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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.

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.

Context: Catha edulis (khat) is a prevalent plant in Yemen and other African regions. In Yemen and other countries, most people chew this plant, which may change the pharmacokinetics of many drugs, such as anti-diabetics (glibenclamide and metformin). Aims: To evaluate the effect of C. edulis presence in the gastrointestinal tract (GIT) on the intestinal perfusion and bioavailability of metformin and glibenclamide and its effectiveness. Methods: The present study was conducted in situ using the closed-loop Doluisio’s method. Rat intestinal perfusion of a reference standard of each test drug alone was compared to the drug intestinal perfusion in the presence of C. edulis (three types of C. edulis agriculture in different regions of Yemen). The type of C. edulis that produced the most influence on the absorption of the drug reference was then re-investigated using the same in situ method against a pharmaceutical dosage form (tablets) of the drug. Results: The intestinal absorptions (perfusion) of reference standards of metformin and glibenclamide were decreased in the presence of C. edulis by 30.53-35.9% and 14.71-27.93%, respectively, while such decrease with pharmaceutical dosage form (tablets) of the two drugs was 24.24 and 19.77%, respectively. Conclusions: Based on the results reached from this study, the anti-diabetic bioavailability was significantly reduced in the presence of C. edulis, and this effect may affect the drug efficacy.

Aim. To develop and validate a spectrophotometric technique for quantitative determination of glibenclamide in tablets by reaction with 2,3-dichloro-1,4-naphthoquinone. Materials and methods. In the study, the substance glibenclamide of pharmacopoeial purity was used, tablets – “Maninil” 5 mg and “Glibenclamid-Zdorovye” 5 mg, 2,3-dichloro-1,4-naphthoquinone of the “CFA” qualification was chosen as a reagent, as a solvent – dimethylformamide (DMF) “CFA”. The following analytical equipment was used for the research: spectrophotometer “Specord-200” (Analytic Jena AG, Germany), water bath “MEMMERT WNB7”, laboratory electronic scales RADWAG XA 210. 4Y, measuring laboratory vessels of class A. Results. A new, simple spectrophotometric method of quantitative determination of glibenclamide in tablets by reaction with 2,3-dichloro-1,4-naphthoquinone in DMF medium was developed. The absorption maximum was at 489–491 nm. The value of the detection limit is 10.9 μg/ml, which indicates sufficient sensitivity of the reaction. Subordination to the basic law of light absorption is within the limits of concentrations of 13.7–27.4 mg/100 ml. In the process of developing the methodology, the following validation characteristics were determined: specificity, linearity, precision, correctness, and robustness. Conclusions. The methodology for the quantitative determination of glibenclamide was developed and validated according to the requirements of the State Pharmacopoeia of Ukraine. It has been proven that the method is simple, accessible, and validated for such characteristics as linearity, convergence and robustness and can be used for application in laboratories for quality control of medicinal products.

Tilahun Tesfaye,1,2 Firehiwot Teka,3 Gudeta Duga,2 Temesgen Obsa,4 Beyene Dereje,5 Eyasu Makonnen1,6 1Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Science, Addis Ababa University, Addis Ababa, Ethiopia; 2Department of Pharmacy, College of Medicine and Health Science, Ambo University, Ambo, Ethiopia; 3Department of Traditional and Modern Medicine Research Directorate, Ethiopian Public Health Institute, Addis Ababa, Ethiopia; 4Department of Pharmacology, School of Pharmacy, College of Medicine and Health Science, Jigjiga University, Jigjiga, Ethiopia; 5Department of Pharmacology, School of Medicine, College of Medicine and Health Science, Dire Dawa University, Dire Dawa, Ethiopia; 6Center for Innovative Drug Development and Therapeutic Trials for Africa (CDT-Africa), Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Tilahun Tesfaye, Email tilahuntesfaye21@gmail.comBackground: Globally, the prevalence of diabetes mellitus is rising. Due to the scarcity, high cost, and many adverse effects of modern treatments, traditional medicine is commonly used in rural areas to treat a variety of illnesses, including diabetes mellitus. The aim of this study was to assess the antihyperglycemic and hypoglycemic effects of Ocimum lamiifolium Hochst ex Benth leaves.Methods: A crude methanol 80% extract’s and its solvent fractions’ effects on healthy, oral glucose-given, and STZ-induced diabetic mice were examined. Swiss albino mice of either sex were assigned into sixteen groups, each containing six mice, for the OGTT and hypoglycemia tests. Male mice were used in the study, and they were divided into groups for the negative control (citrate buffer for diabetic mice), the normal control (Tween 2%), the test groups, and a positive control (glibenclamide) for the antihyperglycemic test in STZ (200 mg/kg body weight)-induced diabetic mice.Results: A crude 80% methanol extract of 200 mg/kg effectively lowered blood glucose levels (p < 0.05) and none of the fractions extracts caused hypoglycemia shock in norma mice. The aqueous residue at 100, 200, and 400 mg/kg, the n-butanol fraction at 100 and 200 mg/kg, and the chloroform fraction at 200 mg/kg demonstrated higher glucose tolerance in orally glucose-loaded mice (p < 0.05). The crude 400 mg/kg of an 80% methanol extract, 100 and 200 mg/kg of the n-butanol fraction, 200 and 400 mg/kg of the chloroform fraction, and 5 mg/kg of glibenclamide significantly reduced blood glucose levels in STZ-induced diabetic mice (p < 0.05).Conclusion: The current research demonstrates that a crude 80% methanol extract of Ocimum lamiifolium Hochst ex Benth leaves, as well as its solvent fractions, significantly reduce blood sugar levels in mice that are healthy, loaded with glucose, and streptozotocin induced diabetic mice.Keywords: blood glucose, diabetes mellitus, glibenclamide, hyperglycemia, Ocimum lamiifolium, oral glucose tolerance test, streptozotocin

The study examines the impact of caffeine consumption during prepubertal development and recovery on the contractile function of the adult corpus cavernosum in Wistar rats. Prepubertal male rats consumed distilled water (vehicle) and caffeine (5 mg/kg). A third group consumed caffeine and was allowed a period of recovery. Cavernosa tissues were excised at adulthood, and their contractile functions in the presence of Ca2+, K+, indomethacin, glibenclamide, methyl blue, L-NAME, and sodium nitroprusside were assessed. K+-induced increase in contraction in the caffeine-treated group was similar to that in the recovery group. Ca2+ ions, however, increased contraction significantly in the caffeine group compared to the recovery group. Acetylcholine-mediated relaxation (%) was significantly higher in the recovery compared to the caffeine treated after incubation with indomethacin and methyl blue. Acetylcholine-mediated relaxation, however, was higher in caffeine as compared to the recovery group after incubation with glibenclamide and L-NAME. Relaxation in the presence of sodium nitroprusside was significantly reduced in recovery than in the caffeine-treated group. Prepubertal caffeine intake had an erectogenic effect on the cavernous tissues in the presence of glibenclamide, nifedipine, and L-NAME. Inhibitors of prostacyclin (indomethacin) and cGMP (methyl blue) militate caffeine-induced relaxation. Effects were reversed after recovery.

