Different Mechanisms Of Action Research Articles

Cereal leaf beetle-associated bacteria enhance the survival of their host upon insecticide treatments and respond differently to insecticides with different modes of action.

The cereal leaf beetle (CLB, Oulema melanopus) is one of the major cereal pests. The effect of insecticides belonging to different chemical classes, with different mechanisms of action and the active substances' concentrations on the CLB bacterial microbiome, was investigated. Targeted metagenomic analysis of the V3-V4 regions of the 16S ribosomal gene was used to determine the composition of the CLB bacterial microbiome. Each of the insecticides caused a decrease in the abundance of bacteria of the genus Pantoea, and an increase in the abundance of bacteria of the genus Stenotrophomonas, Acinetobacter, compared to untreated insects. After cypermethrin application, a decrease in the relative abundance of bacteria of the genus Pseudomonas was noted. The dominant bacterial genera in cypermethrin-treated larvae were Lactococcus, Pantoea, while in insects exposed to chlorpyrifos or flonicamid it was Pseudomonas. Insecticide-treated larvae were characterized, on average, by higher biodiversity and richness of bacterial genera, compared to untreated insects. The depletion of CLB-associated bacteria resulted in a decrease in larval survival, especially after cypermethrin and chlorpyrifos treatments. The use of a metagenome-based functional prediction approach revealed a higher predicted function of bacterial acetyl-CoA C-acetyltransferase in flonicamid and chlorpyrifos-treated larvae and tRNA dimethyltransferase in cypermethrin-treated insects than in untreated insects.

Fixed combination of non-steroidal anti-inflammatory drug and muscle relaxant as the basis for rational therapy of pain syndromes: A review

The incidence of pain in the lower back ranges from 10% to 25% of all cases of algia. 37–64.7% of the world's population have muscle spasms of varying severity during an exacerbation of pain. The problem of pain therapy is far from being solved. Achieving greater or equal pain relief can be achieved through combination drug therapy, where drugs have different mechanisms of action or combine pharmacokinetic properties to produce a synergistic effect. Fixed combinations of non-steroidal anti-inflammatory drugs and a muscle relaxant (chlorzoxazone 500 mg and ibuprofen 400 mg) are the basis of rational therapy, allowing them to achieve a number of clinical and pharmacological advantages.

PECULIARITIES OF DYSURIA TREATMENT IN MEN WITH BENIGN PROSTATIC HYPERPLASIA

Objective of the work is to analyze the practical aspects of medical treatment of urination disorders in men with benign prostatic hyperplasia (BPH). Results. Recently, more and more patients with BPH are being treated conservatively due to the increased availability of drug therapy. Traditional alpha-blockers (AB) do not always have a sufficient effect in reducing dysuria in such patients. In recent years, a number of new treatment options have been introduced into the Guidelines of the European Association of Urology (EAU) for the diagnosis and treatment of non-neurogenic voiding disorders - phosphodiesterase 5 inhibitors and beta-3 adrenomimetics have been added to cholinolytics (CL). These groups of drugs have different mechanisms of action, and some of the recommended drugs (such as CL) help relax the bladder wall and have traditionally been used in women with symptoms of overactive bladder (OAB). CL has been well studied in this category of patients both in terms of safety and efficacy. At the same time, when used in men with BPH, especially in the presence of benign prostatic obstruction (BPO), there remains the question of safety in terms of worsening urination. Although most current studies do not demonstrate an increased risk of acute urinary retention as a side effect, a number of recommendations should be followed for safe treatment of such patients. It is recommended to use CL in patients with severe and moderate urinary disorders with a predominance of irritative symptoms. However, the size of the prostate gland is not a criterion for the use of CL. Conducting urodynamic studies is also not recommended to determine the necessity or safety of one or another treatment option, they are reserved only for complicated cases or when neurogenic urination disorders are suspected. Conclusions. Complex urodynamic studies are not routinely used, while uroflowmetry should be used as a method of general evaluation of urination efficiency, diagnosis of BPO and effectiveness of patient treatment. Residual urine should be determined before taking the drugs (it is recommended that it not exceed 150 ml) and after a week of treatment.

