Different Mechanisms Of Action Research Articles

Drug-drug interactions and synergy: from pharmacological models to clinical application.

This review explores the concept of synergy in pharmacology, emphasizing its importance in optimizing treatment outcomes through the combination of drugs with different mechanisms of action. Synergy, defined as an effect greater than the expected additive effect elicited by individual agents according to specific predictive models, offers a promising approach to enhance therapeutic efficacy while minimizing adverse events. The historical evolution of synergy research, from ancient civilizations to modern pharmacology, highlights the ongoing quest to understand and harness synergistic interactions. Key concepts such as concentration-response curves, additive effects, and predictive models are discussed in detail, emphasizing the need for accurate assessment methods throughout translational drug development. While various mathematical models exist for synergy analysis, selecting the appropriate model and software tools remains a challenge, necessitating careful consideration of experimental design and data interpretation. Furthermore, this review addresses practical considerations in synergy assessment, including preclinical and clinical approaches, mechanism of action, and statistical analysis. Optimizing synergy requires attention to concentration/dose ratios, target site localization, and timing of drug administration, ensuring that the benefits of combination therapy detected at bench-side are translatable into clinical practice. Overall, the review advocates for a systematic approach to synergy assessment, incorporating robust statistical analysis, effective and simplified predictive models, and collaborative efforts across pivotal sectors such as academic institutions, pharmaceutical companies, and regulatory agencies. By overcoming critical challenges and maximizing therapeutic potential, effective synergy assessment in drug development holds promise for advancing patient care. Significance Statement Combining drugs with different mechanisms of action for synergistic interactions optimizes treatment efficacy and safety. Accurate interpretation of synergy requires the identification of the expected additive effect. Despite innovative models to predict the additive effect, consensus in drug interaction research is lacking, hindering the bench-to-bedside development of combination therapies. Collaboration among science, industry, and regulation is crucial for advancing combination therapy development, ensuring rigorous application of predictive models in clinical settings.

Antiplatelet Therapy and Platelet Activity Testing for Neurointerventional Procedures

The management of antiplatelet medications in neurointerventional procedures remains a subject of considerable variability and debate. This review article explores the diverse clinical practices and the impact of different antiplatelet regimens and platelet activity testing on patient outcomes in neurointerventional treatments. While much of the evidence around antiplatelet therapies largely stems from randomized trials in cardiac and peripheral vascular diseases, their application in neurointerventional settings requires nuanced consideration. Various assays exist to assess individual platelet function, yet the optimal assay, thresholds, and agents remain uncertain due to interpatient variability in medication responsiveness. Expert consensus groups have attempted to standardize antiplatelet management, which is summarized for elective and emergent neurointerventional procedures. Clopidogrel, a commonly used antiplatelet, faces challenges such as genetic variability in metabolism and drug–drug interactions, impacting its effectiveness. Other agents, such as ticagrelor and prasugrel, offer alternatives with different mechanisms of action and potential advantages. Additionally, short‐acting intravenous P2Y 12 inhibitors, such as cangrelor, and glycoprotein IIb/IIIa inhibitors provide options for acute bridging therapy in neurointerventional cases. Despite advancements, significant gaps persist in understanding the optimal antiplatelet management for neurovascular procedures. While platelet function testing is commonly used, its clinical utility and standardization remain an area of investigation. This review underscores the need for further multicenter studies to delineate best practices and optimize patient outcomes in neurointerventional settings.

