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

Understanding the interaction between pharmaceuticals and serum proteins is crucial for optimizing therapeutic strategies, especially in patients with coexisting chronic diseases. The primary goal of this study was to assess the potential changes in binding affinity and competition between glipizide (GLP, a second-generation sulfonylurea hypoglycemic drug) and losartan (LOS, a medication commonly prescribed for hypertension, particularly for patients with concurrent diabetes) with non-glycated (HSA) and glycated (gHSAGLC, gHSAFRC) human serum albumin using multiple spectroscopic techniques (fluorescence, UV-visible absorption, and circular dichroism spectroscopy). The results indicated that FRC is a more effective glycation agent for HSA than GLC, significantly altering the albumin structure and affecting the microenvironment around critical amino acid residues, Trp-214 and Tyr. These modifications reduce the binding affinity of LOS and GLP to gHSAGLC and gHSAFRC, compared to HSA, resulting in less stable drug–protein complexes. The study revealed that LOS and GLP interact nonspecifically with the hydrophobic regions of the albumin surface in both binary (ligand–albumin) and ternary systems (ligand–albumin–ligandconst) and specifically saturate the binding sites within the protein molecule. Furthermore, the presence of an additional drug (GLP in the LOS–albumin complex or LOS in the GLP–albumin complex) complicates the interactions, likely leading to competitive binding or displacement of the initially bound drug in both non-glycated and glycated albumins. Analysis of the CD spectra suggests mutual interactions between GLP and LOS, underscoring the importance of closely monitoring patients co-administered these drugs, to ensure optimal therapeutic efficacy and safety. [ABSTRACT FROM AUTHOR]

The objective of this study was to prepare a co-amorphous blend of BCS class II drug, glipizide (GPZ), using arginine (ARG) as co former. The co-amorphous GPZ-ARG mixtures (molar ratios 1:1, 1:2 and 2:1) were prepared by mechanical activation (ball milling) with different milling times. The obtained mixtures were characterized with respect to their thermal properties, possible molecular interactions, dissolution properties and physical stability and compared to the behaviour of pure crystalline form. Solid-state characterization of mixture revealed amorphization of GPZ after 90 min. of ball milling. GPZ-ARG co amorphous mixture (1:2) upon ball milling for 90 min. exhibited maximum solubility (3876.8 µg/ml) compared to pure drug (300.89 µg/ml). The resulting best co amorphous blend was incorporated into pellets which were prepared by extrusion spheronisation technique. The parameters related to process of pelletisation and product related parameters were optimized by using 4-factor, 5-level Central Composite Design. The pellets containing co amorphous blend, prepared by using optimal parameter settings, showed 95.67% Drug Release in 120 min. (F23). The co-amorphous mixture and the optimized formulation were found to be stable when subjected to stability study as per ICH guideline. It was concluded that co amorphous is a promising approach to overcome the solubility constraint of Glipizide which would be helpful in better management of the disease. [ABSTRACT FROM AUTHOR]

Accurate, sensitive and green HPTLC chromatographic method was proposed for simultaneous determination of metformin, glipizide and sitagliptin in the presence of metformin potential toxic impurities melamine and cyanoguanidine. The separation was completed on silica gel HPTLC F254 plates using a mixture of ethyl acetate: methanol: ammonia: formic acid (7: 2: 0.2: 0.2, by volume) as a developing system with UV scanning for the developed bands at 235 nm. The R f values for metformin, glipizide, sitagliptin, melamine and cyanoguanidine were 0.17, 0.84, 0.67, 0.47 and 0.75, respectively. Linear responses were observed in the ranges of 0.2–3, 0.07–1.5, 1.5–5, 0.8–4 and 0.4–2 μg/band with correlation coefficients of 0.9999, 0.9998, 0.9997, 0.9996 and 0.9998 for metformin, glipizide, sitagliptin, melamine and cyanoguanidine, respectively. The proposed method was validated as per ICH criteria with respect to linearity, accuracy, precision, specificity and robustness. The validated method was successfully applied for determination of the studied drugs in Janumet® and Engilor® tablets; also, the results were statistically compared to those obtained by the reported spectrophotometric method and no significant difference was found between them. This method permitted the accurate simultaneous determination of the studied drugs, indicating its ability to be used for routine quality control assays of these drugs. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the impact of a simple algorithm piloted for evaluation of peri-procedural diabetic ketoacidosis (DKA) risk in cases where individuals inadvertently continue their sodium-glucose cotransporter 2 (SGLT2) inhibitor in the days before an elective procedure. It presents cases of common elective procedures that would have been canceled because of inadvertent SGL2 inhibitor use but were allowed to continue based on algorithm.