Glibenclamide (GB), oral antidiabetic sulfonylurea, is used in the management of diabetes mellitus type II. It suffers from low bioavailability due to low water solubility. This work aimed to enhance the dissolution of GB by formulating the drug as a proniosomes which then improves the pharmacological effect. GB proniosomal formulations were prepared using a slurry method with sucrose as a carrier. The formulations were characterized by particle size, zeta potential, entrapment efficiency %, flow properties of the powder, and in vitro dissolution study. The pharmacological effect was also assessed by determining and measuring the fasting blood glucose level (BGL) before and after the treatment. Formulating GB proniosomes with the slurry method produces a free-flowing powder with a particle size range from 190.050 ± 43.204 to 1369.333 ± 150.407 nm and the zeta potential was above 20 mV (-24 to −58 mV), indicating good stability. The dissolution rate for all formulations was higher than that of the pure drug, indicating the efficiency of the proniosome in enhancing the drug solubility. A significant reduction in the fasting blood glucose level (73 %) was observed in animals treated with proniosomal formulation with no sign of liver damage. In contrast, the pharmacodynamics results show a significant reduction in fasting blood glucose level for animals treated with proniosomes compared to a 17.6 % reduction in BGL after treatment with pure drug. Moreover, the histopathological results showed no sign of liver damage that occurred with proniosomal treatment. GB proniosomal formulations is a promising drug delivery system with good therapeutic efficacy and stability.

The development of analytical procedures capable of simultaneous determination of two or more drugs is in crucial demand due to the availability of different formulations that are composed of different APIs. The presented study aimed to optimize and validate a simple, accurate, and sensitive UPLC analytical method for the simultaneous determination of thymoquinone (TQ) and Glibenclamide (GB) using response surface methodology, and apply this method in pharmaceutical formulations. A 32 full design of experiment was utilized to study the impacts of the independent parameters (acetonitrile ACN concentration, A; and column temperature, B) on the drugs' analytical attributes (viz, retention time, peak area, and peak asymmetry, in addition to the resolution between TQ and GB peaks). The results revealed that the independent parameters exhibited highly significant (p < 0.05) antagonistic effects on retention times for TQ and GB peaks, in addition to the agnostic effect on GB peak symmetry (p-value = 0.001). Moreover, antagonistic impacts (p < 0.05) on the resolution between TQ and GB peaks were found for both independent factors (A and B). The statistical software suggested 46.86% of ACN (A) and 38.80 °C for column temperature (B) for optimum analytical responses. The optimized green method was discovered to be acceptable in terms of selectivity, precision, accuracy, robustness, sensitivity, and specificity. Moreover, the optimized simultaneous method was successfully able to determine the contents of TQ and GB in self-nanoemulsifying drug delivery (SNEDD) formulation, in which the results showed that GB and TQ content within the prepared formulations were 1.54 ± 0.023 and 3.62 ± 0.031 mg/gm, respectively. In conclusion, the developed assay was efficient and valid in analyzing TQ and GB simultaneously in bulk and self-nanoemulsifying drug delivery system (SNEDDs) formulations. [ABSTRACT FROM AUTHOR]

The anti-hyperglycemic drug glibenclamide (Glb) might represent an interesting therapeutic option in human neurodegenerative diseases because of its anti-inflammatory activity and its ability to downregulate activation of the NLRP3 inflammasome. Bi-functionalized liposomes that can cross the blood–brain barrier (BBB) may be used to release Glb into the central nervous system (CNS), overcoming its poor solubility and bioavailability. Here, we analyzed in vitro the effect of Glb-loaded nanovectors (GNVs) and Glb itself on NLRP3 inflammasome activation using a lipopolysaccharide- and nigericine-activated THP-1 cell model. Apoptosis-associated speck-like protein containing a CARD (ASC) aggregation and NLRP3-related cytokine (IL-1β, caspase 1, and IL-18) production and gene expression, as well as the concentration of miR-223-3p and miR-7-1-5p, known to modulate the NLRP3 inflammasome, were evaluated in all conditions. Results showed that both GNVs and Glb reduced significantly ASC-speck oligomerization, transcription and translation of NLRP3, as well as the secretion of caspase 1 and IL-1β (p < 0.05 for all). Unexpectedly, GNVs/Glb significantly suppressed miR-223-3p and upregulated miR-7-1-5p expression (p < 0.01). These preliminary results thus suggest that GNVs, similarly to Glb, are able to dampen NLRP3 inflammasome activation, inflammatory cytokine release, and modulate miR-223-3p/miR-7-1-5p. Although the mechanisms underlying the complex relation among these elements remain to be further investigated, these results can open new roads to the use of GNVs as a novel strategy to reduce inflammasome activation in disease and rehabilitation. [ABSTRACT FROM AUTHOR]

Piper nigrum Linn. (Pepper) is a very well-known spice used for different purposes such as human dietaries, medicine and preservative. In Thai traditional medicine, white pepper is a component of herbal formulas used to treat many disorders including symptoms of dysmenorrhea. It is of interest to investigate the effect of methanolic extract of white pepper (MEWP) on the isolated rat uterus contractions induced by various uterine stimulants and the possible mechanism(s) involved. Strips of uterus were prepared from estrogen-primed female Wistar rats, fixed in the organ bath filled with an appropriate physiological solution with carbogen bubbled continuously at 37 °C. The measurement of isometric tension was then performed using force transducer attached to a polygraph. MEWP was tested its effect on the uterine contraction and found the inhibitory effects on the contraction induced by oxytocin, PGF2α and depolarizing solution. TEA inhibited the uterine relaxing effect of MEWP while glibenclamide had no effects when the uterus was induced to contract with oxytocin. Propranolol abolished the uterine relaxing effect of isoproterenol while it had no effects on the relaxing effect of MEWP. The results suggested that MEWP is likely to be a general uterine relaxant. The effects may be due to the interference on Ca2+ influx into the uterine muscle cells which may involve the opening of KCa channel. The effect was unlikely to occur via the KATP-channel and may not involve the interaction of MEWP on β-adrenergic receptor on the uterine muscle cells. [ABSTRACT FROM AUTHOR]

Liver fibrosis is a typical pathological state/stage involved in most chronic liver diseases and its persistence results in cirrhosis. Inflammasomes are cytoplasmic sensors that induce inflammation in response to stress. Glibenclamide (GLB) is an USFDA-approved drug for type 2 diabetes and is reported to possess anti-inflammatory activity by inhibiting inflammatory cytokines. Dimethyl fumarate (DMF) is an USFDA-approved drug for multiple sclerosis and has been reported to activate the Nrf2/ARE pathway to maintain the cellular antioxidant balance. A total of 36 rats were randomized into six groups (n = 6 each). The rats were injected with thioacetamide (TAA) 200 mg/kg, intraperitoneally every third day for eight consecutive weeks to induce liver fibrosis and oral treatment of GLB 0.5 mg/kg/day and DMF 25 mg/kg/day, and their combinations were provided for the last four consecutive weeks. Treatment with GLB, DMF, and GLB+DMF significantly protected against TAA-mediated oxidative stress and inflammatory conditions by improving hepatic function test, triglycerides, hydroxyproline, and histopathological alterations, by inhibiting the NLRP3 inflammasome signaling and fibrogenic markers, and by activating Nrf2/ARE pathway in Wistar rats. The present results suggest that simultaneous Nrf2/ARE activation and NLRP3 inflammasome inhibition could significantly contribute to developing a novel therapy for patients with liver fibrosis. [ABSTRACT FROM AUTHOR]