Effect of Hb conformational changes on oxygen transport physiology.

Red blood cells (RBCs) are the primary mediators of oxygen transport in the human body, and their function is mainly achieved through conformational changes of hemoglobin (Hb). Hb is a tetramer composed of four subunits, with HbA being the predominant Hb in healthy adults, existing in two forms: tense state (T state) and relaxed state (R state). Endogenous regulators of Hb conformation include 2,3-diphosphoglyceric acid, carbon dioxide, protons, and chloride ions, while exogenous regulators include inositol hexaphosphate, inositol tripyrophosphate, benzabate, urea derivative L35, and vanillin, each with different mechanisms of action. The application of Hb conformational regulators provides new insights into the study of hypoxia oxygen supply issues and the treatment of sickle cell disease.

Exploring the Prospects of Transcranial Electrical Stimulation (tES) as a Therapeutic Intervention for Post-Stroke Motor Recovery: A Narrative Review.

Stroke survivors often have motor impairments and related functional deficits. Transcranial Electrical Stimulation (tES) is a rapidly evolving field that offers a wide range of capabilities for modulating brain function, and it is safe and inexpensive. It has the potential for widespread use for post-stroke motor recovery. Transcranial Direct Current Stimulation (tDCS), Transcranial Alternating Current Stimulation (tACS), and Transcranial Random Noise Stimulation (tRNS) are three recognized tES techniques that have gained substantial attention in recent years but have different mechanisms of action. tDCS has been widely used in stroke motor rehabilitation, while applications of tACS and tRNS are very limited. The tDCS protocols could vary significantly, and outcomes are heterogeneous. the current review attempted to explore the mechanisms underlying commonly employed tES techniques and evaluate their prospective advantages and challenges for their applications in motor recovery after stroke. tDCS could depolarize and hyperpolarize the potentials of cortical motor neurons, while tACS and tRNS could target specific brain rhythms and entrain neural networks. Despite the extensive use of tDCS, the complexity of neural networks calls for more sophisticated modifications like tACS and tRNS.

CK2 Inhibitors Targeting Inside and Outside the Catalytic Box

CK2 is a protein kinase that plays an important role in numerous cellular pathways involved in cell growth, differentiation, proliferation, and death. Consequently, upregulation of CK2 is implicated in many disease types, in particular cancer. As such, CK2 has gained significant attention as a potential therapeutic target in cancer, and over 40 chemical probes targeting CK2 have been developed in the past decade. In this review, we highlighted several chemical probes that target sites outside the conventional ATP-binding site. These chemical probes belong to different classes of molecules, from small molecules to peptides, and possess different mechanisms of action. Many of the chemical probes discussed in this review could serve as promising new candidates for drugs selectively targeting CK2.

Development of Multi-particulate Formulation of Glabridin with L-Phenylalanine and Its Pre-clinical Evaluation for Anti-obesity Activity

Obesity is a chronic condition that is defined by pathophysiological mechanisms that lead to an increase in adipose tissue mass as a result of positive energy balance. Obesity is a multi-factorial disorder involving different mechanisms of action like humoral and neurogenic actions. Hypertrophied and hyperplastic adipocytes are indicative of pathological obesity. In the current treatment regimen, the drugs used mainly focus on a single mechanism of action. Herbal medicines are reported to have anti-obesity activity but due to the presence of multiple phytoconstituents its very difficult for one to finalize the dose and issue of palatability. So the best solution is to focus on usage of active phytoconstituent as an anti-obesity medicine. A high protein diet proved to have anti-obesity activity, the main constituent responsible for this activity is L-phenylalanine which is an essential amino acid that produces its activity by stimulating the satiety centre and thus decreases food intake. In this study, we are combining glabridin from Glycyrrhiza glabra and L-phenylalanine as both show anti-obesity activity through different action mechanisms, which may result in synergism. The study aims to prepare multi-particulate system (granules) of glabridin with L-phenylalanine and evaluate their anti-obesity and hypo-lipidemic action in HFD-treated rats.

Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) protein. This epithelial anion channel regulates the active transport of chloride and bicarbonate ions across membranes. Mutations result in reduced surface expression of CFTR channels with impaired functionality. Correctors are small molecules that support the trafficking of CFTR to increase its membrane expression. Such correctors can have different mechanisms of action. Combinations may result in a further improved therapeutic benefit. We describe the identification and optimization of a new pyrazolol3,4-bl pyridine-6-carboxylic acid series with high potency and efficacy in rescuing CFTR from the cell surface. Investigations showed that carboxylic acid group replacement with acylsulfonamides and acylsulfonylureas improved ADMET and PK properties, leading to the discovery of the structurally novel co-corrector GLPG2737. The addition of GLPG2737 to the combination of the potentiator GLPG1837 and C1 corrector 4 led to an 8-fold increase in the F508del CFTR activity.

Cuminaldehyde and Tobramycin Forestall the Biofilm Threats of Staphylococcus aureus: A Combinatorial Strategy to Evade the Biofilm Challenges.

Staphylococcus aureus, an opportunistic Gram-positive pathogen, is known for causing various infections in humans, primarily by forming biofilms. The biofilm-induced antibiotic resistance has been considered a significant medical threat. Combinatorial therapy has been considered a reliable approach to combat antibiotic resistance by using multiple antimicrobial agents simultaneously, targeting bacteria through different mechanisms of action. To this end, we examined the effects of two molecules, cuminaldehyde (a natural compound) and tobramycin (an antibiotic), individually and in combination, against staphylococcal biofilm. Our experimental observations demonstrated that cuminaldehyde (20μg/mL) in combination with tobramycin (0.05μg/mL) exhibited efficient reduction in biofilm formation compared to their individual treatments (p < 0.01). Additionally, the combination showed an additive interaction (fractional inhibitory concentration value 0.66) against S. aureus. Further analysis revealed that the effective combination accelerated the buildup of reactive oxygen species (ROS) and increased the membrane permeability of the bacteria. Our findings also specified that the cuminaldehyde in combination with tobramycin efficiently reduced biofilm-associated pathogenicity factors of S. aureus, including fibrinogen clumping ability, hemolysis property, and staphyloxanthin production. The selected concentrations of tobramycin and cuminaldehyde demonstrated promising activity against the biofilm development of S. aureus on catheter models without exerting antimicrobial effects. In conclusion, the combination of tobramycin and cuminaldehyde presented a successful strategy for combating staphylococcal biofilm-related healthcare threats. This combinatorial approach holds the potential for controlling biofilm-associated infections caused by S. aureus.

Abstract 2920: In vitro assays for investigating the effects of cancer therapeutics on bone