Control of a phytopathogenic infection in an apple orchard in the forest-steppe of Samara Oblast

The study evaluates a protection system by selecting and alternating fungicides having different mechanisms of action to exclude the emergence of resistant populations of apple tree pathogens. The experiments were started at Koshelevsky Posad LLC (Syzransky District, Samara Oblast) in 2022-2023. The orchard was planted in 2013-2014, with trees arranged in a 3.5×1.5 m grid; the 62-396 rootstock was used. The biological effectiveness of fungicide protection against apple scab (Venturia inaequalis (Cooke) Wint.) and fruit rot (Monilia fructigena Pers.) was analyzed using ‘Berkutovskoye,’ ‘Kulikovskoye,’ ‘Kuibyshevskoye,’ ‘Lobo,’ and ‘Northern Sinap’ varieties. The protection system including contact and systemic agents having different mechanisms of action was developed according to the FRAC diagram for assessing the combined risk of fungicide resistance developing in phytopathogens, which takes into account the adaptation rate of organisms (emergence of new resistant types) to changing environmental conditions. An analysis of the correlation between the growth rate of apple-specific phytopathogens and weather conditions shows no significant relationship (0.032-0.245). In these studies, the anthropogenic factor-chemical treatment with fungicides – had a predominant effect on the development of scab and monilia in apple orchards along with weather factors. The yield of marketable apples in the experimental quarter of the orchard differed insignificantly from year to year. In 2023, the yield was lower; however, this fact can be probably attributed to the return of late frosts during apple blossom in Samara Oblast. Noteworthy is that for the ‘Berkutovskoye’ and ‘Lobo’ varieties, unmarketable apples did not exceed 5 and 12 %, respectively, in the studied quarter of the orchard. The protection system using fungicides (GC Shans) helped to optimize the phytosanitary condition of the orchard, thus reducing the amount of fallen fruit and providing a stable harvest of marketable apples.

Unsymmetric Co-Facial "Salixpyrrole" Hydrogen Evolution Catalysts: Two Metals are Better than One.

Designing ligand architectures that can mimic enzyme active sites is a promising approach for developing efficient small molecule activation catalysts for sustainable energy applications. Some key design features include chemically distinct binding pockets for multiple metal centers and a three-dimensional structure that controls the positioning of catalytic sites. With these principles in mind, mono- and bimetallic unsymmetric cofacial palladium complexes, 2 and 3, respectively, bearing ligands with calixpyrrole and salen coordination sites, or "salixpyrrole" ligands, are reported. These species were accessed in a straightforward Schiff-base reaction with appreciable yields. In addition, both 2 and 3 were found to be active hydrogen evolution electrocatalysts using para-toluenesulfonic acid monohydrate as the proton source. The two salixpyrrole species displayed different mechanisms of action, with 2 showing a second-order dependence on acid concentration, whereas 3 exhibited a first-order dependence. Moreover, the bimetallic catalyst was significantly more efficient, with higher turnover frequencies, 4640 s-1 vs 1680 s-1 for 2, and lower overpotentials, 0.39 V vs 0.69 V for 2. The results reported herein provide proof-of-concept that bimetallic catalysts with chemically distinct binding sites demonstrate enhanced catalytic properties in comparison to monometallic or symmetric analogues.

Alkaloid-Based Isoxazolylureas: Synthesis and Effect in Combination with Anticancer Drugs on C6 Rat Glioma Model Cells

Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

Ube3a unsilencer for the potential treatment of Angelman syndrome

Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.

Ube3a unsilencer for the potential treatment of Angelman syndrome

Deletion of the maternal UBE3A allele causes Angelman syndrome (AS); because paternal UBE3A is epigenetically silenced by a long non-coding antisense (UBE3A-ATS) in neurons, this nearly eliminates UBE3A protein in the brain. Reactivating paternal UBE3A holds promise for treating AS. We previously showed topoisomerase inhibitors can reactivate paternal UBE3A, but their therapeutic challenges prompted our search for small molecule unsilencers with a different mechanism of action. Here, we found that (S)-PHA533533 acts through a novel mechanism to significantly increase paternal Ube3a mRNA and UBE3A protein levels while downregulating Ube3a-ATS in primary neurons derived from AS model mice. Furthermore, peripheral delivery of (S)-PHA533533 in AS model mice induces widespread neuronal UBE3A expression. Finally, we show that (S)-PHA533533 unsilences paternal UBE3A in AS patient-derived neurons, highlighting its translational potential. Our findings provide a lead for developing a small molecule treatment for AS that could be safe, non-invasively delivered, and capable of brain-wide unsilencing of paternal UBE3A.

