Pharmacodynamic Characteristics Research Articles

A Decades-Long Journey of Palmitoylethanolamide (PEA) for Chronic Neuropathic Pain Management: A Comprehensive Narrative Review.

Palmitoylethanolamide (PEA) has been prescribed in neuropathic pain management for over 20years. This study aims to summarize what has been published on the topic in the last 15years and determine the appropriateness of the prescribing. It describes the pharmacological aspect of PEA, especially focusing on its pharmacodynamics and pharmacokinetics. Then, it deeply explores why PEA may be useful in the pharmacological management of both neuropathic and mixed pain. Finally, it examines some innovative patent, which aims to address obstacles encountered with conventional PEA formulations, for its pharmacodynamic characteristics. One of them (Equisetum-PEA) seems promising. It partially ameliorates the bioavailability and the targeted distribution. It seems to introduce novel advancements that can potentially enhance the therapeutic effectiveness of PEA in terms of its anti-inflammatory, antioxidant, and analgesic properties. The deep literature analysis aims to examine the potential advantages of PEA, in the context of several pathological conditions that may benefit from this molecule. It focuses on various published data regarding the clinical efficacy of PEA in managing neuropathic and mixed pain. Also, it tries to understand if it can modernize the field of therapy based on PEA, thus offering a better treatment option for individuals with chronic long-term inflammation, oxidative stress, and neuropathic or mixed pain with a neuropathic component. The study examines the possible impact of PEA on personalized medicine strategies and its potential for translation into clinical practice. It analyses the possibilities that PEA has in enhancing patient outcomes in a range of central nervous system and inflammatory conditions. A complete analysis of the therapeutic potentialities of this product was missing. This extensive narrative review makes a valuable contribution to the ongoing comprehension of PEA therapy. It establishes a foundation for further exploration in research and potential uses in clinical settings.

Unveiling the Anti-convulsant Potential of Novel Series of 1,2,4-Triazine- 6H-Indolo[2,3-b]quinoline Derivatives: In Silico Molecular Docking, ADMET, DFT, and Molecular Dynamics Exploration.

Epilepsy is a chronic neurological disorder caused by irregular electrical activity in the brain. To manage this disorder effectively, it is imperative to identify potential pharmacological targets and to understand the pathophysiology of epilepsy in depth. This research aimed to identify promising leads from a library of 1,2,4-triazine-6Hindolo[ 2,3-b]quinoline derivatives and optimize them using in silico and dynamic processes. We used computational studies to examine 1,2,4-Triazine-6H-indolo[2,3-b]quinoline derivatives. Some methods were used to strengthen the stability of binding sites, including Docking, ADMET, IFD, MMGBSA, Density Functional Theory (DFT), and Molecular Dynamics. HRSN24 and HRSN34 exhibited promising pharmacokinetic and pharmacodynamic characteristics compared to standard drugs (Carbamazepine and Phenytoin) and a co-crystal ligand (Diazepam). Both HRSN24 and HRSN34 presented notable Glide Xp docking scores (-4.528 and -4.633 Kcal/mol), IFD scores (-702.22 and -700.3 Kcal/mol), and MMGBSA scores (-45.71 and -14.46 Kcal/mol). HRSN24 was selected for molecular dynamics and DFT analysis. During MD, HRSN24 identified LYS21, GLY22, ASP24, ARG26, VAL53, MET55, and SER308 as the most important amino acid residues for hydrophobic interactions. A DFT computation was performed to determine the physicochemical properties of HRSN24, revealing a total energy of -1362.28 atomic units, a HOMO value of -0.20186, and a LUMO value of -0.01915. Based on computational modelling techniques, an array of 1,2,4-triazine-6H-indolo [2,3-b]quinoline derivatives were evaluated for their anti-convulsant properties. A stable compound within the GABAA receptor was identified by HRSN24, suggesting its affinity as an anti-convulsant.

Novel Benzothiazole-Benzonitrile-Based Fluorescent Chromophore: Synthesis, DFT, Antimicrobial Properties.

