Combination Drug Research Articles

Additive Cytotoxic and Colony-Formation Inhibitory Effects of Aspirin and Metformin on PI3KCA-Mutant Colorectal Cancer Cells.

Human malignancies are one of the major health-related issues throughout the world and are anticipated to rise in the future. Despite huge investments made in anticancer drug development, limited success has been obtained and the average number of FDA approvals per year is declining. So, an increasing interest in drug repurposing exists. Metformin (MET) and aspirin (ASP) possess anticancer properties. This work aims to test the effect of these two drugs in combination on colorectal cancer (CRC) cells in vitro. The effects of MET and/or ASP on cell proliferation, viability, migratory ability, anchorage-independent growth ability (colony formation), and nutrient uptake were determined in two (HT-29 and Caco-2) human CRC cell lines. Individually, MET and ASP possessed antiproliferative, cytotoxic, and antimigratory effects and reduced colony formation in HT-29 cells (BRAF- and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PI3KCA)-mutant), although MET did not affect either 3H-deoxy-D-glucose or 14C-butyrate uptake and lactate production, and ASP caused only a small decrease in 14C-butyrate uptake. Moreover, in these cells, the combination of MET and ASP resulted in a tendency to an increase in the cytotoxic effect and in a potentiation of the inhibitory effect on colony formation, although no additive antiproliferative and antimigratory effects, and no effect on nutrient uptake and lactate production were observed. In contrast, MET and ASP, both individually and in combination, were almost devoid of effects on Caco-2 cells (BRAF- and PI3KCA-wild type). We suggest that inhibition of PI3K is the common mechanism involved in the anti-CRC effect of both MET, ASP and their combination and, therefore, that the combination of MET + ASP may especially benefit PI3KCA-mutant CRC cases, which currently have a poor prognostic.

Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine, and chloroquine in Rhesus macaques.

Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding Anopheles, resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of Plasmodium vivax and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.

Most commonly prescribed analgesic among 6 to 12-year-olds after extraction in paediatric dentistry - A retrospective study

Background: Using their expertise in analgesics, the dentist should recommend the best prescription at the right dosage to reduce pain without going overboard. Aim: To determine the most commonly prescribed analgesics which are used post-extraction for 6 to 12-year-old children Materials & Methods: A total of 4160 patient data was collected from OPD data from the Department of Pediatric Dentistry, Saveetha Dental College & Hospital of 6 to 12-year-old children who have gotten dental treatment and have received analgesic medication. The dentist should use his or her knowledge of analgesics to prescribe the most effective drug and appropriate dose to alleviate pain while avoiding overmedication. The treatment records of these patients were assessed and data was analyzed. Descriptive analysis and chi-square tests were performed. Results: The majority of the patients (16.7%) were 9 years old. The most commonly prescribed analgesic was found to be paracetamol (56.6%). The most common combination drug prescribed to children was Paracetamol and Ibuprofen (19.5%). P value for the comparison between gender and age with different types of analgesics [0.0005 (<0.05)] was found to be statistically significant. Conclusion: In both males and females, paracetamol was the most prescribed analgesic and most commonly prescribed analgesic, a combination drug; Paracetamol & Ibuprofen.

Therapeutic Potential of Withaferin-A and Propolis Combinational Drug Therapy for Breast Cancer: An In Vivo Interpretation for Validating the Antiproliferative Efficacy and Ameliorative Potential in Benzo[a]pyrene-Induced Breast Metastasis

Therapeutic Potential of Withaferin-A and Propolis Combinational Drug Therapy for Breast Cancer: An In Vivo Interpretation for Validating the Antiproliferative Efficacy and Ameliorative Potential in Benzo[a]pyrene-Induced Breast Metastasis

A systematic review of the mechanism of action and potential medicinal value of codonopsis pilosula in diseases.

