Action Profile Research Articles

Emerging Frontiers in Cancer Immunotherapy: Recent Advances in CAR-NK Cell and CAR-Macrophage Therapies

Chimeric antigen receptor (CAR) cell therapies have revolutionized the field of cancer treatment with the breakthrough successes of CAR-T cell therapy in hematological malignancies. However, CAR-T cell efficacy in solid tumors has been limited by challenges such as the immunosuppressive tumor microenvironment (TME) and safety concerns like cytokine release syndrome (CRS) and graft-versus-host disease (GvHD). This review focuses on the latest advancements in CAR-NK cell and CAR-macrophage therapies, which offer potential solutions to these limitations. CAR-NK cells exhibit natural cytotoxicity and MHC-independent tumor targeting, providing a safer profile with lower risks of GvHD and CRS compared to CAR-T cells. Innovations in CAR-NK cell therapy includes structural optimizations, gene editing with CRISPR-Cas9, and the development of multispecific CARs, all contributing to enhanced anti-tumor efficacy, especially in solid tumors. Meanwhile, CAR-macrophages are effective in remodeling the TME through phagocytosis and immune activation, addressing the challenges of solid tumor infiltration. This review compares the mechanisms of action, clinical applications, and safety profiles of CAR-NK cells and CAR-macrophages, highlighting the synergistic potential of these therapies. Although clinical research on both therapies is still in its early stages, the promising preclinical and early clinical trial results underscore their potential as alternative immunotherapies for refractory cancers. Future research will focus on overcoming challenges in production scalability, improving in vivo persistence, and personalizing CAR therapies through precision medicine approaches. These two therapies will likely play pivotal roles in the next generation of cancer immunotherapies.

Glatiramer Acetate for the Treatment of Multiple Sclerosis: From First-Generation Therapy to Elucidation of Immunomodulation and Repair.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS), with a putative autoimmune origin and complex pathogenesis. Modification of the natural history of MS by reducing relapses and slowing disability accumulation was first attained in the 1990 s with the development of the first-generation disease-modifying therapies. Glatiramer acetate (GA), a copolymer of L-alanine, L-lysine, L-glutamic acid, and L-tyrosine, was discovered due to its ability to suppress the animal model of MS, experimental autoimmune encephalomyelitis. Extensive clinical trials and long-term assessments established the efficacy and the safety of GA. Furthermore, studies of the therapeutic processes induced by GA in animal models and in MS patients indicate that GA affects various levels of the innate and the adaptive immune response, generating deviation from proinflammatory to anti-inflammatory pathways. This includes competition for binding to antigen presenting cells; driving dendritic cells, monocytes, and B-cells toward anti-inflammatory responses; and stimulating T-helper 2 and T-regulatory cells. The immune cells stimulated by GA reach the CNS and secrete in situ anti-inflammatory cytokines alleviating the pathological processes. Furthermore, cumulative findings reveal that in addition to its immunomodulatory effect, GA promotes neuroprotective repair processes such as neurotrophic factors secretion, remyelination, and neurogenesis. This review aims to provide an overview of MS pathology diagnosis and treatment as well as the diverse mechanism of action of GA. SIGNIFICANCE STATEMENT: Understanding the complex MS immune pathogenesis provided multiple targets for therapeutic intervention, resulting in a plethora of agents, with various mechanisms of action, efficacy, and safety profiles. However, promoting repair beyond the body's limited spontaneous extent is still a major challenge. GA, one of the first approved disease-modifying therapies, induces diverse immunomodulatory effects. Furthermore, GA treatment results in elevated neurotrophic factors secretion, remyelination and neurogenesis, supporting the notion that immunomodulatory treatment can support in situ a growth-promoting and repair environment.

Role of Medicinal Plants in the Management of Multiple Sclerosis.