Protective efficacy of ramelteon on methotrexate-induced DNA damage

Ramelteon (RMLT) is a melatonin receptor agonist that it has antioxidative and anti-inflammatory effects associated with DNA damage through different mechanisms of action. In this regard, we investigated the potential usefulness of RMLT as a protective agent against methotrexate (MTX)-induced DNA damage. Four groups were constituted from 32 Wistar albino rats: Negative control, RMLT, MTX, and MTX + RMLT. Twenty mg/kg MTX (i.p., single dose) and RMLT 10 mg/kg (oral, 7 days) was administered. Comet assay was used and the parameter %TailDNA was used to detect DNA damage. %TailDNA was 4.90 ± 0.19 in the control group, 7.85 ± 0.33 in the MTX group, 5.49 ± 0.24 in the RMLT group, and 5.86 ± 0.23 in the MTX + RMLT group. While there was a significant increase in DNA damage in the MTX-treated group compared to the control group, there was a significant reduction in DNA damage in the MTX + RMLT group, compared to the MTX group (p < 0.001). In conclusion, it was observed that combined treatment with RMLT significantly reduced MTX-induced DNA damage.

Metronomic chemotherapy in pediatric neurooncology: insight the problem. A review

Metronomic chemotherapy (MCT) is a promising direction of anticancer therapy, as well as in pediatric oncology, and its administration in patients with refractory and recurrent tumors of the central nervous system becomes increasingly relevant. Being a regimen of low doses of antitumor agents with different mechanisms of action in a continuous mode for a long time, it allows to overcome the resistance of tumor cells and to minimize the toxic effects of treatment. Today, the issues of rational choice of MCT regimens, which are dependent on the type of tumor, and the application of biomarkers of its effectiveness, remain controversial. The article discusses in detail the biological effects of MCT with an accent on antiangiogenic one, as well as the possibilities and limitations of MCT application in pediatric practice and the results of studies in tumors of the central nervous system.

Anti-Influenza activity of compounds derived from medicinal plants (Part I)

This review (I part) presents an analysis of publications devoted to the ant-viral antiinfluenza activity of medicinal plants. It has shown that 63 species are found to be promising sources for obtaining anti-influenza drugs. Their roots, stems, leaves and fruits contain different chemical compounds inhibiting reproduction of influenza virus, both in vitro and in vivo. These compounds have different mechanisms of action. Some of them act upon components of the viral particle, others upon signaling pathways in the host cells. The first part of our review focuses on 28 species.

Chemical Compositions and In Vitro Antioxidant Activities of the Essential Oils of Sawdust and Resin-Rich Bark from Azorean Cryptomeria japonica (Cupressaceae).

In the Azores archipelago (Portugal), forest operations and wood industry generate large amounts of Cryptomeria japonica biomass residues (CJBR), which can be used to produce valuable essential oils (EOs). In this study, we evaluated the chemical composition and antioxidant activities of EOs from Azorean C. japonica sawdust (CJS) and resin-rich bark (CJRRB). The CJS and CJRRB EOs, obtained via hydrodistillation, showed different yield values (0.27% vs. 0.80% v/w, dry weight) and also different chemical profiles, as assessed using GC/MS. A total of 64 and 85 components were identified in CJS and CJRRB EOs, representing 95.7% and 96.9% of the total composition, respectively. The major components in CJS EO were oxygenated sesquiterpenes (mainly α+β-eudesmol, 1-epicubenol, and cubebol), while in CJRRB EO, the major components were monoterpene hydrocarbons, including α-pinene, δ-3-carene, and limonene (66.6% vs. 6.4% for oxygenated sesquiterpenes and 0% vs. 64% for monoterpene hydrocarbons, respectively). Antioxidant activity was estimated using (i) two radical-based assays, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activity, and (ii) a lipid model assay, β-carotene-linoleic acid bleaching activity (BCBA). Both CJS and CJRRB EOs exhibited concentration-dependent antioxidant activities, and their DPPH, ABTS, and BCBA EC50 values were 1107 vs. 1275 µg/mL, 260 vs. 498 µg/mL, and 1764 vs. 662 µg/mL, respectively. The results indicate that both EOs were able to exert antioxidant activity via different mechanisms of action. Therefore, Azorean CJS and CJRRB may be sustainable sources for antioxidant compounds. This study expands the chemical and biological knowledge of CJBR EOs and, consequently, adds more value to the C. japonica EO industry.

