Metformin Research Articles

Pyrazine and Furan Derivative Activity Prediction on Type 2 Diabetic Mellitus: In silico Study

Diabetes Mellitus (DM) is a chronic disease that occurs when the pancreas does not produce enough insulin, or the body cannot use insulin effectively. Type 2 DM treatment can be done using antidiabetic drugs, but the continuous use of synthetic drugs will cause side effects. Empirically, the people of Nias Indonesia use palm juice (Arenga pinnata Merr.) as an antidiabetic, which can reduce blood glucose levels. This study aimed to find the active compounds in palm juice that can potentially be an antidiabetic type 2 using an in silico approach. The methods used were toxicity screening, profile pharmacokinetics, drug scanning, docking, and molecular dynamics simulation. Screening, molecular docking, and molecular dynamics of 30 compounds generated from pyrazine and furan revealed that two compounds, PF 16 and PF 30, can bind to receptors and produce lower ∆G values than metformin HCl. Molecular dynamics simulation results using the MM-GBSA calculation method showed that the PF 16 compound was more selective than the 2PDY (aldose reductase) with a value of -39.23 kcal/mol, while compound PF 30 was more selective to 1Z89 (aldose reductase) with a value of -7.36 kcal/mol. It can be concluded that the level of affinity of the PF 30 compound to the 1Z89 receptor and the PF 16 compound to the 2PDY were predicted to have the potential as antidiabetic (DM type 2).

The Incorporated Drug Affects the Properties of Hydrophilic Nanofibers.

Hydrophilic nanofibers offer promising potential for the delivery of drugs with diverse characteristics. Yet, the effects of different drugs incorporated into these nanofibers on their properties remain poorly understood. In this study, we systematically explored how model drugs, namely ibuprofen, carvedilol, paracetamol, and metformin (hydrochloride), affect hydrophilic nanofibers composed of polyethylene oxide and poloxamer 188 in a 1:1 weight ratio. Our findings reveal that the drug affects the conductivity and viscosity of the polymer solution for electrospinning, leading to distinct changes in the morphology of electrospun products. Specifically, drugs with low solubility in ethanol, the chosen solvent for polymer solution preparation, led to the formation of continuous nanofibers with uniform diameters. Additionally, the lower solubility of metformin in ethanol resulted in particle appearance on the nanofiber surface. Furthermore, the incorporation of more hydrophilic drugs increased the surface hydrophilicity of nanofiber mats. However, variations in the physicochemical properties of the drugs did not affect the drug loading and drug entrapment efficiency. Our research also shows that drug properties do not notably affect the immediate release of drugs from nanofibers, highlighting the dominant role of the hydrophilic polymers used. This study emphasizes the importance of considering specific drug properties, such as solubility, hydrophilicity, and compatibility with the solvent used for electrospinning, when designing hydrophilic nanofibers for drug delivery. Such considerations are crucial for optimizing the properties of the drug delivery system, which is essential for achieving therapeutic efficacy and safety.

Metformin treatment prevents experimental metabolic syndrome-induced femoral bone marrow adiposity in rats.

Motivation for the study. Most research supports a negative association between metabolic syndrome and bone health, although there is an overall lack of consensus. Therefore, there is a need for research in this area to develop a better understanding. Main findings. Metabolic syndrome induced by a fructose-rich diet increases the adipogenic predisposition of bone marrow progenitor cells and femoral medullary adiposity in rats. Furthermore, this can be partially prevented by co-treatment with metformin. Implications. Experimental metabolic syndrome has negative effects on bone tissue and can be prevented by oral treatment with metformin as a normoglycemic drug. To determine the effect of metformin (MET) treatment on adipogenic predisposition of bone marrow progenitor cells (BMPC), bone marrow adiposity and bone biomechanical properties. 20 young adult male Wistar rats were sorted into four groups. Each of the groups received the following in drinking water: 100% water (C); 20% fructose (F); metformin 100 mg/kg wt/day (M); or fructose plus metformin (FM). After five weeks the animals were sacrificed. Both humeri were dissected to obtain BMPC, and both femurs were dissected to evaluate medullary adiposity (histomorphometry) and biomechanical properties (3-point bending). BMPC were cultured in vitro in adipogenic medium to evaluate RUNX2, PPAR-γ and RAGE expression by RT-PCR, lipase activity and triglyceride accumulation. The fructose-rich diet (group F) caused an increase in both triglycerides in vitro, and medullary adiposity in vivo; being partially or totally prevented by co-treatment with metformin (group FM). No differences were found in femoral biomechanical tests in vivo, nor in lipase activity and RUNX2/PPAR-γ ratio in vitro. DRF increased RAGE expression in BMPC, being prevented by co-treatment with MET. Metabolic syndrome induced by a fructose-rich diet increases femoral medullary adiposity and, in part, the adipogenic predisposition of BMPC. In turn, this can be totally or partially prevented by oral co-treatment with MET.

