabolites from horse urine. The final extract was analyzed using UHPLC/HRMS in positive electrospray ionization (ESI) mode under both full scan and data independent acquisition (DIA, for MS2). The estimated limits of detection (LoD) for most of the targets could reach down to 10 pg/mL in horse urine. This method was validated for qualitative detection purposes. The validation data, including method specificity, method sensitivity, extraction recovery, method precision, and matrix effect were reported. A thorough in vitro study was also performed on four gonadotrophin-releasing factors (GnRHs), namely leuprorelin, buserelin, goserelin, and nafarelin, using the S9 fraction isolated from horse liver. The identified in vitro metabolites have been incorporated into the method for controlling the misuse of GnRHs. The applicability of this method was demonstrated by the identification of leuprorelin and one of its metabolites, Leu M4, in urine obtained after intramuscular administration of leuprorelin to a thoroughbred gelding (castrated horse).

Granulosa cells control oocyte maturation through paracrine signalling and changes to the microenvironment around the oocyte. Apoptosis occurs as a physiological mechanism of granulosa cell renewal, but how it relates with the ovarian response to induced ovulation is still unclear. Therefore, this study evaluated apoptosis-related gene expression levels in granulosa cells of patients undergoing controlled ovarian stimulation. We enrolled prospectively 59 consecutive IVF patients referred to a tertiary academic hospital for couple infertility treatment. Luteinized granulosa cells were isolated from follicular fluid and the RNA was extracted, reverse-transcribed and the gene expression of apoptosis inducers (caspase-3, caspase-8 and bax) and inhibitor (Bcl-2) was quantified by real-time polymerase chain reaction. Caspase-3 gene expression correlated negatively with the number of pre-ovulatory follicles (Spearman's r = -0.308), the number of collected oocytes (r = -0.451), the number of mature oocytes (r = -0.526), the number of fertilized oocytes (r = -0.439) and the number of viable embryos (r = -0.443, all statistically significant at p < 0.02 level). No such associations were found with caspase-8, bax or bcl-2. These preliminary findings suggest that increased caspase-3 gene expression in granulosa cells is associated with a worse ovulatory response in humans.