Metformin/glipizide tablets are a compound formulation composed of metformin hydrochloride and glipizide. This study aimed to assess the pharmacokinetics and bioequivalence of two fixed-dose combination (FDC) tablets of metformin/glipizide (500 mg/2.5 mg) in healthy Chinese subjects. We conducted a single-center, open-label, randomized, two-way crossover study with a total of 48 subjects enrolled (24 in each dietary group). The test or reference formulations were given to the subjects at random at a ratio of 1 : 1, with a seven-day washout period. Blood samples, collected at prearranged intervals before and up to 24 hours after dosage, were analyzed using validated LC-MS/MS technology to ascertain plasma concentrations of metformin and glipizide. Finally, 23 subjects completed the fasting and fed studies, respectively. In both studies, the 90% confidence intervals for the geometric mean ratios (test/reference) of the C m ax , AUC0-t, and AUC0-∞ were all found to fall within the acceptable range for bioequivalence (80%–125%). The exposure of metformin/glipizide FDC tablets in vivo was not significantly affected by food. No serious adverse events were observed. In conclusion, this study demonstrated that both the test and reference metformin/glipizide tablets exhibited bioequivalence and were well tolerated under both fasting and fed conditions. This trial is registered with CTR202686. [ABSTRACT FROM AUTHOR]

A diabetic‐induced ulcer is a complication of diabetes in which the formation of an ulcer increases and also causes a delay in ulcer healing. Diabetes adds a bonus to various factors like starvation and stress, imbalanced acid‐pepsin secretions, impaired mucosal resistance, acid‐back diffusion, and neuronal dysfunction. Feeding a high‐fat diet for 15 days after induction of STZ in rats develops diabetes mellitus simultaneously with growth, resulting in an acceleration of ulcers for any of the above reasons. The OGTT investigation included both normal and diabetic rats, and the researchers establish a consistently low dosage of conventional oral hypoglycemic agents for the treatment. Clinical studies in the literature highlight that effectively treating patients with diabetes complications has been demonstrated through glycemic control. Hence, effective palliative hypoglycemic agents are employed. Long‐term usage has revealed that they exert a drastic negative effect. Hence, herbal drug combinations with these standard drugs have proved to be effective in minimizing the side effects. QE, which has hypoglycemic, dyslipidemia, and antioxidant properties, has been effective when administered with Glipizide (5 mg kg−1). The monotherapy of this Glipizide and QE has not shown a beneficial effect in protecting the stomach from ulcers. The combination (G + QE) showed effective control of glucose without any hypoglycemia. QE as a single adjunct with Glipizide has proven promising in preventing and treating diabetic ulcers. [ABSTRACT FROM AUTHOR]

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

Glipizide, a poor water-soluble drug belongs to BCS class II. The proposed work aimed to enhance the solubility of glipizide by preparing solid dispersions, using polyvinyl pyrrolidone (PVP) and polyethylene glycol (PEG). Solvent evaporation method was used for the preparation of glipizide solid dispersions. Solid dispersions were prepared in four different drug-to-polymer ratios i.e. 1:1, 1:2, 1:3 and 1:4. Mainly effect of three polymers (PVP K30, PVP K90 and PEG 6000) was evaluated on the solubility and dissolution of glipizide. The in-vitro dissolution of all prepared formulations was performed under pH 6.8 at 37°C using USP type II apparatus. In-vitro dissolution results revealed that the formulations having high concentrations of the polymer showed enhanced solubility. Enhancements in the solubility and rate of dissolution of the drug were noted in solid dispersion formulations compared to the physical blends and pure drug. Solid dispersions containing polyvinyl pyrrolidone exhibited a more favorable pattern of drug release compared to the corresponding solid dispersions with PEG. An increase in the maximum solubility of the drug within the solid dispersion systems was observed in all instances. Two solid dispersion formulations were optimized and formulated into immediate-release tablets, which passed all the pharmacopoeial and non-pharmacopoeial tests. Fourier transformed Infrared (FTIR) spectroscopy X-ray diffraction (XRD) and Differential scanning calorimetry (DSC) were used to indicate drug: polymer interactions in solid state. Analysis of the solid dispersion samples through characterization tests indicated the compatibility between the drug and the polymer. [ABSTRACT FROM AUTHOR]