Changes in serum ghrelin and resistin levels after sleeve gastrectomy versus one anastomosis gastric bypass: prospective cohort study.

Humoral factors and neural mechanisms play a central role in the pathogenesis of obesity and in weight loss following bariatric surgery. Although various hormones and adipokines, including ghrelin and resistin, are linked to obesity, studies analyzing the changes in fasting ghrelin and resistin levels in patients following one anastomosis gastric bypass are lacking. We aimed to investigate resistin and ghrelin levels before and after two commonly used bariatric procedures with different mechanisms of action: sleeve gastrectomy (SG) and one anastomosis gastric bypass (OAGB). Fasting serum ghrelin and resistin levels were evaluated by using ELISA in a non-randomized, prospective cohort study for the pattern of changes in the preoperative period and one week, one month, three months and, 12 months after surgery in age and sex-matched patients with BMI ≥40kg/m2 undergoing either sleeve gastrectomy (n=40) or one anastomosis gastric bypass (n=40). Their relationships with demographic parameters such as body weight, Body mass index (BMI), presence of T2DM, HbA1C, and HOMA-IR index were also evaluated. OAGB was superior in weight control compared to the SG group. There were significant differences in resistin and ghrelin levels between the OAGB and SG groups. Ghrelin decreased more in the SG group than the preoperative values. This change in ghrelin levels was more significant at one year after sleeve gastrectomy (preoperative mean(range) level of 334.2 (36.6-972.1) pg/mL decreased to 84 (9.1-227) pg/ml at one year) whereas in the OAGB group no significant change was observed (preoperative mean(range) level of 310 (146-548)pg/mL decreased to 264 (112-418)pg/mL at one year). Resistin levels decreased in both groups, especially after three months and onward following both operations (the mean(range) resistin levels were 2.6 (0.87-5.4)ng/mL and decreased to 1.1 (0.5-2.4)ng/mL in the SG group vs 2.48 (0.89-6.43)ng/mL decreased to 0.72 (0.35-1.8)ng/mL in OAGB group at one year), which was in parallel with changes in HOMA-IR index, body weight, and BMI changes at 1st year. HOMA-IR index changes were similar, but more prominent after OAGB. OAGB was also superior in T2DM control, parallel with weight loss, fasting resistin levels (especially after three months and onward), and HOMA-IR changes. This is the first study to compare fasting ghrelin and resistin levels after one anastomosis gastric bypass and sleeve gastrectomy. Although similar changes were observed, ghrelin changes were more prominent after SG, whereas resistin were observed after OAGB. OAGB was superior in T2DM control which was in parallel with weight loss, fasting resistin levels, and HOMA-IR changes suggesting a possible effect of resistin after OAGB in glucose metabolism and insulin resistance.