Early life interventions metformin and trodusquemine metabolically reprogram the developing mouse liver through transcriptomic alterations.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Photocatalytic degradation of metformin on a rectangular baffled reactor: CFD modeling and validation investigation

Solar-irradiated photocatalysis is an advanced oxidation process (AOP) commonly used for water purification due to its excellent potential to break down a diverse range of persistent organic compounds into non-toxic byproducts. Reactor design is crucial in the photocatalysis process's efficiency, effectiveness, and scalability. Computational fluid dynamics (CFD) is an effective tool to study and comprehend reactor designs, reduce system cost, design time, and optimise reactor performance. This investigation focuses on designing and developing a rectangular baffled photocatalytic reactor that can effectively degrade metformin (MTF). The experimental study optimized the value of pH and catalyst dosage for efficient removal. The photoreactor demonstrated an efficiency of 58.14 % and was validated. The CFD results, including velocity profile and mass fraction of metformin, strongly agreed with the experimental results with an R2 value of 0.9826. The combination of various baffle sizes and spacing configurations was modeled and analyzed to develop a rectangular baffled photocatalytic reactor with maximum removal efficiency. The inclusion of baffles increased the flow path, improved mixing and enhanced the degrading efficiency. The investigation findings indicated the highest degradation efficiency of 78.03 % with the seven number of baffles.

Electrochemical Detection of the Antidiabetic Medication Metformin in Human Urine and Pharmaceutical Tablets Using Boron-Doped Diamond Electrode

Electrochemical Detection of the Antidiabetic Medication Metformin in Human Urine and Pharmaceutical Tablets Using Boron-Doped Diamond Electrode

Anti-Alzheimer's effect of memantine/donepezil/metformin-loaded PVA/PEO composite nanofibers produced by pressurized gyration: Production, characterization, and in vitro evaluation

In this study, memantine (MM) and donepezil (DO) were combined with metformin (MF) as a new approach to Alzheimer's disease (AD) treatment sublingually. MM, DO, and MF were loaded in polyvinyl alcohol (PVA)/polyethylene oxide (PEO) composite nanofibers (NFs), which were produced in three different ratios (9/1, 8/2, and 7/3) by pressurized gyration. The diameter of fibers was decreased by reducing the PEO ratios and adding the drugs in polymer solutions. MM, DO, and MF were successfully loaded and distributed in NFs by the results of FTIR, XRD, and DSC tests. The drug release percentages were enhanced with an increasing ratio of PVA in fibers by the dissolution test results. All fibers at various ratios were found suitable for the sublingual route by disintegrating quickly. No significant toxicity of nanofibers at 24 and 48 h was observed on SH-SY5Y cells. The highest neuroprotection activity was observed in the cells treated with MM/DO/MF-loaded NFs at 7/3. The mRNAs of APP and BACE-1 of the MM/DO/MF-loaded NF group were lower than those of the Aβ1-42 group. While, ADAM-10 mRNA expression increased in the MM/DO/MF-loaded NFs treatment group via PCR results. The morphological structure of the cells treated with the MM/DO/MF-loaded NFs was protected from Aβ1-42-induced neurotoxicity according to confocal laser scanning microscopy images.

