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Glyburide, a sulfonylurea drug used to treat type 2 diabetes, boasts neuroprotective effects by targeting the sulfonylurea receptor 1 (SUR1) and associated ion channels in various cell types, including those in the central nervous system and the retina. Previously, we demonstrated that glyburide therapy improved retinal function and structure in a rat model of diabetic retinopathy. In the present study, we explore the application of glyburide in non-neovascular ("dry") age-related macular degeneration (AMD), another progressive disease characterized by oxidative stress-induced damage and neuroinflammation that trigger cell death in the retina. We show that glyburide administration to a human cone cell line confers protection against oxidative stress, inflammasome activation, and apoptosis. To corroborate our in vitro results, we also conducted a case-control study, controlling for AMD risk factors and other diabetes medications. It showed that glyburide use in patients reduces the odds of new-onset dry AMD. A positive dose-response relationship is observed from this analysis, in which higher cumulative doses of glyburide further reduce the odds of new-onset dry AMD. In the quest for novel therapies for AMD, glyburide emerges as a promising repurposable drug given its known safety profile. The results from this study provide insights into the multifaceted actions of glyburide and its potential as a neuroprotective agent for retinal diseases; however, further preclinical and clinical studies are needed to validate its therapeutic potential in the context of degenerative retinal disorders such as AMD. [ABSTRACT FROM AUTHOR]

The present study aimed to develop and optimize solidified supersaturated self-nanoemulsifying drug delivery systems (SNEDDS) for the combined administration of antihypertensive, antihyperglycemic, and antihyperlipidemic drugs to enhance their solubility and dissolution during the treatment of metabolic syndrome. Various SNEDDS formulations were prepared and subjected to pharmaceutical assessment. The solubility of candesartan (CC), glibenclamide (GB), and rosuvastatin (RC) in SNEDDS and supersaturated SNEDDS formulations was evaluated. The optimized formulation was solidified using Syloid adsorbent at different ratios. Pharmaceutical characterization of the formulations included particle size, zeta potential, in-vitro dissolution, PXRD, FTIR, and SEM analysis. The prepared optimized formulation (F6) was able to form homogeneous nanoemulsion droplets without phase separation, which is composed of Tween 20: PEG-400: Capmul MCM (4: 3: 3). It was mixed with 5% PVP-K30 to prepare a supersaturated liquid SNEDDS formulation (F9). In addition, it was found that the addition of PVP-K30 significantly increased solubility CC and GB from 20.46 ± 0.48 and 6.73 ± 0.05 to 27.67 ± 1.72 and 9.45 ± 0.32 mg/g, respectively. In-vitro dissolution study revealed that liquid and solid SNEDD formulations remarkably improved the dissolution rates of CC, GB, and RC compared to pure drugs. XRPD and FTIR analysis revealed that all drugs present in an amorphous state within prepared solidified supersaturated SNEDDS formulation. SEM images showed that liquid SNEDDS formulation was successfully adsorbed on the surface of Syloid. Overall, optimized F9 and solidified supersaturated SNEDDS formulations showed superior performance in enhancing drug solubility and dissolution rate. The present study revealed that the proposed triple combination therapy of metabolic syndrome holds a promising strategy during the treatment of metabolic syndrome. Further in-vivo studies are required to evaluate the therapeutic efficacy of prepared solidified supersaturated SNEDDS formulation. [ABSTRACT FROM AUTHOR]

Background Objective Results Conclusion Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)‐mediated vasorelaxation is still unclear, and data about human vessels are limited.To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium‐hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).NaHS (1 × 10−6–3 × 10−3 mol/L) induced a concentration‐dependent relaxation of HIMA pre‐contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4‐aminopyridine (4‐AP), and margatoxin significantly inhibited NaHS‐induced relaxation of phenylephrine‐contracted HIMA (P < 0.01), whereas in the presence of apamin/1‐[(2‐chlorophenyl) diphenylmethyl]‐1H‐pyrazole (TRAM‐34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L‐NAME and KT5823, and by cyclo‐oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM‐34 and glibenclamide caused further decrease in NaHS‐induced vasorelaxation (P < 0.01), while iberiotoxin, 4‐AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01).Our results demonstrated that H2S donor, NaHS, induced concentration‐dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx. [ABSTRACT FROM AUTHOR]

The study aims to compare the action of Pleurotus cornucopiae and glibenclamide on alloxan-induced diabetes and ascertain how an aqueous extract of the edible mushroom regulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), oxidative stress biomarkers and renal toxicity in a diabetic male Wistar rat model. Twenty-five adult male Wistar rats were randomly grouped into five groups with five rats per. Group 1 and those in the treatment groups received normal feed and water ad libitum. Group 2 received intraperitoneal administration of alloxan monohydrate (150 mg/kg body weight). Group 3 received alloxan monohydrate and glibenclamide (5 mg/kg body weight bwt), group 4 received alloxan monohydrate plus the extract (250 mg/kg bwt) and group 5 received alloxan monohydrate plus the extract (500 mg/kg bwt). The administration of glibenclamide plus the extract was oral for 14 days. Glibenclamide and the extract lowered blood glucose level, catalase, and glutathione peroxidase activities, increased the superoxide dismutase (SOD) activity in rats with alloxan induced diabetes. The extract at 500 mg/kg bwt reduced the plasma urea and sodium concentration in the treated rats. The extract and glibenclamide could detoxify alloxan and restore its induced renal degeneration and glomeruli atrophy, intra renal hemorrhage and inflammation and oxidative biomarkers through activation of Nrf2 expression. The drug glibenclamide and P. cornucopiae have appreciable hypoglycemic activity and potential to restore the normal renal architecture in the rats, hence they offer similar curative effects. Additionally, the extract at 500 mg/kg bwt activated SOD and Nrf2 expression more than glibenclamide in rats with alloxan-induced diabetes. [ABSTRACT FROM AUTHOR]

Overdose can cause hypoglycemia, which is unresponsive to dextrose treatment alone. Octreotide, though not universally used, is an antidote for sulfonylurea overdose. We present a case report of a 62-year-old male who mistakenly consumed six tablets of sulfonylurea (Glibenclamide®), thinking they were loperamide for diarrhea. He developed dizziness, diaphoresis, vomiting, and unconsciousness. Physical examination revealed a GCS of 225, blood pressure of 188/79 mmHg, heart rate of 85 bpm, respiratory rate of 24/min, and oxygen saturation of 99%. Blood results showed RBS at 13 mg/dl, normal CBC, unremarkable blood gas analysis, hypokalemia at 2.87 mmol/l, and normal RFT and LFT. The patient was treated with bolus Dextrose 40%, maintenance Dextrose 10%, and hydrocortisone 100 mg, but blood sugar remained refractory for 1 hour despite increasing glucose infusion. After 5 hours without satisfactory results, we administered the first dose of octreotide (50 IU IV), resulting in a hypoglycemic interval lasting 2.5 hours. After a second dose of 50 IU octreotide, hypoglycemia was resolved. The patient was moved to the general ward and survived. In this case, octreotide extended the interval of hypoglycemia and reduced the need for dextrose. Using octreotide for conditions other than sulfonylurea overdose is not recommended.

