Search Results (25)

Cytochrome P450 3A4 (CYP3A4) is a key enzyme involved in the metabolism of nearly half of all clinically used drugs, including widely prescribed statins and antidiabetic agents. Dietary constituents can modulate CYP3A4 expression and activity through various mechanisms, thereby altering drug pharmacokinetics and potentially leading to therapeutic failure or toxicity. This narrative review compiles current evidence on dietary modulation of CYP3A4, with a particular focus on pharmacological and clinical implications for lipid-lowering and glucose-lowering drugs. Literature was identified through a comprehensive search in PubMed, Scopus, and Web of Science, including preclinical and clinical studies addressing food–drug interactions involving CYP3A4 substrates. Numerous dietary compounds, such as citrus furanocoumarins, polyphenols, herbal extracts, and vitamins, act as CYP3A4 inhibitors or inducers through competitive, mechanism-based, or nuclear receptor-mediated pathways. Specific examples include simvastatin, atorvastatin, repaglinide, and saxagliptin, whose systemic exposure can be significantly altered by dietary factors. Moreover, interindividual variability in CYP3A4 activity may be shaped by genetic polymorphisms, microbiota-derived metabolites, and epigenetic regulation, further influencing drug response. Understanding these interactions is crucial, especially in polymedicated patients or those receiving drugs with a narrow therapeutic index. Clinicians should remain aware of potential CYP3A4-related food–drug interactions and consider dietary habits and supplement use in therapeutic decision-making. Future research should aim to integrate pharmacogenomics, gut microbiome profiling, and personalized nutrition in order to improve the prediction and prevention of clinically significant interactions. Full article

Background/Objectives: Hyperlipidemia is a silent threat lurking in the bloodstream of millions worldwide. The nano-based platform has emerged as a promising drug delivery technology. Repaglinide, an anti-diabetic drug, was investigated recently as an antihyperlipidemic candidate that could supersede the available antihyperlipidemic drugs. Our goal was to optimize albumin-based nanoparticles loaded with Repaglinide for parenteral delivery and conduct in silico and in vivo studies to explore the efficacy of Repaglinide for the management of hyperlipidemia along with its anti-diabetic effect. Methods: The impact of three independent factors, the albumin%, acetone volume, and glutaraldehyde/albumin, on the particle size, zeta potential, and entrapment efficiency was investigated. Results: The optimized formulation was spherical, homogenous of an average diameter (~181.86 nm) with a narrow size distribution, a zeta potential of −24.26 mV, and 76.37% as the EE%. The in vitro release of Repaglinide from nanoparticles showed a sustained release pattern for 168 h, with an initial burst release after 24 h, and was fitted to the Fickian diffusion mechanism. A molecular docking simulation showed a strong affinity to several protein targets, and the results were very promising, where Repaglinide gave a score of −7.70 Kcal/mol compared to Mevastatin (−6.71 Kcal/mol) and Atorvastatin (−8.36 Kcal/mol). On conducting in vivo studies on animal models, the optimized formula recorded a statistically significant decrease in the serum levels of total cholesterol, triglyceride, and low-density lipoproteins, with an increased high-density lipoprotein. Conclusions: This study suggested albumin nanoparticles as potential nanocarriers for the parenteral delivery of Repaglinide to ameliorate its antihyperlipidemic benefits, especially in diabetic patients. Full article

Background: Diffuse intrinsic pontine glioma [DIPG] is a fatal pediatric disease characterized by a post-translational modification, a replacement of lysine by methionine in position 27 of the N-terminal [H3K27M] tail of histone 3 isoform-1 [H3.1] or histone 3 isoform-3 [H3.3], respectively, expressed in the DIPG-36 and DIPG-50 cells. We investigated the role of cation channels in DIPG cells for the first time and the effects of ATP-sensitive K⁺[KATP] and TRPV1 channel modulators. Methods: Experiments were performed using “in vitro” cytotoxic assays combined with the patch clamp technique, RT-PCR, Western blot, and flow cytometry assays. Results: The most effective anti-proliferative drugs were repaglinide and glibenclamide after short and long-term incubation [6–96 h]. These drugs reduced macroscopic currents of the DIPG cells recorded in whole-cell patch clamp. Repaglinide concentration dependently enhanced the target protein H3K27ac in Western blotting after 48 h of incubation. This drug reduced cell diameter and enhanced cleaved caspase-3 in DIPG cells; total AKT/mTOR levels and phospho-mTOR were downregulated in DIPG-36. Conclusions: KATP and TRPV1 channels are functionally expressed, and sulphonylureas are effective antiproliferative upregulating H3K27ac with apoptosis in DIPG cells and the sub-micromolar concentrations in DIPG-50. Full article