INVESTIGATION OF THE ANALGESIC ACTIVITY OF NEW LIGANDS OF THE NMDA RECEPTOR COMPLEX

According to the Russian Society for the Study of Pain, 90% of patients seeking medical help experience pain, with 70% suffering from chronic pain [15, 16]. It should be acknowledged that the capabilities of traditional analgesic methods are limited, and the prescription of opioids is associated with an increase in complications, the development of tolerance, drug dependence, and an increase in the patient's hospital stay costs. Thus, the main directions for improving pain relief include the rational combination of analgesics with different mechanisms of action and the development of new effective and safe medicinal substances with analgesic activity. It is known that the activation of spinal cord NMDA receptors is a key factor in the pathogenesis of acute and chronic pain. Therefore, the use of existing NMDA antagonists in analgesic schemes, as well as the development of new compounds targeting the NMDA receptor complex, is of particular interest. New ligands of the glutamate NMDA receptor complex are derivatives of imidazole-4,5-dicarboxylic acid. The conformational rigidity of the molecules of imidazole-4,5-dicarboxylic acid derivatives allow for increased selectivity of interaction and reduced side effects. The aim of the study was to investigate the analgesic effect of new ligands of the glutamate NMDA receptor complex - derivatives of imidazole-4,5-dicarboxylic acid in mice using the tail-flick test and the formalin test. The tested compounds (IEM-303 and IEM-2044) were administered intraperitoneally at doses of 5, 10, 15, 20 mg/kg. Мetamizole was used as a comparison drug. The experiments demonstrated a significant dose-dependent analgesic effect of the tested compounds in experimental models of acute pain at doses of 5-20 mg/kg. In the groups receiving IEM-2044 and IEM-303, the tail-flick latency increased by 1.4-1.7 times compared to the control group. The analgesic activity of the tested compounds at doses of 10-20 mg/kg was comparable to the analgesic activity of metamizole, indicating the prospect of developing these agents and further searching for effective and safe analgesics among this pharmacological class.

Development of silver-doped copper oxide and chitosan nanocomposites for enhanced antimicrobial activities.

Antimicrobial resistance (AMR) has emerged as a significant and pressing public health concern, posing serious challenges to effectively preventing and treating persistent diseases. Despite various efforts made in recent years to address this problem, the global trends of AMR continue to escalate without any indication of decline. As AMR is well-known for antibiotics, developing new materials such as metal containing compounds with different mechanisms of action is crucial to effectively address this challenge. Copper, silver, and chitosan in various forms have demonstrated significant biological activities and hold promise for applications in medicine and biotechnology. Exploring the biological properties of these nanoparticles is essential for innovative therapeutic approaches in treating bacterial and fungal infections, cancer, and other diseases. To this end, the present study aimed to synthesize silver@copper oxide (Ag@CuO) nanoparticles and its chitosan nanocomposite (Chi-Ag@CuO) to investigate their antimicrobial efficacy. Various established spectroscopic and microscopic methods were employed for characterization purposes, encompassing scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). Subsequently, the antimicrobial activity of the nanoparticles was assessed through MIC (minimum inhibitory concentration), MBC (minimum bactericidal concentration), and well-disk diffusion assays against Pseudomonas aeruginosa, Acinetobacter baumannii Staphylococcus aureus, Staphylococcus epidermidis, and Candida albicans. The size of the CuO-NPs, Ag@CuO, and Chi-Ag@CuO NPs was found to be 70-120 nm with a spherical shape and an almost uniform distribution. The nanocomposites were found to possess a minimum inhibitory concentration (MIC) of 5 μg/mL and a minimum bactericidal concentration (MBC) of 250 μg/mL. Moreover, these nanocomposites generated varying clear inhibition zones, with diameters ranging from a minimum of 9±0.5 mm to a maximum of 25±0.5 mm. Consequently, it is evident that the amalgamation of copper-silver-chitosan nanoparticles has exhibited noteworthy antimicrobial properties in the controlled laboratory environment, surpassing the performance of other types of nanoparticles.

Comparative assessment of structural changes in the prostate after bipolar plasma and thulium fiber laser enucleation of benign prostatic hyperplasia