BACKGROUND: In the treatment of diabetes mellitus (DM) for a persistent reduction in blood glucose levels it was widely used glibenclamide — a KATP channels blocker. However, its effects on cerebral circulation have been studied very little. A decrease in the functional activity of KATP channels due to their blocking by glibenclamide against the background of developed endothelial dysfunction may lead to impaired cerebral circulation (especially at the microcirculatory level) and promote remodeling of the vascular network.AIM: To evaluate the effect of glibenclamide on the reactivity of cerebral arteries in rats with streptozotocin-induced diabetes mellitus (STZ-T2DM).TASKS: 1. To study changes in the functional state of KATP channels of pial arteries in STZ-T2DM. 2. To evaluate the effect of glibenclamide on the participation of KATP channels in the formation of basal tone and endothelium-dependent dilatation of pial arteries.MATERIALS AND METHODS: The study was performed on 54 male Sprague Dawley rats. Streptozotocin-induced diabetes mellitus (STZ-T2DM) was modeled by keeping animals on a high-fat diet and administering streptozocin (35 mg/kg). Using an installation for intravital study of pial vessels reactivity, 3 months from the beginning of the experiment, the diameter of the arteries was measured when the brain surface was irrigated with Krebs-Henseleit solution, acetylcholine, glibenclamide, pinacidil and acetylcholine against the background of the action of glibenclamide or pinacidil.RESULTS: With modeling STZ-T2DM, rats developed glucose tolerance and insulin resistance. Compared to control animals, body weight was 1,3 times higher, the percentage of visceral fat was 3 times higher, and the blood glucose level was 3,2 times higher. It was shown that in STZ-T2DM the number of pial artery constrictions under the action of glibenclamide decreased by 1,3 — 1,9 times compared to intact rats. Glibenclamide did not block endothelium-dependent dilation.CONCLUSION: In rats with streptozotocin diabetes, KATP channels take part in the formation of the basal tone of the pial arteries, but the contribution of these channels is reduced on average by 1.5 times compared to healthy rats.The use of glibenclamide in STZ-T2DM does not affect endothelium-dependent dilatation of cerebral arteries.

Background: The chronic disease known as diabetes mellitus is brought on by either the pancreas's inability to make enough insulin or the body's inability to use it. Purpose: This plant finds applications for treating diarrhea, dysentery, gastroenteritis, hypertension, diabetes, caries and pain relief. Purpose: The current study aimed to determine how Psidium guajava fruit extract affected the blood glucose, body weights, and insulin levels of streptozotocin (STZ)-induced diabetic rats over 21 days. Methods: The extract's effectiveness was compared to that of glibenclamide, a common hypoglycemic medication. 30 male Wistar albino rats were divided into 5 groups with 6 animals in each group. V: Normal control (Group-I), diabetic control (Group-II), diabetic rats treated with glibenclamide 0.6mg/kg bw (Group-III), diabetic rats treated with Psidium guajava fruit extract 200 mg/kg bw (Group-IV) and Psidium guajava fruit extract 400 mg/kg bw (Group-V). All group of rats were subjected to evaluation of body weight, blood glucose and serum insulin levels on day 0, 7, 14 and 21 of the experiment. Results: There was significant (P

Traumatic spinal cord injury (SCI) results in immediate tissue necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progressive hemorrhagic necrosis (PHN) and excessive excitation are the main sources of secondary neural injury. Recent approaches to attenuate PHN by glibenclamide can improve locomotor function after SCI. However, use of glibenclamide can exacerbate development of SCI-induced chronic pain by inhibiting KATP channels to increase neuronal excitation and glial activation. In this study, we explored a treatment strategy involving administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals following spinal cord contusion. Our goal was to determine whether this combined approach enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult rats. We found that KATP channels opener, diazoxide, decreased the hyperexcitability of primary sensory neurons after SCI by electrophysiology. Timed application of glibenclamide and diazoxide following contusion significantly improved locomotor function and mitigated development of SCI-induced chronic pain, as shown by behavioral evidence. Finally, we found that timed application of glibenclamide and diazoxide attenuates the inflammatory activity in the spinal cord and increases the survival of spinal matters following SCI. These preclinical studies introduce a promising potential treatment strategy to address SCI-induced dysfunction. [ABSTRACT FROM AUTHOR]

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs. [ABSTRACT FROM AUTHOR]

In this work, the solubility of glibenclamide in the non-aqueous mixtures of carbitol and 1-propanol was studied at temperatures ranging from 293.2 K to 313.2 K using a shake-flask technique. The findings were represented by five computational models, including the van’t Hoff, the Jouyban-Acree, the Jouyban-Acree-van’t Hoff, the mixture response surface and the modified Wilson models. These models showed strong correlation and prediction capabilities, as indicated by the mean relative deviations for the back-calculated data. Furthermore, the thermodynamic analysis was conducted for solubility data using van’t Hoff and Gibbs equations. [ABSTRACT FROM AUTHOR]

This research work dives into the complexity of hot-melt extrusion (HME) and its influence on drug stability, focusing on solid dispersions containing 30% of glibenclamide and three 50:50 polymer blends. The polymers used in the study are Ethocel Standard 10 Premium, Kollidon SR and Affinisol HPMC HME 4M. Glibenclamide solid dispersions are characterized using thermal analyses (thermogravimetric analysis (TGA) and differential scanning calorimetry), X-ray diffraction and scanning electron microscopy. This study reveals the transformation of glibenclamide into impurity A during the HME process using mass spectrometry and TGA. Thus, it enables the quantification of the extent of degradation. Furthermore, this work shows how polymer–polymer blend matrices exert an impact on process parameters, the active pharmaceutical ingredient's physical state, and drug release behavior. In vitro dissolution studies show that the polymeric matrices investigated provide extended drug release (over 24 h), mainly dictated by the polymer's chemical nature. This paper highlights how glibenclamide is degraded during HME and how polymer selection crucially affects the sustained release dynamics. [ABSTRACT FROM AUTHOR]

Inward rectifying potassium channels sensitive to ATP levels (KATP) have been the subject of investigation for several decades. Modulators of KATP channels are well-established treatments for metabolic as well as cardiovascular diseases. Experimental studies have also shown the potential of KATP modulation in neurodegenerative disorders. However, to date, data regarding the effects of KATP antagonists/agonists in experiments related to neurodegeneration remain inconsistent. The main source of confusion in evaluating available data seems to be the choice of experimental models. The present study aims to provide a comprehensive understanding of the effects of both opening and blocking KATP channels in two forms of SH-SY5Y cells. Our results offer valuable insights into the significance of metabolic differences between differentiated and non-differentiated SH-SY5Y cells, particularly in the context of glibenclamide and diazoxide effects under normal conditions and during the initiation of pathological events simulating Parkinson's disease in vitro. We emphasize the analysis of mitochondrial functions and changes in mitochondrial network morphology. The heightened protein expression of KATP channels identified in non-differentiated SH-SY5Y cells seems to be a platform for a more significant impact of KATP modulators in this cell type. The efficiency of rotenone treatment in inducing morphological changes in the mitochondrial network depends on the differentiation status of SH-SY5Y cells. [ABSTRACT FROM AUTHOR]