The synthetic strategy for the benzothiazole-benzonitrile chromophore 6 involved three sequences of reactions. It was initiated by condensation of 2-amino-4-nitrothiophenol (2) with 4-(piperidin-1-yl)benzaldehyde (1) to produce the corresponding 5-nitrobenzothiazole compound 3 followed by reduction of compound 3 into the 5-aminobenzothiazole compound 4 and then ended by condensation of 5-aminobenzothiazole compound 4 with 4-formylbenzonitrile (5). The chromophore's absorption and emission spectra have been measured in EtOH and presented good Stokes' shift ( = 8363 cm-1). The DFT configuration of the frontier molecular orbits in gas and solvated ground state (So) were compared with the solvated excited state (S1). The synthesized chromophore 6 was assessed for its antimicrobic properties against a group of bacterial and fungal strains. The minimum inhibitory concentration (MIC) values were determined using standard broth microdilution assay. Notably, chromophore 6 exhibited remarkable MIC values against Staphylococcus aureus and Escherichia coli (< 48 and < 118 μg/mL). Regarding the antibacterial effectiveness against both S. aureus and E. coli, molecular docking was performed to simulate their binding interactions with two protein structures, PDB:2eg7 and PDB:3u2k. The SwissADME study has been applied to explore the pharmacokinetic and pharmacodynamic characteristics of chromophore 6.

Comparison of Ketamine/Diazepam and Tiletamine/Zolazepam Combinations for Anaesthesia Induction in Horses Undergoing Partial Intravenous Anaesthesia (PIVA): A Retrospective Clinical Study

The aim of this retrospective clinical study was to compare the combinations of ketamine/diazepam (KD group) and tiletamine/zolazepam (TZ group) for the induction of general anaesthesia in horses undergoing elective surgery. The data from the clinical and the anaesthetic records of 138 horses from 2021 to 2023 were evaluated, and the horses were divided in two groups: KD (n = 60) and TZ (n = 72). The horses were premedicated with romifidine and methadone IV; anaesthesia was induced with ketamine/diazepam for the KD group and tiletamine/zolazepam for the TZ group and was maintained with isoflurane and a constant rate infusion of romifidine. The data encompassed sex and neuter status, age, breed, weight, American Society of Anaesthesiologists physical status, type of surgical procedure performed under anaesthesia, induction time, induction score, surgery time, recovery time, and the recovery score using a descriptive scale. Baseline heart rate (HR), intraoperative HR, baseline respiratory rate (fR), intraoperative fR, mean arterial pressure (MAP), oxygen saturation (SpO2), and fraction of expired isoflurane (FE’Iso) were also recorded. The induction time was significantly longer (p = 0.004) in the TZ group (60 (40–120)) as compared to the KD group (50 (30–120)). Recovery time was also significantly longer (p ≤ 0.001) in the TZ group (46.5 (15–125)) as compared to the KD group (30 (5–105)). These findings suggested that, in adult horses undergoing elective surgery, TZ could be considered a valid alternative to KD for the induction of general anaesthesia. Additional experimental studies comparing the two induction regimens and their pharmacokinetic and pharmacodynamic characteristics are needed.

Durlobactam to boost the clinical utility of standard of care β-lactams against Mycobacterium abscessus lung disease.

β-Lactams present several desirable pharmacodynamic features leading to the rapid eradication of many bacterial pathogens. Imipenem (IPM) and cefoxitin (FOX) are injectable β-lactams recommended during the intensive treatment phase of pulmonary infections caused by Mycobacterium abscessus (Mab). However, their potency against Mab is many-fold lower than against Gram-positive and Gram-negative pathogens for which they were optimized, putting into question their clinical utility. Here, we show that adding the recently approved durlobactam-sulbactam (DUR-SUL) pair to either IPM or FOX achieves growth inhibition, bactericidal, and cytolytic activity at concentrations that are within those achieved in patients and below the clinical breakpoints established for each agent. Synergies between DUR-SUL and IPM or FOX were confirmed across a large panel of clinical isolates. Through in vitro resistant mutant selection, we also show that adding DUR-SUL abrogates acquired resistance to IPM and FOX. Since the use of β-lactam injectables is firmly grounded in clinical practice during the intensive treatment phase of Mab pulmonary disease, their potentiation by FDA-approved DUR-SUL to bring minimum inhibitory concentration distributions within achievable concentration ranges could offer significant short-term benefits to patients, while novel β-lactam combinations are optimized specifically against Mab pulmonary infections, for which no reliable cure exists.

Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science.

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated invitro, invivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

A promise of nose to brain delivery of bevacizumab intranasal sol-gel formulation substantiated in rat C6 glioma model.

Glioblastoma is one of the rapidly spreading cancers, with its potent malignancy often linked to pronounced angiogenesis within tumors. To mitigate this vascularization profile, bevacizumab (Avastin®), a monoclonal antibody, has been utilized for its antiangiogenic activity. However, its effectiveness is hindered by challenges in crossing the blood-brain barrier and the risk of off-target organ toxicity. Delivering drugs directly from the nose to the brain through the olfactory or trigeminal nerves bypassing the blood-brain barrier offers enhanced bioavailability and a more precise targeting strategy. To overcome these challenges, we aimed to develop bevacizumab in situ gel loaded mesoporous silica nanoparticles for intranasal delivery and further examine their pharmacokinetic and pharmacodynamic characteristics. The intranasal gel of mesoporous silica nanoparticles loaded with bevacizumab was optimized and formulated using a factorial and quality by design approach. In the case of bevacizumab mesoporous silica nanoparticles, lower particle size and most negative zeta potential were selected as quality target product profiles which is important for drug loading on the mesoporous silica nanoparticles and also transport of these nanoparticles across the nasal mucosa to the brain. A design space with a multidimensional combination of input variables and process parameters has been demonstrated to assure quality. To optimize the design space and achieve the desired quality standards, the base catalyst and surfactant concentration were chosen as the critical process parameters, while particle size and zeta potential were identified as the critical quality attributes. The novel formulation was assessed for physicochemical parameters such as particle size, zeta potential, entrapment efficiency, appearance, color, consistency, and pH. Additionally, studies on in vitro release, ex vivo permeation, stability, nasal toxicity, organ safety, and bioavailability were conducted. The efficacy study was conducted in an orthotopic murine glioblastoma rat model in which C6 Luc cells were instilled in the striatum of the rat's brain. In vivo, bioluminescence imaging of brain tumors was carried out to observe the tumor regression after treatment with the intranasal and intravenous bevacizumab formulation. Biochemical parameters and histopathology were performed for organ safety studies. The optimized intranasal formulation exhibited an average particle size of 318.8nm and a zeta potential of - 14.7mV for the mesoporous silica nanoparticles. The formulation also demonstrated an entrapment efficiency of 91.34% and a loading capacity of 45.67%. Further pharmacokinetic studies revealed that the optimized intranasal bevacizumab formulation achieved a significantly higher brain concentration Cmax = 147.9ng/ml, indicating improved bioavailability compared to rats administered with intravenous bevacizumab formulation (BEVATAS®), which had a Cmax of 127.2ng/ml. Moreover, this nanoparticle formulation entirely mitigated systemic exposure to bevacizumab. Organ safety evaluation of different biochemical parameters and histopathological analyses revealed that the intranasal bevacizumab-treated group was showing less off-target organ toxicity compared to the group treated with intravenous bevacizumab formulation. Subsequently, the efficacy of this nanosystem was evaluated in an orthotopic glioblastoma rat model, monitoring tumor growth over time through in vivo bioluminescence imaging and assessing anti-angiogenic effects. Twenty-one days post-induction, mesoporous silica nanoparticles loaded with bevacizumab in situ gel exhibited a marked reduction in average bioluminescence radiance (4.39 × 103) from day 7 (1.35 × 107) emphasizing an enhanced anti-angiogenic effect compared to the group treated with intravenous bevacizumab formulation which showed a gradual decrease in average bioluminescence radiance (4.82 × 104) from day 7 (1.42 × 107). These results suggest that the proposed novel formulation of mesoporous silica nanoparticles loaded bevacizumab in situ gel could serve as a promising avenue to enhance glioblastoma treatment efficacy, thereby potentially improving patient quality of life and survival rates significantly. Furthermore, the success of this delivery method could open new avenues for treating other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. By providing effective brain-targeted therapies, this approach has the potential to revolutionize treatment options and improve outcomes for a broad spectrum of neurological conditions.