Background. Benign prostatic hyperplasia (BPH) is a common disease in older men. Transurethral surgery in BPH is the gold standard for treatment, but the techniques differ in the energy used. Considering the different mechanisms of action of bipolar plasma and thulium fiber laser energy on prostate tissue, the study of structural changes under their influence is relevant.The aim. To study the features of structural changes in the prostate during bipolar plasma and thulium fiber laser enucleation of benign prostatic hyperplasia.Methods. Thirty one patients with BPH were divided into two groups. Group 1 (n = 17) underwent transurethral plasma enucleation of the prostate; Group 2 (n = 14) underwent transurethral thulium fiber laser enucleation. Fragments of the surgical prostate capsule were collected intraoperatively and were processed according to standard examination protocols using light and electron microscopy. The width of coagulation necrosis, the relief of the dissection line, the severity of cell and the prostate intercellular matrix destruction were taken into account.Results. Studies have shown the clinical and functional perioperative homology of the compared methods of surgical treatment of BPH. Data from light and electron prostate microscopy showed a greater damaging effect of bipolar plasma energy, which is manifested by a larger width of the zone of coagulation necrosis, a torn and raised appearance of the dissection line, and pronounced integrity violations of cellular elements and intercellular matrix components. Laser exposure causes less pronounced changes, which indicates a more gentle effect of the thulium fiber laser on the prostate components.Conclusion. The obtained microscopy results indicate that the intraoperative action of a thulium fiber laser is less traumatic for the cells and intercellular matrix of the surgical prostate capsule compared to bipolar plasma exposure.

Outcomes in patients (pts) with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) treated with systemic therapy from real world experience (ORCHID) study.

e19067 Background: Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, has shown compelling efficacy (objective response rate [ORR] 52%, complete response [CR] rate 31.5%) and a generally manageable safety profile in pts with heavily pretreated R/R DLBCL in the single-arm ELM-2 trial (NCT03888105; Ayyappan et al. ASH 2023). We evaluated outcomes in pts with R/R DLBCL treated with currently available third-line or later (3L+) therapies in a real-world setting (ORCHID; NCT05338892) to better evaluate results from ELM-2 in the absence of a randomized control arm. Methods: ORCHID is a multicenter, retrospective, observational study, using electronic medical record or research databases, of pts with R/R DLBCL who have received ≥2 prior lines of therapy (LoTs; including an anti-CD20 and an alkylator) and initiated 3L+ systemic therapy for DLBCL between January 1, 2015 and June 30, 2021. After applying similar eligibility criteria to those in the ELM-2 trial, inverse-probability of treatment weighting (IPTW) was used to balance key prognostic variables between the trial and real-world cohorts. Pts were followed from the start of qualifying LoT until death, end of study period (December 31, 2021), or loss to follow up, whichever occurred first. The primary endpoint was ORR per Lugano criteria assessed by independent central review (ICR). Secondary endpoints included ICR-assessed CR rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) (see Thieblemont et al. ASH 2022). Results: Pts in ORCHID (N=148) generally had less severe disease than trial pts prior to IPTW. The most commonly used regimens were anti-CD20 based therapies, CAR T, and chemotherapy alone. The IPTW cohort had a median age 65 y, 79% Ann Arbor stage III/IV, 66% primary refractory, 88% refractory to last LoT, and median (range) prior LoT: 2 (2–6). In the IPTW cohort, ORR was 44%, CR 18%, and DCR 50%. Median (m) PFS (mPFS), DOR (mDOR), and OS (mOS) were 7.2, 9.0, and 10.8 mo, respectively. Given the lack of regular scans in routine practice (47% of pts had only one ICR response assessment over the study period), sensitivity analysis that considered subsequent treatment as progression resulted in shorter mPFS (4.6 mo) and mDOR (6.1 mo). In the majority of LoTs initiating non-CAR T therapy (n=111), ORR was 33%, CR 15%, DCR 43%. The mOS in non-CAR T group was 7.5 mo and was not reached in those intended for CAR T. Conclusions: Pts in the ORCHID study, especially those who did not receive CAR Ts, had markedly lower response rates than those in the R/R DLBCL cohort of ELM-2. Despite prior failure, most pts still received an anti-CD20 based regimen in 3L+ setting in routine practice, highlighting the need for treatment options with different mechanisms of action that provide deep and durable responses and improve outcomes in this pt population. Clinical trial information: NCT05338892 .

Pharmacological Profile of Novel Anti-cancer Drugs Approved by USFDA in 2022: A Review.