Oral bioavailability of glibenclamide (Glb) was appreciably improved by the formation of an amorphous solid dispersion with Poloxamer‐188 (P‐188). Poloxamer‐188 substantially enhanced the solubility and thereby the dissolution rate of the biopharmaceutics classification system (BCS) class II drug Glb and simultaneously exhibited a better stabilizing effect of the amorphous solid dispersion prepared by the solvent evaporation method. The physical state of the dispersed Glb in the polymeric matrix was characterized by differential scanning calorimetry, X‐ray diffraction, scanning electron microscope and Fourier transform infrared studies. In vitro drug release in buffer (pH 7.2) revealed that the amorphous solid dispersion at a Glb–P‐188 ratio of 1:6 (SDE4) improved the dissolution of Glb by 90% within 3 h. A pharmacokinetic study of the solid dispersion formulation SDE4 in Wistar rats showed that the oral bioavailability of the drug was greatly increased as compared with the market tablet formulation, Daonil®. The formulation SDE4 resulted in an AUC0–24h ~2‐fold higher. The SDE4 formulation was found to be stable during the study period of 6 months. [ABSTRACT FROM AUTHOR]

The rising prevalence of diabetes and the high cost of treatment necessitate the search for natural, safe, and effective treatment methods. This study examined the in vitro and in silico pancreatic lipase inhibitory activity as well as the hypoglycemic effect of the ethanol extract of Tapinanthus cordifolius (TC) leaves in mice. TC leaves were extracted with ethanol by Soxhlet extraction technique. The pancreatic lipase inhibitory activity of TC extract at various concentrations (50, 100, 200, 400, 800, and 1600 µg/mL) was evaluated using spectrophotometric method. The effect of bioactive compounds from TC extract on pancreatic lipase was assessed in silico using molecular docking approach. The hypoglycaemic effect of TC extract was evaluated in vivo by an oral glucose tolerance test (OGTT) in normoglycaemic mice. Glibenclamide (5 mg/kg) was used as the positive control. TC extract showed significant pancreatic lipase (PL) inhibitory activity with IC50 value of 294.30 ± 0.67 µg/mL, which was comparable to that of orlistat (IC50 = 195.70 ± 4.60 µg/mL). In silico studies identified campesterol, heptadecafluorononanoic acid, α-tocopherol-β-d-mannoside, clionasterol, and β-tocopherol as potent pancreatic lipase inhibitors. TC extract (200, 400, and 800 mg/kg) significantly reduced hyperglycemia in glucose-challenged mice. It exhibited a significant (p<0.05) increase in glucose absorption, similar to glibenclamide, with the most notable effect at 60 minutes post-glucose load. These findings suggest that Tapinanthus cordifolius leaf can effectively inhibit pancreatic lipase and reduce blood glucose levels, and may serve as a natural treatment alternative for diabetes mellitus. [ABSTRACT FROM AUTHOR]

Glibenclamide (GBN) is a commonly used oral medication for treating type-II diabetes that acts by reducing high blood sugar levels. The effectiveness of GBN depends on the quality of the product. The quality is influenced by the solubility properties of a drug. This study aimed to measure the solubility of GBN in various solvent mixtures including some glycols and alcohols. The solubility was determined using a shake-flask method at 298.2 K under atmospheric pressure. The results showed that GBN had the highest solubility in ethylene glycol monomethyl ether and alcohol mixtures compared to the other tested glycols. [ABSTRACT FROM AUTHOR]

The objective of this investigation was to formulate an ideal nanostructured lipid carrier (NLC) for glib-enclamide in oral capsules. Employing factorial design, the NLC formulation was achieved through high-pressure homogenization using Design-Expert® software, optimized using a 32-factor experimental design and response surface analysis. Comprehensive analyses were conducted to characterize NLCs and determine the optimal formulation. Rigorous evaluations, including drug content, in vitro diffusion and stability studies, were performed. Safety assessments, efficacy studies and optimization led to the identification of an optimal NLC formulation with specific lipid and surfactant percentages, resulting in a desirable particle size (nm) and a robust zeta potential indicative of strong physical stability. [ABSTRACT FROM AUTHOR]

The NLRP3 inflammasome plays a significant role in the development of neurodegeneration, physiological aging and metabolic inflammation, which actualizes the search for effective NLRP3 inflammasome inhibitors and assessing their effects. This study was aimed to assess the effect of pharmacological modulation of NLRP3 activity by an indirect NLRP3 inflammasome inhibitor, glibenclamide, on the in vitro expression of metaflammasome components in brain cells derived from middle-aged mice. It was found that glibenclamide reduces the expression of pro-inflammatory markers NLRP3 and IL18 in cell culture, which in turn prevents the phosphorylation of metaflammasome complex protein kinases, PKR and IKKβ. At the same time, there were no changes in the expression of pathologically phosphorylated IRS, as well as in the number of senescent cells in cultures after glibenclamide exposure. [ABSTRACT FROM AUTHOR]

The combination of drugs with herbs is a prevalent treatment for metabolic and chronic diseases. This study combined glibenclamide with vitexin and performed in vivo and in vitro investigations aiming to evaluate their synergistic effect on type 2 diabetes mellitus (T2DM). T2DM rat models were established by injecting streptozotocin, and the sham group was injected with a normal saline solution as the control. A single dosage was orally performed with 10 mg/kg glibenclamide, while the co-administered was conducted by the pre-treatment of 20 mg/kg vitexin for seven days to avoid potential chemical interactions. The pharmacokinetics of glibenclamide was evaluated in both sham and T2DM rats. The blood glucose of T2DM rats was detected in the presence of different administration strategies. The metabolic stability of glibenclamide was assessed in rat liver microsomes. Glibenclamide showed a significant hypoglycemic effect on T2DM rats, which was enhanced by the co-administration of vitexin. Vitexin significantly affected the pharmacokinetics of glibenclamide in both sham and T2DM rats, where the AUC0-t, Cmax, and t1/2 of glibenclamide significantly increased, and the clearance rate decreased. Moreover, vitexin increased the in vitro half-life and decreased intrinsic clearance of glibenclamide in rat liver microsomes. The previously reported inhibitory effect of vitexin on CYP2C9 activity was hypothesized as the mechanism underlying the interaction. The co-administration of glibenclamide and vitexin could increase the systemic exposure and metabolic stability of glibenclamide and exert a synergistic effect on T2DM. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The ATP-sensitive potassium (KATP) channel couples beta cell electrical activity to glucose-stimulated insulin secretion. Loss-of-function mutations in either the pore-forming (inwardly rectifying potassium channel 6.2 [Kir6.2], encoded by KCNJ11) or regulatory (sulfonylurea receptor 1, encoded by ABCC8) subunits result in congenital hyperinsulinism, whereas gain-of-function mutations cause neonatal diabetes. Here, we report a novel loss-of-function mutation (Ser118Leu) in the pore helix of Kir6.2 paradoxically associated with sulfonylurea-sensitive diabetes that presents in early adult life. Methods: A 31-year-old woman was diagnosed with mild hyperglycaemia during an employee screen. After three pregnancies, during which she was diagnosed with gestational diabetes, the patient continued to show elevated blood glucose and was treated with glibenclamide (known as glyburide in the USA and Canada) and metformin. Genetic testing identified a heterozygous mutation (S118L) in the KCNJ11 gene. Neither parent was known to have diabetes. We investigated the functional properties and membrane trafficking of mutant and wild-type KATP channels in Xenopus oocytes and in HEK-293T cells, using patch-clamp, two-electrode voltage-clamp and surface expression assays. Results: Functional analysis showed no changes in the ATP sensitivity or metabolic regulation of the mutant channel. However, the Kir6.2-S118L mutation impaired surface expression of the KATP channel by 40%, categorising this as a loss-of-function mutation. Conclusions/interpretation: Our data support the increasing evidence that individuals with mild loss-of-function KATP channel mutations may develop insulin deficiency in early adulthood and even frank diabetes in middle age. In this case, the patient may have had hyperinsulinism that escaped detection in early life. Our results support the importance of functional analysis of KATP channel mutations in cases of atypical diabetes. [ABSTRACT FROM AUTHOR]