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumours, mostly resulting from mutations in predisposing genes. Mutations of succinate dehydrogenase (SDH) subunit B (SDHB) are associated with high probability of metastatic disease. Since bioelectrical properties and signalling in cancer are an emerging field, we investigated the metabolic, functional and electrophysiological characteristics in human succinate dehydrogenase subunit B (SDHB)-deficient pheochromocytoma cells. These cells exhibited reduced SDH function with elevated succinate-to-fumarate ratio and reduced intracellular ATP levels. The analysis of membrane passive properties revealed a more hyperpolarized membrane potential and a lower cell capacitance of SDHB-deficient cells compared to the parental ones. These bioelectrical changes were associated with reduced proliferation and adhesion capacity of SDHB-deficient cells. Only in SDHB-deficient cells, we also observed an increased amplitude of potassium currents suggesting an activation of ATP-sensitive potassium channels (KATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific KATP inhibitor, or to ATP caused normalization of potassium current features and altered proliferation and adhesion. In this work, we show for the first time that reduced intracellular ATP levels in SDHB-deficient chromaffin cells impaired cell bioelectrical properties, which, in turn, are associated with an increased cell aggressiveness. Moreover, we first ever demonstrated that glibenclamide not only reduced the outward potassium currents in SDHB-deficient cells but increased their growth capacity, reduced their ability to migrate and shifted their phenotype towards one more similar to that of parental one. [ABSTRACT FROM AUTHOR]

Aim: Simple RP-HPLC method was developed and validated for the simultaneous estimation of Glimepiride, Glibenclamide and Moxifloxacin in pharmaceutical preparation. Materials and Methods: Mediterranean C18 column with dimensions of 150mm×4.6mm was used with HPLC Shimadzu_ LC-20 AT model, Version 1:62 is used for processing of chromatograms at room temperature (25± 2°C). 1 mL per minute was the flow rate and detector were set at 254nm with mobile Phase consisting of 85:10:5 v/v methanol: water: acetonitrile. Results: The developed method proved to be accurate, simple, effective precise and reproducible. One way ANOVA was also applied for further confirmation of the results. Conclusion: The method is applicable for the routine analysis of drugs in API and in formulation and for studying in vitro interaction studies. [ABSTRACT FROM AUTHOR]

The proposed objective of this study is to attenuate cardiac fibrosis by inhibiting NLRP3 inflammasome and related genes in uninephrectomized-DOCA fed rat model. Cardiac fibrosis was induced in male Sprague Dawley rats by uninephrectomy and by subsequent administration of deoxycorticosterone acetate (DOCA) every 4th day till 28 days along with 1% NaCl in drinking water. Further, the animals in treatment groups were treated with Glibenclamide (10, 20 and 40 mg/kg) for 28 days which was selected based on docking study. Interim analysis was carried out on the 14th day to assess the hemodynamic parameters. On the 28th day, anthropometric, hemodynamic, biochemical and oxidative stress parameters, gene expression (TGF-β1, pSmad 2/3, NLRP3, IL-1β and MMP-9), ex vivo Langendorff studies and Masson's trichrome staining of heart was carried out. Results were interpreted using ANOVA followed by post hoc Bonferroni test. Glibenclamide treatment significantly reduced the increase in blood pressure. Furthermore, the ECG patterns of the treatment groups displayed a lower frequency of the slow repolarizing events seen in the model animals. Moreover, Glibenclamide treatment demonstrated normal LV function as evidenced by a significant decrease in LVEDP. Besides, this intervention improved the anthropometric parameters and less collagen deposition in Masson's trichrome staining. The cascade of TGF-β1-pSmad2/3-NLRP3 was downregulated along with suppression of IL-1β. Our study repositioned anti-diabetic drug Glibenclamide to treat cardiac fibrosis by inhibiting the TGF-β1-pSmad2/3-NLRP3 cascade. [ABSTRACT FROM AUTHOR]

Intracerebral hemorrhage (ICH) is a devastating stroke with many mechanisms of injury. Edema worsens outcome and can lead to mortality after ICH. Glibenclamide (GLC), a sulfonylurea 1- transient receptor potential melastatin 4 (Sur1-Trpm4) channel blocker, has been shown to attenuate edema in ischemic stroke models, raising the possibility of benefit in ICH. This meta-analysis synthesizes current pre-clinical (rodent) literature regarding the efficacy of post-ICH GLC administration (vs. vehicle controls) on behaviour (i.e., neurological deficit, motor, and memory outcomes), edema, hematoma volume, and injury volume. Six studies (5 in rats and 1 in mice) were included in our meta-analysis (PROSPERO registration = CRD42021283614). GLC significantly improved behaviour (standardized mean difference (SMD) = −0.63, [−1.16, −0.09], n = 70–74) and reduced edema (SMD = −0.91, [−1.64, −0.18], n = 70), but did not affect hematoma volume (SMD = 0.0788, [−0.5631, 0.7207], n = 18–20), or injury volume (SMD = 0.2892, [−0.4950, 1.0734], n = 24). However, these results should be interpreted cautiously. Findings were conflicted with 2 negative and 4 positive reports, and Egger regressions indicated missing negative edema data (p = 0.0001), and possible missing negative behavioural data (p = 0.0766). Experimental quality assessed via the SYRCLE and CAMARADES checklists was concerning, as most studies demonstrated high risks of bias. Studies were generally low-powered (e.g., average n = 14.4 for behaviour), and future studies should employ sample sizes of 41 to detect our observed effect size in behaviour and 33 to detect our observed effect in edema. Overall, missing negative studies, low study quality, high risk of bias, and incomplete attention to key recommendations (e.g., investigating female, aged, and co-morbid animals) suggest that further high-powered confirmatory studies are needed before conclusive statements about GLC's efficacy in ICH can be made, and before further clinical trials are performed. [ABSTRACT FROM AUTHOR]

Opening or closing of KATP channels affects some signaling pathways in the brain. These signaling pathways are thought to be associated with epilepsy. Here, we investigated the effect of KATP channel opener and blocker on the AKT mTOR mRNA expressions in the hippocampus and cortex regions in the penicillin model of epilepsy in rats. Four groups were created viz. Control (C), Epilepsy (E), Epilepsy-Opener (E-O) and Epilepsy-Blocker (E-B). Epileptic focus was created by administering penicillin into the brain, and the seizure-related AKT, mTOR mRNA levels were determined by qPCR on days 1st, 4th, and 8th after the seizure. The AKT mRNA expression levels in the hippocampus were statistically significant (P <0.05) in the E 1st day group. mTOR mRNA expression levels were observed to be significantly higher in the E 1st day and 8th day groups than in control and all opener groups. (P <0.05). mTOR mRNA expression levels were significantly higher in the E-B 1st day and 8th day group compared to the control and opener groups (P <0.05). AKT mRNA expression levels in the cortex were found to be statistically significantly higher in the E 1st day group than in the other groups. mTOR mRNA expression was significantly higher in the E 4th day group than in the control group. The results suggest that activation of the AKT/mTOR signaling pathway is effective in the development of epilepsy and that the effect of KATP channels on epilepsy may be via the AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is a significant risk factor of blood vessel related diseases of diabetes and this study evaluate the effect of adding Momordica charantia (Mc) to glibenclamide (GLB) on ED markers in diabetic rats. Streptozotocin (STZ-40mg/kg b. w.) induced diabetic rats were randomly put into 3 groups with 10 rats/group; diabetic control [DC] group, glibenclamide treated group (GLB -2.5mg/kg) and GLB-Mc treated group (2.5mg/kg + 400mg/kg). Serum glucose was measured weekly for eight weeks whereas insulin, sVCAM-1, vWF-Ag and interleukin-6 [IL-6] were measured at week0 and week8. Luciferase assay was performed to determine luminescence. At week8, GLB and GLB-Mc groups revealed improvements in blood glucose and insulin concentrations (P≤0.05) when compared to corresponding baseline values with GLB-Mc group showing slightly greater improvements. GLB-M c group also revealed improvement (P≤0.05) in vWF-Ag, sVCAM-1 and IL-6 concentrations but was non-significant in GLB group when compared to corresponding baseline values. Comparison between GLB and GLB-Mc group showed significantly high concentration of sVCAM-1 in GLB group (P≤0.05) due to its minimal effect on TGR5 activation. We conclude that adding M. charantia to GLB may be a useful choice for modulating diabetes induced ED due to its stimulatory effect on TGR5 receptors. [ABSTRACT FROM AUTHOR]