Organ-protective effects of the alternative renin-angiotensin system and prospects for therapeutic treatment. Review

The article is devoted to review the data regarding the identification of biochemical and functional features of the components of the renin‑angiotensin system using the tools of bibliometric analysis of scientific literature. A modern interpretation by the dividing of the multifunctional complex into two systems, namely the classical renin‑angiotensin system and alternative renin‑angiotensin system, in accordance with the definition of biological effects, is given. The enzymatic cascade involved in the production and metabolism of peptides in both classical and non‑classical pathways of renin‑angiotensin systems is shown from the point of view of the evolution of scientific concepts. The triggering role of components of the classical renin‑angiotensin system in pathophysiological processes with transformation into cardiovascular diseases and metabolic dysfunction has been proven. The history of the creation of pharmacological drugs for the correction of the classic renin‑angiotensin system is presented. In view of the achievement of recent years, the revision of the alternative renin‑angiotensin system is emphasized due to the discovery of the counter‑regulatory action of the angiotensin‑converting enzyme 2, angiotensin‑(1—7), the Mas receptor in relation to their correction of metabolic processes, regulation of blood pressure, and the presence of anti‑fibrotic, anti‑inflammatory and antioxidant properties. The positive effect of the components of the non‑classical renin‑angiotensin system on the protection of the cardiovascular system and kidney is presented based on the results of experimental studies on animals. Pharmacokinetic and pharmacodynamics characteristics of recombinant angiotensin‑converting enzyme 2 in experiments on healthy volunteers are highlighted. The potential protective effects of angiotensin‑converting enzyme 2 and angiotensin‑(1—7) concerning cardiometabolic risk are presented. The available data indicate the need for further comprehensive scientific investigations of the components of alternative renin‑angiotensin system to create a new class of pharmacological agents with their implementation in medical practice.

Using an in vitro pharmacokinetics / pharmacodynamics model to simulate and assess the pharmacodynamic characteristics of voriconazole against some Candida albicans isolates in humans

Using an in vitro pharmacokinetics / pharmacodynamics model to simulate and assess the pharmacodynamic characteristics of voriconazole against some Candida albicans isolates in humans

Unique Pharmacological Properties and Safety Profiles of Loop Diuretics.

Loop diuretics are regarded as essential for the treatment of edematous conditions in heart failure, cirrhosis, and renal disease. The principal mechanism of action involves inhibiting the reabsorption of ions (Na+, 2Cl-, and K+) from the ascending loop of Henle. The pharmacokinetic (PK) and pharmacodynamic (PD) features of the commonly used diuretics (torsemide, furosemide, and bumetanide) influence the selection of diuretics in various disease states and dosing regimens. However, torsemide demonstrates superior PK and PD qualities, making it the preferred choice. Genetic polymorphisms must be explored to better understand the diversity of PK and PD parameters of loop diuretics between individuals.

53968 Pharmacokinetic and Pharmacodynamic Characteristics of ESK-001, an Oral Allosteric TYK2 Inhibitor, in Phase 1 Healthy Volunteer Trials

53968 Pharmacokinetic and Pharmacodynamic Characteristics of ESK-001, an Oral Allosteric TYK2 Inhibitor, in Phase 1 Healthy Volunteer Trials

Rethinking the use of direct oral anticoagulants for secondary thromboprophylaxis in patients with thrombotic antiphospholipid syndrome.