Metabolic syndrome is an associated condition that occurs together and increases the risk of heart disease and diabetes. These conditions include high blood pressure, high blood sugar, and high body mass index (BMI) in terms of cholesterol and triglyceride levels. Most of the elderly population may administer three drugs to control the above conditions. Therefore, this study aims to develop an analytical assay for the precise analysis of three components and to formulate a Self-Nanoemulsifying Drug-Delivery System (SNEDDS) loaded with three drugs: Rosuvastatin Calcium (RC; antilipidemic), Glibenclamide (GB; antidiabetic), and Candesartan Cilexetil (CC; antihypertensive). A design of the experiment was developed at a level of 32, and the influence of column temperature and flow rate was studied in terms of retention time, peak area, peak asymmetry, and resolution. The assay was subjected to several studies to ensure its validation. Under the optimized conditions—column temperature at 50 °C and flow rate at 0.25 mL/min—the three drugs, RC, GB, and CC, are separated. Their retention times are 0.840, 1.800, and 5.803 min, respectively. The assay was valid in terms of linearity, accuracy, and precision. Moreover, the developed assay shows a good tolerance against any change in the condition. The assay was tested also to separate the drugs in a pharmaceutical formulation as SNEDDs. The assay successfully separates the drug with a good resolution. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare the sex-dependent intergenerational effects of insulin, glibenclamide, and metformin on glucose and lipid metabolism in the offspring born to GDM mice. The murine GDM was induced by high fat diet. The offspring were grouped based on the treatments in maternal mice. ITT and GTT were performed at 4th and 8th weeks of age, respectively. Serum levels of TC, TG, HDL-C, and LDL-C plus hepatic levels of TG and TC, were respectively determined by enzymatic kits. Western blotting was conducted to detect related proteins in the livers from offspring. The dyslipidaemia, hepatic lipid abnormality, and insulin insensitivity caused by GDM were persistently normalised in male adult offspring by the respective therapies of insulin, glibenclamide, and metformin during maternal pregnancy. Specifically, the decreases in plasma TC, TG, and LDL-C levels (29%, 37.8%, and 57.7%, respectively, p ˂.05) and in hepatic lipid contents (TC 31.3% and TG 39.2%, p ˂.05), the increases in hepatic phosphorylation levels of AKT, CPT1A, PPAR-α, and PPAR-γ (57.1%, 91.7%, 68%, and 173.3%, respectively, p ˂.05) and the inhibition of G6Pase, PEPCK, and HMGCS1 (35.7%, 68.8%, and 77.3% respectively, p ˂.05) were still observed in the male offspring born to treated GDM mice from 4th to 8th week of age. Unexpectedly, the aforementioned parameters in female progenies in different groups were not significantly changed compared with controls. Respective treatments in GDM mice during pregnancy with insulin, glibenclamide, and metformin have the long-term persistent effects in male offspring, while female progenies born to untreated dams showed an autonomous inhibition of intergenerational relay of glucose and lipid dysregulation. Our current findings may imply a sex-dependent strategy of medical care for GDM mothers and their offspring. Respective interventions of insulin, glibenclamide, and metformin on dams exerted the persisted effects on male progenies. Therapies of three drugs on dams had the similarly improved effects in offspring. Female offspring autonomously corrected their dysregulated glucose-lipid metabolism caused by gestational diabetes mellitus (GDM) in dams. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the impact of physical solid dispersions of spray-dried glibenclamide (SG) on the surface of microcrystalline cellulose (MC) and mannitol (M) surfaces, as well as their combination with phosphatidylcholine (P), on enhancing the dissolution rate of glibenclamide (G). Solid dispersions were prepared using varying proportions of 1:1, 1:4, and 1:10 for SG on the surface of MC (SGA) and M (SGM), and then combined with P, in a proportion of 1:4:0.02 using spray drying. The particle size, specific surface area, scanning electron microscopy (SEM), X-ray diffraction (XRD), and dissolution rate of SGA and SGM were characterized. SEM analysis revealed successful adhesion of SG onto the surface of the carrier surfaces. XRD showed reduced crystalline characteristic peaks for SGA, while SGM exhibited a sharp peaks pattern. Both SGA and SGM demonstrated higher dissolution rates compared to SG and G alone. Furthermore, the dissolution rates of the solid dispersions of SG, MC and P (SGAP), and SG, M, and P (SGMP) were sequentially higher than that of SGA and SGM. The study suggests that physical solid dispersions of SG on MC and M, along with their combination with P, can effectively enhance the dissolution rate of G. These findings may be valuable in developing of oral solid drug dosage forms utilizing SGA, SGM, SGAP, and SGMP. [ABSTRACT FROM AUTHOR]