Abstract Early treatment of neonatal diabetes with sulfonylureas has been proven to produce marked improvements of neurodevelopment, beside the demonstrated efficacy on glycemic control. Several barriers still prevent an early treatment in preterm babies including the limited availability of suitable galenic form of glibenclamide. We adopted oral glibenclamide suspension (Amglidia) for the early treatment of neonatal diabetes due to an homozygous variant of KCNJ11 gene c.10C>T [p.Arg4Cys] in an extremely preterm infant born at 26 + 2 weeks' of gestational age. After ~6 weeks of insulin treatment with a low glucose intake (4.5 g/kg/day), the infant was switched to Amglidia 6 mg/ml diluted in maternal milk, via nasogastric tube (0.2 mg/kg/day) progressively reduced to 0.01 mg/kg/day (after ~3 months). While on glibenclamide, the patient exhibited a mean daily growth of 11 g/kg/day. The treatment was suspended at month 6 of birth (weight 4.9 kg [5th–10th centile], M3 of c.a.) for normalization of glucose profile. During the treatment, the patient exhibited a stable glucose profile within the range of 4–8 mmol/L in the absence of hypo or hyperglycemic episodes with 2–3 blood glucose tests per day. The patient was diagnosed with retinopathy of prematurity Stade II in Zone II without plus disease at 32 weeks, with progressive regression and complete retinal vascularization at 6 months of birth. Amglidia could be regarded as the specific treatment for neonatal diabetes even in preterm babies due to its beneficial effect on the metabolic and neurodevelopmental side.

This study compared the bioavailability and antihyperglycemic effect of 5 mg glibenclamide tablets available in Sudan. Nine healthy subjects were given a 5 mg dose of either micronized glibenclamide tablets (Euglucon®) or conventional non-micronized glibenclamide tablets (locally manufactured items). Blood samples were collected at 0, 1, 2, 3, 4, 5, 6, 7, and 8 hours and analyzed for glucose concentrations. The maximum mean serum concentration of the drug (Cmax) and the mean time to maximum serum concentration (Tmax) were calculated, and the area under the concentration versus time curve (AUC) and the drug clearance (Cl) were also recorded. The mean glucose concentration was also determined in different time intervals. The results show no significant difference in the mean Tmax between the tested items. However, the mean Cmax is significantly higher (p 0.001) when the non-micronized tablets are taken (456 ng/mL) rather than the micronized tablets (291 ng/mL). Similarly, the mean AUC0-8h is significantly higher (p 0.001) with the non-micronized tablets (1915 ng/mL.h) than with the micronized tablets (1163 ng/mL.h). After 8 hours, the subjects in the micronized group had a drug clearance of 0.0430 L/Kg.h, and a clearance of 0.0260 L/Kg.h was recorded in the unmicronized group. Both tablets lower the mean glucose concentrations of the nine volunteers after 8 hours, 99 mg/dL for micronized tablets and 98 mg/dL for non-micronized tablets. Overall, the non-micronized glibenclamide tablet used in this study similarly lowered the glucose concentrations in healthy volunteer subjects to that of imported micronized glibenclamide tablets.

Summary: Background: Glibenclamide alleviates brain edema and improves neurological outcomes in experimental models of stroke. We aimed to assess whether glibenclamide improves functional outcomes in patients with acute ischemic stroke treated with recombinant tissue plasminogen activator (rtPA). Methods: In this randomized, double-blind, placebo-controlled trial, patients with acute ischemic stroke were recruited to eight academic hospitals in China. Patients were eligible if they were aged 18–74 years, presented with a symptomatic anterior circulation occlusion with a deficit on the NIHSS of 4–25, and had been treated with rtPA within 4.5 h of symptom onset. We used web-based randomization (1:1) to allocate eligible participants to the glibenclamide or placebo group, stratified according to endovascular treatment and baseline stroke severity. Glibenclamide or placebo was taken orally or via tube feeding at a loading dose of 1.25 mg within 10 h after symptom onset, followed by 0.625 mg every 8 h for 5 days. The primary outcome was the proportion of patients with good outcomes (modified Rankin Scale of 0–2) at 90 days, assessed in all randomly assigned patients who had been correctly diagnosed and had begun study medication. The study is registered with ClinicalTrials.gov, NCT03284463, and is closed to new participants. Findings: Between January 1, 2018, and May 28, 2022, 305 patients were randomly assigned, of whom 272 (142 received glibenclamide and 130 received placebo) were included in the primary efficacy analysis. 103 (73%) patients in the glibenclamide group and 94 (72%) in the placebo group had a good outcome (adjusted risk difference 0.002, 95% CI −0.098 to 0.103; p = 0.96). 12 (8%) patients allocated to glibenclamide and seven (5%) patients allocated to placebo died from any cause at 90 days (p = 0.35). The number and type of adverse events were similar between the two groups. There were no drug-related adverse events and no drug-related deaths. Interpretation: The addition of glibenclamide to thrombolytic therapy did not increase the proportion of patients who achieved good outcomes after stroke compared with placebo, but it did not lead to any safety concerns. Funding: Southern Medical University and Nanfang Hospital.

Herein, we report a novel, simple, specific, accurate and cost-friendly validated reverse phase-high performance liquid chromatographic (RP-HPLC) method for the quantification of second generation sulphonylurea based antidiabetic drug, glibenclamide (GLB) in rat plasma and its application to calculate pharmacokinetic parameters in wistar rats. The internal standard used was flufenamic acid. The chromatographic separation was conducted on C18 column (250 mm × 4.6 mm x 5 μm, Agilent-Zorbax, SB) using isocratic elution with mobile phase containing Acetonitrile: Water (1:1; v/v) pH adjusted to 4.0 with 0.03 % glacial acetic acid and detected by photo-diode array as detector. Calibration curves made in the rat plasma were linear in the range of 50–1200 ng/ml with r2 = 0.998. The LLOQ was 40 ng/ml. This method was effectively applied for pharmacokinetic studies of Glibenclamide following administration through oral route as solid dispersion formulation to Wistar rats. Several methods are available in the literature which can be employed for the quantification of Glibenclamide but such methods are tedious, provide lower sensitivity, less simultaneous resolution and are time-consuming. Therefore the present methods suits best for the quantification of Glibenclamide from Wistar rats.

