Different Mechanisms Of Action Research Articles

Benzimidazole scaffold as a potent anticancer agent with different mechanisms of action (2016-2023).

Benzimidazole scaffolds have potent anticancer activity due to their structure similarity to nucleoside. In addition, benzimidazoles could function as hydrogen donors or acceptors and bind to different drug targets that participate in cancer progression. The literature had many anticancer agents containing benzimidazole cores that gained much interest. Provoked by our endless interest in benzimidazoles as anticancer agents, we summarized the successful trials of the benzimidazole scaffolds in this concern. Moreover, we discuss the substantial opportunities in cancer treatment using benzimidazole-based drugs that may direct medicinal chemists for a compelling future design of more active chemotherapeutic agents with potential clinical applications. The uniqueness of this work lies in the highlighted benzimidazole scaffold hybridization with different molecules and benzimidazole-metal complexes, detailed mechanisms of action, and the IC50 of the developed compounds determined by different laboratories after 2015.

A critical review of therapeutic interventions in sickle cell disease: Progress and challenges.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder that occurs due to the point mutation in the β-globin gene, which results in the formation of sickle hemoglobin (HbS) in the red blood cells (RBCs). When HbS is exposed to an oxygen-depleted environment, it polymerizes, resulting in hemolysis, vaso-occlusion pain, and impaired blood flow. Still, there is no affordable cure for this inherited disease. Approved medications held promise but were met with challenges due to limited patient tolerance and undesired side effects, thereby inhibiting their ability to enhance the quality of life across various individuals with SCD. Progress has been made in understanding the pathophysiology of SCD during the past few decades, leading to the discovery of novel targets and therapies. However, there is a compelling need for research to discover medications with improved efficacy and reduced side effects. Also, more clinical investigations on various drug combinations with different mechanisms of action are needed. This review comprehensively presents therapeutic approaches for SCD, including those currently available or under investigation. It covers fundamental aspects of the disease, such as epidemiology and pathophysiology, and provides detailed discussions on various disease-modifying agents. Additionally, expert insights are offered on the future development of pharmacotherapy for SCD.

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.

Involvement of P450s in the metabolic resistance of Digitaria sanguinalis (L.) Scop. To ALS-inhibiting herbicides

Weed resistance to a range of herbicides has rapidly evolved, often with different mechanisms of action. The resulting uninhibited growth of weeds poses demonstrable threats to crop production and sustainable agriculture. Digitaria sanguinalis (L.) Scop., a troublesome weed in corn and other agricultural fields, has developed resistance to herbicides that inhibiting ALS (Acetolactate Synthase), such as nicosulfuron. Understanding the weed's resistance patterns and mechanisms is crucial. However, little is known of the non-target site resistance (NTSR) mechanisms of D. sanguinalis owing to a lack of relevant genome sequences and other materials. Therefore, in this study, a population of D.sanguinalis presenting multiple resistance was tested and found that its high level of resistance to ALS-inhibiting herbicides was not associated with target-related alterations.Administration of P450 inhibitors reversed the resistance to ALS-inhibiting herbicides. Following the application of ALS-inhibiting herbicides, the activities of NADPH-P450 reductase and p-nitroanisole O-demethylase (PNOD) were notably greater in the resistant population of D. sanguinalis than those in the susceptible population. The results suggested P450 enzyme familyplays a major role in the metabolic resistance mechanism, that increased P450 enzyme activity promote cross-resistance in D. sanguinalis to ALS-inhibiting herbicides. RNA-seq analysis showed that five genes from the P450 family (CYP709B2, CYP714C2, CYP71A1, CYP76C2, and CYP81E8) were upregulated in resistant D. sanguinalis. In conclusion, the upregulation of several P450 genes is responsible for establishing resistance to ALS-inhibiting herbicides in D. sanguinalis.

Intersite communication in dimeric enzymes highlighted by structural and thermodynamic analysis of didansyltyrosine binding to thymidylate synthases

Intersite communication in dimeric enzymes, triggered by ligand binding, represents both a challenge and an opportunity in enzyme inhibition strategy. Though often understestimated, it can impact on the in vivo biological mechansim of an inhibitor and on its pharmacokinetics. Thymidylate synthase (TS) is a homodimeric enzyme present in almost all living organisms that plays a crucial role in DNA synthesis and cell replication. While its inhibition is a valid strategy in the therapy of several human cancers, designing specific inhibitors of bacterial TSs poses a challenge to the development of new anti-infective agents. N,O-didansyl-l-tyrosine (DDT) inhibits both Escherichia coli TS (EcTS) and Lactobacillus casei TS (LcTS). The available X-ray structure of the DDT:dUMP:EcTS ternary complex indicated an unexpected binding mode for DDT to EcTS, involving a rearrangement of the protein and addressing the matter of communication between the two active sites of an enzyme dimer. Combining molecular-level information on DDT binding to EcTS and LcTS extracted from structural and FRET-based fluorometric evidence with a thermodynamic characterization of these events obtained by fluorometric and calorimetric titrations, this study unveiled a negative cooperativity between the DDT bindings to the two monomers of each enzyme dimer. This result, complemented by the species-specific thermodynamic signatures of the binding events, implied that communication across the protein dimer was triggered by the first DDT binding. These findings could challenge the conventional understanding of TS inhibition and open the way for the development of novel TS inhibitors with a different mechanism of action and enhanced efficacy and specificity.

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.

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.