Due to the increased prevalence of diabetes, the consumption of anti-diabetic drugs for its treatment has likewise increased. Metformin is an anti-diabetic drug that is commonly prescribed for patients with type 2 diabetes and has been frequently detected in surface water and wastewaters, thus representing an emerging contaminant. Metformin can be prescribed in combination with other classes of anti-diabetic drugs; however, these drugs are not sufficiently investigated in environmental samples. Fabric phase sorptive extraction (FPSE) has emerged as a simple and green method for the extraction of analytes in environmental samples. In this study, FPSE coupled with a high-performance liquid chromatography diode array detector (HPLC-DAD) was employed for the simultaneous analysis of different classes of anti-diabetic drugs (metformin, dapagliflozin, liraglutide, pioglitazone, gliclazide, glimepiride, glargine, repaglinide, sitagliptin, and vildagliptin) in environmental water samples. Four different fabric membranes were synthesized but the microfiber glass filter coated with sol-gel polyethylene glycol (PEG 300) was observed to be the best FPSE membrane. The parameters affecting the FPSE process were optimized using a combination of one-factor-at-a-time processes and the design of experiments. The FPSE was evaluated as a green extraction method, based on green sample preparation criteria. The FPSE-HPLC-DAD method achieved acceptable validation results and was applied for the simultaneous analysis of anti-diabetic drugs in surface and wastewater samples. Glimepiride was detected below the quantification limit in both lake and river water samples. Dapagliflozin, liraglutide, and glimepiride were detected at 69.0 ± 1.0 μg·L⁻¹, 71.9 ± 0.4 μg·L⁻¹, and 93.9 ± 1.3 μg·L⁻¹, respectively, in the city wastewater influent. Dapagliflozin and glimepiride were still detected below the quantification limit in city wastewater effluent. For the hospital wastewater influent, metformin and glimepiride were detected at 1158 ± 21 μg·L⁻¹ and 28 ± 0.8 μg·L⁻¹, respectively, while only metformin (392.6 ± 7.7 μg·L⁻¹) was detected in hospital wastewater effluent. Full article

Background/Objectives: Index substrates are used to understand the processes involved in pharmacokinetic (PK) drug–drug interactions (DDIs). The aim of this analysis is to review metabolite measurement in clinical DDI studies, focusing on index substrates for cytochrome P450 (CYP) enzymes, including CYP1A2 (caffeine), CYP2B6 (bupropion), CYP2C8 (repaglinide), CYP2C9 ((S)-warfarin, flurbiprofen), CYP2C19 (omeprazole), CYP2D6 (desipramine, dextromethorphan, nebivolol), and CYP3A (midazolam, triazolam). Methods: All data used in this evaluation were obtained from the Certara Drug Interaction Database. Clinical index substrate DDI studies with PK data for at least one metabolite, available from literature and recent new drug application reviews, were reviewed. Further, for positive DDI studies, a correlation analysis was performed between changes in plasma exposure of index substrates and their marker metabolites. Results: A total of 3261 individual index DDI studies were available, with 45% measuring at least one metabolite. The occurrence of metabolite measurement in clinical DDI studies varied widely between index substrates and enzymes. Discussion and Conclusions: For substrates such as caffeine, bupropion, omeprazole, and dextromethorphan, the use of the metabolite/parent area under the curve ratio can provide greater sensitivity to DDI or reduce intrasubject variability. In some cases (e.g., omeprazole, repaglinide), the inclusion of metabolite measurement can provide mechanistic insights to understand complex interactions. Full article

The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6–DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington’s disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM–ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice. Full article

Diabetes is one of the most prevalent diseases worldwide, and the search for therapeutic alternatives in developing countries has been focused on natural products, primarily from plants. This study evaluated the antihyperglycemic and hypoglycemic activities of the albedo (FA) and flavedo (FF) flavonoid fractions obtained from orange peels (often discarded) in normoglycemic Wistar rats. The flavonoid fractions were identified and quantified using HPLC-UV-DAD and compared with glibenclamide, repaglinide, saxagliptin, and acarbose. Additionally, both fractions were tested in a streptozotocin (65 mg/kg)/nicotinamide (100 mg/kg)-induced diabetic model. In normoglycemic rats, the highest glucose variation (%VG) occurred during the first hour after FA (112.8%) and FF (105.30%) administration at 100 mg/kg, indicating a hypoglycemic effect. In diabetic rats, FF at 100 mg/kg showed the highest %VG (140.41%) during the first hour after administration. HPLC-UV-DAD analysis revealed the presence of hesperidin (HSP) and naringenin (NGN), with the highest concentrations found in FA (HSP: 41.41%; NGN: 10.75%). These findings suggest potential antihyperglycemic effects of FA and FF fractions, possibly attributed to the presence of HSP and NGN. The results obtained in this work lay the foundations to explore the therapeutic applications of orange peels for controlling hyperglycemia in diabetes. In conclusion, our results suggest a reevaluation and revalorization of orange peels, as they contain pharmaceutically relevant flavonoids. Full article