As a traditional Chinese medicinal herb with a long history, Codonopsis pilosula (CP) has attracted much attention from the medical community in recent years. This review summarizes the research progress of CP in the medical field in the past 5years. By searching and analyzing the literature, and combining with Cytoscape software, we comprehensively examined the role and mechanism of action of CP in individual application, combination drug application, and the role and mechanism of action of codonopsis pilosula's active ingredients in a variety of diseases. It also analyzes the medicinal use of CP and its application value in medicine. This review found that CP mainly manifests important roles in several diseases, such as cardiovascular system, nervous system, digestive system, immune system, etc., and regulates the development of many diseases mainly through the mechanisms of inflammation regulation, oxidative stress, immunomodulation and apoptosis. Its rich pharmacological activities and diverse medicinal effects endow CP with broad prospects and application values. This review provides valuable reference and guidance for the further development of CP in traditional Chinese medicine.

The impact of cardiovascular and lung comorbidities in patients with pulmonary arterial hypertension: A systematic review and meta-analysis

BackgroundContemporary patients with pulmonary arterial hypertension (PAH) are older and exhibit cardiovascular and/or lung comorbidities. Such patients have typically been excluded from major PAH drug trials. This systematic review compares baseline characteristics, hemodynamic parameters, and mortality rate between PAH patients with significant number of comorbidities compared to those with fewer or no comorbidities. ΜethodsA systematic literature search in PubMed and Cochrane databases was conducted searching for studies comparing PAH patients with more than two cardiovascular comorbidities and/or at least a lung comorbidity against those with fewer comorbidities. ResultsSeven observational studies were included. PAH patients with comorbidities were older, with an almost equal female-to-male ratio, shorter 6-minute walk distance, higher NT-proBNP levels, and lower lung diffusion for carbon monoxide. In terms of hemodynamics, they had higher mean right atrial pressure and pulmonary artery wedge pressure, lower mean pulmonary arterial pressure, pulmonary vascular resistance and mixed venous oxygen saturation. Pooled analysis of six studies demonstrated a higher mortality risk for PAH patients with comorbidities compared to those without (HR 1.86, 95% CI 1.20 to 2.89, p<0.001, I²=92%), with the subgroup of PAH patients with lung comorbidities having an even higher mortality risk (test for subgroup differences: p<0.001). Combination drug therapy for PAH was less frequently used in patients with comorbidities. ConclusionsCardiovascular and lung comorbidities impact the clinical characteristics and outcomes of PAH patients, highlighting the need for optimal phenotyping and tailored management for this high-risk population.

Membrane Fusion Liposomes Deliver Antifibrotic and Chemotherapeutic Drugs Sequentially to Enhance Tumor Treatment Efficacy by Reshaping Tumor Microenvironment.

The intricate tumor microenvironment in triple-negative breast cancer (TNBC) hampers chemotherapy and immunotherapy efficacy due to dense extracellular matrix (ECM) by tumor-associated fibroblasts (TAFs). Nanoparticle-based therapies, especially "all-in-one" nanoparticles, have shown great potential in combined drug delivery strategies to reshape the tumor microenvironment and enhance therapeutic efficiency. However, these "all-in-one" nanoparticles suffer from limitations in targeting different target cells, uncontrollable dosing ratio, and disregarding the impact of delivery schedules. This study prepared cell membrane fusion liposomes (TAFsomes and CCMsomes) to load FDA-approved antifibrotic drug pirfenidone (PFD/TAFsomes) and antitumor drug doxorubicin (DOX/CCMsomes). These liposomes can specifically target TAFs cells and tumor cells, and combined administration can effectively inhibit TAFs activity, reshape the tumor microenvironment (TME), and significantly enhance the tumor chemotherapy efficacy. Combined drug delivery defeats "all-in-one" liposomes (DOX/PFD/Liposomes, DOX/PFD/TAFsomes, and DOX/PFD/CCMsomes) by flexibly adjusting the drug delivery ratio. Moreover, an asynchronous delivery strategy that optimizes the administration schedule not only further improves the therapeutic effect, but also amplifies the effectiveness of α-PD-L1 immunotherapy by modulating the tumor immune microenvironment. This delivery strategy provides a personalized treatment approach with clinical translation potential, providing new ideas for enhancing the therapeutic effect against solid tumors such as TNBC.