The NLR family pyrin domain containing 3 (NLRP3) promotes the growth of colorectal cancer (CRC). However, the therapeutic effect of NLRP3 inhibition on CRC cell progression is controversial. This study comparatively investigated the therapeutic effect of a pharmacological NLRP3 inhibitor, glibenclamide (gli), and the post-translational suppression of NLRP3 by miR-223 on CRC cell progression in HCT-116 and HCT-15 cells. LPS and ATP were used to activate Gli-treated and LSB-hsa-miR-223-3p (WTmiR-223)-expressing HCT-116 cells. NLRP3.AB.pCCL.sin.cPPT.U6.miR-223-Decoy.hPGK.GFP.WPRE plasmid (DmiR-223) was the negative control for miR-223 expression. NLRP3, gasdermin D, and BAX expressions were analyzed using western blotting. Real-time PCR detected the RNA expression of autophagy-related genes ATG5, BECN1, and miR-223 in non-transfected cells. ELISA analyzed IL-1β and IL-18 in the medium. MTS-1, annexin V, wound-healing, and sphere-invasion assays were used to assess cell viability and progression. A multiplex cytokine assay detected proinflammatory cytokine secretion. LPS–ATP-activated NLRP3 produced gasdermin D cleavage, released IL-1b and IL-18, and activated cell migration and sphere invasion. In contrast, reduced cell growth, miR-223 expression, IFN-γ, CXCL10, and LIF secretion were found in cells after inflammasome activation. Both gli and WTmiR-223 induced autophagy genes ATG5 and BECN1 and reduced the NLRP3 activation and its downstream proteins. However, while gli had a limited effect on the production of IFN-γ, CXCL10, and LIF, WTmiR-223 increased the release of those cytokines. In addition, gli did not suppress cell growth, while WTmiR-223 promoted apoptosis. Notably, neither gli nor WTmiR-223 effectively prevented sphere invasion. These data suggest that, while WTmiR-223 could have a better anticancer effect in CRC compared to gli, the sole usage of miR-223-mediated NLRP3 suppression may not be sufficient to prevent CRC metastasis. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic retinopathy is a neurodegenerative, microvascular, and sight-threatening impact of chronic uncontrolled diabetes. Avocado/soybean (ASB), a relatively new nutraceutical mixture, has acquired a significant role as a natural substitutional therapy for numerous diseases. Glibenclamide (Gli), a potent sulfonylurea, was confirmed as a diabetic therapy. Aim of the Study: To explore the protective effects of ASB versus glibenclamide on the diabetic rats' retina induced by streptozotocin (STZ). Materials and Methods: Forty rats were categorized into four groups: Normal control, Diabetic Control, Diabetes+Avocado soybean, and Diabetes+Glibenclamide. Retinal specimens were processed for histological, immunohistochemical, ultrastructural studies. Morphometrical and statistical studies were also performed. Results: Diabetic retinal specimens demonstrated evident disorganization of the retinal layers, degenerated retinal pigment epithelium, photoreceptors, and outer nuclear layers with appearance of empty spaces and multiple vacuolations. Most of ganglion cells were lost, others appeared with pycnotic nuclei. Together with a highly significant decrease (P< 0.001) of the total thickness, and the thickness of the outer and inner nuclear layers of the rats' retina, and the number of the ganglion cells. Immune expression of TNF-α, VEGF, caspase-3, and vimentin illustrated a highly significant elevation (P< 0.001). Ultrastructural findings of retinal pigmented cell layer illustrated; swollen degenerated mitochondria with cytoplasmic vacuolation. Degenerated photoreceptors, ganglion cells have indented irregular nucleus, destructed nuclear membrane, and vacuolated cytoplasm. ASB amends the diabetic retinopathy changes, structurally and immunohistochemically, more than glibenclamide Conclusion: ASB has a more, retinal-protective efficacy on DR, than glibenclamide. [ABSTRACT FROM AUTHOR]

The present study was designed to assess Tradescantia spathacea's antidiabetic ability, as well as the antiulcer activity of the entire plant extract. The diabetic condition was evaluated using Streptozotocin's oral glucose tolerance test, diabetes-alloxan, and diabetes-models. Antiulcer activities were observed in rats where gastric ulcers were either caused by oral administration of ethanol, or pyloric ligation. Standards include ranitidine, glibenclamide and sucralfate. In all models, the blood glucose levels of animals treated with the test extract were found to be significantly lower compared to diabetic care. Similarly, in all models, the ulcer index in the animals treated with the test extract was found to be significantly lower relative to the animals under vehicle supervision. Our findings say T. Spathacea extract has essential anti-diabetic properties, as well as antiulcer properties. [ABSTRACT FROM AUTHOR]

The therapeutic efficacy of bioactives from Anogessius leiocarpus, a medicinal plant widely used in folkloric medicine in Nigeria in the management of diabetes mellitus (DM), can be improved using novel drug delivery systems. The objective of this study is to evaluate the antidiabetic potentials of Anogessius leiocarpus root bark extracts and lipospheres delivery system loaded with A. leiocarpus root-bark methanol extract compared with glibenclamide, a standard antidiabetic. The root bark was powdered and then extracted using methanol, 95% ethanol, and a combination of 95% ethanol and trona using a Soxhlet extractor. Preliminary antidiabetic properties of A. leiocarpus root-bark extracts were determined in alloxanized rats, and thereafter the optimized methanol extract was formulated into lipospheres containing 1, 2 and 3%w/w of the extract by high-shear homogenization using 10%w/w lipid matrix composed of 30% Phospholipon® 90H in 70% beeswax. Physicochemical properties, in vitro drug release in simulated intestinal fluid (SIF, pH=7.4) and simulated gastric fluid (SGF, pH=1.2) and anti-diabetic properties were determined. The phytochemical screening revealed the presence of saponins, alkaloids, glycosides, steroids, reducing sugars, flavonoids and tannins. Spherical particles with particle size range 135±1.58 - 195±2.24µm, which were stable over four weeks were obtained. Higher drug release in SIF (up to 100%) than SGF (<50%) and a mixed order release mechanism were obtained. The formulations caused significant (P<0.05) reduction in blood glucose level which was comparable with that obtained with glibenclamide. Lipospheres are a potentially safer and cheaper alternative therapeutics for DM given the numerous side effects associated with conventional glibenclamide. [ABSTRACT FROM AUTHOR]

Introduction: Herbal medicines are commonly used by many people with diabetes in addition to standard treatment. Plants contain numerous known and unknown compounds that may exacerbate or ameliorate diabetes complications. Therefore, it is crucial to be aware of the side effects of these herbs before prescribing them. This study aimed to investigate the effects of hydroalcoholic extracts of Securigera securidaca (HESS) seeds alone and in combination with glibenclamide on the angiogenic/anti-angiogenic balance in streptozotocin (STZ)-induced diabetic rats. Methods: Groups involved in this animal study included diabetic and healthy controls, three doses of HESS, glibenclamide, and combination therapy. Serum samples were collected and analyzed for a vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), fetal liver kinase 1 (FLK-1), soluble fms-like tyrosine kinase 1 (sFLT-1), and transforming growth factor -beta (TGF-β). Results: Induction of diabetes increased VEGF, FGF21, and TGF-β serum levels and decreased circulating FLK-1 and sFLT-1 factors. Herbal extract, except TGF-β, had little effect on the above blood levels even at the highest doses. Glibenclamide was more effective than the highest dose of HESS in improving the vascular complications of diabetes. Combination therapy with the highest dose of HESS partly enhanced the glibenclamide effects. Conclusion: Compared with glibenclamide as a standard chemical drug, HESS had no significant effects on the blood levels of the pro/anti-angiogenesis factor in diabetic rats. Glibenclamide attenuated the levels of the biomarkers and its effects were somewhat enhanced in combination with the highest dose of HESS. [ABSTRACT FROM AUTHOR]