Attenuation of PI3K/AKT signaling pathway by Ocimum gratissimum leaf flavonoid-rich extracts in streptozotocin-induced diabetic male rats

Diabetes is a group of medical conditions characterized by the body's inability to effectively control blood glucose levels, due to either insufficient insulin synthesis in type 1 diabetes or inadequate insulin sensitivity in type 2 diabetes. According to this research, the PI3K/AKT pathway of Ocimum gratissimum leaf flavonoid-rich extracts in streptozotocin-induced diabetic rats was studied. We purchased and used a total of forty (40) male Wistar rats for the study. We divided the animals into five (5) different groups: normal control (Group A), diabetic control (Group B), low dose (150 mg/kg body weight) of Ocimum gratissimum flavonoid-rich leaf extract (LDOGFL) (Group C), high dose (300 mg/kg body weight) of Ocimum gratissimum flavonoid-rich leaf extract (HDOGFL) (Group D), and 200 mg/kg of metformin (MET) (Group E). Streptozotocin induced all groups except Group A, which serves as the normal control group. The experiment lasted for 21 days, following which we sacrificed the animals and harvested their brains for biochemical analysis on the 22nd day. We carried out an analysis that included reduced glutathione (GSH), glutathione transferases (GST), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), along with GLUT4, MDA, pro-inflammatory cytokines, NO, neurotransmitters, cholinergic enzyme activities, cardiolipin, and the gene expression of PI3K/AKT. The obtained result indicates that the flavonoid-rich extracts of O. gratissimum significantly enhanced the levels of GSH, GST, CAT, GPx, and SOD, as well as GLUT4 and cardiolipin. The levels of GSH, GST, CAT, GPx, and SOD, as well as GLUT4 and cardiolipin, were significantly increased by gratissimum. Moreover, the extracts decrease the levels of MDA, pro-inflammatory cytokines, NO, neurotransmitters, and cholinergic enzyme activities. Additionally, the flavonoid-rich extracts of O. gratissimum significantly improved the AKT and PI3K gene expressions in diabetic rats. gratissimum had their AKT and PI3K gene expressions significantly (p < 0.05) improved. The findings indicate that O. gratissimum leaf flavonoids have the potential to treat diabetes mellitus. gratissimum leaf flavonoids possess therapeutic potential in themselves and can be applied in the management of diabetes mellitus. Although further analysis can be carried out in terms of isolating, profiling, or purifying the active compounds present in the plant's extract.

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.

Stability Indicating RP-HPLC Method Development and Validation for Simultaneous Estimation of Metformin Hydrochloride and Remogliflozin Etabonate in Bulk and Tablet Formulation

A simple efficient stability-indicating validated RP-HPLC method has been developed for the simultaneous determination of Metformin hydrochloride (MET) and Remogliflozin etabonate (REM) in bulk and was applied to marketed formulations. The mobile phase used for detection was Phosphate Buffer (pH 4.0): Acetonitrile (60:40%v/v). Drug peaks were detected by a UV detector at 226nm. The linearity of the developed method was found to be 20-60µg/mL for Metformin hydrochloride and 4-12μg/mL for Remogliflozin etabonate. The Limit of Detection (LOD.) and Limit of Quantitation (LOQ.) were found to be 0.085µg/mL and 0.258µg/mL for MET and 0.010µg/mL and 0.030µg/mL for REM respectively. Hydrolysis by HCl, NaOH, hydrogen peroxide, UV light and temperature were performed on a formulation which proves that the proposed method was specific and will be suitable for routine quality control analysis.