There is a rapid spread of Multiple Sclerosis disorder across the globe, around 2.8 million cases of Multiple Sclerosis in the world. Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by demyelination, neuroinflammation, and a wide spectrum of clinical manifestations. Many drugs have been tested on MS patients but there is no effective treatment for MS till now. So to inhibit the symptoms caused by MS we performed a study in which we identified various naturally occurring materials with neuroprotective effects on the body that can treat Multiple Sclerosis. The therapeutic strategies portion of the paper reviews the array of disease-modifying therapies currently available for MS management. This paper evaluated their mechanisms of action, efficacy, and safety profiles. It also addressed emerging treatment paradigms by using different naturally occurring materials, including personalized medicine approaches and novel therapies in development. This paper provides a comprehensive overview of the current state of knowledge regarding MS, focusing on its pathogenesis, diagnostic approaches, and therapeutic strategies.

Advances in Gouty Arthritis Management: Integration of Established Therapies, Emerging Treatments, and Lifestyle Interventions.

Gouty arthritis, a prevalent inflammatory condition characterized by the deposition of monosodium urate crystals within joints, often results in debilitating pain and inflammation. Conventional therapeutic approaches, including nonsteroidal anti-inflammatory drugs, corticosteroids, and urate-lowering agents such as allopurinol and febuxostat, often have limitations such as adverse effects, drug interactions, and suboptimal patient compliance. This review presents a comprehensive overview of both established and emerging therapeutic strategies, developed between 2019 and 2024, for gouty arthritis; the review focuses on their mechanisms of action, efficacy, and safety profiles. Novel therapeutic approaches include pharmaceutical plant additives (e.g., Citrullus colocynthis, Atractylodes lancea), anti-inflammatory agents such as canakinumab and ozone therapy, and complementary therapies such as warm ginger compresses, Qingpeng ointment, and various lifestyle modifications. These strategies offer promising alternatives to conventional treatments by targeting uric acid metabolism, inflammatory pathways, and crystal formation, potentially reducing reliance on standard medications and minimizing adverse effects. Although therapies such as canakinumab have demonstrated significant efficacy in reducing gout flares, others such as polyphenol-rich foods offer favorable safety profiles. Further research, including large-scale clinical trials, is warranted to validate these findings and integrate these strategies into clinical practice to improve patient outcomes and quality of life.

Differential chemoproteomic analysis of RRS-1 candidate molecule and molecules of several nonsteroidal anti-inflammatory drugs

Background. To plan effective and safe pharmacotherapy for inflammation and pain, it is important to evaluate the mechanisms and spectrum of action of nonsteroidal anti-inflammatory drugs (NSAIDs), including their effects on human proteome.Objective: to identify and evaluate the most significant specific differences of candidate molecule RRS-1 (N-{(Z)-2-(1-methyl-1H-indol-3-yl)-1-[(propylamino)carbonyl]vinyl}benzamide) from other NSAIDs through differential chemoreactome analysis.Materials and methods. Chemoproteomic modeling of pharmacological effects of RRS-1 molecule and a number of well-known NSAIDs (diclofenac, nimesulide, ketorolac) on human proteome was carried out on the basis of numerical prediction algorithms over the space of heterogeneous feature descriptions, developed in the topological approach to recognition by Yu.I. Zhuravlev and K.V. Rudakov scientific school.Results. Significant differences in the effects of the studied molecules were found for 1232 proteins of human proteome. The features of assessing interactions of the studied molecules with 47 target proteins, which most distinguished the effects of RRS-1 molecule from all others were identified. RRS-1 could activate adenosine and dopamine receptors, cannabinoid receptor 2 and GABAA receptor to a greater extent than other molecules. Activation of these receptors corresponded to anti-inflammatory, anti-nociceptive and neuroprotective effects. RRS-1 could preferably inhibit a number of pro-inflammatory proteins, receptor bradykinin 1, metabotropic glutamate receptor 5, matrix metalloproteinases 8, 9, 12, and blood coagulation factor X. Additionally, RRS-1 molecule showed preferable inhibition of a number of kinases targeted in antitumor and anti-inflammatory therapy. RRS-1, less than other studied molecules, interacted with the receptors of vitamin D3, thyroid hormone, acetylcholine, cannabinoids and opioids, orexin, and various metabolic enzymes, which is important in assessment of the safety of using drugs based on this molecule. RRS-1 characteristically exhibited a moderate profile of antivitamin action: the total score of vitamin and mineral loss (7.4±3.7) was significantly less in comparison to diclofenac (11.7±4.5) and was actually on the same level as nimesulide (6.9±3.7) and ketorolac (6.7±3.6).Conclusion. Chemoreactomic and chemoproteomic profiling of RRS-1 candidate molecule provided pre-experimental assessments of its efficacy and safety through modeling interactions with the human proteome.