Glibenclamide is an antidiabetic drug that also acts as an anti-inflammatory factor and reduces oxidative stress, medullary edema, and heart attack. Glibenclamide has high permeability and poor solubility in water (BCS class II). This work addresses particle size reduction of Glibenclamide using the gas antisolvent (GAS) to improve the drug dissolution rate. Three process parameters were studied at three levels: pressure (120, 140, and 160 bar), temperature (308, 318, and 328 K), and initial solute concentration (15, 45, and 75 mg/mL). The Box-Behnken design method was applied to optimize the process conditions. The coprecipitation of Glibenclamide with polyvinyl pyrrolidone (PVP) and hydroxypropyl methylcellulose (HPMC) was investigated by GAS at optimum pressure and temperature conditions (i.e., 160 bar and 308 K). Furthermore, the particles produced were characterized by high performance liquid chromatography, powder x-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectrometry, dynamic light scattering, and field emission scanning electron microscopy. The maximum dissolution rate in water obtained after 75 minutes was 36.6 %, 88.3 %, 94.1 %, and 97.7 % for unprocessed Glibenclamide, Glibenclamide nanoparticles, Glibenclamide-HPMC and Glibenclamide-PVP composites, respectively. Glibenclamide-HPMC nanocomposites produced by GAS showed the smallest particle size, while Glibenclamide-HPMC exhibited the fastest dissolution rate.

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Abstract Background Hematoma expansion is a determinant of poor outcome of intracerebral hemorrhage but occurs frequently, especially in warfarin-associated intracerebral hemorrhage (W-ICH). In the present study, we employ the warfarin-associated intracerebral hemorrhage (W-ICH) rat model, to explore the efficacy and potential mechanism of glibenclamide pretreatment on hematoma expansion after intracerebral hemorrhage, hoping to provide proof of concept that glibenclamide in stroke primary and secondary prevention is also potentially beneficial for intracerebral hemorrhage patients at early stage. Methods In the present study, we tested whether glibenclamide, a common hypoglycemic drug, could attenuate hematoma expansion in a rat model of W-ICH. Hematoma expansion was evaluated using magnetic resonance imaging; brain injury was evaluated by brain edema and neuronal death; and functional outcome was evaluated by neurological scores. Then blood–brain barrier integrity was assessed using Evans blue extravasation and tight junction-related protein. Results The data indicated that glibenclamide pretreatment significantly attenuated hematoma expansion at 24 h after W-ICH, thus mitigating brain edema and neuronal death and promoting neurological function recovery, which may benefit from alleviating blood–brain barrier disruption by suppressing matrix metallopeptidase-9. Conclusions The results indicate that glibenclamide pretreatment in stroke primary and secondary prevention might be a promising therapy for hematoma expansion at the early stage of W-ICH.

Background: Boswellia dalzielli Hutch. (Burseraceae) is a medicinal plant, which is used locally by the local dwellers for the management and treatment of microbial-related diseases, neurological conditions, stomach spasms, diabetes, etc. Objectives: This study aimed at isolating a phytochemical of anti-diabetic potentials from the leaf of Boswellia dalzielii in alloxan-induced diabetic rats. Methods: The n-butanol fraction of the leaf of B. dalzielii was fractionated using column chromatography. Fractions obtained were screened phytochemically and by antidiabetic study. Results: Encoded column fraction B4 (150 mg/kg) produced a maximum reduction (72.45%) in fasting blood glucose (FBG) of animals after 7 hours, which was significantly (P

Metformin HCl (MET) is a mostly used antidiabetic drug and several fixed-dose combinations are available in the market with other antidiabetic drugs for the treatment of insulin-independent diabetes. Numerous chromatographic methods have been reported for the estimation of multiple fixed dose combination (FDC) of MET but each FDC needs a separate and dedicated chromatographic method for analysis. No chromatographic method has been reported yet in the literature which promotes synchronous estimation of multiple FDCs of MET to minimize organic solvent consumption, time and cost of analysis. Hence, the multipurpose-high performance thin layer chromatography (HPTLC) method was developed for the synchronous estimation of FDCs of MET by the implementation of an enhanced analytical quality by design approach. Principal component analysis was applied for the identification of critical method risk parameters. Box–Behnken design was applied for response surface analysis. The method operable design ranges was navigated and the control strategy was framed. The developed method was applied for the analysis of multiple FDCs of metformin. The developed method can synchronously analyze multiple FDCs of MET which required several chromatographic methods. Hence, the present method is multipurpose-HPTLC for the synchronous estimation of multiple FDCs of MET which required minimum organic solvent, time and cost of analysis. [ABSTRACT FROM AUTHOR]

The present research work aimed at the formulation of film-coated microspheres incorporating glibenclamide drug and their evaluation for the management of diabetes mellitus (DM). Microspheres were prepared by solvent evaporation methodology by the usage of ethyl cellulose as polymer, ethanol and dichloromethane as solvents and Tween 80® as a non-ionic surfactant. The film-coated membrane was prepared by pan coating method, incorporating ethyl cellulose, isopropyl alcohol, diethyl phthalate and sodium lauryl sulfate. This film membrane was coated on microspheres with the help of a spray gun. The efficiency of entrapment of the film coated microspheres of F5* batch, among different formulations, is highest and comes out to be in the range of 76.65±0.58. The percentage yield was observed to be 73.32±0.14. Morphological studies conducted by scanning electron microscope show spherical microspheres of uniform size. In vitro drug release study conducted of the coated microspheres of glibenclamide shows the highest amount of release of 97.44% in the F5*batch. The best-fit model was determined by the highest R2 value. Further, the developed formulation helps in reduction in dose dumping, with better patient compliance, and also masks the bitter taste of the drug. [ABSTRACT FROM AUTHOR]

Kynurenic acid is a tryptophan (Trp) metabolite formed along the kynurenine (KYN) pathway in the brain and in peripheral tissues. The disturbed formation of kynurenic acid, which targets glutamate-mediated neurotransmission, GPR35, and aryl hydrocarbon receptors of immune or redox status, was implicated in the development of neuropsychiatric and metabolic disorders among others. Kynurenic acid exerts neuroprotective and immunomodulatory effects, yet its high brain levels may negatively impact cognition. Changes in the Trp–KYN pathway are also linked with the pathogenesis of diabetes mellitus, which is an established risk factor for cardiovascular and neurological diseases or cognitive deficits. Here, the effects of metformin and glibenclamide on the brain synthesis of kynurenic acid were evaluated. Acute exposure of rat cortical slices in vitro to either of the drugs reduced kynurenic acid production de novo. Glibenclamide, but not metformin, inhibited the activity of kynurenic acid biosynthetic enzymes, kynurenine aminotransferases (KATs) I and II, in semi-purified cortical homogenates. The reduced availability of kynurenic acid may be regarded as an unwanted effect, possibly alleviating the neuroprotective action of oral hypoglycemic agents. On the other hand, considering that both compounds ameliorate the cognitive deficits in animal and human studies and that high brain kynurenic acid may hamper learning and memory, its diminished synthesis may improve cognition. [ABSTRACT FROM AUTHOR]