Abstract Bone microenvironment is an important factor in regulating bone metastasis. When cancer cells home to bone they secrete factors that stimulate osteoclast activity leading to increased bone resorption. Stimulatory factors released from the resorbed bone matrix in turn promote proliferation of cancer cells and this process, referred as the vicious cycle, often leads to osteolytic lesions in bone when osteoclastic bone resorption exceeds osteoblastic bone formation. The vicious cycle observed in osteolytic disease occurs also in osteoblastic metastases, and in addition cancer cells produce osteoblast-stimulating factors. Cancers with bone metastases often include both osteolytic and osteoblastic lesions. Our aim was to establish in vitro cell culture models to study the effects of cancer therapeutics on osteoblast and osteoclast differentiation and activity. In the osteoclast differentiation assay, human osteoclast precursor cells (Lonza) were cultured on bovine bone slices for 7 days. Denosumab was added in the cultures at day 0, and tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) activity was measured from the culture medium collected at day 7. Osteoclast activity was studied by allowing osteoclasts resorb bone after 7 days’ maturation period for additional 3 days in the presence of odanacatib. The amount of C-terminal cross-linked telopeptides of type I collagen (CTX-I) was measured in the culture medium collected at day 10 to quantitate osteoclast activity. Denosumab and odanacatib showed strong concentration dependent inhibition of osteoclast differentiation and activity, respectively. A mouse osteoblast progenitor cell line KS483 (Pharmatest Services) was used to study differentiation and activity of osteoblasts with test compounds bone morphogenetic protein 2 (BMP-2) and estradiol (E2). In the osteoblast differentiation assay, the activity of cellular alkaline phosphatase (ALP), a marker of osteoblast differentiation, was measured at day 8. In the osteoblast activity assay, the cells were cultured for 13 days. N-terminal propeptide of type I procollagen (PINP) secreted into the culture medium was determined at day 11 to indicate the effects on organic bone formation and calcium deposition was determined at the end of the study as a marker of inorganic bone formation. BMP-2 and E2 stimulated osteoblast differentiation and activity indicated by the increase in ALP activity, PINP and calcium levels. We conclude that these culture systems can be used for studying the effects of cancer therapeutics and identifying new potential compounds affecting the disease process of bone metastases with different mechanisms of action. Citation Format: Jenni H. Mäki-Jouppila, Mervi Ristola, Jukka Rissanen, Katja Fagerlund. In vitro assays for investigating the effects of cancer therapeutics on bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2920.

Abstract 5805: A novel platform of diversified payloads to drive ADC innovation

Abstract First generation of antibody drug conjugates (ADCs) for anticancer therapy has been described more than two decades ago with gemtuzumab-ozogamicin receiving the first approval in 2000. Over the last 4 years, 8 new ADCs got FDA approval essentially due to the innovation on the linker improving the disposition in patients and the manufacturability together with the technical advantages in the engineering of biologics and the introduction of new cytotoxic payloads such as deruxtecan. In the future, next generation ADCs will be developed exploring payloads beyond the currently used cytotoxins to improve safety, efficacy and durability of responses and therefore the short- and long-term therapeutic benefit to patients. Nerviano Medical Sciences (NMS) generated a portfolio of novel and diversified payload linkers leveraging on its proprietary chemical collection that includes cytotoxic and targeted payloads. A rigorous screening funnel has been applied considering diversification in terms of MoAs, pharmacokinetic properties, mechanism of resistance and combinability with other therapies to identify the optimal match with specific tumor types and targets, generating a new class of ADCs with improved selectivity and efficacy for hard-to-treat cancers even in chemoresistant settings. NMS ADC platform incorporates 1) our patent protected payload linker NMS-P945, a duocarmycin like DNA minor groove binder and alkylating agent inducing DNA damage, acting in chemoresistant cells with bystander effect and immunogenic cell death properties and generating ADCs highly efficacious in mouse xenograft models and safe when administered in NHP, 2) novel anthracyclines (PNU-682 derivatives) with an improved stability and safety profile and 3) targeted molecules with different mechanism of action including payloads active in synthetic lethality contexts. Payload linkers with different functionalization generated from each payload have been evaluated for chemical stability, sensitivity to lysosomal protease cleavage, and conjugability to monoclonal antibodies. The ADCs, generated with proof-of-concept antibodies (e.g. Trastuzumab), were characterized in terms of Drug to Antibody Ratio (DAR), aggregation level, plasma stability, antigen binding and differential antiproliferative activity in target positive vs target negative tumor cells. The best products resulting from the screening funnel have been subjected to a multidimensional analysis taking into consideration payload properties, tumor features and antigen expression in selected populations with the aim of identifying tumor types particularly sensitive to the payload. Our multidimensional approach coupling new payload linker with innovative MoA to careful selection of patients will allow to reach unprecedented efficacy and safety profile. Citation Format: Paolo Orsini, Matteo Salsa, Simona Rizzi, Ulisse Cucchi, Daniela Faiardi, Alessia Burocchi, Antonella Ciavolella, Rosita Lupi, Fabio Gasparri, Barbara Valsasina. A novel platform of diversified payloads to drive ADC innovation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5805.