A Objective: The aim of the present study is to formulate a polyherbal formulation whose formula is given in Ayurvedic Formulary of India and evaluate its antidiabetic potential in animals. Method: The polyherbal formulation was prepared using the methanol extracts and aqueous extracts of the given parts of herbs in AFI. The quality of the finished product was evaluated as per the World Health Organization's guidelines for the quality control of herbal materials. Acute toxicity study was performed for dose selection as per OECD 423 guidelines. The quality testing parameters of the polyherbal formulation were within the limits. Results: The acute toxicity studies of the polyherbal formulation did not show any toxic symptoms in doses up to 2000 mg/kg over 14 days. The extracts of both the formulations were evaluated for In-vitro and In-vivo anti-diabetic study. The oral anti-diabetic activity of the polyherbal formulation (200 and 400 mg/kg, p.o) was screened against intraperitoneal (i.p.) STZ (35 mg/kg) 15 min after i.p. administration of nicotinamide (200 mg/kg) continuously for 2 days, to induced diabetes mellitus in Wistar rats. The investigational drug was administered for 28 consecutive days, and the effect of the polyherbal formulation on blood glucose levels, lipid profile, body weight and Oral Glucose tolerance was studied at regular intervals. At the end of the study, the blood samples were collected from all the animals for biochemical estimation, and the animals were sacrificed, and the kidney, liver and pancreatic tissues were collected for histopathologic analysis. Conclusion: Polyherbal formulations showed significant antidiabetic activity at 200 and 400 mg/kg, respectively, and this effect was comparable with that of Glibenclamide. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus is among the most serious public health problems worldwide, whose incidence is steadily increasing and is now posing a global epidemic danger. Major secondary complications are associated with diabetes that impacts the normal functioning of major organs such as the pancreas, liver, kidney, and eye and is characterized by a high rate of inflammation, oxidative stress, and apoptosis. Indole phytoalexins such as Brassinin exhibit a variety of biological properties, including antimicrobial, oviposition stimulant, antitumor, and cytotoxic. Materials and Methods: The 35mg/kg STZ was intraperitoneally injected to the rats for stimulating the diabetes. Then rats were treated with 25mg/kg of brassinin. The Glibenclamide was used as a positive control. The impact of Brassinin on water and food uptake, body weight, and kidney and liver weight were assessed. The levels of blood glucose, insulin, and glycosylated Haemoglobin (HbA1c), hepatic marker, carbohydrate metabolic enzymes, antioxidants, and inflammatory markers in untreated and treated rats were examined. The histological examination of the pancreas, kidney, and liver were also performed to understand the salutary properties of the Brassinin. Results: Brassinin and Glibenclamide treatment remarkably decreased the glucose and HbA1c levels in diabetic rats, while the insulin levels were substantially elevated. They also increased the antioxidant enzymes in the STZ-stimulated rats and considerably decreased the inflammatory marker and hepatic marker enzyme levels. Histological observations established the protective potential of Brassinin on diabetes-associated injury in the pancreas, liver, and kidney. Conclusion: It can be inferred that Brassinin is an antihyperglycemic, antioxidant, and anti-inflammatory compound that protects the liver, kidney, and pancreas during the onset of diabetes. [ABSTRACT FROM AUTHOR]

Asthma is a condition in which a person's airways become inflamed, narrowed, and produce greater amounts of mucus than normal. It can cause shortness of breath, chest pain, coughing, or wheezing. In some cases, symptoms may be exacerbated. Thus, the current study was designed to determine the mechanism of action of 6-aminoflavone (6-NH2F) in ex vivo experiments, as well as to determine its toxicity in acute and sub-chronic murine models. Tissues were pre-incubated with 6-NH2F, and concentration–response curves to carbachol-induced contraction were constructed. Therefore, tracheal rings pre-treated with glibenclamide, 2-aminopyridine, or isoproterenol were contracted with carbachol (1 µM), then 6-NH2F relaxation curves were obtained. In other sets of experiments, to explore the calcium channel role in the 6-NH2F relaxant action, tissues were contracted with KCl (80 mM), and 6-NH2F was cumulatively added to induce relaxation. On the other hand, tissues were pre-incubated with the test sample, and after that, CaCl2 concentration–response curves were developed. In this context, 6-NH2F induced significant relaxation in ex vivo assays, and the effect showed a non-competitive antagonism pattern. In addition, 6-NH2F significantly relaxed the contraction induced by KCl and CaCl2, suggesting a potential calcium channel blockade, which was corroborated by in silico molecular docking that was used to approximate the mode of interaction with the L-type Ca2+ channel, where 6-NH2F showed lower affinity energy when compared with nifedipine. Finally, toxicological studies revealed that 6-NH2F possesses pharmacological safety, since it did not produce any toxic effect in both acute and sub-acute murine models. In conclusion, 6-aminoflavone exerted significant relaxation through calcium channel blockade, and the compound seems to be safe. [ABSTRACT FROM AUTHOR]

Background: Garcinia kola (Gluttiferae) is recommended traditionally for the management of diabetes in Nigeria. This present study evaluated the effect of the ethanol extract of G. kola seeds on the biochemical and hematological status of alloxan-induced diabetic rats. Methods: Rats were divided into six groups of five rats each. Diabetes was induced in groups 2–6 by intraperitoneal injection of alloxan monohydrate (130 mg/kg bwt.). Group 1 served as normal control, group 2 was left untreated, group 3 was treated with 2.5 mg/kg bwt. glibenclamide (standard drug), and groups 4–6 were given an oral administration of 100, 300, and 500 mg/kg body weights of extract for 21 days. Fasting blood samples were collected at baseline, day 0, 7, 14, and 21 for blood glucose evaluation. Biochemical and hematological parameters were also investigated at the end of treatment. Results: The extract produced the best effects at 500 mg/kg bwt. Blood glucose concentration was significantly (p < 0.05) reduced from days 7 to 21. A reduction from 390.50 ± 28.21 in diabetic rats to 60.50 ± 2.96 mg/dl was observed on day 21. The extract also lowered the total cholesterol (TC), triacylglycerol (TAG), low-density lipoprotein (LDL), and malondialdehyde (MDA) concentrations from 259.64 ± 52.22, 74.41 ± 15.39, 162.81 ± 48.44, and 57.75 ± 2.06 mg/dl to 120.32 ± 24.25, 41.05 ± 0.00, 82.31 ± 20.26, and 37.25 ± 2.21 mg/dl respectively. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities were significantly increased from 31.25 ± 12.50, 33.59 ± 5.94, and 0.50 ± 0.01 IU/L to 68.75 ± 12.50, 81.52 ± 4.16, and 1.07 ± 0.15 IU/L respectively. Red blood cell (RBC) count was restored from 192.50 ± 28.72 to 271.25 ± 47.32 (× 109). At 100 mg/kg bwt., white blood cell (WBC) count was also normalized from 8000.00 ± 2648.26 to 12800.00 ± 365.14 (× 10 mm3). Conclusion: G. Kola seeds possess antidiabetic activity and capability of restoring aberrated biochemical and hematological indices in diabetic rats. This research therefore consolidates its traditional use for the management of diabetes mellitus. [ABSTRACT FROM AUTHOR]

Regulated delivery of drugs plays a key role in control and treatment of diabetes type II. The lack of patient compliance is one of the main hurdles of successful regulated drug delivery. Extended release drug delivery systems are one of the best solutions for this problem. Electrospinning is an easy method for production of nanofibers as drug delivery systems capable of being tailored for various release kinetics, including extended release form. Response surface methodology is employed to fine tune input variables, including electrical field intensity, base polymer ratio, and total polymer concentration to study the behavior of output parameters. The study validates the feasibility of using polyethylene glycol (PEG)/polycaprolctone (PCL) nanofibers drug delivery systems as an extended time release medium for metformin and glibenclamide co-delivery. A new drug release model is presented and its parameters indicate the possibility of using drug for at least T 60 = 60 h with average and sustained release rate of 5.37 μ g drug / g solid h . The system traps as little as 10% of loaded metformin and 23% of loaded glibenclamide. The mathematical model presented in this study can be used to predict the release behavior of various drug release systems. Because it can account for the varying beginning slope of the release profile, it is capable of correctly assessing the release behavior of slow release to burst release drug delivery systems. The degree of swelling and weight loss (2.48 ± 0.26% and 0.44 ± 0.02%) of prepared samples and the effect of slightly acidic pH was investigated showed that these formulations could be considered for trans dermal delivery of metformin and glibenclamide. In-vitro study of L6 myotube cells also indicated that the delivery system is capable of retaining acceptable glucose intake at 72 and 168 h (65.95 ± 4.59 % and 45.17 ± 5.12 % respectively). [ABSTRACT FROM AUTHOR]