This study was designed to evaluate the antidiabetic and lipid profiles of methanol leaf extract of Napoleonaea imperialis in streptozotocin-induced diabetic rats. Forty- two male albino rats of mean weight 140 g were used for the study. The animals were grouped into seven groups of six rats each. Group 1 is the normal control. Group 2 is the diabetic untreated group. Group 3 is the positive control. Groups 4, 5 and 6 were the test groups that were orally given 250, 500 and 1000 mg/kg body weight of the methanol leaf extract, respectively. Group 7 is the group that received the extract only. Treatment lasted for 28 days, after which the animals were sacrificed under mild anesthesia. Blood samples were collected for biochemical analysis. The result from the study showed that there was significant (p < 0.05) decrease in the blood glucose concentration of the test groups, when compared with the diabetic untreated group. The lipid profile showed that there was significant (p < 0.05) decrease in the concentration of total cholesterol, triacylglycerol, low density lipoprotein and very low density lipoprotein and a significant (p < 0.05) increase in high density lipoprotein in the treated groups when compared with the diabetic untreated group. The study indicates that methanol leaf extract of Napoleonae imperialis possesses antidiabetic and hypolipidemic potentials and thus could be utilized in the management of diabetes and cardiovascular disease. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Diabetes mellitus is defined as the increase in blood glucose levels associated with a relative insulin deficiency, insulin resistance or both. Datura stramonium is commonly known as Jimson weed or Datura belongs to family Solanaceae containing different types of alkaloids, saponins, tannins, steroids, flavonoids, phenols and glycosides. MATERIAL AND METHODS: Extraction was done by maceration process using ethanol as solvent. Swiss albino mice of 20-35 gram were taken as study animal. Diabetes was induced by using Alloxan 20 mg/kg body weight and Glibenclamide 10 mg/kg body weight was used as standard. Ethanolic extract of low dose (50 mg/kg) and high dose (100 mg/kg) were subjected for Anti-diabetic activity. RESULTS: The extract treated 50 mg/kg, 100 mg/kg and standard 10 mg/kg showed highly significant reduction in blood glucose level (BGL) on 21st and 28th day respectively when compared to negative control group. Extract treated 100 mg/kg showed significant improvement on high density lipoprotein when compared to negative control group. Extract treated 50 mg/kg, 100 mg/kg and standard 10 mg/kg showed highly significant improvement in lipid profile when compared to negative control group. Extract treated 50 mg/kg, 100 mg/kg and standard 10 mg/kg showed significant body weight gain when compared to negative control group. Extract treated 50 mg/kg and 100 mg/kg showed significant improvement in food intake. Extract treated 50 mg/kg and 100 mg/kg showed highly significant but standard treated 10 mg/kg showed significant improvement in water intake. CONCLUSION: The present study concludes that the extract possesses potent and significant anti-diabetic activity of Datura stramonium leaves. [ABSTRACT FROM AUTHOR]

Copyright of Acta Biologica Slovenica is the property of Drustvo Biologov Slovenije and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Here, we evaluated the antidiabetic and hypoglycaemic activities of Moricandia sinaica, a species of the Brassicaceae family, for the first time. The hypoglycaemic and antidiabetic activities of the M. sinaica shoot's methanol extract (MOR-1), butanol fraction (MOR-2), and aqueous fraction (MOR-3) were examined against streptozotocin-induced diabetes model in albino Swiss mice. The mice were divided into eight groups (each group consisted of 6 mice). MOR-1 (100 and 200 mg/kg), MOR-2 (100 and 200 mg/kg), and MOR-3 (100 and 200 mg/kg) were administered to groups III, IV, V, VI, VII, and VIII, respectively, for 15 days (daily). The blood samples were haematologically and biochemically assessed at 0 days, 7 days, and 15 days. Mice in group I were kept untreated as control while group II was treated with glibenclamide as standard. Antidiabetic effects increased with MOR-1 and MOR-2 doses in a dose-dependent manner. MOR-2 treatment (200 mg/kg) yielded the best results (29.56% and 40.07% after 7 and 15 days, respectively) compared to the results obtained at zero days. MOR-2 (200 mg/kg) showed the greatest decline in glucose levels (27.67% and 41.13% after 7 and 15 days, respectively). The results concluded that M. sinaica exhibited potential hypoglycaemic activity. [ABSTRACT FROM AUTHOR]

Background: Hematoma expansion is a determinant of poor outcome of intracerebral hemorrhage but occurs frequently, especially in warfarin-associated intracerebral hemorrhage (W-ICH). In the present study, we employ the warfarin-associated intracerebral hemorrhage (W-ICH) rat model, to explore the efficacy and potential mechanism of glibenclamide pretreatment on hematoma expansion after intracerebral hemorrhage, hoping to provide proof of concept that glibenclamide in stroke primary and secondary prevention is also potentially beneficial for intracerebral hemorrhage patients at early stage. Methods: In the present study, we tested whether glibenclamide, a common hypoglycemic drug, could attenuate hematoma expansion in a rat model of W-ICH. Hematoma expansion was evaluated using magnetic resonance imaging; brain injury was evaluated by brain edema and neuronal death; and functional outcome was evaluated by neurological scores. Then blood–brain barrier integrity was assessed using Evans blue extravasation and tight junction-related protein. Results: The data indicated that glibenclamide pretreatment significantly attenuated hematoma expansion at 24 h after W-ICH, thus mitigating brain edema and neuronal death and promoting neurological function recovery, which may benefit from alleviating blood–brain barrier disruption by suppressing matrix metallopeptidase-9. Conclusions: The results indicate that glibenclamide pretreatment in stroke primary and secondary prevention might be a promising therapy for hematoma expansion at the early stage of W-ICH. [ABSTRACT FROM AUTHOR]

Unmetabolized human pharmaceuticals may enter aquatic environments, and potentially exert adverse effects on the survival of non-target organisms. Here, Pelophylax nigromaculatus tadpoles were exposed to different concentrations of antidiabetic glibenclamide (GLB) for 30 days to evaluate its potential ecotoxicological effect in amphibians using intestinal microbiomic and metabolomic profiles. The mortality rate of GLB-exposed groups appeared to be lower than that of the control group. Despite not being statistically significant, there was a tendency for a decrease in intestinal microbial diversity after exposure. The relative abundance of bacteria phylum Firmicutes was shown to decrease, but those of other phyla did not in GLB-exposed tadpoles. Some potentially pathogenic bacteria (e.g., Clostridium, Bilophila, Hafnia) decrease unexpectedly, while some beneficial bacteria (e.g., Akkermansia, Faecalibacterium) increased in GLB-exposed tadpoles. Accordingly, GLB-induced changes in intestinal microbial compositions did not seem harmful to animal health. Moreover, minor changes in a few intestinal metabolites were observed after GLB exposure. Overall, our results suggested that exposure to low levels of GLB did not necessarily exert an adverse impact on amphibian larvae. [ABSTRACT FROM AUTHOR]