Abstract 4488: Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines

Abstract In conventional cancer treatment, platinum-based cytostatics are considered as standard therapy; however, they possess severe side effects. This fact leads to a constant effort to develop new non-platinum metallodrugs with different mechanism of action (MoA). In our study we developed new half-sandwich organoiridium(III) complexes, of general formulas [Ir(η5-Cp*)Cl(LNP)]PF6 (1-3) and [Ir(η5-Cpph)Cl(LNP)]PF6 (4-6) involving three different N,P-donor phosphinoalkylamines (LNP), which we tested on 2D and 3D cancer models; HCp* = pentamethylcyclopentadiene, HCpph= (2,3,4,5-tetramethylcyclopenta-2,4-dien-1-yl)benzene. The most effective complexes 3 and 6 bearing 3-(diphenylphosphanyl)propan-1-amine had the highest cytotoxic effect against various cancer cell lines (THP-1, HeLa, SW982, A549, MOR) including a cisplatin-resistant lung carcinoma cell line (MOR/CPR) with IC50 values between 3.1 and 9.1 μM for specific cell lines. The cytotoxic effect was further demonstrated on 3D spheroids of lung cancer cells that revealed anti-cancer and anti-migration potential of complexes 3 and 6. Cell cycle and cell death analysis showed a different mechanism compared to the effect of cisplatin. Moreover, complex 3 did not decrease cell viability of non-cancerous cells (peripheral blood mononuclear cells and porcine chondrocytes) under 50% at a concentration of 20 µM. In addition, we report for the first time that organoiridium complexes showed high cytotoxic activity on cancer cell lines, including cisplatin-resistant cell line, with different MoA from cisplatin. They trigger expression of stress-related genes associated with oxidative stress, DNA damage, and endoplasmic reticulum stress and, moreover, complex 3 showed cytotoxic selectivity towards cancer cells. This work was supported by the Czech health research council of the Ministry of Health of the Czech Republic (AZV Project NU22-08-00236). Citation Format: Renata Hezova, Jan Hosek, Nicol Strakova, Pavlina Simeckova, Josef Masek, Simona Kajabova, Pavel Starcha. Newly developed organoiridium(III) complexes containing N,P-ligands possess antiproliferative activity in selected cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4488.

Abstract 6442: Evaluation of drug target engagement on pharmacodynamic biomarkers in human plucked scalp hair

Abstract Plucked hair is a valuable surrogate tissue to monitor pharmacodynamic (PD) responses in a clinical trial. Hair collection is a minimally invasive, simple technique amenable to frequent sampling and hence patient compliance. We have developed a method to assess target expression changes following exposure of plucked hairs to chemotherapeutic agents and other potential therapeutics. Successful ex vivo responses provide proof of concept data prior to clinical studies. Since hairs are epithelial appendages, many signaling pathways active in other epithelial tissues, including cancers, are also present in hairs. Highly proliferative scalp hair can be utilized as a surrogate tissue to measure proliferation, phosphorylation and DNA damage responses after treatment. Furthermore, hairs are highly vascularized, suggesting administered Test Articles may be delivered efficiently to the hair in a similar manner to other highly vascularized tissues, including many tumor types. Human plucked scalp hair was placed in maintenance media in the presence of chemotherapeutic agents that have different mechanisms of action (e.g. Gemcitabine, Epirubicin, Erlotinib) for a range of timepoints. Hairs were fixed post-exposure and longitudinal sections were immunohistochemically labelled for markers relating to DNA damage/repair or signaling pathways directly relating to target engagement. Examples include p-Chk1, g-H2AX, p-ERK1/2, and p-AKT. Quantitative image analysis to measure the level of labelling was performed using an Aperio ScanScope®. The relative number of positively labelled cell nuclei or relative labelled tissue area (depending on the labelling pattern of the target), of the hair outer root sheath was analyzed, along with label intensity. In subsequent clinical trials, formaldehyde fixed hairs from patients were returned to the lab, sectioned, labelled and quantified. If antibody labelling is not possible or more detailed information on pathway modulation may be useful, drug treated plucked hairs can be subjected to Next Generation Sequencing (NGS) gene expression analysis. The expected changes in labelling were observed, reflecting known tumor responses. For example, Gemcitabine (linked to DNA polymerase inhibition) increased p-Chk1 labelling after 4 hours and strongly induced p53 by 24 hours. Epirubicin (anthracycline topoisomerase II inhibitor) increased g-H2AX labelling up to 24 hours. Erlotinib (EGFr pathway inhibitor) decreased levels of both p-ERK1/2 and p-AKT after only 10 minutes. We have demonstrated that plucked hair is a valuable PD biomarker tissue for various chemotherapy agents. Proof of concept studies performed ex vivo can inform the design of clinical studies by indicating optimum biomarkers and timepoints. Further, each hair is an independent unit thereby allowing replicate tissues (hairs) to be sampled, improving statistical confidence compared to single readout markers. Citation Format: Greg Tudor, Frida Ponthan, Adam Boanas, Matt Brown, Catherine Booth. Evaluation of drug target engagement on pharmacodynamic biomarkers in human plucked scalp hair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6442.