UiO-66@Fe3O4 nanocomposite as an adsorbent in dispersive solid phase extraction of metformin in surface water and wastewater

Metformin, an anti-hypoglycemic medication, has been used for decades due to its efficiency and is the most consumed pharmaceutical drug worldwide. Consequently, monitoring its concentration in environmental water is important due to its suspected effect on human health and aquatic life. This study reported the extraction, preconcentration, separation and determination of metformin (MET) in waters. Dispersive solid phase extraction (dSPE) using UiO-66@Fe3O4 nanocomposite as a sorbent was used to extract and preconcentrate MET. The high-performance liquid chromatography-diode array detector (HPLC-DAD) achieved the separation and quantification of MET in the samples. Experiemental design was used to optimise influential variables in the extraction and preconcentration of MET. The linearity, limit of detection (LOD) and limit of quantification (LOQ) for MET were 0.5–100 μg L−1 (R2 = 0.9987), 0.16 μg L−1 and 0.53 μg L−1, respectively. The intraday (n = 10 same-day replicates) and interday (n = 5 consecutive days) precisions reported as relative standard deviations (RSD %) were less than 5%. The accuracy of the method expressed as percentage recovery (%R) ranged from 84 to 112%. The method was applied to extract and preconcentrate MET in wastewater and river water samples. The MET was detected in greater concentrations in wastewater than in river water samples. The validation based on specificity, trueness, linearity, precision, and application to the analysis of MET in real samples showed that the combination of dSPE and HPLC-DAD methods is applicable for MET monitoring in surface water and wastewater. Furthermore, the dSPE/HPLC-DAD method was rapid, simple and suitable for estimating the concentrations of MET in South African surface water and wastewater for the first time. Lastly, the environmental risk caused by the occurrence of MET in surface water was investigated in terms of hazard quotient (HQ). The HQ values were less than unity, suggesting a low possibility risk for the aquatic organisms.

Long-term combination therapy with metformin and oxymetholone in a Fanconi anemia mouse model.

Fanconi anemia (FA) is a disease caused by defective deoxyribonucleic acid (DNA) repair that manifests as bone marrow failure, cancer predisposition, and developmental defects. We previously reported that monotherapy with either metformin (MET) or oxymetholone (OXM) improved peripheral blood (PB) counts and the number and functionality of bone marrow hematopoietic stem progenitor cells (HSPCs) number in Fancd2-/- mice. To evaluate whether the combination treatment of these drugs has a synergistic effect to prevent bone marrow failure in FA, we treated cohorts of Fancd2-/- mice and wildtype controls with either MET alone, OXM alone, MET+OXM, or placebo diet from age 3weeks to 18months. The OXM treated animals showed modest improvements in blood parameters including platelet count (p=.01) and hemoglobin levels (p<.05). In addition, the percentage of quiescent hematopoietic stem cell (HSC) (LSK [Lin-Sca+c-Kit+]) was significantly increased (p=.001) by long-term treatment with MET alone. The combination of metformin and oxymetholone did not result in a significant synergistic effect in any hematopoietic parameter. Gene expression analysis of liver tissue from these animals showed that some of the expression changes caused by Fancd2 deletion were partially normalized by metformin treatment. Importantly, no adverse effects of the individual or combination therapies were observed, despite the long-term administration. We conclude that androgen therapy is not a contraindication to concurrent metformin administration in clinical trials. HIGHLIGHTS: Long-term coadministration of metformin in combination with oxymetholone is well tolerated by Fancd2-/- mice. Hematopoietic stem cell quiescence in mutant mice was enhanced by treatment with metformin alone. Metformin treatment caused a partial normalization of gene expression in the livers of mutant mice.

Regulating the absorption and excretion of perfluorooctane sulfonate and its alternatives through influencing enterohepatic circulation

Enterohepatic circulation has been reported to play a significant role in the bioaccumulation of PFASs. In this study, the tissue distribution and excretion of PFOS and its alternatives, namely 6:2 and 8:2 fluorotelomer sulfonic acid (FTSA) was investigated using a mouse assay with a focus on role of enterohepatic circulation. Liver was the primarily accumulating organ for PFOS and 8:2 FTSA (33.4 % and 25.8 % of total doses absorbed after 14 days), whereas 65 % of 6:2 FTSA was excreted via urine within 24 h. Peak levels of 8:2 FTSA and PFOS were found in the gallbladder, implying the important role of enterohepatic circulation in PFASs reabsorption. The role of enterohepatic circulation was further evaluated through co-exposure of 8:2 FTSA and PFOS with medicines (namely metformin (MET) and ursodeoxycholic acid (UDCA)). MET reduced accumulation of 8:2 FTSA and PFOS in the liver by 68.6 % and 65.8 %, through down-regulation of bile acid transporter (Asbt) and enhancement of fecal excretion. Conversely, UDCA raised their concentrations by 21.9 % and 34.6 % compared to that exposed solely to PFASs. A strong positive correlation was identified between PFASs serum levels and Asbt expression. This study illuminated PFAS bioaccumulation mechanisms and suggested potential strategies to mitigate the exposure risks.

