Search Results (37)

In the context of expanding research on the development of compounds with multiple therapeutic actions, this study aims to consolidate findings from the last decade on new synthetic sulfonamide therapies for managing type 2 diabetes mellitus (T2DM) associated with oxidative stress (OS). The novelty of this synthesis study lies in the synergistic approach of antidiabetic molecular targets with those against oxidative stress, having the sulfonylurea class as a common point. By utilizing international databases, we identified and selected conclusive studies for this review. Promising results have been achieved through dual therapies that combine antioxidants (such as sesame oil, naringin, alpha-lipoic acid, resveratrol, and quercetin) with sulfonylureas (including glipizide, glibenclamide, gliclazide, and glimepiride). Additionally, triple therapies that associated sulfonylureas with other classes of antidiabetic medications have also shown encouraging outcomes. These findings are supported by in vivo tests conducted on experimental laboratory models as well as on human subjects. These recent advancements in synthetic sulfonamide research point to a promising future in diabetes management, especially considering the dual functionalities demonstrated by in vivo studies—specifically, their antidiabetic and antioxidant effects. Moreover, the synergy between sulfonamides and other antioxidant agents represents a beneficial strategy for optimizing future chemical structures, potentially allowing for their integration into personalized treatments aimed at combating T2DM. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Background: The antidiabetic drug gliclazide is often taken with antacids due to its gastrointestinal side effects. However, patients rarely report antacid use, making drug–drug interactions a potential cause of therapy failure. Therefore, this study aimed to investigate the in vitro effects of various antacids on gliclazide permeability and to explore the underlying mechanisms. Methods: The permeability of gliclazide alone and in the presence of antacids (sodium bicarbonate, calcium carbonate, aluminum hydroxide, hydrotalcite and calcium carbonate/magnesium carbonate) was investigated using the parallel artificial membrane permeability assay (PAMPA) in four media (buffers pH 1.2, pH 4.5, pH 6.8 and water). The permeability coefficients were calculated, and the effect of pH on gliclazide permeability was also evaluated. Results: At simulated fasting gastric conditions (pH 1.2), groups with calcium carbonate, hydrotalcite and the combination of calcium carbonate/magnesium carbonate showed significantly higher permeability of gliclazide than the control group. At fed-state gastric conditions (pH 4.5), only hydrotalcite did not significantly change the permeability of gliclazide. Sodium bicarbonate, aluminum hydroxide and hydrotalcite significantly reduced the gliclazide permeability in comparison to the control group at pH 6.8 as a representative of fasted-state intestinal fluid. Conclusions: Antacids significantly impact the permeability of gliclazide at different pH values, potentially influencing its bioavailability. Gliclazide permeability is mainly influenced by pH-dependent ionization, though complex or salt formation may also play a role. Since both gliclazide and antacids are taken with food, and gliclazide is primarily absorbed in the small intestine, calcium- and magnesium-based antacids can be considered the most suitable choice. Full article

Aims: Despite its high prevalence, studies on glucocorticoid-induced hyperglycemia are lacking. We examined the glucose profiles of patients with type 2 diabetes undergoing dexamethasone-containing chemotherapy using continuous glucose monitoring (CGM). We also investigated the effects of gliclazide on the management of hyperglycemia in these patients. Materials and Methods: Seventeen patients with type 2 diabetes who received cyclic chemotherapy with dexamethasone were enrolled in this study. During the first cycle, iPro2, a blinded CGM device, was applied for 7 days. If a patient’s CGM data exhibited an increase of 20% or more in the mean glucose level after dexamethasone administration, they received the second cycle, unless they had already received sulfonylurea or their chemotherapy regimen had changed. During the second cycle, the patients were treated with gliclazide as an add-on to their routine diabetic medication. Results: Dexamethasone treatment significantly increased glucose levels, especially in patients with a longer diabetes duration (8.4 years vs. 1.2 years, p = 0.009). For the nine patients who proceeded to the second cycle, gliclazide treatment significantly ameliorated hyperglycemia. Time in range increased from 33.11% to 45.22% (p = 0.020), and time above range significantly decreased from 66.89% to 52.78% (p = 0.003). The glucose management indicators were 9.52% and 8.40% for pre- and post-gliclazide treatment, respectively. One patient visited the emergency department because of symptomatic hypoglycemia. Conclusions: Chemotherapy regimens containing dexamethasone result in high blood glucose levels even after the last dexamethasone dose in patients with pre-existing diabetes. Adding gliclazide could be beneficial in managing hyperglycemia during dexamethasone-containing chemotherapy. Full article