Relevant Aspects of Combined Protocols for Prevention of N(M)AFLD and Other Non-Communicable Diseases.

Obesity is a global health issue characterized by the excessive fat accumulation, leading to an increased risk of chronic noncommunicable diseases (NCDs), including metabolic dysfunction-associated fatty liver disease (MAFLD), which can progress from simple steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Currently, there are no approved pharmacological protocols for prevention/treatment of MAFLD, and due the complexity lying beneath these mechanisms, monotherapies are unlikely to be efficacious. This review article analyzes the possibility that NCDs can be prevented or attenuated by the combination of bioactive substances, as they could promote higher response rates, maximum reaction results, additive or synergistic effects due to compounds having similar or different mechanisms of action and/or refraining possible side effects, related to the use of lower doses and exposures times than monotherapies. Accordingly, prevention of mouse MAFLD is observed with the combination of the omega-3 docosahexaenoic acid with the antioxidant hydroxytyrosol, whereas attenuation of mild cognitive impairment is attained by folic acid plus cobalamin in elderly patients. The existence of several drawbacks underlying published monotherapies or combined trials, opens space for adequate and stricter experimental and clinical tryouts to achieve meaningful outcomes with human applicability.

Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.

Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice. C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated. There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15mg once daily or adalimumab 40mg every other week were switched to the alternate therapy by week26. Efficacy was evaluated through 228weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week264. Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week26. Clinically relevant improvements in all efficacy measures were observed through 228weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. NCT02629159.

Functional Roles of Two β-Tubulin Isotypes in Regulation of Sensitivity of Colletotrichum fructicola to Carbendazim.

Colletotrichum fructicola is the major pathogen of anthracnose in tea-oil trees in China. Control of anthracnose in tea-oil trees mainly depends on the application of chemical fungicides such as carbendazim. However, the current sensitivity of C. fructicola isolates in tea-oil trees to carbendazim has not been reported. Here, we tested the sensitivity of 121 C. fructicola isolates collected from Guangdong, Guangxi, Guizhou, Hainan, Hunan, Jiangsu, and Jiangxi provinces in China to carbendazim. One hundred and ten isolates were sensitive to carbendazim, and 11 isolates were highly resistant to carbendazim. The growth rates, morphology, and pathogenicity of three resistant isolates were identical to those of three sensitive isolates, which indicates that these resistant isolates could form a resistant population under carbendazim application. These results suggest that carbendazim should not be the sole fungicide in control of anthracnose in tea-oil trees; other fungicides with different mechanisms of action or mixtures of fungicides could be considered. In addition, bioinformatics analysis identified two β-tubulin isotypes in C. fructicola: Cfβ1tub and Cfβ2tub. E198A mutation was discovered in the Cfβ2tub of three carbendazim-resistant isolates. We also investigated the functional roles of two β-tubulin isotypes. CfΔβ1tub exhibited slightly increased sensitivity to carbendazim and normal phenotypes. Surprisingly, CfΔβ2tub was highly resistant to carbendazim and showed a seriously decreased growth rate, conidial production, pathogenicity, and abnormal hyphae morphology. Promoter replacement mutant CfΔβ2-2×β1 showed partly restored phenotypes, but it was still highly resistant to carbendazim, which suggests that Cfβ1tub and Cfβ2tub are functionally interchangeable to a certain degree.