Self‐Delivered Transformable Nanosystem Capable of Enhancing Photodynamic Effectiveness and Multi‐Target Ameliorating Immunosuppression for Treatment of Breast Cancer and Lung Metastasis

AbstractHomogeneous distribution and adequate accumulation of photosensitizer in tumor are essential for effective photodynamic therapy (PDT). However, the intricate tumor microenvironment (TME) often poses great challenges to the deep penetration and retention of therapeutic agents in tumor. Moreover, the important effect of PDT to induce specific antitumor immune response is impeded by multiple immunosuppressive mechanisms within TME. Confronting these issues, here a rationally designed nanosystem (SUN‐NPA) with acid‐responsive sphere‐to‐fiber transformation ability by leveraging the characters of drug molecules is proposed to achieve self‐delivery of photosensitizer Chlorin e6 (Ce6) and two small‐molecule immunomodulators, metformin (MET) and sunitinib (SUN). The spatiotemporal controlled transformation enables homogeneous distribution and high accumulation of drugs to achieve enduring PDT and complete tumor elimination. Meanwhile, the co‐delivered MET and SUN alleviate tumor immunosuppression from multiple aspects, effectively synergizing with PDT to ignite potent host immune response and long‐lasting immunological memory against tumor cells. The artful integration of enhanced PDT and activated antitumor immunity realized by SUN‐NPA leads to the significant inhibition of tumor growth and metastasis, exhibiting great potential for oncotherapy.

Exploring The Differences : A Comparative Analysis of Pharmaceutical Quality of Different Brands of Metformin Hydrochloride Tablets

Type 2 diabetic patients can regulate their increased blood sugar levels using metformin, an antidiabetic medicine approved by the FDA. It decreases the quantity of glucose produced by the liver, lessens the glucose absorption from the intestines, and raises insulin sensitivity. For best effects, metformin should be used in conjunction with dietary modifications and physical activity. The first-line oral hypoglycemic medication for type 2 DM(Diabetes Mellitus) is thought to be metformin. The recommended medication for obese people is MET. AMPK- Adenosine monophosphate-activated protein kinase, a liver enzyme crucial to insulin signaling, is triggered by metformin. Metformin’s inhibitory effect on hepatic cell glucose synthesis necessitates AMPK activation. This study aims to compare the pharmaceutical quality of three different brands of metformin hydrochloride tablets. All the three brands were evaluated for uniformity of weight, friability, hardness, dissolution, disintegration and assay was performed. All the brands tested were within the specification, thus all the tablets passed the pharmaceutical quality test, however, variations exist between brands, which could be due to differences in excipients, pressure during compression, manufacturing procedure etc.

Metformin as adjunctive therapy in combination with multidrug treatment for multibacillary leprosy: A protocol for a randomized double-blind, controlled Phase 2 trial in Indonesia (MetLep Trial).

The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR. We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary outcomes are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary outcomes are the severity and time to first LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks. LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological outcomes. NCT05243654 (17/02/2022).