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme’s active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC₅₀) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC₅₀ values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with K_I = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease. Full article

Diabetes-related cognitive impairment (DCI) is a severe complication of type 2 diabetes mellitus (T2DM), with limited understanding of its molecular mechanisms hindering effective therapeutic development. This study identified SERPINA3 as a potential therapeutic target for DCI through integrated machine learning and molecular docking analyses. Transcriptomic data from cortical neuronal samples of T2DM patients were analysed using support vector machine recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression, revealing SERPINA3 as a significantly upregulated gene in DCI. Experimental validation via Western blot confirmed elevated SERPINA3 protein levels in DCI patient plasma. Molecular docking demonstrated the stable binding of sulfonylurea hypoglycaemic agents, such as gliclazide and glimepiride, to SERPINA3, with binding energies of −6.8 and −6.6 kcal/mol, respectively. These findings suggest that SERPINA3 plays a pivotal role in DCI pathogenesis and that sulfonylurea drugs may exert neuroprotective effects through SERPINA3-mediated pathways. This study provides novel insights into the molecular mechanisms of DCI and highlights the potential of SERPINA3-targeted therapies for early intervention and treatment. Further research is warranted to validate these findings in larger cohorts and explore their clinical applicability. Full article

This review describes our current understanding of the role of the mitochondria in the repurposing of the anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, and obesity. Metformin, the most prominent of these diabetes drugs, has been called the “Drug of Miracles and Wonders,” as clinical trials have found it to be beneficial for human patients suffering from these maladies. To promote viral replication in all infected human cells, SARS-CoV-2 stimulates the infected liver cells to produce glucose and to export it into the blood stream, which can cause diabetes in long COVID patients, and metformin, which reduces the levels of glucose in the blood, was shown to cut the incidence rate of long COVID in half for all patients recovering from SARS-CoV-2. Metformin leads to the phosphorylation of the AMP-activated protein kinase AMPK, which accelerates the import of glucose into cells via the glucose transporter GLUT4 and switches the cells to the starvation mode, counteracting the virus. Diabetes drugs also stimulate the unfolded protein response and thus mitophagy, which is beneficial for healthy aging and mental health. Diabetes drugs were also found to mimic exercise and help to reduce body weight. Full article

The antidiabetic drugs metformin, glipizide and gliclazide have been used for many years to control blood glucose levels. In recent years, they have gained importance in non-diabetic pharmacological purposes including cancer and hearing loss treatment. Co-administration of these therapeutics represents a challenge to some clinicians seeking an efficient, sensitive and rapid analytical method to use in the pharmacokinetic studies and the therapeutic monitoring of these agents. This research outlines the development and validation of a new precise, robust, sensitive, selective and rapid ion-pairing reversed-phase HPLC method for the simultaneous determination of a ternary mixture of metformin, glipizide and gliclazide in the same isocratic chromatographic run within 5 min. The limits of detection were 59.22 ng/mL for metformin, 169.48 ng/mL for glipizide and 151.29 ng/mL for gliclazide. The method was applied in quantifying metformin uptake by the auditory cell line HEI-OC1, to gain an insight into the kinetics of this biguanide in the organ of Corti. Metformin exhibited a concentration-dependent uptake by HEI-OC1 cells up to 5 mM, after which, saturation of the uptake was noticed. When HEI-OC1 cells were subjected to diabetes-simulated conditions, metformin was able to mitigate the hyperglycaemic stress and revealed a protective role in this cell line. 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

A novel organic–inorganic gliclazide-loaded composite bead was developed by an ionic gelation process using acidified CaCl₂, chitosan and tetraethylorthosilicate (TEOS) as a crosslinker. The beads were manufactured by crosslinking an inorganic silicone elastomer (-OH terminated polydimethylsiloxane, PDMS) with TEOS at different ratios before grafting onto an organic backbone (Na-alginate) using a 3² factorial experimental design. Gliclazide’s encapsulation efficiency (EE%) and drug release over 8 h (% DR 8 h) were set as dependent responses for the optimisation of a pharmaceutical formula (herein referred to as ‘G op’) by response surface methodology. EE % and %DR 8 h of G op were 93.48% ± 0.19 and 70.29% ± 0.18, respectively. G op exhibited a controlled release of gliclazide that follows the Korsmeyer–Peppas kinetic model (R² = 0.95) with super case II transport and pH-dependent swelling behaviour. In vitro testing of G op showed 92.17% ± 1.18 cell viability upon testing on C2C12 myoblasts, indicating the compatibility of this novel biomaterial platform with skeletal muscle drug delivery. Full article