Glipizide; an insulin secretagogue belonging to the sulfonylurea class, is a widely used antidiabetic drug for managing type 2 diabetes. However, the need for life-long administration and repeated doses poses challenges in maintaining optimal blood glucose levels. In this regard, orally active sustained-release nano-formulations can be a better alternative to traditional antidiabetic formulations. The present study explored an innovative approach by formulating orally active sustained-release nano-micelles using the amphiphilic lauric acid-conjugated-F127 (LAF127) block copolymer. LAF127 block copolymer was synthesized through esterification and thoroughly characterized before being employed to develop glipizide-loaded nano-micelles (GNM) via the thin-film hydration technique. The optimized formulation exhibited mean particle size of 341.40 ± 3.21 nm and depicted homogeneous particle size distribution with a polydispersity index (PDI)

BackgroundOral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used.Case reportA 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (

The anti-diabetic glipizide (GLN) drug has notable pharmaceutical advantages, but poor aqueous solubility restricts its wide applications. The present work was to develop a mixed polymeric micelle system composed of SA-F127 and TPGS to improve the water solubility and effective delivery of the GLN. First, we synthesized SA-F127 and confirmed it through FTIR, NMR, and GPC techniques. The GLN-PMM were fabricated with the thin-film technique and optimized with CCD design. The developed GLN-PMM was characterized using DLS, Zeta, TEM, Rheology, FTIR, DSC, and XRD measurements. The GLN-PMM manifested a spherical morphology with 67.86 nm particle size, a −3.85 mV zeta potential, and a 0.582±0.06 PDI value. The polymeric mixed micelles showed excellent compatibility with GLN and were amorphous in nature. NMR studies confirmed the encapsulation of GLN in the core of the mixed micelle. In addition, the GLN-PMM micelles were tested in vitro for cumulative drug release, ex vivo for permeation, and in vivo for anti-diabetic investigations. The GLN-PMM release profile in the various pH environments showed over 90% after 24 h, clearly indicating sustained release. The GLN-PMM micelles gave higher 88.86±3.39% GLN permeation from the goat intestine compared with free GLN. In-vivo anti-diabetic investigation proves the powerful anti-diabetic properties of GLN-PMM in comparison to the marketed formulation. These findings demonstrated that the polymeric mixed micelles of SA-F127 and TPGS could be a promising, effective, and environment-friendly approach for oral delivery of the GLN. [ABSTRACT FROM AUTHOR]

Glipizide is an antidiabetic drug used for the treatment of type 2 diabetes. A simple, reliable and robust reverse‐phase liquid chromatographic method (RP‐HPLC) was developed and validated as per International Conference on Harmonization Q2(R1) for estimating the impurities of glipizide in pharmaceutical formulations. The chromatographic separation was carried out on a Phenomenex Luna C18 (2), 250 × 4.6 mm, 5 μm with a binary solvent delivery system [MP‐A, a homogenous mixture of water and acetonitrile in a ratio of 90:10 (v/v) and 1 ml of orthophosphoric acid; and MP‐B, a homogenous mixture of water and acetonitrile in a ratio of 10:90 (v/v) and 1 ml of orthophosphoric acid] with a detection wavelength of 225 nm, a column temperature of 30°C, a flow rate of 1.5 ml/min, and an injection volume of 20 μl. All process, degradant and unknown impurities were separated well with a resolution >2.2 and were estimated accurately without any interference. The recovered values and regression values were 98.7–100.5% and R2 > 0.9999, respectively. The recovery and linearity studies covered the quantitation limit to 150% of the specification limit. The stability‐indicating properties of the developed RP‐HPLC method was assessed from the forced degradation studies. The developed method was successfully applied for real‐time sample analysis of the glipizide dosage form. [ABSTRACT FROM AUTHOR]