Experience with the fixed combination of benzoyl peroxide and clindamycin in acne therapy

Background. Acne is one of the most common dermatoses, affecting more than 9% of the world’s population. Acne negatively affects the patient’s quality of life and self-esteem, often leading to the development of anxiety and depression. The combination of pharmacological drugs with different mechanisms of action in one external dosage form can provide higher therapeutic efficacy.&#x0D; Aims. To evaluate the effectiveness and tolerability of a combination drug with a fixed dose of clindamycin 1% and benzoyl peroxide 5% in the treatment of patients with mild to moderate papulopustular acne.&#x0D; Methods. A single-center, open-label, observational, prospective study lasting 6 weeks was performed, which included 40 patients with mild to moderate papulopustular acne who received a gel with a fixed dose of clindamycin 1% and benzoyl peroxide 5% once a day. A clinical assessment of the effectiveness of therapy was carried out, PH, greasiness and moisture of the facial skin were measured, and the dynamics of the dermatological quality of life index was studied.&#x0D; Results. The proportion of patients who showed significant improvement at the end of 6 weeks of treatment was 32/40 (80%). The total proportion of patients who showed significant and moderate improvement at the end of therapy reached 36/40 (90%).&#x0D; Conclusion. The results obtained showed the high therapeutic effectiveness of the gel with a fixed dose of clindamycin 1% and benzoyl peroxide 5% in the treatment of mild to moderate papulopustular acne.

Difficult-to-treat rheumatoid arthritis

Rheumatoid arthritis is the most common inflammatory arthritis and has benefited from significant advances in its management in the past years. However, specific challenges persist, including the management of difficult-to-treat rheumatoid (D2TRA), which is defined by the failure of at least two biological or targeted synthetic disease-modifying antirheumatic drugs with a different mechanism of action. D2TRA reported prevalence is from 5 to 20 %. EULAR (European Alliance of Associations for Rheumatology) proposed a step-by-step approach for managing D2TRA, starting with confirmation of diagnosis, assessment of inflammatory activity, immunosuppressive treatment choice and non-pharmacological treatment.

Advances in nanotechnology-enabled drug delivery for combining PARP inhibitors and immunotherapy in advanced ovarian cancer.

Advanced ovarian cancer is a malignancy that spreads beyond the ovaries to the pelvis, abdomen, lungs, or lymph nodes. Effective treatment options are available to improve survival rates in patients with advanced ovarian cancer. These include radiation, surgery, chemotherapy, immunotherapy, and targeted therapy. Drug resistance, however, remains a significant challenge in pharmacotherapeutic interventions, leading to reduced efficacy and unfavorable patient outcomes. Combination therapy, which involves using multiple drugs with different mechanisms of action at their optimal dose, is a promising approach to circumvent this challenge and it involves using multiple drugs with different mechanisms of action at their optimal dose. In recent years, nanotechnology has emerged as a valuable alternative for enhancing drug delivery precision and minimize toxicity. Nanoparticles can deliver drugs to specific cancer cells, resulting in higher drug concentrations at the tumor site, and reducing overall drug toxicity. Nanotechnology-based drug delivery systems have the potential to improve the therapeutic effects of anti-cancer drugs, reduce drug resistance, and improve outcomes for patients with advanced ovarian cancer. This literature review aims to examine the current understanding of combining poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy in treating advanced ovarian cancer and the potential impact of nanotechnology on drug delivery.