Background: The first-line treatment for gestational diabetes mellitus remains insulin, but oral hypoglycemic agents are easier and cheaper to use. The aim of the current study was to compare the efficacy and safety of oral glibenclamide and subcutaneous insulin on the serum glucose control and perinatal outcome of patients with gestational diabetes mellitus. Materials and methods: This randomized clinical trial was conducted during a 2-year period from 2017 to 2019 in two tertiary healthcare centers in Shiraz, Iran. We included 84 singleton pregnancies between 24 and 34 weeks of gestation diagnosed with gestational diabetes mellitus. Patients were randomly assigned to oral glibenclamide (n = 44) or subcutaneous insulin (n = 40) according to a standard protocol and followed until delivery. The primary endpoint was to compare the glycemic level of patients, and the secondary outcomes included pregnancy adverse events and neonatal complications such as preeclampsia, preterm and premature rupture of membranes, preterm labor, placental abruption, maternal hypoglycemia, birth weight, neonatal hypoglycemia, hyperbilirubinemia, respiratory distress syndrome, and neonatal intensive care unit admission. Results: The two study groups had comparable baseline characteristics. After treatment, the two study groups were comparable regarding fasting blood glucose (p = 0.398) and 2 h postprandial glucose (p = 0.085). There was no significant difference between the two groups regarding the rate of preeclampsia (p = 0.250), preterm rupture of membranes (p = 0.998), preterm labor (p = 0.495), hypoglycemia (p = 0.476), and abruption (p = 0.815). There was no significant difference between the two study groups in birth weight (p = 0.863) and the Apgar score at 1 (p = 0.190) and 5 min (p = 0.055). The rates of neonatal adverse events including hypoglycemia (p = 0.999), hyperbilirubinemia (p = 0.160), neonatal intensive care unit admission (p = 0.852), and respiratory distress syndrome (p = 0.665) were comparable between the two groups. Conclusion: The results of the current study demonstrate that oral glibenclamide is as effective and safe as subcutaneous insulin in glycemic control and maternal and neonatal outcomes in women with gestational diabetes mellitus. Thus, it could be used as first-line treatment of gestational diabetes mellitus. [ABSTRACT FROM AUTHOR]

Euphorbia prostrata is traditionally used alongside antidiabetic agents to manage diabetes. Bioactive ingredients of medicinal herbs may alter the overall pharmacokinetics of antidiabetic agents. We assessed hypoglycemic activities of ethanolic plant extract (EPE) singly and its effects on antidiabetic properties of gliclazide, glibenclemide and metformin in allaxonized rats. Varying concentrations of EPE (250 and 500 mg/kg) with or without metformin (10 mg/kg), glibenclemide (2 mg/kg) and gliclazide (5 mg/kg) were orally administered to evaluate herb-drug interaction. The levels of blood glucose declined significantly after treatment with metformin, glibenclemide and gliclazide singly (p<0.01) or concomitantly with EPE (p<0.001). Concentration dependent mild to moderate reduction (5.2 and 10.0%) was registered in blood glucose for 250 and 500 mg/kg of EPE respectively. The overall reduction in blood glucose due to combined treatment with EPE and standard agents was additive. On the other hand, synergistic herb-drug interaction was registered for insulin levels in rats that received glibenclamide and gliclazide alongside EPE. Extract with metformin had antagonistic insulin outcome. Regarding the duration of hypoglycemic activities, periodical changes were similar in case of glibenclamide and gliclazide separately or in combination with EPE. However, in case of metformin with extract, the blood glucose continued to decline for 14 h and retained at 15.0% below the baseline values even after 24 h of treatment. In conclusion, the extract itself had weak hypoglycemic effects but prolonged the therapeutic duration of metformin to more than 24 h when administered combinedly. [ABSTRACT FROM AUTHOR]

A severe endocrine condition known as diabetes mellitus (DM) is defined by excessive blood sugar levels brought on by an absolute or relative lack of insulin synthesis or activity. At present, the existing diabetes mellitus drugs have many adverse reactions. Therefore, it is needed to investigate novel methods to improve DM treatment. Thus plant-based management could be a possible antidiabetic strategy. The objective of the most recent study was to assess Verbascum thapsus's ability to combat hyperlipidemia and diabetes. Mice were given an intraperitoneal injection of alloxan (150 mg kg-1, b.w.) to cause diabetes. There were five groups of mice (n=10): group 1 (normal control) received normal food and water, group 2 (diabetic control) received normal food and clean water, group 3 (diabetic mice) received 200 mg of methanolic plant extract, group 4 (diabetic mice) received 400 mg of methanolic extract, and group 5 (diabetic mice) received 10 mg of the medication Glibenclamide for 28 days. Glucose was measured four times and after 28 days, blood samples were collected to measure the lipid profile. The result showed that methanolic extract of V. thapsus significantly (P>0.05) reduced the blood glucose level, TC, TG, LDL, increase HDL and body weight at 400mg kg-1 compared to 200 mg and 10 mg of the standard drug after 28 days of treatment. The results of our study suggested that methanolic extract of V. thapsus have potent anti-diabetic activity, with comparatively less toxicity for its use in ethno-medicine for diabetes management. [ABSTRACT FROM AUTHOR]

Cerebral edema and contusion expansion are major determinants of morbidity and mortality after TBI. Current treatment options are reactive, suboptimal and associated with significant side effects. First discovered in models of focal cerebral ischemia, there is increasing evidence that the sulfonylurea receptor 1 (SUR1)-Transient receptor potential melastatin 4 (TRPM4) channel plays a key role in these critical secondary injury processes after TBI. Targeted SUR1-TRPM4 channel inhibition with glibenclamide has been shown to reduce edema and progression of hemorrhage, particularly in preclinical models of contusional TBI. Results from small clinical trials evaluating glibenclamide in TBI have been encouraging. A Phase-2 study evaluating the safety and efficacy of intravenous glibenclamide (BIIB093) in brain contusion is actively enrolling subjects. In this comprehensive narrative review, we summarize the molecular basis of SUR1-TRPM4 related pathology and discuss TBI-specific expression patterns, biomarker potential, genetic variation, preclinical experiments, and clinical studies evaluating the utility of treatment with glibenclamide in this disease.

Introduction: Follow-up of the mothers and their offspring recruited to a randomized controlled trial comparing neonatal outcomes in women with gestational diabetes treated with metformin or glibenclamide was conducted 9 years ago. A significant decrease in neonatal hypoglycemia in the group treated with metformin was seen in the original study. Methodology: Results of clinical examination, blood sample collection, and dual-energy X-ray absorptiometry (DEXA) scan not published in a brief communication are described in this study. The nutritional status was assessed using a 3-day recall method using the Indian Food Composition Table 2017. The physical activity of offspring was assessed using the Global Physical Activity Questionnaire. Results: The overall follow-up rate of the cohort was 49% and similar in both the groups. The anthropometric details, blood tests, and DEXA in the women and their offspring were similar except that the offspring of the group on metformin had higher triglyceride values than the offspring of the women treated with glibenclamide. The average body mass index of the offspring was similar and was 18. Currently, women who were treated with glibenclamide 9 years ago had higher fasting plasma glucose levels (9.2 [7.3, 12.6]) than the metformin group (7.2 [6.1, 8.4] median [interquartile range]), P = 0.02. They also had significantly higher diastolic blood pressure readings 77.1mmHg (8.9) and 72.1mmHg (11.7) mean (SD), P = 0.035. (Information from the previously published brief communication). Conclusion: No significant adverse outcome was seen in women treated with metformin and the offspring 9 years later.