The reaction of the vanadyl ion (VO²⁺) with imidazole-4-carboxylic acid (Im4COOH), imidazole-2-carboxylic acid (Im2COOH) and methylimidazole-2-carboxylic acid (MeIm2COOH), respectively, in the presence of small bioligands (bL) [oxalate (Ox), lactate (Lact), citrate (Cit) and phosphate (Phos)] and high-molecular-weight (HMW) human serum proteins [albumin (HSA) and transferrin (hTf)] were studied in aqueous solution using potentiometric acid–base titrations. The species distribution diagrams for the high-molecular-mass (HMM) proteins with oxidovanadium(IV) under physiological pH were dominated by VO(HMM)₂, VOL(HMM) for unsubstituted ligands (L⁻ = Im4COO⁻ and Im2COO⁻). However, for the N-substituted MeIm2COOH, the species distribution diagrams under physiological pH were dominated by VOL₂, VO(HMM)₂ and VO₂L₂(HMM). These species were further confirmed by LC-MS, MALDI-TOF-MS and EPR studies. The glucose-stimulated insulin secretion (GSIS) action of the complexes was investigated using INS-1E cells at a 1 µM concentration, which was established through cytotoxicity studies via the MTT assay. The neutral complexes, especially VO(MeIm2COO)₂, showed promising results in the stimulation of insulin secretion than the cationic [VO(MeIm2CH₂OH)₂]²⁺ complex and the vanadium salt. Oxidovanadium(IV) complexes reduced insulin stimulation significantly under normoglycaemic levels but showed positive effects on insulin secretion under hyperglycaemic conditions (33.3 mM glucose media). The islets exposed to oxidovanadium(IV) complexes under hyperglycaemic conditions displayed a significant increase in the stimulatory index with 1.19, 1.75, 1.53, 1.85, 2.20 and 1.29 observed for the positive control (sulfonylurea:gliclazide), VOSO₄, VO(Im4COO)₂, VO(Im2COO)₂, VO(MeIm2COO)₂ and VO(MeIm2CH₂OH)₂²⁺, respectively. This observation showed a potential further effect of vanadium complexes towards type 2 diabetes and has been demonstrated for the first time in this study. Full article

The aim of this study was to discover bioactive constituents of Angelica reflexa that improve glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. Herein, three new compounds, namely, koseonolin A (1), koseonolin B (2), and isohydroxylomatin (3), along with 28 compounds (4–31) were isolated from the roots of A. reflexa by chromatographic methods. The chemical structures of new compounds (1–3) were elucidated through spectroscopic/spectrometric methods such as NMR and HRESIMS. In particular, the absolute configuration of the new compounds (1 and 3) was performed by electronic circular dichroism (ECD) studies. The effects of the root extract of A. reflexa (KH2E) and isolated compounds (1–31) on GSIS were detected by GSIS assay, ADP/ATP ratio assay, and Western blot assay. We observed that KH2E enhanced GSIS. Among the compounds 1–31, isohydroxylomatin (3), (−)-marmesin (17), and marmesinin (19) increased GSIS. In particular, marmesinin (19) was the most effective; this effect was superior to treatment with gliclazide. GSI values were: 13.21 ± 0.12 and 7.02 ± 0.32 for marmesinin (19) and gliclazide at a same concentration of 10 μM, respectively. Gliclazide is often performed in patients with type 2 diabetes (T2D). KH2E and marmesinin (19) enhanced the protein expressions associated with pancreatic β-cell metabolism such as peroxisome proliferator-activated receptor γ, pancreatic and duodenal homeobox 1, and insulin receptor substrate-2. The effect of marmesinin (19) on GSIS was improved by an L-type Ca²⁺ channel agonist and K+ channel blocker and was inhibited by an L-type Ca²⁺ channel blocker and K⁺ channel activator. Marmesinin (19) may improve hyperglycemia by enhancing GSIS in pancreatic β-cells. Thus, marmesinin (19) may have potential use in developing novel anti-T2D therapy. These findings promote the potential application of marmesinin (19) toward the management of hyperglycemia in T2D. Full article