Analysis of antimicrobial drug usage in psychiatric specialized hospitals during the pandemic in China

ABSTRACT Background This study aims to compare antimicrobial drug usage in our hospital to Jiangsu Province and China from 2020 to 2022. Research design and methods A detailed analysis was performed using data from the National Antimicrobial Drug Clinical Application Monitoring Network. Several parameters were studied: the rate of antimicrobial drug use, number and types of drugs used, the rate of combined use, rate of microbiological examinations, drug use intensity, and cumulative Defined Daily Doses (DDDs). Results From 2020 to 2022, our hospital’s antimicrobial drug usage rate was consistently lower than Jiangsu Province and China. The average number of drug types and the combined drug use rate were higher in 2020 but fell below those in Jiangsu Province and China in 2021 and 2022. Our microbiological examination rate consistently surpassed that of Jiangsu Province and China. Furthermore, our Antimicrobial Usage Density and cumulative DDDs were notably lower. While AUD remained stable, DDDs showed a decreasing trend. The most dominant drug in DDDs was cefditoren, a third-generation cephalosporin. Conclusions During the pandemic years, our hospital not only met the requirements for antimicrobial drug usage, microbiological examination, AUD, and cumulative DDDs but also demonstrated a consistent year-by-year decrease in drug usage and DDDs.

Analysis of local anesthetics side effects and determination of ways for their minimization

According to the World Health Organization (WHO), the development of side effects of drugs is one of the serious medical problems.The relevance of this problem is proven by numerous statistical data obtained in different countries of the world. The aim of the study was to determine the assortment of local anesthetics (LAs) on the pharmaceutical market of Ukraine, to analyze the evidence base of the effectiveness and safety of modern LAs, to monitor the side effects (SEs) of LAs in Kharkiv and Kharkiv region for the period 2018–2021, and to provide recommendations for their minimization. The methods of passive pharmacovigilance, method of spontaneous reports, method of system approach and system analysis were used in the study. To analyze the clinical effectiveness and conditions of rational use of LAs, well-known data bases were used: Cochrane Library, Trip Database, and PubMed. These databases contain systematized primary or secondary information on a specific clinical issue: the effectiveness and safety of various medical technologies. The results of the analysis of the assortment of LAs on the pharmaceutical market of Ukraine showed that in 2023, based on 9 international non-patented names of LAs, 65 trade names were presented. Bupivacaine and procaine drugs (16 trade names each) and articaine drugs in combinations (13 trade names) are market leaders. The results of the analysis of notification cards with cases of SEs for 4 years revealed that the majority of them in the form of dizziness, weakness, changes in blood pressure, heart rate, edema, itching, hyperemia at the site of application were recorded when using lidocaine drugs, which are the most in demand and popular among doctors. According to the data of systematic reviews, the main directions for reducing the side effects of LAs have been established, such as administration under ultrasound control, the use of the least toxic modern anesthetics ropivacaine and levobupivacaine (not available on the Ukrainian market), the addition of substances with vasoconstrictive properties to the anesthetic solution, the use of combinations of long-acting and short-acting anesthetics. The results obtained can be used by practicing doctors and health care organizers to optimize LAs.