Neonatal diabetes mellitus (NDM) is a rare genetic disease characterized by severe hyperglycemia requiring insulin therapy with onsetmostly within the first 6 months and rarely between 6-12 months of age. The disease can be classified into transient (TNDM) or permanent neonatal diabetes mellitus (PNDM), or it can be a component of a syndrome. The most frequent genetic causes are abnormalities of the 6q24 chromosomal region and mutations of the ABCC8 or KCNJ11 genes coding for the pancreatic beta cell's potassium channel (KATP). After the acute phase, patients with ABCC8 or KCNJ11 mutations treated with insulin therapy can switch to hypoglycemic sulfonylureas (SU). These drugs close the KATP channel binding the SUR1 subunit of the potassium channel and restoring insulin secretion after a meal. The timing of this switch can be different and could affect long-term complications. We describe the different management and clinical outcome over the time of two male patients with NDM due to KCNJ11 pathogenetic variants. In both cases, continuous subcutaneous insulin infusion pumps (CSII) were used to switch therapy from insulin to SU, but at different times after the onset. The two patients kept adequate metabolic control after the introduction of glibenclamide; during the treatment, insulin secretion was evaluated with c-peptide, fructosamine, and glycated hemoglobin (HbA1c), which were within the normal range. In neonates or infants with diabetes mellitus, genetic testing is an indispensable diagnostic tool and KCNJ11 variants should be considered. A trial of oral glibenclamide must be considered, switching from insulin, the first line of NDM treatment. This therapy can improve neurological and neuropsychological outcomes, in particular in the case of earlier treatment initiation. A new modified protocol with glibenclamide administered several times daily according to continuous glucose monitoring profile indications, was used. Patients treated with glibenclamide maintain good metabolic control and prevent hypoglycemia, neurological damage, and apoptosis of beta cells during long-term administration. [ABSTRACT FROM AUTHOR]

Gestational diabetes is a common condition during pregnancy; this condition is associated with significant fetal and neonatal morbidity, as well as considerable cost. The management of gestational diabetes was traditionally based on the rules of hygiene and dietetics and insulin therapy. Oral antidiabetic drugs have been gradually introduced into the proposed therapeutic panel and remain a subject of debate among practitioners. Our work aims to comfort the data of the literature on the use of glibenclamide in the treatment of gestational diabetes. Materials and methods: We carried out a prospective cohort involving two groups of patients with gestational diabetes requiring hypoglycemic treatment, the first group receiving glybenclamide (41 patients) and insulin for the second group (40 patients). Results: Our study showed that these two therapies gave comparable results in terms of glycemic balance and neonatal outcomes without increasing the risk of fetal or perinatal complications. Conclusion: Glibenclamide could replace insulin in the treatment of gestational diabetes while recalling that its use during pregnancy remains off-label (marketing authorization). [ABSTRACT FROM AUTHOR]

Cantú Syndrome (CS) is an autosomal dominant disorder caused by gain-of-function (GoF) mutations in the Kir6.1 and SUR2 subunits of KATP channels. KATP overactivity results in a chronic reduction in arterial tone and hypotension, leading to other systemic cardiovascular complications. However, the underlying mechanism of lymphedema, developed by >50% of CS patients, is unknown. We investigated whether lymphatic contractile dysfunction occurs in mice expressing CS mutations in Kir6.1 (Kir6.1[V65M]) or SUR2 (SUR2[A478V], SUR2[R1154Q]). Pressure myograph tests of contractile function of popliteal lymphatic vessels over the physiological pressure range revealed significantly impaired contractile strength and reduced frequency of spontaneous contractions at all pressures in heterozygous Kir6.1[V65M] vessels, compared to control littermates. Contractile dysfunction of intact popliteal lymphatics in vivo was confirmed using near-infrared fluorescence microscopy. Homozygous SUR2[A478V] vessels exhibited profound contractile dysfunction ex vivo, but heterozygous SUR2[A478V] vessels showed essentially normal contractile function. However, further investigation of vessels from all three GoF mouse strains revealed significant disruption in contraction wave entrainment, decreased conduction speed and distance, multiple pacemaker sites, and reversing wave direction. Tests of 2-valve lymphatic vessels forced to pump against an adverse pressure gradient revealed that all CS-associated genotypes were essentially incapable of pumping under an imposed outflow load. Our results show that varying degrees of lymphatic contractile dysfunction occur in proportion to the degree of molecular GoF in Kir6.1 or SUR2. This is the first example of lymphatic contractile dysfunction caused by a smooth muscle ion channel mutation and potentially explains the susceptibility of CS patients to lymphedema. Graphical Abstract [ABSTRACT FROM AUTHOR]

Metformin and its combinations are widely used to treat type 2 diabetes. The drugs commonly used in combination with Metformin are Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride. Combination therapy is preferred over monotherapy of Metformin in most diabetics. About eighteen pharmaceutical manufacturers have lately recalled metformin formulation batches from the U.S. market due to N-nitrosodimethylamine (NDMA) impurities based on the food and drug administration (USFDA) guideline "Control of Nitrosamine in Human Drugs." European Medicines Agency (EMA) and Health Canada have also established guidelines for nitrosamine impurities. Nitrosamines are well-known mutagenic impurities and probable human carcinogens found in pharmaceutical formulations. Thus, global regulatory agencies require pharmaceutical and formulation manufacturers to complete risk assessments for nitrosamine impurities for patient safety. Therefore, drug manufacturers must develop analytical techniques for monitoring trace nitrosamine impurities. Quantifying nitrosamine impurities in formulations requires modern equipment like LC-MS/MS and great intellect. The present study intends to give a single pre-packaged LC-MS/MS method parameters, including liquid chromatography and triple quadrupole mass spectrometer configuration. This method could quantify eight nitrosamine impurities from five different Metformin combinations (Metformin with Glipizide, Glibenclamide, Gliclazide, Evogliptin, and Glimepiride). The atmospheric pressure chemical ionisation (APCI) was used as an ionisation source, and the mass spectrometer was set to multiple reaction monitoring (MRM) mode for all eight nitrosamine impurities. A unified pre-packaged analytical setup allows analytical chemists to develop a reliable, sensitive, robust, and precise method for quantifying eight nitrosamine impurities from five different Metformin formulations of varying manufacturers. This analytical method saves time, money, and the environment using fewer pharmaceutical chemicals. [ABSTRACT FROM AUTHOR]