Phase behaviour and thermodynamics of triton X-100 + metformin hydrochloride mixture: influences of several polyols and polymer media

The applications of surfactants and drugs in a wide variety of fields such as pharmaceuticals, food industry, textile, fabrics, etc. are increasing significantly. Herein, we investigated the clouding behavior and thermodynamics of triton X-100 (TX-100) and metformin hydrochloride (MNH) drug mixture in the effect of several polyols and polyethylene glycol (PEG) polymer. The phase separation behavior of the mixture of TX-100 + MNH has been deduced with the help of the cloud point technique. The cloud point (CP) values for the TX-100 and drug mixtures were documented in a decreased and increased manner with the augmentation of the concentration of polyol and PEG respectively. With the subsequent enhancement of polyol and PEG content, the CP values were recorded in the following order: C P H 2 O + PEG > C P H 2 O + fructose > C P H 2 O + glucose > C P H 2 O + galactose > C P H 2 O + maltose . The standard enthalpy change ( Δ H c o ) and entropy change ( Δ S c o ), of TX-100 + MNH mixture in aq. polyols solutions were documented as negative; the negative values reduce in magnitudes with the polyols contents and become positive at the highest polyol content while opposite trend was obtained in presence of PEG. The presence of electrostatic and hydrophobic interactions among TX-100/MNH/polyols/polymer has been recommended as the interaction forces.

Exploring the anticancer potential of double-active pharmaceutical ingredient, metforminium ibuprofenate: Integrating in vivo and in silico investigations

Rationale: A novel double active pharmaceutical ingredient (d-API), metforminium ibuprofenate (MtHIb) was synthesised by combining metformin hydrochloride (MtHCl) and sodium ibuprofen (NaIb). This formulation exhibits anti-diabetic and anti-inflammatory properties similar to its parent compounds, along with a remarkable antiproliferative effect on diverse cancer cells. AimThe present study is aimed to analyse the anticancer potential of MtHIb by mouse tumour model and molecular docking. MethodsSolid tumour was induced by Dalton's Lymphoma Ascites (DLA) cells in Swiss albino mice, and d-API was administered orally. The tumour volume was measured using Vernier calliper and the activity of γ-glutamyl transferase (GGT) was assessed. The potential interactions of MtHIb with target proteins mTOR, HER2, EGFR, CDK4, CDK6, ERα/β, progesterone, COX2, BUB1, and KEAP2 were analyzed in silico. ResultsA significant reduction in tumour size was observed in mice treated with MtHIb. On the 30th day, the tumour volume, which was 8.12 cm3 in untreated animals, decreased to 1.311 cm3 with the treatment of 5 mg/kg b.wt of MtHIb, representing an 83.8 % reduction. The activity of GGT, a marker enzyme of proliferative activity, was considerably reduced from 394.87 to 51.26 U/mg protein/L. Molecular docking studies indicated that MtHIb exhibited strong binding affinity towards all the screened target proteins, specifically HER2, EGFR, CDK4, and BUB1. DiscussionThe findings suggest that MtHIb has promising anti-tumour effect, as evidenced by its significant reduction in tumour size and GGT activity in mice. The strong binding affinity of MtHIb towards the key cancer related proteins further supports its potential as a therapeutic agent against cancer, particularly in targeting pathways involved in cell proliferation and survival. Further preclinical and clinical studies are required to validate these findings and to explore the full therapeutic potential of MtHIb in cancer treatment.

Abstract PO1-25-12: Metformin enhances response to chemotherapy combined with immunotherapy in a triple negative breast cancer in vivo model