For any drug molecule, it is mandatory to pass the drug approval process of the concerned regulatory authority, before being marketed. The Food and Drug Administration (FDA), throughout the year, approves several new drugs for safety and efficacy. In addition to new drug approvals, FDA also works on improving access to generic drugs, aimed to lower the cost of drugs for patients and improve access to treatments. In the year 2022 twelve new drug therapies were approved for managing varying cancers. This manuscript is focused to describe the pharmacological aspects including therapeutic uses, mechanisms of actions, pharmacokinetics, adverse effects, doses, indication for special cases, contraindications, etc., of novel FDA-approved anticancer drug therapies in the year 2022. FDA has approved about 29% (11 out of 37) novel drug therapies for varying types of cancers such as lung cancer, breast cancer, prostate cancer, melanoma, leukemia, etc. The Center for Drug Evaluation and Research CDER has reported that 90% of these anticancer drugs (e.g. Adagrasib, Futibatinib, Mirvetuximabsoravtansinegynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Olutasidenib, Pacritinib, Tebentafusp-tebn, Teclistamab-cqyv, and Tremelimumab-actl) as orphan drugs and recommended to treat rare or uncommon cancers such as non-small cell lung cancer, metastatic intrahepatic cholangio-carcinoma, epithelial ovarian cancer, follicular lymphoma, metastatic melanoma, metastatic uveal melanoma, etc. CDER has identified six anticancer drugs (e.g. Lutetium (177Lu)vipivotidetetraxetan, Mirvetuximabsoravtansine- gynx, Mosunetuzumab-axb, Nivolumab and relatlimab-rmbw, Tebentafusp-tebn, Teclistamab-cqyv) as first-in-class drugs i.e. drugs having different mechanisms of action from the already existing ones. The newly approved anticancer drugs shall provide more efficient treatment options for cancer patients. Three FDA-approved anticancer drugs in the year 2023 are also briefly described in the manuscript. This manuscript, describing the pharmacological aspects of eleven anticancer novel drug therapies approved by the FDA, shall serve as a helpful document for cancer patients, concerned academicians, researchers, and clinicians, especially oncologists.

Results from the follicular lymphoma (FL) outcomes in patients (pts) with relapsed/refractory (R/R) disease treated with systemic therapy in a real-world assessment (FLORA) study.

7076 Background: Odronextamab, an off-the-shelf CD20×CD3 bispecific antibody, has shown compelling efficacy (objective response rate [ORR] 80%, complete response [CR] rate 73%) and a generally manageable safety profile in pts with heavily pretreated R/R FL in the single-arm ELM-2 trial (NCT03888105; Villasboas, et al. ASH 2023). We evaluated outcomes in pts with R/R FL treated with currently available third-line or later (3L+) therapies in a real-world setting (FLORA; NCT05338879) to better evaluate the results from ELM-2 in the absence of a randomized control arm. This is the first real-world study in 3L+ FL that evaluated scans from 100% of the cohort. Methods: FLORA is a multicenter, retrospective, observational study, using electronic medical record or research databases, of pts with R/R FL who have received ≥2 prior lines of therapy (LoTs; including an anti-CD20 and an alkylator) and initiated 3L+ systemic therapy for FL between January 1, 2015 and December 31, 2020. After applying similar eligibility criteria to those in the ELM-2 trial, inverse-probability of treatment weighting (IPTW) was used to balance key prognostic characteristics between the trial and the real-world cohorts. Pts were followed from the start of qualifying LoT until death, end of study (December 31, 2021), or lost to follow-up, whichever occurred first. The primary endpoint was ORR assessed by independent central review (ICR). Secondary endpoints included ICR-assessed CR rate, disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) (see Bachy, et al. ASH 2022). Results: Pts in FLORA (N=100) generally had less severe disease than trial pts prior to IPTW. The most commonly used regimens were chemotherapy + anti-CD20, chemotherapy alone, and anti-CD20 + immunomodulatory agent. The IPTW cohort had a median age of 61 y, 59% POD24, 56% high FLIPI, 60% chemo-immuno refractory, 73% refractory to last LoT, and median (range) prior LoT: 3 (2–8). In the IPTW cohort, ORR was 52%, CR 31%, and DCR 62%. Median PFS (mPFS) was 11.5 mo, median OS was 26.1 mo, and median DOR (mDOR; responders in IPTW cohort: n=54) was 28.2 mo. Given the lack of regular scans in routine practice (37% of responders did not have any subsequent ICR assessment after CR/PR), sensitivity analysis that considered subsequent treatment as a progression event resulted in shorter mDOR (8.1 mo) and mPFS (7.2 mo). Conclusions: Pts in the FLORA study had markedly lower response rates than those in the R/R FL cohort of ELM-2. This study also showed that most pts still received an anti-CD20–based regimen in 3L+ in routine practice, highlighting the need for treatment options with different mechanisms of action that provide deep and durable responses and improve outcomes in this pt population. Clinical trial information: NCT05338879 .