Patients with thrombotic antiphospholipid syndrome (APS) are at high risk for recurrent thrombosis, and indefinite anticoagulation is recommended. Patients with APS merit indefinite anticoagulation, and vitamin K antagonists (VKAs) have historically been the standard treatment. Direct oral anticoagulants (DOACs) present an appealing alternative to VKAs. Due to their pharmacokinetic and pharmacodynamic characteristics, DOACs offer advantages over VKAs, namely the lack of need for laboratory monitoring, the usage of a fixed dosage, and the absence of significant interaction with dietary components and drugs. The efficacy and safety of DOACs in patients with APS have been studied in four phase II/III clinical trials (three with rivaroxaban and one with apixaban). These studies showed DOACs' inferiority compared to VKAs in preventing recurrent thrombosis. Recurrence was significantly greater in patients with arterial thrombotic events and a triple positivity for antiphospholipid antibodies. No differences were observed in the incidence of venous thromboembolism between both groups. Major bleeding was similar in patients treated with DOACs or VKAs. Several observational studies have reported similar results. This review aims to analyse the existing evidence on the efficacy and safety of DOACs for secondary prevention in patients with APS.

High adsorption capacity of hemoperfusion on imipenem in critically ill patients with septic shock: a case report

BackgroundSepsis is a life-threatening organ dysfunction caused by an excessive host response to infection, manifested by elevated levels of inflammatory cytokines. At present, the use of hemoperfusion to remove inflammatory cytokines from the bloodstream has been expanding. Meanwhile, the pharmacokinetics and pharmacodynamics characteristics of antibiotics in critically ill patients may be impacted by hemoperfusion.Case presentationThe patient was a 69-year-old male with poorly controlled type 2 diabetes. When admitted to the ICU, Multiple Organ Dysfunction Syndrome (MODS) appeared within 48 h, and he was suspected of septic shock due to acute granulocytopenia and significantly increased procalcitonin. Broad-spectrum antibiotics imipenem was administered according to Sepsis 3.0 bundle and hemoperfusion lasting 4 h with a neutron-macroporous resin device (HA-380, Jafron, China) five times was conducted to lower the extremely high value of serum inflammatory factors. Blood samples were collected to measure imipenem plasma concentration to investigate the effect of hemoperfusion quantitatively. This study showed that 4 h of hemoperfusion had a good adsorption ability on inflammatory factors and could remove about 75.2% of imipenem.ConclusionsThis case demonstrated the high adsorption capacity of hemoperfusion on imipenem in critically ill patients. It implies a timely imipenem supplement is required, especially before hemoperfusion.

In vitro pharmacological characterization of growth hormone secretagogue receptor ligands using the dynamic mass redistribution and calcium mobilization assays

Ghrelin modulates several biological functions via selective activation of the growth hormone secretagogue receptor (GHSR). GHSR agonists may be useful for the treatment of anorexia and cachexia, while antagonists and inverse agonists may represent new drugs for the treatment of metabolic and substance use disorders. Thus, the identification and pharmacodynamic characterization of new GHSR ligands is of high interest. In the present work the label-free dynamic mass redistribution (DMR) assay has been used to evaluate the pharmacological activity of a panel of GHSR ligands. This includes the endogenous peptides ghrelin, desacyl-ghrelin and LEAP2(1–14). Among synthetic compounds, the agonists anamorelin and HM01, the antagonists HM04 and YIL-781, and the inverse agonist PF-05190457 have been tested, together with HM03, R011, and H1498 from patent literature. The DMR results have been compared to those obtained in parallel experiments with the calcium mobilization assay. Ghrelin, anamorelin, HM01, and HM03 behaved as potent full GHSR agonists. YIL-781 behaved as a partial GHSR agonist and R011 as antagonist in both the assays. LEAP2(1–14) resulted a GHSR inverse agonist in DMR but not in calcium mobilization assay. PF-05190457, HM04, and H1498 behaved as GHSR inverse agonists in DMR experiments, while they acted as antagonists in calcium mobilization studies. In conclusion, this study provided a systematic pharmacodynamic characterization of several GHSR ligands in two different pharmacological assays. It demonstrated that the DMR assay can be successfully used particularly to discriminate between antagonists and inverse agonists. This study may be useful for the selection of the most appropriate compounds to be used in future studies.

In silico evaluation of potential breast cancer receptor antagonists from GC-MS and HPLC identified compounds in Pleurotus ostreatus extracts.