Abstract Background Triple-negative breast cancer (TNBC) is a heterogeneous group comprising several well-defined molecular subtypes. Classical chemotherapy remains the standard of care for advanced TNBC, although blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity. Atezolizumab is an immune checkpoint inhibitor targeting PD-L1 that has been approved for use in combination with paclitaxel for the treatment of advanced TNBC. Metformin (MTF) is a prescribed drug for type 2 diabetes with well-tolerated side-effects and has been reported to have anticancer effects. Xenograft mouse models studies of breast, lung and prostate cancer, have reveal a synergistic effect of MTF when combined with paclitaxel, carboplatin or doxorubicin and has been reported to enhance the efficacy of immunotherapy. In this work we want to explore the effect of including MTF in a chemo-immunotherapy scheme using an in vivo model. Methods 1x106 EMT6 TNBC cell line (ATCC® CRL-2755™) were implanted subcutaneously in the back of immunocompetent BALB/c mice. Treatment began when tumours reached a volume size of 30-100 mm3. At that moment, mice received the drug, or drugs combinations, for 21 days. All drugs were administered intraperitoneally, except for MTF, which was given orally in drinking water at a concentration of 1g/L. The anti PD-L1 drug anti-hPD-L1-mIgG1 (mATZ, 300 mg/week) was administered twice per week and doxorubicin (DOXO) every three days (0.3 mg/Kg or 6 mg/kg). The primary outcome will be tumour response. Tumour size was measured using a digital caliper every day until mice were euthanized. For tumour volume determination (mm3), two measures were taken (length and width). Volume was calculated as (length x wide2)/2. We tested three different arms: DOXO(0,3mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ+MTF, and DOXO(6mg/Kg)+m-ATZ. Each arm included 10 mice. Differences in tumour volume and mice weight were assessed by Kruskall-Wallis analysis. Results EMT6 cells produced a tumour mass in twenty seven out of thirty mice. Follow-up in mice in the DOXO(0.3mg/Kg)+m-ATZ and DOXO(6mg/Kg)+m-ATZ arms was interrupted in two weeks due to extended tumour growth and quality of live criteria, respectively. Mice in the DOXO(0.3mg/Kg)+m-ATZ+MTF arm were followed for three weeks. Increase of tumoral volume was assessed at 14 days. Mean increase was 205, 1096 and 365 mm3in the DOXO(6mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ, and DOXO(0,3mg/Kg)+m-ATZ+MTF arms respectively, being the volume increase between DOXO(0,3mg/Kg)+m-ATZ treated mice significantly higher. Regarding mice, mean weight at the beginning of the treatments was 19.8 gr for the complete mice population, whereas mean weight after 14 days of treatment was 15.4, 20.9 and 21.7 gr in the DOXO(6mg/Kg)+m-ATZ, DOXO(0,3mg/Kg)+m-ATZ, and DOXO(0,3mg/Kg)+m-ATZ+MTF arms respectively, showing a significant decrease of body weight in mice receiving a high dose of DOX, while no differences associated to the inclusion of MTF in the treatment scheme was found. Conclusions MTF addition to a combination of chemotherapy and immunotherapy in the treatment of TNBC increased therapy efficacy, with no added side effects. These result paves the way to explore treatment schemes with lower chemotherapy doses, decreasing toxicity side effects. Citation Format: Pilar Zamora, Angelo Gamez Pozo, Luz Vega-Clemente, Elena Lopez-Camacho, Lucia Trilla-Fuertes, David Alonso-Martin, Juan Angel Fresno Vara, Mariano Garcia-Arranz, Enrique Espinosa. Metformin enhances response to chemotherapy combined with immunotherapy in a triple negative breast cancer in vivo model [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 PO1-25-12.

Tamarind seed polysaccharide-metformin insert: Higher ocular retention, slow-release, and efficacy against corneal burn

Metformin (MET) can be an alternative therapeutic strategy for managing ocular burn primarily because of its pleiotropic mechanism. Longer retention on the ocular surface and sustained release are necessary to ensure the efficacy of MET for ocular application. Although the high aqueous solubility of MET is good for formulation and biocompatibility, it makes MET prone to high nasolacrimal drainage. This limits ocular residence and may be a challenge in its application. To address this, polymers approved for ophthalmic application with natural origin were analyzed through in silico methods to determine their ability to bind to mucin and interact with MET. An ocular insert of MET (3 mg/6 mm) was developed using a scalable solvent casting method without using preservatives. The relative composition of the insert was 58 ± 2.06 %w/w MET with approximately 14 %w/w tamarind seed polysaccharide (TSP), and 28 %w/w propylene glycol (PG). Its stability was demonstrated as per the ICH Q1A (R2) guidelines. Compatibility, ocular retention, drug release, and other functional parameters were evaluated. In rabbits, efficacy was demonstrated in the 'corneal alkali burn preclinical model'. TSP showed potential for mucoadhesion and interaction with MET. With adequate stability and sterility, the insert contributed to adequate retention of MET (10–12 h) in vivo and slow release (30 h) in vitro. This resulted in significant efficacy in vivo.