Clinical research progress of fruquintinib in the treatment of malignant tumors.

Malignant tumors represent an important cause of mortality within the global population. Tumor angiogenesis, recognized as one of the key hallmarks of malignant tumors, is crucial for supplying essential nutrients and oxygen for tumor growth. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are key drivers of tumor angiogenesis. Targeted therapeutic interventions not only effectively inhibit tumor growth by specifically blocking tumor angiogenesis but have also made breakthroughs in the treatment of malignant tumors. Fruquintinib, an anti-angiogenic small molecule drug developed independently in China, functions as a potent tyrosine kinase inhibitor with high selectivity. It effectively curtails tumor growth by binding to and inhibiting VEGFR-1, VEGFR-2, and VEGFR-3. Additionally, fruquintinib offers several advantages including minimal off-target toxicity, robust resistance profiles, and commendable efficacy. This agent can be used alone or in combination with other treatments. It has shown high effectiveness and survival benefits across various malignant tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, breast cancer, and other malignant tumors. Therefore, this article conducts a systematic review encompassing the mechanism of action, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib. Through this review, we aimed to offer a reference for the clinical application and subsequent development of fruquintinib.

GET73 modulates lipopolysaccharide- and ethanol-induced increase in cytokine/chemokine levels in primary cultures of microglia of rat cerebral cortex.

- Alcohol-induced pro-inflammatory activation might influence cellular and synaptic pathology, thus contributing to the behavioral phenotypes associated with alcohol use disorders. In the present study, the possible anti-inflammatory properties of N-[(4-trifluoromethyl)-benzyl]4-methoxybutyramide (GET73), a promising therapeutic agent for alcohol use disorder treatment, were evaluated in primary cultures of rat cortical microglia. - Primary cultures of cerebral cortex microglial cells were treated with 100 ng/ml lipopolysaccharide (LPS; 8h, 37°C) or 75 mM ethanol (EtOH; 4 days, 37°C) alone or in the presence of GET73 (1-30 µM). At the end of the incubation period, multiparametric quantification of cytokines/chemokines was performed by using the xMAP technology and Luminex platform. Furthermore, cultured microglial cell viability following the treatment with EtOH and GET73, alone or in combination, has been measured by a colorimetric assay (i.e. MTT assay). - GET73 (10 and 30 µM) partially or fully prevented the LPS-induced increase of IL-6, IL-1β, RANTES/CCL5 protein and MCP-1/CCL2 levels. On the contrary, GET73 failed to attenuate the TNF-α level increase induced by LPS. Furthermore, GET73 treatment (10-30 µM) significantly attenuated or prevented the EtOH-induced increase of TNF-α, IL-6, IL-1β and MCP-1/CCL2 levels. Finally, at all the concentrations tested (1-30 µM), the GET73 treatment did not alter the EtOH-induced reduction of microglial cell viability. - The current results provide the first in vitro evidence of GET73 protective properties against EtOH-induced neuroinflammation. These data add more information on the complex and multifactorial profile of action of the compound, further supporting the significance of developing GET73 as a therapeutic tool for the treatment of individuals with alcohol use disorders.