Introduction: Pharmacotherapeutic targets for breast cancer include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (EGFR). Inhibitors of these receptors could be interesting therapeutic candidates for the treatment and management of breast cancer (BC). Aim: This study used GC-MS and HPLC to identify bioactive compounds in Pleurotus ostreatus (P. ostreatus) extracts and applied in silico methods to identify potent EGFR, ER, and PR inhibitors from the compounds as potential drug candidates. Method: GC-MS and HPLC were used to identify bioactive chemicals in P. ostreatus extracts of aqueous (PO-A), methanol (PO-M), ethanol (PO-E), chloroform (PO-C), and n-hexane (PO-H). The ER, PR, and EGFR model optimization and molecular docking of compounds/control inhibitors in the binding pocket were simulated using AutoDock Vina in PyRx. The drug-likeness, pharmacokinetic, and pharmacodynamic features of prospective docking leads were all anticipated. Result: The results indicated the existence of 29 compounds in PO-A, 36 compounds in PO-M and PO-E, 42 compounds in PO-C, and 22 compounds in PO-H extracts. With ER, only o-tolylamino-acetic acid (4-nitro-benzylidene)-hydrazide (-7.5 kcal mol-1) from the ethanolic extract could bind to the receptor. PR and EGFR, on the other hand, identified several compounds with higher binding affinities than the control. Ergotaman-3',6',18-trione (-8.1 kcal mol-1), 5,10-diethoxy-2,3,7,8-tetrahydro-1H,6H-dipyrrolo[1,2-a:1',2'-d]pyrazine (-7.8 kcal mol-1) from the aqueous extract; o-tolylamino-acetic acid (4-nitro-benzylidene)-hydrazide (-8.4 kcal mol-1) from the ethanolic extract had better binding affinity compared to progesterone (-7.7 kcal mol-1). Likewise, ergotaman-3',6',18-trione (-9.7 kcal mol-1) from the aqueous extract and phenol, 2,4-bis(1,1-dimethyl ethyl) (-8.2 kcal mol-1) from the chloroform extract had better binding affinities compared to the control, gefitinib (-7.9 kcal mol-1) with regards to EGFR. None of the PO-H or PO-M extracts outperformed the control for any of the proteins. Phenols and flavonoids such as quercetin, luteolin, rutin, chrysin, apigenin, ellagic acid, and naringenin had better binding affinity to PR and EGFR compared to their control. Conclusion: The identified compounds in the class of phenols and flavonoids were better lead molecules due to their ability to strongly bind to the proteins' receptors. These compounds showed promising drug-like properties; they could be safe and new leads for creating anticancer medicines.

A Review on Indole-triazole Molecular Hybrids as a Leading Edge in Drug Discovery: Current Landscape and Future Perspectives.

Molecular hybridization is a rational design strategy used to create new ligands or prototypes by identifying and combining specific pharmacophoric subunits from the molecular structures of two or more known bioactive derivatives. Molecular hybridization is a valuable technique in drug discovery, enabling the modulation of unwanted side effects and the creation of potential dual-acting drugs that combine the effects of multiple therapeutic agents. Indole-triazole conjugates have emerged as promising candidates for new drug development. The indole and triazole moieties can be linked through various synthetic strategies, such as click chemistry or other coupling reactions, to generate a library of diverse compounds for biological screening. The achievable structural diversity with indole-triazole conjugates offers avenues to optimize their pharmacokinetic and pharmacodynamic attributes, amplifying their therapeutic efficacy. Researchers have extensively tailored both indole and triazole frameworks with diverse modifications to comprehend their impact on the drug's pharmacokinetic and pharmacodynamic characteristics. The current review article endeavours to explore and discuss various research strategies to design indoletriazole hybrids and elucidate their significance in a variety of pathological conditions. The insights provided herein are anticipated to be beneficial for the researchers and will likely encourage further exploration in this field.

Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions.

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.

A phase 1 dose-escalation and expansion study of an intratumorally administered dual STING agonist (ONM-501) alone and in combination with cemiplimab in patients with advanced solid tumors and lymphomas.