By means of a computational method based on Density Functional Theory (DFT), using commercially available software, a novel method for simulating equilibrium geometry harmonic vibrational frequencies is proposed. Finasteride, Lamivudine, and Repaglinide were selected as model molecules to study the adaptability of the new method. Three molecular models, namely the single-molecular, central-molecular, and multi-molecular fragment models, were constructed and calculated by Generalized Gradient Approximations (GGAs) with the PBE functional via the Material Studio 8.0 program. Theoretical vibrational frequencies were assigned and compared to the corresponding experimental data. The results indicated that the traditional single-molecular calculation and scaled spectra with scale factor exhibited the worst similarity for all three pharmaceutical molecules among the three models. Furthermore, the central-molecular model with a configuration closer to the empirical structure resulted in a reduction of mean absolute error (MAE) and root mean squared error (RMSE) in all three pharmaceutics, including the hydrogen-bonded functional groups. However, the improvement in computational accuracy for different drug molecules using the central-molecular model for vibrational frequency calculation was unstable. Whereas, the new multi-molecular fragment interception method showed the best agreement with experimental results, exhibiting MAE and RMSE values of 8.21 cm⁻¹ and 18.35 cm⁻¹ for Finasteride, 15.95 cm⁻¹ and 26.46 cm⁻¹ for Lamivudine, and 12.10 cm⁻¹ and 25.82 cm⁻¹ for Repaglinide. Additionally, this work provides comprehensive vibrational frequency calculations and assignments for Finasteride, Lamivudine, and Repaglinide, which have never been thoroughly investigated in previous research. Full article

The technologies for fabrication of nanocrystals have an immense potential to improve solubility of a variety of the poor water-soluble drugs with subsequent enhanced bioavailability. Repaglinide (Rp) is an antihyperglycemic drug having low bioavailability due to its extensive first-pass metabolism. Microfluidics is a cutting-edge technique that provides a new approach for producing nanoparticles (NPs) with controlled properties for a variety of applications. The current study’s goal was to engineer repaglinide smart nanoparticles (Rp-Nc) utilizing microfluidic technology (Dolomite Y shape), and then to perform in-vitro, in-vivo, and toxicity evaluations of them. This method effectively generated nanocrystals with average particle sizes of 71.31 ± 11 nm and a polydispersity index (PDI) of 0.072 ± 12. The fabricated Rp’s crystallinity was verified by Differential scanning calorimetry (DSC) and Powder X-ray diffraction (PXRD). In comparison to the raw and commercially available tablets, the fabricated Rp’s nanoparticles resulted in a higher saturation solubility and dissolving rate (p < 0.05). Rp nanocrystals had a considerably lower (p < 0.05) IC₅₀ value than that of the raw drug and commercial tablets. Moreover, Rp nanocrystals at the 0.5 and 1 mg/kg demonstrated a significant decrease in blood glucose level (mg/dL, p < 0.001, n = 8) compared to its counterparts. Rp nanocrystals at the 0.5 mg/kg demonstrated a significant decrease (p < 0.001, n = 8) in blood glucose compared to its counterparts at a dose of 1 mg/kg. The selected animal model’s histological analyses and the effect of Rp nanocrystals on several internal organs were determined to be equivalent to those of the control animal group. The findings of the present study indicated that nanocrystals of Rp with improved anti-diabetic properties and safety profiles can be successfully produced using controlled microfluidic technology, an innovative drug delivery system (DDS) approach. Full article

Herein, we have reported on a simple, environmentally friendly, and ultra-sensitive electrode material, SnO₂@p-rGO, used in a clean sustainable manner for rapid electrochemical determination of an anti-diabetic agent, repaglinide (RPG). Three-dimensional porous reduced graphene oxide nanostructure (p-rGO) was prepared via a low-temperature solution combustion method employing glycine. The aqueous extract of agricultural waste “cotton boll peel” served as stabilizing and reducing agents for the synthesis of SnO₂ nanoparticles. The structural and morphological characterization was carried out by XRD, Raman, SEM, EDX, FTIR, absorption, and TGA. The oxidation process of RPG was realized under adsorption controlled with the involvement of two protons and electrons. The sensor displayed a wider linearity between the concentration of RPG and oxidation peak current in the ranges of 1.99 × 10⁻⁸–1.45 × 10⁻⁵ M and 4.99 × 10⁻⁸–1.83 × 10⁻⁵ M for square-wave voltammetric and differential pulse voltammetric methods, respectively. The lower limit of detection value of 0.85 × 10⁻⁹ M was realized with the SWV method. The proposed sensor was applied for the quantification of RPG in fortified urine samples and pharmaceutical formulations. Furthermore, the sensor demonstrated reproducibility, long-term stability, and selectivity in the presence of metformin and other interferents, which made the proposed sensor promising and superior for monitoring RPG. Full article

