Current Issue : January-March Volume : 2025 Issue Number : 1 Articles : 5 Articles
Pharmacokinetic issues were the leading cause of drug attrition, accounting for approximately 40% of all cases before the turn of the century. To this end, several high-throughput in vitro assays like microsomal stability have been developed to evaluate the pharmacokinetic profiles of compounds in the early stages of drug discovery. At NCATS, a single-point rat liver microsomal (RLM) stability assay is used as a Tier I assay, while human liver microsomal (HLM) stability is employed as a Tier II assay. We experimentally screened and collected data on over 30,000 compounds for RLM stability and over 7000 compounds for HLM stability. Although HLM stability screening provides valuable insights, the increasing number of hits generated, along with the time- and resource-intensive nature of the assay, highlights the need for alternative strategies. One promising approach is leveraging in silico models trained on these experimental datasets. Methods:We describe the development of an HLM stability prediction model using our in-house HLM stability dataset. Results: Employing both classical machine learning methods and advanced techniques, such as neural networks, we achieved model accuracies exceeding 80%. Moreover, we validated our model using external test sets and found that our models are comparable to some of the best models in literature. Additionally, the strong correlation observed between our RLM and HLM data was further reinforced by the fact that our HLM model performance improved when using RLM stability predictions as an input descriptor. Conclusions: The best model along with a subset of our dataset (PubChem AID: 1963597) has been made publicly accessible on the ADME@NCATS website for the benefit of the greater drug discovery community. To the best of our knowledge, it is the largest open-source model of its kind and the first to leverage cross-species data....
Formulations designed to address ocular conditions and diseases are predominantly administered topically. While in vitro test systems have been developed to assess corneal permeation under extended contact conditions, methods focusing on determining the penetration depth and kinetics of a substance within the cornea itself rather than through it, are scarce. This study introduces a method for time-dependent penetration depth analysis (10 and 60 min) by means of a semiquantitative imaging method in comparison with a quantitative corneal depth-cut technique, employing fluorescein sodium at concentrations of 0.2 and 0.4 mg/mL as a small molecule model substance and sheep cornea as a human surrogate. Excised tissues exhibited sustained viability in modified artificial aqueous humor and maintained thickness (746 ± 43 μm) and integrity (electrical resistance 488 ± 218 Ω·cm2) under the experimental conditions. Both methods effectively demonstrated the expected concentration- and time-dependent depth of penetration of fluorescein sodium, displaying a significantly strong correlation. The traceability of the kinetic processes was validated with polysorbate 80, which acted as a penetration enhancer. Furthermore, the imaging-based method enabled detecting the retention of larger structures, such as hyaluronic acid and nanoemulsions from the commercial eyedrop formulation NEOVIS® TOTAL multi, inside the lacrimal layer....
The inflammatory response has evolved as a protective mechanism against pathogens and tissue damage. However, chronic inflammation can occur, potentially leading to severe disease. Low-grade chronic inflammation is associated with obesity, and the Th1 cytokine profile plays an important role in this proinflammatory environment. Diet-induced obesity (DIO) can lead to persistent dysbiosis and maintain high concentrations of circulating lipopolysaccharides (LPSs) over prolonged periods of time, resulting in metabolic endotoxemia. In this context, the study of natural immunomodulators has recently increased. Objective: The aim of this study is improve scientific evidence for the immunomodulatory role of L-Alliin in obesity and inflammation. Methods: In the present work, we describe the effect of L-Alliin on serum levels of cytokines in DIO mice after an acute inflammatory challenge. L-Alliin is the main organosulfurized molecule of garlic that has been studied for its numerous beneficial physiological effects in health and disease and is beginning to be considered a nutraceutical. Two situations are simulated in this experimental model, health and chronic, low-grade inflammation that occurs in obesity, both of which are confronted with an acute, inflammation-inducing challenge. Results: Based on our findings, L-Alliin seems to somehow stimulate the cellular chemotaxis by eliciting the release of key molecules, including IL-2, IFN-γ, TNF-α, MCP-1, IL-6, IL-9, and G-CSF. However, the molecular mechanism involved remains unknown. This, in turn, mitigates the risk of severe inflammatory symptoms by preventing the release of IL-1β and its downstream molecules such as IL-1α, GM-CSF, and RANTES. Conclusions: Taken together, these results indicate that L-Alliin can boost immunity in healthy organisms and act as an immunomodulator in low-grade inflammation....
Avocado seed contains 64% of the phenolic compounds of the whole fruit. This makes avocado seed a potential candidate for the development of treatments for different illnesses, including obesity (the major risk factor for metabolic disorders). The aim of this study was to investigate the effects of avocado seed powder on high-fat diet-induced obesity in rats. Sprague Dawley rats (16 rats) were fed a high-fat diet for 10 weeks. After 10 weeks, the rats were assigned into two groups of eight animals each and were fed either a high-fat diet (HFD; control group) or a high-fat diet containing avocado seed powder (HFD-A; treatment group) for 6 weeks. Animals were weighed weekly, and weekly weight gain was determined. Animals in the treatment (avocado seed) group showed significantly lower body weight gain (7.8 ± 9.63 g) than animals in the control group (33.9 ± 10.84 g) at the end of this study. The treatment group presented with lower triglycerides than the control, with LDL and HDL comparable to the control group. Avocado seed powder showed potential to reduce obesity in rats fed a high-fat diet. Avocado seed can therefore be investigated further as a potential anti-obesity nutraceutical....
Background and Objectives: Postoperative ileus (POI) is a delay in gastrointestinal transit following surgery that leads to various complications. There is limited understanding of its effective treatment options. CKD-495 and eupacidin are natural products licensed for treating mucosal lesions in acute and chronic gastritis; however, little is known about their effects on intestinal permeability. This study evaluated the effects of CKD-495, eupacidin, and its components (eupatilin and cinnamic acid) on intestinal permeability in an animal model of POI. Materials and Methods: Guinea pigs underwent surgical procedures and were randomly assigned to different treatment groups. Drugs were administered orally prior to surgery. Intestinal permeability, leukocyte count, and the expression of calprotectin and tight junction proteins were measured in the harvested ileum tissue. Results: The intestinal permeability and leukocyte count were higher in the POI group than in the control group. The pre-administration of CKD-495, cinnamic acid, eupacidin, and eupatilin effectively prevented these changes in the POI model. No significant differences were observed in the expression of tight junction proteins. Conclusions: CKD-495, cinnamic acid, eupacidin, and eupatilin exerted protective effects against increased intestinal permeability and inflammation in an animal model of POI. These natural products have potential as therapeutic options for the treatment of POI....
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