Tuberous sclerosis complex (TSC) is a rare autosomal dominant neurocutaneous syndrome. It is manifested mainly in cutaneous lesions, epilepsy and the emergence of hamartomas in several tissues and organs. The disease sets in due to mutations in two tumor suppressor genes: TSC1 and TSC2. The authors present the case of a 33-year-old female patient registered with the Bihor County Regional Center of Medical Genetics (RCMG) since 2021 with a TSC diagnosis. She was diagnosed with epilepsy at eight months old. At 18 years old she was diagnosed with tuberous sclerosis and was referred to the neurology department. Since 2013 she has been registered with the department for diabetes and nutritional diseases with a type 2 diabetes mellitus (T2DM) diagnosis. The clinical examination revealed: growth delay, obesity, facial angiofibromas, sebaceous adenomas, depigmented macules, papillomatous tumorlets in the thorax (bilateral) and neck, periungual fibroma in both lower limbs, frequent convulsive seizures; on a biological level, high glycemia and glycated hemoglobin levels. Brain MRI displayed a distinctive TS aspect with five bilateral hamartomatous subependymal nodules associating cortical/subcortical tubers with the frontal, temporal and occipital distribution. Molecular diagnosis showed a pathogenic variant in the TSC1 gene, exon 13, c.1270A>T (p. Arg424*). Current treatment targets diabetes (Metformin, Gliclazide and the GLP-1 analog semaglutide) and epilepsy (Carbamazepine and Clonazepam). This case report presents a rare association between type 2 diabetes mellitus and Tuberous Sclerosis Complex. We suggest that the diabetes medication Metformin may have positive effects on both the progression of the tumor associated with TSC and the seizures specific to TSC and we assume that the association of TSC and T2DM in the presented cases is accidental, as there are no similar cases reported in the literature. Full article

A novel gliclazide-loaded elastomeric carbohydrate pharmaceutical vehicle was successfully developed. This new siliconized alginate platform showed pseudoplastic rheology with a zeta potential ranging from (−43.8 mV to −75.5 mV). A Buchi-B390 encapsulator was employed to formulate different types of silicone-grafted alginate microcapsules loaded with gliclazide relying on the vibrational ionic gelation technology. The use of tetraethyl orthosilicate (TEOS) to crosslink the silicone elastomer (hydroxy terminated polydimethylsiloxane) of this new platform had improved the gliclazide encapsulation (>92.13% ± 0.76) of the free-flowing composite microcapsules, which showed good mechanical durability (up to 12 h in PBS pH 6.8) and promising results to sustain the drug release. Full article

Background: SARS-CoV-2 has undergone mutations, yielding clinically relevant variants. Hypothesis: We hypothesized that in SARS-CoV-2, two highly conserved Orf3a and E channels directly related to the virus replication were a target for the detection and inhibition of the viral replication, independent of the variant, using FDA-approved ion channel modulators. Methods: A combination of a fluorescence potassium ion assay with channel modulators was developed to detect SARS-CoV-2 Orf3a/E channel activity. Two FDA-approved drugs, amantadine (an antiviral) and amitriptyline (an antidepressant), which are ion channel blockers, were tested as to whether they inhibited Orf3a/E channel activity in isolated virus variants and in nasal swab samples from COVID-19 patients. The variants were confirmed by PCR sequencing. Results: In isolated SARS-CoV-2 Alpha, Beta, and Delta variants, the channel activity of Orf3a/E was detected and inhibited by emodin and gliclazide (IC₅₀ = 0.42 mM). In the Delta swab samples, amitriptyline and amantadine inhibited the channel activity of viral proteins, with IC₅₀ values of 0.73 mM and 1.11 mM, respectively. In the Omicron swab samples, amitriptyline inhibited the channel activity, with an IC₅₀ of 0.76 mM. Conclusions: We developed an efficient method to screen FDA-approved ion channel modulators that could be repurposed to detect and inhibit SARS-CoV-2 viral replication, independent of variants. Full article