Effects of imidacloprid combined with validamycin on the population fitness and symbiotic of Nilaparvata lugens (Hemiptera: Delphacidae)

Using a high-efficiency insecticide in combination with fungicides that have different mechanisms of action is a conventional method in the current management of brown planthopper (BPH) resistance. In this study, we investigate the separate and combined effects of the low-toxicity fungicide validamycin and the non-cross-resistant insecticide imidacloprid on the fitness and symbiosis of BPH. These research results indicate that when the proportion of active ingredients in validamycin is combined with imidacloprid at a ratio of 1:30, the toxicity ratio and co-toxicity coefficient are 1.34 and 691.73, respectively, suggesting that the combination has a synergistic effect on the control of BPH. The number of yeast-like symbiotic (YLS) and dominant symbiotic (Noda) in the imidacloprid + validamycin groups were significantly lower than the other three treatment groups (validamycin, imidacloprid, and water). The results of the study on population fitness show that the lifespan of the BPH population in validamycin, imidacloprid, and imidacloprid + validamycin was shortened. Notably, the BPH populations in the imidacloprid + validamycin groups were significantly lower than other groups in terms of average generation cycle, intrinsic growth rate, net reproduction rate, finite rate of increase, and fitness. The Real-time quantitative PCR showed that validamycin and imidacloprid + validamycin can significantly inhibit the expression of the farnesyl diphosphate farnesyl transferase gene (EC2.5.1.21) and uricase gene (EC1.7.3.3), with imidacloprid + validamycin demonstrating the most pronounced inhibitory effect. Our research results can provide insights and approaches for delaying resistance and integrated management of BPH.

Slow Sulfide Donor GYY4137 Increased the Sensitivity of Two Breast Cancer Cell Lines to Paclitaxel by Different Mechanisms.

Paclitaxel (PTX) is a chemotherapeutic agent affecting microtubule polymerization. The efficacy of PTX depends on the type of tumor, and its improvement would be beneficial in patients' treatment. Therefore, we tested the effect of slow sulfide donor GYY4137 on paclitaxel sensitivity in two different breast cancer cell lines, MDA-MB-231, derived from a triple negative cell line, and JIMT1, which overexpresses HER2 and is resistant to trastuzumab. In JIMT1 and MDA-MB-231 cells, we compared IC50 and some metabolic (apoptosis induction, lactate/pyruvate conversion, production of reactive oxygen species, etc.), morphologic (changes in cytoskeleton), and functional (migration, angiogenesis) parameters for PTX and PTX/GYY4137, aiming to determine the mechanism of the sensitization of PTX. We observed improved sensitivity to paclitaxel in the presence of GYY4137 in both cell lines, but also some differences in apoptosis induction and pyruvate/lactate conversion between these cells. In MDA-MB-231 cells, GYY4137 increased apoptosis without affecting the IP3R1 protein, changing the morphology of the cytoskeleton. A mechanism of PTX sensitization by GYY4137 in JIMT1 cells is distinct from MDA-MB-231, and remains to be further elucidated. We suggest different mechanisms of action for H2S on the paclitaxel treatment of MDA-MB-231 and JIMT1 breast cancer cell lines.