New consensus indicates type 2 diabetes mellitus (T2DM) and periodontitis as comorbidity and may share common pathways of disease progression. Sulfonylureas have been reported to improve the periodontal status in periodontitis patients. Glipizide, a sulfonylurea widely used in the treatment of T2DM, has also been reported to inhibit inflammation and angiogenesis. The effect of glipizide on the pathogenicity of periodontitis, however, has not been studied. We developed ligature-induced periodontitis in mice and treated them with different concentrations of glipizide and then analyzed the level of periodontal tissue inflammation, alveolar bone resorption, and osteoclast differentiation. Inflammatory cell infiltration and angiogenesis were analyzed using immunohistochemistry, RT-qPCR, and ELISA. Transwell assay and Western bolt analyzed macrophage migration and polarization. 16S rRNA sequencing analyzed the effect of glipizide on the oral microbial flora. mRNA sequencing of bone marrow-derived macrophages (BMMs) stimulated by P. gingivalis lipopolysaccharide (Pg-LPS) after treatment with glipizide was analyzed. Glipizide decreases alveolar bone resorption, periodontal tissue degradation, and the number of osteoclasts in periodontal tissue affected by periodontitis (PAPT). Glipizide-treated periodontitis mice showed reduced micro-vessel density and leukocyte/macrophage infiltration in PAPT. Glipizide significantly inhibited osteoclast differentiation in vitro experiments. Glipizide treatment did not affect the oral microbiome of periodontitis mice. mRNA sequencing and KEGG analysis showed that glipizide activated PI3K/AKT signaling in LPS-stimulated BMMs. Glipizide inhibited the LPS-induced migration of BMMs but promoted M2/M1 macrophage ratio in LPS-induced BMMs via activation of PI3K/AKT signaling. In conclusion, glipizide inhibits angiogenesis, macrophage inflammatory phenotype, and osteoclastogenesis to alleviate periodontitis pathogenicity suggesting its' possible application in the treatment of periodontitis and diabetes comorbidity. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration's Sentinel System is a leading distributed data network for drug safety surveillance in the world. The National Health Insurance Research Database (NHIRD) in Taiwan was converted into the Taiwan Sentinel Data Model (TSDM) based on the Sentinel Common Data Model (SCDM) version 6.0.2. The goal of this study was to investigate the feasibility of applying the same study designs, analytic choices, and analytic tools as used by the U.S. Sentinel System to examine the same drug--outcome associations in the TSDM-formatted NHIRD. Four known drug--outcome associations previously examined by the U.S. Sentinel System were selected as the use cases: (1) use of angiotensin-converting enzyme inhibitors (ACEIs) and risk of angioedema, (2) use of warfarin and risk of gastrointestinal bleeding, (3) use of oral clindamycin and risk of Clostridioides difficile infection (CDI), and (4) use of glyburide and risk of serious hypoglycemia. We followed the same study designs and analytic choices used by the U.S. Sentinel System and applied the Sentinel Routine Querying Tools to answer the same study questions within the TSDM-formatted NHIRD. The results showed that ACEIs were associated with a non-significant increase in risk of angioedema compared to beta-blockers (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 0.89-1.64); warfarin was associated with a higher risk of gastrointestinal bleeding compared to statins (HR: 1.72; 1.50-1.98); glyburide was associated with an increased risk of hypoglycemia compared to glipizide (HR: 1.61, 1.30-2.00). We were unable to evaluate the association between oral clindamycin and risk of CDI due to the low event number. Our study demonstrated that it was feasible to directly apply the publicly available Sentinel Routine Querying Tools within the TSDM-formatted NHIRD. However, sources of heterogeneity other than design and analytic differences should be carefully considered when comparing the results between the two systems. [ABSTRACT FROM AUTHOR]