ASPECTS OF THE USE OF ANTIDIABETIC DRUGS IN PHARMACEUTICAL PRACTICE ON THE BASIS OF RATIONAL PHARMACOTHERAPY

The aim of the article. To study of the incidence of diabetes mellitus in Ukraine and to determine the prospects for the use and pharmaceutical development of antidiabetic drugs. Materials and methods. Data from the State Registers of Medicinal Products of Ukraine, of Wholesale and Retail Prices for Medicinal Products declared in Ukraine under an international non-proprietary or generic name (01.01.2024). Were used: systematic and comparative analysis, processing and synthesis, and generalization to determine the forecasted prospects. Results. In Ukraine the number of diabetes patients increased by 11% in the group of children and adolescents; in the group of elderly patients – by 12.5%, among the adult working – 20%, diabetes of the II type predominates. The trend of increase in the number of studies on the search for therapeutic alternatives for the treatment of type II diabetes and list of medicines on the pharmaceutical market has been revealed. In Ukraine drugs for oral use include APIs of the following pharmacological groups: sulfonylureas; meglitinides; biguanides; thiazolidinedione; α-glucosidase inhibitors; DPP-4 inhibitors; SGLT-2 inhibitors. Mechanism of action of the new class of oral hypoglycemic agents, approved by the FDA, consists in blocking SGLT-2 proteins from the proximal convoluted tubule in the kidney, leads to the prevention of reabsorption and excretion of the glucose molecule. This allows its use in combination with insulin and other antidiabetic drugs for the treatment of type I and II diabetes in patients of various age categories. According to the volume of clinical studies, SGLT-2 inhibitor SGLT-2 derivative gliflozin API drugs are the second largest group of antidiabetic drugs recommended for use by FDA and EMA regulatory bodies. Conclusions. The pharmaceutical development of mono and combined drugs with APIs SGLT-2 inhibitors gliflozin derivatives in combination with APIs with metformin, DPP-4 inhibitors, APIs thiazolidinedione derivatives is promising for solving the problem of diabetes treatment and prevention of complications for patients of different age groups including working population in Ukraine.

A randomised trial comparing block characteristics of a mixture versus sequential injections of lignocaine and ropivacaine for supraclavicular brachial plexus nerve block in patients undergoing upper limb surgery.

There is no consensus on the appropriate use of mixtures of local anaesthetic drugs in various combinations for nerve blocks. We intended to compare short-acting lignocaine and long-acting ropivacaine as a mixture versus undiluted sequential injections on block characteristics of ultrasound-guided (USG) supraclavicular brachial plexus block for upper limb surgeries. A double-blinded randomised study was conducted on 64 adult patients scheduled for upper limb surgery who received 15 mL each of 2% lignocaine with adrenaline and 0.75% ropivacaine as a 1:1 mixture in the mixed group (Group M) or sequential injections in the sequential group (Group S) by using a USG technique. The primary outcome was the percentage of participants with complete four nerve sensory blocks at 10 minutes post block injection. Secondary outcomes were sensory and motor block characteristics till 30 minutes, total duration of analgesia, sensory and motor block, and complications. Demographic characteristics and time taken for the procedure were similar. The percentage of participants with a complete four-nerve sensory block at 10 minutes was higher in Group S (69%) versus Group M (41%) (P = 0.04). Complete sensory and motor block rates were similar at 30 minutes. The block procedure time, total duration of analgesia, and sensory and motor block were similar in both groups. There were no major complications. Sequential lignocaine-ropivacaine, compared to the mixed injection technique, has a higher initial rate of sensory and motor block onset with a similar total block duration.

Mycobactin analogue interacting with siderophore efflux-pump protein: insights from molecular dynamics simulations and whole-cell assays

IntroductionIn response to continued public health emergency of antimicrobial resistance (AMR), a significant key strategy is the discovery of novel mycobacterial efflux-pump inhibitors (EPIs) as potential adjuvants in combination drug therapy. Interest in identifying new chemotypes which could potentially synergize with the existing antibiotics and can be deployed as part of a combination therapy. This strategy could delay the emergence of resistance to existing antibiotics and increase their efficacy against resistant strains of mycobacterial species. In recent decades, notable approaches have been accounted for EPI development and have resulted in the discovery of several EPIs including SQ109 and AU1235. In context, to accelerate newer EPIs with novel mode of action here we have discussed mycobactin analogues and highlighted in silico binding orientation with siderophore efflux-pump proteins MmpL4/5.Methods3-(2-hydroxyphenyl)-5-(aryl)-pyrazoline series was investigated for whole-cell efflux-pump inhibitory activity against Mycobacterium smegmatis and Mycobacterium abscessus. Machine learning and molecular dynamics were performed to construct a MmpL4/5 complex embedded in a lipid bilayer to identify the putative binding site and to predict ligand-protein binding energetics. Furthermore, the identified HIT compound was investigated in synergistic assay with bedaquiline.ResultsCompound Il, 2-(5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenol, was identified as the most potent efflux pump inhibitor against M. smegmatis in whole-cell efflux-pump investigation. Followed HIT Il employed against M. abscessus for efflux-pump inhibition investigations and notable whole-cell efflux-pump inhibitory profile has been observed. The theoretical investigations predicted compound Il to be selective towards MmpL4, with significant hydrogen bonding and π-π stacking interactions effectively blocking a critical Asp-Tyr dyad interaction network necessary for proton translocation. Compound Il with bedaquiline highlighted an additive profile against the M. abscessus pathogen.ConclusionsMD simulations and whole-cell assays are indicating potential development of compound Il as an adjunct to the existing therapeutic regimen against mycobacterial infections.