TPS2693 Background: The Stimulator of Interferon Genes (STING) pathway has garnered significant interest as a target for anticancer interventions due to its role in driving the production of pro-inflammatory cytokines and activating tumor-specific cell killing. Cyclic dinucleotides (CDNs) such as cGAMP, the endogenous STING agonist, are not ideal clinical candidates for exogenous routes of delivery. Early trials showed limited efficacy with CDNs due to rapid clearance, degradation and/or off-target toxicity. ONM-501 is comprised of a STING-activating pH-sensitive PC7A polymer conjugated with cGAMP. At physiologic pH, ONM-501 forms a micelle, preventing degradation of cGAMP. In the acidic tumor microenvironment, ONM-501 effects STING agonism through a multi-faceted mode of action: 1) endocytosis of nanoparticles and pH-activated micelle dissociation and payload release in endolysosomes enhances intracellular delivery of cGAMP 2) the combination of cGAMP canonical binding, and PC7A polymer noncanonical binding on STING yields synergistic STING activation and 3) stabilization of STING by PC7A polymers delays its degradation and prolongs STING activation. In pre-clinical models, these factors combine to help generate a stronger and more prolonged innate immune response that more effectively translates to a robust adaptive immune response. ONM-501 is being investigated in this first-in-human Phase 1 trial as monotherapy and combination therapy with the anti-PD1 antibody, cemiplimab, for patients with solid tumors and lymphomas. Methods: ONM5001 (NCT06022029) is a first-in-human, open-label, multi-center clinical trial. Adult patients with solid tumors or lymphomas for which no standard therapy exists or for which patients decline palliative standard therapy who have at least one injectable lesion are eligible for this study. This Phase 1 study consists of three parts: monotherapy dose escalation; combination therapy dose finding; and combination therapy dose expansion in specific tumor indication(s) that will be selected based on data from mono- and combination therapy dose finding. Each dosing cycle of ONM-501 is 21 days: patients receive an intratumoral injection of ONM-501 weekly for three weeks, followed by three weeks without injection. Cemiplimab is administered intravenously during combination therapy arms according to standard administration protocol, once every three weeks. The primary endpoint is to evaluate safety of ONM-501 monotherapy as evidenced by the number of dose limiting toxicities and treatment-emergent adverse events, and to determine the recommended dose for expansion. Secondary endpoints include characterization of pharmacokinetics and pharmacodynamics, as well as initial efficacy based on RECIST evaluation criteria. Enrollment began in November 2023. Clinical trial information: NCT06022029 .

#2341 WS016, a novel potassium binder: safety, tolerability and pharmacodynamics in first-in-human phase 1 healthy volunteer study