The role of flozins in managing cardiovascular risk in patients with type 2 diabetes - narrative review

Introduction. Cardiovascular disease is a leading cause of morbidity and mortality among patients with type 2 diabetes mellitus. The emergence of flozins, a class of sodium-glucose co-transporter-2 inhibitors, has introduced a novel therapeutic avenue with potential cardiovascular benefits beyond glycemic control. Objective. This review aims to synthesize current evidence on the role of flozins in managing cardiovascular risk among patients with T2DM, examining their efficacy, safety profile, and mechanisms of action. Review methods. A comprehensive literature search was conducted using databases, covering studies published between 2015 and 2024. Clinical trials, meta-analyses, and observational studies evaluating the cardiovascular outcomes associated with flozins in T2DM patients were included. Brief description of the state of knowledge. Research shows that flozins improve glycemic control and provide significant cardiovascular protection, reducing major adverse cardiovascular events, heart failure hospitalizations, and cardiovascular mortality in T2DM patients. These benefits are likely due to hemodynamic changes, enhanced cardiac function, and reduced inflammation and oxidative stress. Summary. Flozins represent a promising therapeutic option for reducing cardiovascular risk in T2DM patients. Their dual benefits on both metabolic and cardiovascular health position them as a cornerstone in the management of T2DM. Further research is needed to fully elucidate their long-term benefits and safety in diverse patient populations.

Renaissance of Ketamine

The history of ketamine began in the 1960s. Ketamine is a specific anesthetic drug that exhibits analgesia, has a stabilizing impact on the cardiovascular system and does not significantly depress the respiratory system. It is responsible for causing the so-called dissociative effect. The effects of ketamine depend on the dose. Its mechanism of action is based primarily on the blockade of N-methyl D-aspartic acid receptors (NMDA) in the central nervous system. Due to its favorable action profile and small number of contraindications, ketamine is becoming an increasingly popular drug. In medicine, it is commonly used as an analgesic and an anesthetic. Studies conducted over recent years have noted that it can be effective in conditions such as: status epilepticus, status asthmaticus, agitation, alcohol dependence and alcohol withdrawal syndrome, depression, and suicidal thoughts. This paper reviews current reports on the uses of ketamine, beneficial especially to physicians with the Specialty in emergency medicine.

Overview of Leech Therapy as an Alternative Treatment for Varicose Ulcers: Mechanisms and Efficacy

Varicose ulcer, the most severe and debilitating complication of chronic venous insufficiency in the lower limbs, impart substantial obstacles in medical management because of their chronicity and propensity for recurrence. About 80 percent of ulcerations on the lower extremities are triggered by varicose ulcer. Despite advances in diagnosis and treatment, varicose ulceration remains a major healthcare concern due to its potential for life-threatening complications. The morbidity has a detrimental effect on life expectancy. Venous ulceration results from persistent venous pressure brought on by venous insufficiency. Although the diagnosis is primarily clinical, it must be distinguished from other lower limb ulcer causes. Reduction of edema, enhancement of ulcer healing, and avoidance of recurrence are the objectives of treatment. Although conservative care, mechanical treatment, pharmaceutical, and surgical methods are available for the treatment of venous ulcers, but Hirudotherapy, also known as leech therapy, has grown into a prominent complementary treatment option. It has the potential to promote wound healing and alleviate varicose ulcer symptoms. The objective of this review is to accord a thorough overview of the application of leech therapy to the management of varicose ulcers. The present study emphasizes on the mechanisms of action, efficacy and safety profile of leech therapy in the context of managing varicose ulcers by synthesizing a collection of available literature, clinical investigations, and case reports.

Recent Advances in Anticancer Research of Osmium and Rhodium Complexes

Abstract: Although platinum and ruthenium complexes have been clinically recognized to be the most efficient metal-based anticancer candidates, applied in a wide range of cancer cell lines, their serious toxic effects and drug resistance require the necessity for new metal antitumor complexes. There is excessive interest in the design of new Pt-group metal complexes, including osmium and rhodium, which have revealed great chemotherapeutic potential. They have demonstrated modes of action that differ from those of the most broadly-used in clinical practice platinum- and rutheniumbased compounds. Os and Rh complexes are equipotent to their platinum and ruthenium analogues. Many Os- and Rh-based complexes with strong antitumor activity and low toxic effects have been developed and recognized for their antineoplastic activity in the last few years. Some of them have exposed different action profiles from the conventional anticancer metal complexes. That is why they might serve as a possible alternative that deserves more investigation, though limited studies on their biological effects have been reported, which is in contrast with the classical isoelectronic Pt and Ru complex compounds. Studies of Os and Rh complexes are currently attracting scientific attention. Recent developments of this interesting class of novel chemotherapeutic agents have been reviewed.