The application of Global Trigger Tool in monitoring antineoplastic adverse drug events: a retrospective study.

This study aimed to establish an antineoplastic drugs trigger tool based on Global Trigger Tool (GTT), to examine the performance by detecting adverse drug events (ADEs) in patients with cancer in a Chinese hospital (a retrospective review), and to investigate the factors associating with the occurrence of antineoplastic ADEs. Based on the triggers recommended by the GTT and those used in domestic and foreign studies and taking into account the scope of biochemical indexes in our hospital, some of them were adjusted. A total of 37 triggers were finally developed. Five hundred medical records of oncology patients discharged in our hospital from 1 June 2020 to 31 May 2021 were randomly selected according to the inclusion and exclusion criteria. These records were reviewed retrospectively by antineoplastic drugs trigger tool. The sensitivity and specificity of the triggers were analyzed, as well as the characteristics and risk factors for the occurrence of ADEs. Thirty-three of the 37 triggers had positive trigger, and the sensitivity rate was 91.8% (459/500). For the specificity, the positive predictive value of overall ADEs was 46.0% (715/1556), the detection rate of ADEs was 63.0% (315/500), the rate of ADEs per 100 admissions was 136.0 (95% CI, 124.1-147.9), and the rate of ADEs per 1,000 patient days was 208.33 (95% CI, 201.2-215.5). The top three antineoplastic drugs related to ADEs were antimetabolic drugs (29.1%), plant sources and derivatives (27.1%), and metal platinum drugs (26.3%). The hematologic system was most frequently involved (507 cases, 74.6%), followed by gastrointestinal system (89 cases, 13.1%). Multivariate logistic regression analysis showed that the number of combined drugs (OR = 1.14; 95% CI, 1.07-1.22; P < 0.001) and the previous history of adverse drug reaction (ADR) (OR = 0.38; 95% CI, 0.23-0.60; P < 0.001) were the risk factors for ADEs. The length of hospital stay (OR = 0.40; 95% CI, 0.14-1.12; P < 0.05) and the previous history of ADR (OR = 2.18; 95% CI, 1.07-4.45; P < 0.05) were the risk factors for serious adverse drug events (SAE). The established trigger tool could be used to monitor antineoplastic drugs adverse events in patients with tumor effectively but still needs to be optimized. This study may provide some references for further research in order to improve the rationality and safety of antineoplastic medications.

Single Drug Intervention in Treatment of Amlapitta with special reference to Bhavprakash Samhita

Bhavprakash Samhita deals with detailed description medicinal plants used in treatment of various disorders along with knowledge of other aspects of Ayurveda. Amongst them Acharya Bhavmishra in the Madhyam khanda has elaborated the Amlapitta disease. Bhrihatrayee has scattered description of Amlapitta disease whereas the elaboration of this disorder is explained in Madhav nidan, Kashyap Samhita, Bhavprakash Yogratnakar and Harit Samhita. In Bhavprakash Samhita, Amlapitta is explained along with Shleshmapitta. In both these types, Amlata is Vikruti and vitiated Dosha are Kaphapitta with difference in symptoms as per the dominant Dosha. Other Granthakars have mentioned Kaphapittaj as a type of Amlapitta according to its Dosha predominance. Whereas in Bhavprakash Samhita Shleshmapitta is described as a separate entity. The treatment mentioned in Bhavprakash Samhita comprises of Shodhan and Shaman Chikitsa. In Shaman Chikitsa Acharya Bhavmishra has used Single drugs in various combinations. This article deals with details of Shaman chikitsa and single Dravyas used in it.