Objective: Preclinical and clinical studies implicate the vascular ATP-sensitive potassium (KATP) channel in the signaling cascades underlying headache and migraine. However, attempts to demonstrate that the KATP channel inhibitor glibenclamide would attenuate triggered headache in healthy volunteers have proven unsuccessful. It is questionable, however, whether target engagement was achieved in these clinical studies. Methods: Literature data for human glibenclamide pharmacokinetics, plasma protein binding and functional IC50 values were used to predict the KATP receptor occupancy (RO) levels obtained after glibenclamide dosing in the published exploratory clinical headache provocation studies. RO vs. time profiles of glibenclamide were simulated for the pancreatic KATP channel subtype Kir6.2/SUR1 and the vascular subtype Kir6.1/SUR2B. Results: At the clinical dose of 10 mg of glibenclamide used in the headache provocation studies, predicted maximal occupancy levels of up to 90% and up to 26% were found for Kir6.2/SUR1 and Kir6.1/SUR2B, respectively. Conclusions: The findings of the present study indicate that effective Kir6.1/SUR2B target engagement was not achieved in the clinical headache provocation studies using glibenclamide. Therefore, development of novel selective Kir6.1/SUR2B inhibitors, with good bioavailability and low plasma protein binding, is required to reveal the potential of KATP channel inhibition in the treatment of migraine. [ABSTRACT FROM AUTHOR]

Abstract Objective: Potassium channels have an important role in the vascular adaptation during pregnancy and a reduction in the expression of adenosine triphosphate-sensitive potassium channels (Katp) has been linked to preeclampsia. Activation of Katp induces vasodilation; however, no previous study has been conducted to evaluate the effects of the inhibition of these channels in the contractility of preeclamptic arteries. Glibenclamide is an oral antihyperglycemic agent that inhibits Katp and has been widely used in vascular studies. Methods: To investigate the effects of the inhibition of Katp, umbilical arteries of preeclamptic women and women with healthy pregnancies were assessed by vascular contractility experiments, in the presence or absence of glibenclamide. The umbilical arteries were challenged with cumulative concentrations of potassium chloride (KCl) and serotonin. Results: There were no differences between the groups concerning the maternal age and gestational age of the patients. The percentage of smokers, caucasians and primiparae per group was also similar. On the other hand, blood pressure parameters were elevated in the preeclamptic group. In addition, the preeclamptic group presented a significantly higher body mass index. The newborns of both groups presented similar APGAR scores and weights. Conclusion: In the presence of glibenclamide, there was an increase in the KCl-induced contractions only in vessels from the PE group, showing a possible involvement of these channels in the disorder.

Type 2 diabetes causes high blood sugar due to insulin malfunction and is linked to male infertility. Using proniosomes can enhance the effectiveness of Glibenclamide, a medication that stimulates insulin secretion. In our study, male rats with diabetes were treated with GLB with or without proniosomal for 14 days. Proniosomal formulations maintained glucose levels prevented weight loss and showed normal testicular tissue.GLB-proniosomal reduces ROS caused by T2DM through Nrf2, HO-1 pathway and increases CAT, SOD, and GSH production in response to insulin and glucose uptake. The reference and proniosomal treatments showed CAT and SOD significant enzymatic elevation compared to the positive and negative control. CAT significantly correlated with Gpx4 expression with P = 0.0169 and r = 0.98; similarly, the enzymatic activity of SOD also showed a positive correlation between the average glucose levels (r = 0.99 and P = 0.0037). Intestinally, GSH analysis revealed that only proniosomal-GLB samples are significantly elevated from the positive control, with a P value of 0.0210. The data showed proniosomal-GLB was more effective than pure GLB, confirmed by higher Nrf2 (2.050 folds), HO-1 (2.148 folds), and GPx4 (1.9 folds) transcript levels relative to the control with less sample diversity compared to the reference samples, indicating proniosomal stabilized GLB in the blood.Administering GLB and proniosomes formulation has effectively restored testicular function and sperm production in diabetic rats by regulating ROS levels and upregulating anti-ROS in response to glucose uptake. These findings may lead to better treatments for diabetic patients who have infertility issues.

Transient receptor potential melastatin 4 (TRPM4) is a Ca2+-activated, monovalent cation channel that is expressed in a wide range of cells. We previously reported two gain-of-function (GoF) mutations of TRPM4 as the cause of progressive symmetric erythrokeratodermia (PSEK), which shares similar clinical and histopathological features with psoriasis. Using CRISPR/Cas9 technology, we generated TRPM4I1029M mice that have the equivalent mutation to one of the two genetic mutations found in human PSEK (equivalent to human TRPM4I1033M). Using this mutant mice, we examined the effects of TRPM4 GoF at the cellular and phenotypic levels to elucidate the pathological mechanisms underlying PSEK. In the absence of experimental stimulation, TRPM4I1029M mice did not show a phenotype. When treated with imiquimod (IMQ), however, TRPM4I1029M mice were predisposed to more severe psoriasiform dermatitis (PsD) than wild-type (WT), which was characterized by greater accumulation of CCR6-expressing γδ T cells and higher mRNA levels of Il17a. In TRPM4I1029M mice, dendritic cells showed enhanced migration and keratinocytes exhibited increased proliferation. Moreover, a TRPM4 inhibitor, glibenclamide, ameliorated PsD in WT and TRPM4I1029M mice. Our results indicate elevated TRPM4 activities boosted susceptibility to cutaneous stimuli, likely through elevation of membrane potential and alteration of downstream cellular signaling, resulting in enhanced inflammation. Our results further suggest a possible therapeutic application of TRPM4 inhibitors in psoriasis.

Sulfonylureas (SUs) are a class of antidiabetic drugs widely used in the management of diabetes mellitus type 2. They promote insulin secretion by inhibiting the ATP-sensitive potassium channel in pancreatic β-cells. Recently, the exchange protein directly activated by cAMP (Epac) was identified as a new class of target proteins of SUs that might contribute to their antidiabetic effect, through the activation of the Ras-like guanosine triphosphatase Rap1, which has been controversially discussed. We used human embryonic kidney (HEK) 293 cells expressing genetic constructs of various Förster resonance energy transfer (FRET)-based biosensors containing different versions of Epac1 and Epac2 isoforms, alone or fused to different phosphodiesterases (PDEs), to monitor SU-induced conformational changes in Epac or direct PDE inhibition in real time. We show that SUs can both induce conformational changes in the Epac2 protein but not in Epac1, and directly inhibit the PDE3 and PDE4 families, thereby increasing cAMP levels in the direct vicinity of these PDEs. Furthermore, we demonstrate that the binding site of SUs in Epac2 is distinct from that of cAMP and is located between the amino acids E443 and E460. Using biochemical assays, we could also show that tolbutamide can inhibit PDE activity through an allosteric mechanism. Therefore, the cAMP-elevating capacity due to allosteric PDE inhibition in addition to direct Epac activation may contribute to the therapeutic effects of SU drugs.