Analysis of the anti-Candida activity of tricyclic antidepressants in association with amphotericin B and their antifungal mechanisms.

Candida species are among the priority pathogens in the area of research and development. Due to the problems associated with resistance to antifungals, new therapeutic alternatives are necessary. In this regard, drug repositioning has gained prominence. The objective of this study was to evaluate the activity of three tricyclic antidepressants (TCAs) - amitriptyline (AMT), nortriptyline (NOR) and clomipramine (CLO) - isolated or associated with antifungals against strains of Candida spp., as well as to analyze the possible mechanism of action. Among the methods used were broth microdilution tests, tolerance level assessment, checkerboard assays, flow cytometry and fluorescence microscopy. Furthermore, Candida cells were visualized after treatments by scanning electron microscopy (SEM). AMT presented MIC 50% in the range of 16 to 128µg/mL, NOR from 8 to 128µg/mL, and CLO from 8 to 64µg/mL, with all three TCAs having a fungicidal inhibitory action profile. For these TCAs, there was synergism with amphotericin B (AMB) in 100% of the isolates. In association with fluconazole (FLC) and itraconazole (ITR), there were mostly indifferent interactions. TCAs isolated and associated with AMB reduced cell viability, promoted DNA fragmentation and damage, caused mitochondrial depolarization, externalization of phosphatidylserine, produced reactive oxygen species (ROS), decreased reduced glutathione (GSH) and increased carbonyl protein levels, causing morphological changes. The results suggest the antifungal mechanism of the TCAs works via the apoptotic pathway.

The methods of synthesis of 2-aminobenzophenones — key precursors of 1,4-benzodiazepines

The review article briefly presents the pharmacological profile and mechanism of action of 1,4-dibenzodiazepines, and the structures of the most important drugs from this class of compounds. The strongest emphasis is placed on presentation of various methods for the synthesis of 2-aminobenzophenones — the most often used precursors in the synthesis of 1,4-benzodiazepines and numerous classes of azaarenes. The reactions or their sequences were grouped according to retrosynthetic strategies based on structural similarities and differences of the reagents used. There were presented not only the most classical methods like Friedel-Crafts acylation or Grignard reaction, but also more advanced transformations utilizing various catalysts and more sophisticated approaches involving the synthesis of heterocyclic systems followed by their reductive or oxidative cleavage. Selected nuances of the presented reactions were discussed, including fragments of mechanisms, limitations of the applicability of a given method, and the advantages of modern solutions over the oldest and more classical methods.

The Role of Mycobacterium indicus pranii in Sepsis Management: A Comprehensive Review of Clinical Outcomes and Therapeutic Potential.

Sepsis is a critical condition characterized by a dysregulated immune response to infection, leading to systemic inflammation, multi-organ failure, and high mortality rates. Current treatments primarily involve antibiotics and supportive care, which address the infection and stabilize hemodynamics but do not directly modulate the inflammatory response. This limitation highlights the need for novel therapeutic approaches. This review aims to evaluate the role of Mycobacterium indicus pranii (MIP) in sepsis management, focusing on its clinical outcomes and therapeutic potential. By examining preclinical and clinical evidence, we seek to understand the efficacy, safety, and practical applications of MIP in treating sepsis. A comprehensive review of existing literature was conducted, including preclinical studies, clinical trials, and case reports involving MIP. The review synthesizes findings related to its mechanism of action, therapeutic efficacy, and safety profile. MIP has demonstrated significant immunomodulatory effects, including enhancing innate and adaptive immune responses and reducing excessive inflammation. Clinical trials have shown promising results, with MIP improving clinical outcomes and reducing sepsis-related complications. The agent's unique ability to modulate the cytokine storm associated with sepsis positions it as a potential adjunctive therapy. MIP offers a novel approach to managing sepsis by addressing immune dysregulation and inflammation. The evidence suggests that MIP could be a valuable adjunct to current treatments, improving patient outcomes and addressing some limitations of conventional therapies. Further research is needed to establish its role in clinical practice and to optimize treatment protocols.