MUC1 promotes cervical squamous cell carcinoma through ERK phosphorylation-mediated regulation of ITGA2/ITGA3

In contrast to the decreasing trends in developed countries, the incidence and mortality rates of cervical squamous cell carcinoma in China have increased significantly. The screening and identification of reliable biomarkers and candidate drug targets for cervical squamous cell carcinoma are urgently needed to improve the survival rate and quality of life of patients. In this study, we demonstrated that the expression of MUC1 was greater in neoplastic tissues than in non-neoplastic tissues of the cervix, and cervical squamous cell carcinoma patients with high MUC1 expression had significantly worse overall survival than did those with low MUC1 expression, indicating its potential for early diagnosis of cervical squamous cell carcinoma. Next, we explored the regulatory mechanism of MUC1 in cervical squamous cell carcinoma. MUC1 could upregulate ITGA2 and ITGA3 expression via ERK phosphorylation, promoting the proliferation and metastasis of cervical cancer cells. Further knockdown of ITGA2 and ITGA3 significantly inhibited the tumorigenesis of cervical cancer cells. Moreover, we designed a combination drug regimen comprising MUC1-siRNA and a novel ERK inhibitor in vivo and found that the combination of these drugs achieved better results in animals with xenografts than did MUC1 alone. Overall, we discovered a novel regulatory pathway, MUC1/ERK/ITGA2/3, in cervical squamous cell carcinoma that may serve as a potential biomarker and therapeutic target in the future.

Fabrication of Rhenium Disulfide/Mesoporous Silica Core-Shell Nanoparticles for a pH-Responsive Drug Release and Combined Chemo-Photothermal Therapy.

A stimuli-responsive drug delivery nanocarrier with a core-shell structure combining photothermal therapy and chemotherapy for killing cancer cells was constructed in this study. The multifunctional nanocarrier ReS2@mSiO2-RhB entails an ReS2 hierarchical nanosphere coated with a fluorescent mesoporous silica shell. The three-dimensional hierarchical ReS2 nanostructure is capable of effectively absorbing near-infrared (NIR) light and converting it into heat. These ReS2 nanospheres were generated by a hydrothermal synthesis process leading to the self-assembly of few-layered ReS2 nanosheets. The mesoporous silica shell was further coated on the surface of the ReS2 nanospheres through a surfactant-templating sol-gel approach to provide accessible mesopores for drug uploading. A fluorescent dye (Rhodamine B) was covalently attached to silica precursors and incorporated during synthesis in the mesoporous silica walls toward conferring imaging capability to the nanocarrier. Doxorubicin (DOX), a known cancer drug, was used in a proof-of-concept study to assess the material's ability to function as a drug delivery carrier. While the silica pores are not capped, the drug molecule loading and release take advantage of the pH-governed electrostatic interactions between the drug and silica wall. The ReS2@mSiO2-RhB enabled a drug loading content as high as 19.83 mg/g doxorubicin. The ReS2@mSiO2-RhB-DOX nanocarrier's cumulative drug release rate at pH values that simulate physiological conditions showed significant pH responsiveness, reaching 59.8% at pH 6.8 and 98.5% and pH 5.5. The in vitro testing using HeLa cervical cancer cells proved that ReS2@mSiO2-RhB-DOX has a strong cancer eradication ability upon irradiation with an NIR laser owing to the combined drug delivery and photothermal effect. The results highlight the potential of ReS2@mSiO2-RhB nanoparticles for combined cancer therapy in the future.

Abstract PO3-06-12: Targeting Fatty Acid Synthase in Brain Metastatic Triple-negative Breast Cancer