Abstract Background and Aims Hyperkalemia is a common and potentially serious medical condition in patients with chronic kidney disease and is associated with high rates of mortality. Partiromer and Lokelma are available recently, however, edema is the common adverse event resulted from the exceed sodium exchanged by Lokelma and constipation, hypomagnesemia are frequently found using Partiromer because of the basic structure of them. WS016 is a highly selective, non-absorbed, cation-exchange polymer binder with the potential characteristics of no edema and hypomagnesemia. The objective of the trials was to assess the safety/tolerability and pharmacodynamics (PD) profiles of WS016. Method This is a randomized, double-blind, placebo-controlled phase 1 clinical trial. 40 healthy volunteers were randomized (6:2 randomization within a cohort) into five different cohorts administered with 6 g, 12 g, 24 g, 36 g, 48 g WS016 orally once daily for only one dose during the single dose ascending (SAD) stage and 24 healthy volunteers were randomized (6:2 randomization within a cohort) into three different cohorts administered with 12 g, 36 g, 48 g orally once daily for consecutive seven days during the multiple dose ascending(MAD) stage. Adverse events (AE) were collected, and physical examination, laboratory tests were done at baseline and different visits according to the protocol. Urinary potassium and fecal potassium were collected, tested and calculated per 24 hour. Serum potassium was evaluated alone with the timing after administration of WS016 in different cohort. Results Data of subjects from different placebo cohorts were pooled together for analysis in SAD and MAD stage. 40 healthy volunteers, including 6 in different WS016 cohorts and 10 in placebo cohort completed the SAD trial. 9, 5, 6, 7, 12 grade 1 AEs were reported from 12-48 g WS016 cohorts, respectively; 11 AEs were reported from placebo cohort and 1 is grade 2 AE. Totally, 5 cases with hypertriglyceridemia, 4 cases with prolonger activated partial thromboplastin time (APTT), 4 cases with decreased blood fibrinogen, 3 cases with sinus bradycardia were reported from WS016 cohort and 2 cases with hypertriglyceridemia, 1case with prolonged APTT, 1 case with decreased fibrinogen were reported from placebo cohort. 24 healthy volunteers, 6 from different WS016 cohorts and 6 from placebo cohort completed the MAD trial. 12, 10, 12 AEs were reported from 12 g, 24 g, 48 g cohort, respectively and 6 AEs were from placebo cohort. Only 1 AE as hypertriglyceridemia from 24 g cohort is grade 2, while others are grade 1. 5 cases with sinus bradycardia, 4 cases with hypertriglyceridemia, 3 cases with hyperuricacidemia, 3 cases with hypotension, 3 cases with prolonged APTT were reported from all WS016 cohort totally and 1 cases with hyperuricacidemia,1 cases with hypotension, 1 cases with prolonged APTT were reported from placebo cohort. There is no AE related to gastrointestinal tract and no side effects on the other electrolytes such as magnesium, calcium, sodium and phosphorus, reported from both SAD and MAD. It was found that fecal potassium excretion increased and urinary potassium decreased on D2 in SAD (Fig. 1) and on D7 in MAD (Fig. 2) compared to baseline. The serum potassium decreased quickly at about 1-2 hour after first administration of WS016 both in SAD and MAD (Figs 1 and 2) and the mean serum potassium of placebo cohort is higher than that in other WS016 cohorts during MAD (Fig. 2). Conclusion WS016 was generally well-tolerated following single doses and multiple doses. The AEs like constipation, hypomagnesemia commonly found in Patiromer and edema commonly found in Lokelma were not reported in WS016 cohorts. In accordance to the results from pre-clinical studies, the clinical pharmacodynamics characteristics was the increased fecal potassium along with the decreased urinary potassium, meanwhile the serum potassium decreased, especially during the first 4 hours after administration of WS016 although in the normal range among the healthy volunteers.

Insights of potential trypanocidal effect of the synthetic derivative (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one: in vitro assay, MEV analysis, quantum study, molecular docking, molecular dynamics, MPO analysis, and predictive ADMET.

This study aims to evaluate the antitrypanosomiasis activity of a synthetic dichloro-substituted aminochalcone via in vitro assays against infected cell cultures, as well as a theoretical characterization of pharmacokinetics and pharmacodynamics against the protein targets of the evolutionary cycle of T. cruzi. The in vitro evaluation of parasite proliferation inhibition was performed via cytotoxicity analysis on mammalian host cells, effect on epimastigote and trypomastigote forms, and cell death analysis, while computer simulations characterized the electronic structure of (2E)-1-(4-aminophenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one (DCl), the mechanism of action against the proteins of the evolutionary cycle of T. cruzi: Cruzain, Trypanothione reductase, TcGAPDH, and CYP51 by molecular docking and dynamics and predictive pharmacokinetics by MPO-based ADMET. The in vitro tests showed that the DCl LC50 in order of 178.9 ± 23.9 was similar to the BZN, evidencing the effectiveness of chalcone against Trypomastigotes. Molecular docking and dynamics simulations suggest that DCl acts on the active site of the CYP51 receptor, with hydrogen interactions that showed a high degree of occupation, establishing a stable complex with the target. MPO analysis and ADMET prediction tests suggest that the compound presents an alignment between permeability and hepatic clearance, although it presents low metabolic stability. Chalcone showed stable pharmacodynamics against the CYP51 target, but can form reactive metabolites from N-conjugation and C = C epoxidation, as an indication of controlled oral dose, although the estimated LD50 rate > 500mg/kg is a indicative of low incidence of lethality by ingestion, constituting a promising therapeutic strategy.