The rational combination of oral antidiabetic agents is more likely to provide better glycemic control than monotherapy. Metformin glibenclamide tablets can be used as second‐line therapy for patients with type 2 diabetes mellitus who cannot successfully control their blood glucose levels by diet and exercise plus metformin or sulfonylureas. The aim of this study was to evaluate the bioequivalence and safety of metformin hydrochloride and glibenclamide tablets (500 mg/5 mg) prepared by 2 different vendors in healthy Chinese subjects under fasting and fed conditions. This is an open‐label, single‐center, randomized, 2‐formulation, 2‐period crossover study. After screening, 40 subjects were enrolled in the fasting trial, while 40 subjects were enrolled in the fed trial. Qualified subjects were randomly assigned to receive a monotherapy dose of 500 mg/5 mg of the test or reference formulation, and after a 1‐week washout period, they took the alternative formulation. Blood samples were collected from 24 blood collection sites per cycle for pharmacokinetic analysis until 36 hours after oral administration. In total, 78 subjects completed the study. Under fasting and fed conditions, the geometric mean ratios of maximum plasma concentration, area under the plasma concentration–time curve (AUC) from time 0 to time of last quantifiable drug level , and AUC from time 0 to infinity between the 2 products, as well as the corresponding 90%CIs, were all within the range of 80%–125%. It was found that exposure (AUC from time 0 to infinity) to metformin is decreased by about 25% in the fed state compared to fasting, whereas glibenclamide exposure is increased by about 30% in the fed state. No severe adverse events were observed in the study. [ABSTRACT FROM AUTHOR]

This study was to investigate three agents possible protective effect against DM-induced cardiovascular dysfunction in spontaneously hypertensive rats (SHR). Control group was fed normal diet, DM group was injected with STZ/NA and fed high fat diet (HFD), and treatment groups were given STZ/NA, fed HFD, and then oral gavaged with eugenosedin-A (Eu-A), glibenclamide (Gli), or pioglitazone (Pio) 5 mg/kg/per day for 4-week, respectively. Eu-A, Gli, and Pio clearly ameliorated the changes of body weight, cardiac weight, and the biochemical parameters, cardiovascular disorders and inflammation. Like Gli and Pio, Eu-A may be effectively to control DM and the cardiovascular dysfunction. [ABSTRACT FROM AUTHOR]

Diabetes Mellitus (DM) is one of a group of metabolic diseases characterized by hyperglycemia caused by a disturbance in insulin so that blood glucose levels increase. Prevention of absorption of blood glucose by the intestine can be done with the help of the enzyme a-glucosidase. Based on the results of phytochemical tests, it is known that the methanol fraction of sungkai leaves contains flavonoid compounds. The Fourier Transform Infra-Red (FTIR) spectrum showed that the isolates had phenolic O-H groups (3,354.53 cm-1, 1,359.28 cm-1), aromatic C=C group (1,615.48 cm-1), C-O-C ether group (1,046.60 cm-1) and aromatic C-H group (822.21 cm-1). In vivo antidiabetic activity test was carried out using test animals of white male mice which were induced by alloxan. Antidiabetic testing was carried out using 6 treatment groups with glibenclamide, Na-Carboxymethyl cellulose (Na-CMC) 0.5%, dose 175 mg/kgBW, 350 mg/kgBW, 700 mg/kg Body Weight (BW) and isolates 2 mg/kgBW. The results showed that the methanol fraction of sungkai leaves had the best antidiabetic activity at a dose of isolate and 700 mg/kgBW which was able to reduce blood glucose levels by 42.20% and 42.00%. In vitro antidiabetic testing through aglucosidase enzyme inhibition mechanism did not show any antidiabetic activity at concentrations of fractions 5, 10, 25, 50 and 100 ppm. [ABSTRACT FROM AUTHOR]

In recent years, the prevalence of diabetes in China has significantly increased, and glibenclamide is widely used as a basic hypoglycemic drug in China's primary clinical practice. There are many left-behind children in the grass-roots areas in China and various dangerous incidents of children taking drugs by mistake continue to occur. This article reports a case of cerebral edema and fatal cerebral hernia caused by hypoglycemia induced by mistakenly ingesting glibenclamide in a child. This is the first reported case in China of a child who died from brain herniation caused by accidental administration of glibenclamide. This case reminded that clinicians must comprehensively consider the cause of convulsions and coma in children with unknown causes, ask the history in detail and cannot ignore the risk of hypoglycemic convulsions and coma. When hypoglycemic is detected, high concentration of glucose should be given promptly to normalize blood glucose. When dealing with unexplained convulsions and comatose children, clinical pediatricians must be alert to the possibility of accidental medication. [ABSTRACT FROM AUTHOR]

Background and Objectives: Type 2 diabetes mellitus is a common metabolic disorder with immense social impact. Millions of patients are being treated with insulin either after primary failure or secondary failure with sulphonylurea therapy. Sulphonylureas have the potential to reduce the glucose levels by increasing the insulin secretion and insulin sensitivity. This study intends to know the effect on fasting and postprandial glucose levels on adding glibenclamide to daily insulin regimens and reduction of the dose of insulin requirement. Methods: The study conducted at Department of General Medicine, Siddartha Medical College, Vijaywada, Andhra Pradesh, India from July 2021 to June 2022. In 50 patients who met the inclusion criteria the fasting and postprandial glucose levels were recorded prior to the addition of glibenclamide and after addition of glibenclamide FBG and PPBG were recorded again and following statistical tests i.e., Fisher's F test and Student's 't' test and Gaussian tests were used to find significance. Results: At the end of study FBG decreased by 32.5%which was statistically significant (p<0.01) and the mean PPBG value decreased by 27.7% which was also statistically significant (p<0.05). Conclusion: Combination therapy with insulin and glibenclamide results in a significant improvement in glycemic control compared to insulin therapy alone. Combination therapy has no significant effect on insulin dosage. Risk of hypoglycemia can be lowered if the dose of glibenclamide is tailored to each patient's requirement. Compared to other insulin sensitizers' traditional drug like glibenclamide is the cheapest and most economical option available currently in the Indian market. [ABSTRACT FROM AUTHOR]

: Diabetic mellitus (DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance and dyslipidemia. There are several natural products have been identified to treat the DM, fish oils are one of the natural products, which can control DM. In the present study the efficacy of the trash fish Odonus niger liver oil was tested to control DM in Wistar albino rats. Initially, the Wistar albino rats were induced to create type 2 diabetics with alloxan (120mg/kg). Then the rats were grouped into nine sets, with six numbers in each group. Followed by the first three groups of rats were administered orally with three different dosages (500, 750 and 1000mg/kg) of O. niger liver oil, similarly, the other three groups of rats were administered the same doses of cod liver oil. Simultaneously one group of rats was administered with the standard drug glibenclamide (500µg/kg). In the remaining two groups, one set was considered as normal rats (no inducement of diabetic & no treatment) and another set of diabetic control group (diabetic induced, but no treatment). All the groups of experimental and control rats were fed with basal diet during the study period of 8 weeks. Body weight and blood glucose level were recorded once in a week. At the end of the study, i.e. after 56 days of treatment, blood samples were collected from the individual group of rats to determine the hematological and biochemical changes and the rats were sacrificed to collect the kidney samples for enzyme analysis. Pancreatic tissue samples were also collected for histological studied. The study revealed that both O. niger and cod liver oils exhibited an excellent antidiabetic activity, when compared with non-treated diabetic control and standard drug glibenclamide treated animals. The experimental rats administrated with both O. niger and cod liver oils significantly decreased the level of blood glucose, lipid profile (total triglycerides, total cholesterol, LDL &VLDL) and increased the hematological parameters (RBC, WBC, HGB & HCT) and HDL level with respect to increase in concentrations of oils. Administration of both O. niger and cod liver oils protected the liver and kidney functions by reducing the ALP, ALT, LDH, AST, creatinine, uric acid and urea and increasing the protein level in response with increase in concentrations of oils. Further, it was evidenced that both oils protect the β-cells in the pancreas. All the above results suggested that, O. niger liver oil possessed equally good antidiabetic activity as like that of cod liver oil and standard drug glibenclamide. [ABSTRACT FROM AUTHOR]