A Systematic Review on Sedative and Hypnotics

Abstract: Sedative and hypnotic drugs are central nervous system depressants primarily used to induce calmness, reduce anxiety, and promote sleep. These medications include benzodiazepines, barbiturates, and various non-benzodiazepine sleep aids, each varying in their mechanism of action, efficacy, and safety profiles. Benzodiazepines, such as diazepam and alprazolam, enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-A receptor, resulting in sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. They are commonly prescribed for anxiety disorders, insomnia, seizures, and muscle spasms. However, their use is associated with risks of tolerance, dependence, and withdrawal symptoms. Barbiturates, such as phenobarbital, were once widely used for their sedative and hypnotic properties but have largely been replaced by benzodiazepines and other safer alternatives due to their higher risk of overdose and dependence. Barbiturates enhance GABAergic transmission but also directly activate GABA receptors, leading to more profound central nervous system depression. Non-benzodiazepine sleep aids, including drugs like zolpidem, eszopiclone, and zaleplon, act on the benzodiazepine receptor site but have a different chemical structure. These drugs are often preferred for short-term treatment of insomnia due to their relatively lower risk of dependence and adverse effects compared to benzodiazepines.

Robustness in binary-action supermodular games revisited

AbstractWe show that in all (whether generic or nongeneric) binary-action supermodular games, an extreme action profile is robust to incomplete information if and only if it is a monotone potential maximizer. The equivalence does not hold for nonextreme action profiles.

Nicotinamide: Bright Potential in Glaucoma Management.

Glaucoma is a major cause of incurable ocular morbidity and poses significant challenges in its management due to the limited treatment options and potential adverse effects. Nicotinamide, a naturally occurring diet-rich nutrient, has emerged as a promising therapeutic agent for glaucoma, offering neuroprotective effects and the potential modulation of intraocular pressure (IOP) regulation pathways. This comprehensive review sought to analyze the current literature on nicotinamide in glaucoma management, exploring its mechanisms of action, efficacy, and safety profile. A systematic search of the PubMed database was conducted to identify relevant records on the therapeutic actions of nicotinamide in ocular hypertension and glaucoma. Publications evaluating nicotinamide's effects on retinal ganglion cells (RGCs), optic nerve function, IOP regulation, and neuroinflammatory pathways were included. The literature review revealed the preclinical evidence supporting nicotinamide's neuroprotective effects on RGCs, the preservation of optic nerve integrity, and the modulation of glaucoma-associated neuroinflammation. Additionally, nicotinamide may exert IOP-lowering effects through its influence on ocular blood flow and aqueous humor dynamics. Nicotinamide holds promise as a novel therapeutic approach in glaucoma management, offering potential neuroprotective and IOP-lowering effects. The authors recommend more research to determine the nicotinamide efficacy, safe dosing parameters, and any long-term safety concerns in glaucoma patients.

Current and Future Strategies in Insulin Development and Treatment.

Recent advances in insulin research open new avenues for treatment, both, for type 1 and type 2 diabetes. In developed countries, standardized "ultra-rapid-acting insulins" are now also used in addition to rapid-acting insulins. First- and second-generation basal analogs are available. Third-generation basal analogs, which only need to be applied once a week, are in the pipeline. Second-generation "ultra-rapid-acting insulins" insulins with faster onset and offset of action may be particularly useful for multiple daily injections and automated insulin delivery systems. An improved time-action profile of bolus insulin would be able to cover the rapid increase in glucose after meals with a rapid fall thereafter to avoid postprandial hypoglycemia. The third-generation basal insulins allowing once-weekly dosing made major steps toward becoming a clinical reality. However, issues with insulin affordability and availability remain problematic even in more affluent countries. Biosimilar insulins products can provide people with additional safe, high-quality, and potentially cost-effective options for treating diabetes. Particularly in low-middle income countries insulin therapy is facing issues not only of access but also storage, lack of diabetes education, and stigma. With the new bolus insulins, the physiological insulin secretion pattern can be mimicked better and better and hypoglycemia can be avoided. With the ever longer pharmacokinetic action profiles of the basal analogs, the injection frequency is reduced, which leads to better adherence and quality of life, but these insulins are not available for everyone who needs it worldwide.