Abstract Introduction: Treating triple-negative breast cancer (TNBC) is challenging due to the lack of clearly defined and targetable biomarkers, and treatment options become increasingly limited with TNBC brain metastases (BM). Since the brain microenvironment has relatively low lipid availability, breast cancer cells that colonize the brain increase their reliance on the endogenous biosynthesis of fatty acids. This reveals a potential metabolic vulnerability that can be targeted, and fatty acid synthase (FASN) inhibition has been shown to decrease breast cancer cell invasion in preclinical models. Methods: In our study, we utilized the TNBC cell line MDA-MB-231-Luc/GFP, its brain-seeking subclone, MDA-MB-231-BR-GFP, and two novel cell lines generated from patient-derived organoids obtained from serial collection of brain-metastatic TNBC resections from the same patient, denoted PDO-BC25 and PDO-BC25-2. Cell lines were screened with FASN inhibitors as single agents vs. combined with SN-38 (topoisomerase I inhibitor) and synergy was assessed by the Chou-Talalay method. To characterize signaling changes with FASN inhibition and identify any off-target signaling, we used a Nanostring metabolic pathways nCounter panel to perform differential expression analysis on cells treated with the FASN inhibitor, TVB-2640, vs. vehicle control across the four cell lines. This panel detects the expression of 768 metabolism-related genes. We used 4 biological replicates per sample and the Benjamini-Hochberg statistical method to control for the false discovery rate after performing a t-test to calculate P-values. In addition, we performed spheroid outgrowth assays to identify any phenotypic impacts of FASN inhibition on spheroid outgrowth. Results: Combinatory drug screening between FASN inhibitors and SN-38 revealed synergy in MDA-MB-231-BR-GFP, PDO-BC25, and PDO-BC25-2, but not in the parental MDA-MB-231-Luc/GFP. The Nanostring nCounter metabolic pathways panel identified direct target engagement where FASN, SCD, and the transcription factor SREBP1 were significantly upregulated in the cells treated with TVB-2640 compared to vehicle control (P-adjusted &amp;lt; 0.05). Other upregulated genes were related to the pentose phosphate pathway, nucleotide salvage and synthesis, reactive oxygen species response, amino acid synthesis and transport, and autophagy. Genes that were down-regulated are involved in cell cycle progression, deoxynucleotide synthesis, DNA damage repair, fatty acid oxidation, and cytokine and chemokine signaling. Moreover, despite no decrease in cell viability, TVB-2640 alone was able to slow the outgrowth and invasion of Matrigel-embedded spheroids in a spheroid outgrowth assay. Conclusions: In our study, we have shown that the combination of SN-38 and FASN inhibitors is synergistic in the TNBC brain-seeking cell lines, and that FASN inhibition alone causes on-target transcriptome-level changes and a decrease in spheroid invasion. Next, we plan on testing the brain-metastatic potential of these cell lines in the presence and absence of a FASN inhibitor using an organ-on-chip microfluidic device developed by our lab that mimics the blood-brain barrier, to identify if this strategy has a potential role in prevention of brain metastases. Further studies to refine the molecular basis of the mechanism of action of the combination are underway. Citation Format: Habib Serhan, Liwei Bao, Xu Cheng, Matthew Soellner, Sofia Merajver, Aki Morikawa, Nathan Merrill. Targeting Fatty Acid Synthase in Brain Metastatic Triple-negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-12.

From cell lines to cancer patients: personalized drug synergy prediction.

Combination drug therapies are effective treatments for cancer. However, the genetic heterogeneity of the patients and exponentially large space of drug pairings pose significant challenges for finding the right combination for a specific patient. Current in silico prediction methods can be instrumental in reducing the vast number of candidate drug combinations. However, existing powerful methods are trained with cancer cell line gene expression data, which limits their applicability in clinical settings. While synergy measurements on cell line models are available at large scale, patient-derived samples are too few to train a complex model. On the other hand, patient-specific single-drug response data are relatively more available. In this work, we propose a deep learning framework, Personalized Deep Synergy Predictor (PDSP), that enables us to use the patient-specific single drug response data for customizing patient drug synergy predictions. PDSP is first trained to learn synergy scores of drug pairs and their single drug responses for a given cell line using drug structures and large scale cell line gene expression data. Then, the model is fine-tuned for patients with their patient gene expression data and associated single drug response measured on the patient ex vivo samples. In this study, we evaluate PDSP on data from three leukemia patients and observe that it improves the prediction accuracy by 27% compared to models trained on cancer cell line data. PDSP is available at https://github.com/hikuru/PDSP.