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis–Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates’ efficacy in alleviating pain. Full article

Mucoadhesive polymers have an essential role in drug localization and target-specific actions in oral delivery systems. The current work aims to develop and characterize a new mucoadhesive polysaccharide polymer (thiolated xanthan gum-TXG and S-Protected thiolated xanthan gum-STX) that was further utilized for the preparation of repaglinide mucoadhesive tablets. The thiolation of xanthan gum was carried out by ester formation through the reaction of the hydroxyl group of xanthan gum and the carboxyl group of thioglycolic acid. Synthesis of TXG was optimized using central composite design, and TXG prepared using 5.303 moles/L of TGA and 6.075 g/L of xanthan gum can accomplish the prerequisites of the optimized formulation. Consequently, TXG was further combined with aromatic 2-mercapto-nicotinic acid to synthesize STX. TXG and STX were further studied for Fourier-transform infrared spectroscopy, rheological investigations, and Ellman’s assay (to quantify the number of thiol/disulfide groups). A substantial rise in the viscosity of STX might be due to increased interactions of macromolecules liable for improving the mucosal adhesion strength of thiolated gum. STX was proven safe with the support of cytotoxic study data. Mucoadhesive formulations of repaglinide-containing STX showed the highest ex vivo mucoadhesion strength (12.78 g-RSX-1 and 17.57 g- RSX-2) and residence time (>16 h). The improved cross-linkage and cohesive nature of the matrix in the thiolated and S-protected thiolated formulations was responsible for the controlled release of repaglinide over 16 h. The pharmacokinetic study revealed the greater AUC (area under the curve) and long half-life with the RSX-2 formulation, confirming that formulations based on S-protected thiomers can be favorable drug systems for enhancing the bioavailability of low-solubility drugs. Full article

Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer. Full article

Naegleria fowleri and Balamuthia mandrillaris are pathogenic free-living amoebae that infect the central nervous system with over 95% mortality rates. Although several compounds have shown promise in vitro but associated side effects and/or prolonged approval processes for clinical applications have led to limited success. To overcome this, drug repurposing of marketed compounds with known mechanism of action is considered a viable approach that has potential to expedite discovery and application of anti-amoebic compounds. In fact, many of the drugs currently employed in the treatment of N. fowleri and B. mandrillaris, such as amphotericin B, fluconazole, rifampin and miltefosine, are repurposed drugs. Here, we evaluated a range of clinical and laboratory compounds including metformin, quinclorac, indaziflam, inositol, nateglinide, 2,6-DNBT, trans-cinnamic acid, terbuthylazine, acarbose, glimepiride, vildagliptin, cellulase, thaxtomin A, repaglinide and dimethyl peptidase (IV) inhibitor against N. fowleri and B. mandrillaris. Anti-amoebic assays revealed that indaziflam, nateglinide, 2,6-DNBT, terbuthylazine, acarbose and glimepiride exhibited potent amoebicidal properties against both N. fowleri and B. mandrillaris. Notably, all compounds tested showed minimal human (HaCaT) cell cytotoxicity as determined by lactate dehydrogenase release. Prospective research using animal models is warranted to determine the potential of these repurposed compounds, as well as the need for investigating the intranasal route of delivery to treat these devastating infections. Full article

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of—among others—CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically based pharmacokinetic (PBPK) model of clopidogrel including the relevant metabolites, clopidogrel carboxylic acid, clopidogrel acyl glucuronide, 2-oxo-clopidogrel, and the active thiol metabolite, with subsequent application for drug–gene interaction (DGI) and drug–drug interaction (DDI) predictions. Model building was performed in PK-Sim^® using 66 plasma concentration-time profiles of clopidogrel and its metabolites. The comprehensive parent-metabolite model covers biotransformation via carboxylesterase (CES) 1, CES2, CYP2C19, CYP3A4, and uridine 5′-diphospho-glucuronosyltransferase 2B7. Moreover, CYP2C19 was incorporated for normal, intermediate, and poor metabolizer phenotypes. Good predictive performance of the model was demonstrated for the DGI involving CYP2C19, with 17/19 predicted DGI AUC_last and 19/19 predicted DGI C_max ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUC_last and 13/13 predicted DDI C_max ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository. Full article