Antifungal activity of synthetic xanthenone against fluconazole-resistant Candida auris and its mechanism of action

Candida auris, an emerging multidrug-resistant fungal pathogen discovered in Japan in 2009, poses a significant global health threat, with infections reported in about 25 countries. The escalation of drug-resistant strains underscores the urgent need for new treatment options. This study aimed to investigate the antifungal potential of 2,3,4,4a-tetrahydro-1H-xanthen-1-one (XA1) against C. auris, as well as its mechanism of action and toxic profile. The antifungal activity of XA1 was first evaluated by determining the minimum inhibitory concentration (MIC), time-kill kinetics and biofilm inhibition. In addition, structural changes, membrane permeability, reactive oxygen species (ROS) production, and in vitro and in vivo toxicity of C. auris after exposure to XA1 were investigated. The results indicated that XA1 exhibited an MIC of 50 μg/mL against C. auris, with time-kill kinetics highlighting its efficacy. Field emission scanning electron microscopy (FE-SEM) showed structural damage in XA1-treated cells, supported by increased membrane permeability leading to cell death. Furthermore, XA1 induced ROS production and significantly inhibited biofilm formation. Importantly, XA1 exhibited low cytotoxicity in human epidermal keratinocytes (HaCaT), with a cell viability of over 90 % at 6.25 μg/mL. In addition, an LD50 of 17.68 μg/mL was determined in zebrafish embryos 24 h post fertilization (hpf), with developmental delay observed at prolonged exposure at 6.25 μg/mL (48–96 hpf). These findings position XA1 as a promising candidate for further research and development of an effective antifungal agent.

Taurolidine and Heparin as Catheter Lock Solution for Central Venous Catheters in Hemodialysis.

Chronic kidney disease can lead to end-stage renal disease, and the prevalence is increasing. Many patients starting hemodialysis require central venous catheters (CVCs). Catheter-related bloodstream infections (CRBSIs) are a common complication and lead to significant morbidity and mortality. Interventions to prevent CRBSI include antimicrobial lock therapy but concern for the development of antimicrobial resistance and adverse effects. Nonantimicrobial antiseptics as catheter lock solutions have also been used. Taurolidine and heparin catheter lock solution is first approved by the Food and Drug Administration for the prevention of CRBSI in patients on hemodialysis. Taurolidine has a unique mechanism of action and favorable safety profile. Taurolidine and heparin catheter lock solution have both antimicrobial and anticoagulant properties. Taurolidine is derivative of the amino acid taurine, and heparin is derived from porcine intestinal mucosa. Taurolidine not only damages microbial cell walls but also prevents the adherence of microorganisms to biological surfaces, preventing biofilm formation. Taurolidine and heparin catheter lock solution is intended to be used intraluminally within the catheter and should be aspirated. Because it is used locally, limited pharmacokinetic and pharmacodynamic data are available. The LOCK-IT-100 trial is a randomized, double-blind, phase 3 study, which included 795 end-stage renal disease patients on hemodialysis with CVC. Taurolidine and heparin was compared with the control heparin alone. The results of the study showed a 71% risk reduction in CRBSI for taurolidine and heparin arm (95% confident interval, 38%-86%, P = 0.0006). Other studies have also shown that taurolidine lock solution leads to decreased CRBSI episodes. Several systematic reviews and meta-analysis consisted of taurolidine in adult, and pediatric populations also showed reduction in the incidence of CRBSIs. Taurolidine and heparin lock solution represents a novel preventive strategy for those undergoing hemodialysis through a CVC by reducing the risk of CRBSI. This is significant progress because there are no other similar options available for patients for whom catheters are the only options for their life-saving treatment.