Experience of using drospirenone/ethinyl estradiol combination in women of reproductive age

Introduction. A woman’s unwillingness to enter pregnancy due to social and somatic factors is associated with a high risk of its termination and concomitant complications. A personalized selection of a method of contraception is necessary, which best meets the needs of a woman, including in achieving non-contraceptive effects.Aim. To evaluate the effectiveness, safety and compliance indicators when using a combined drug (3 mg of drospirenone + 20 mcg of ethinyl estradiol) in women in the early and mature reproductive period.Materials and methods. A study involving 68 women (polycystic ovary syndrome (PCOS), n = 31, adenomyosis, n = 20, uterine fibroids, n = 7, a combination of 2 or more diagnoses) was conducted on the basis of the Scientific polyclinic Department of the V.I. Kulakov National Research Medical Center of the Ministry of Health of the Russian Federation) of reproductive age (18–34 years) who took a combined contraceptive drug for 6 months or more. The control of the results was carried out on the basis of monitoring in the form of a survey.Results. The average time of use of the drug was 9 (Q₁–Q₃: 8–11) months. After 3 and 6 months, 77.8% (21/27) and 100% of the observed patients, respectively, noted a decrease in the severity of PMS symptoms. 91.7% (n = 11/12) of patients noted a subjective decrease in the severity of acne and/or hirsutism after 6 months. 91.3% (n = 21/23) of women with copious painful menstruation noted normalization of the bleeding profile (volume of menstrual blood loss). 95.6% (65 patients out of 68) noted 100% compliance in the use of the drug.Conclusions. The drug Dimia has a favorable profile of clinical and pharmacological safety and efficacy, along with the complete reversibility of contraceptive action when actualizing the issue of the realization of reproductive function. The advantages of the drug are to achieve well-studied non-contraceptive effects, in which patients with PCOS, internal endometriosis and uterine fibroids are interested, in the form of relieving manifestations of PMS and reducing the severity of dysmenorrhea, as well as cosmetic skin imperfections (acne-type rashes, hirsutism). Thus, the drug can be recommended to women of reproductive age as a reliable contraceptive, as well as to achieve non-contraceptive effects.

Recurrent cystitis: how to achieve perfection in treatment?

Introduction. Urinary tract infections are the second most common type of bacterial infections worldwide. Treatment of patients with chronic (recurrent) cystitis remains challenging and requires an individual approach.Aim. To assess the efficacy of combined therapy for exacerbation of chronic cystitis.Materials and methods. A total of 65 women aged 18–48 years were enrolled in an open comparative bidirectional study. All participants received antibacterial therapy for exacerbation of chronic cystitis in accordance with the clinical guidelines for the treatment of cystitis in women. After the therapy was completed, the comparison group (35 patients) did not receive any drugs, whereas 30 patients from the treatment group were prescribed Cystenium II biologically active dietary supplement at a dose of 1 orally disintegrating tablet twice daily for 2 weeks. The examination included a measurement of the severity of complaints using the Acute Cystitis Symptom Score (ACSS), a clinical urinalysis and urine culture + sensitivity test. The efficacy of treatment was assessed following completion of antibiotic therapy and two weeks after the therapy.Results. After finishing antibiotic treatment, no patient has achieved full recovery (improvement of urinalyses, no growth of pathogenic microbial flora, no complaints). Both groups showed statistically significant decreases in ACSS scores on Visit 2. Over the following two weeks, the symptoms in the comparison group did not change (p &gt; 0.05), and in the treatment group the sum of scores continued to decrease, reaching an average of 3.62 ± 0.42, which is 5.5 times less than the baseline level and almost 3 times less than the sum of scores following completion of antibacterial therapy (p &lt; 0.05). The positive changes in leukocyturia and bacteriuria were also more pronounced in the treatment group.Conclusion. After completion of antibiotic therapy for relapse of chronic (recurrent) cystitis, the patients usually have residual effects that cannot be regarded as presentations of an active disease, but they disturb patients. A two-week course of pathogenetic therapy with a combination drug containing A-type Vaccinium macrocarpon proanthocyanidins, vitamin C and D-mannose to be received as the second step can increase the efficacy of treatment.