Rats are a common model for diabetes mellitus in humans, but spontaneous diabetes in pet rats has not been described. A 1-year, 5-month-old, intact male domestic rat (Rattus norvegicus) was evaluated for polydipsia and weight loss. Diagnostics revealed glucosuria and hyperglycemia (414 mg/dL; normal 89–165 mg/dL) consistent with diabetes mellitus. Hypercholesteremia and elevated liver enzymes were also noted. Treatment with glipizide (0.5–1 mg/kg, orally, every 12 hours), metformin (50–150 mg/kg, orally, every 12 hours), and intermediate-acting porcine insulin (1–3 units, subcutaneously, every 12 hours) were ineffective at producing normoglycemia. Long-acting glargine insulin (1 unit, subcutaneously, every 12 hours) resulted in improved body weight and longer periods of normoglycemia for 3 months. Eleven months after diagnosis, the rat presented with rapid weight loss and tail necrosis; euthanasia was elected. On histopathology of the pancreas, the few visible islets and lack of amyloid production was considered more consistent with insulin-dependent (type I) diabetes mellitus than insulin-independent (type II). Other necropsy findings included bronchopneumonia, radiculoneuropathy, skeletal muscle necrosis of the tail, and chronic renal disease. Although uncommon, diabetes mellitus should be considered in pet rats presenting with polydipsia, polyuria, and weight loss. Insulin therapy may be useful for treatment of diabetes mellitus in pet rats but requires careful monitoring and further evaluation. [ABSTRACT FROM AUTHOR]

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Aims/hypothesis: Characterisation of genetic variation that influences the response to glucose-lowering medications is instrumental to precision medicine for treatment of type 2 diabetes. The Study to Understand the Genetics of the Acute Response to Metformin and Glipizide in Humans (SUGAR-MGH) examined the acute response to metformin and glipizide in order to identify new pharmacogenetic associations for the response to common glucose-lowering medications in individuals at risk of type 2 diabetes. Methods: One thousand participants at risk for type 2 diabetes from diverse ancestries underwent sequential glipizide and metformin challenges. A genome-wide association study was performed using the Illumina Multi-Ethnic Genotyping Array. Imputation was performed with the TOPMed reference panel. Multiple linear regression using an additive model tested for association between genetic variants and primary endpoints of drug response. In a more focused analysis, we evaluated the influence of 804 unique type 2 diabetes- and glycaemic trait-associated variants on SUGAR-MGH outcomes and performed colocalisation analyses to identify shared genetic signals. Results: Five genome-wide significant variants were associated with metformin or glipizide response. The strongest association was between an African ancestry-specific variant (minor allele frequency [MAFAfr]=0.0283) at rs149403252 and lower fasting glucose at Visit 2 following metformin (p=1.9×10−9); carriers were found to have a 0.94 mmol/l larger decrease in fasting glucose. rs111770298, another African ancestry-specific variant (MAFAfr=0.0536), was associated with a reduced response to metformin (p=2.4×10−8), where carriers had a 0.29 mmol/l increase in fasting glucose compared with non-carriers, who experienced a 0.15 mmol/l decrease. This finding was validated in the Diabetes Prevention Program, where rs111770298 was associated with a worse glycaemic response to metformin: heterozygous carriers had an increase in HbA1c of 0.08% and non-carriers had an HbA1c increase of 0.01% after 1 year of treatment (p=3.3×10−3). We also identified associations between type 2 diabetes-associated variants and glycaemic response, including the type 2 diabetes-protective C allele of rs703972 near ZMIZ1 and increased levels of active glucagon-like peptide 1 (GLP-1) (p=1.6×10−5), supporting the role of alterations in incretin levels in type 2 diabetes pathophysiology. Conclusions/interpretation: We present a well-phenotyped, densely genotyped, multi-ancestry resource to study gene–drug interactions, uncover novel variation associated with response to common glucose-lowering medications and provide insight into mechanisms of action of type 2 diabetes-related variation. Data availability: The complete summary statistics from this study are available at the Common Metabolic Diseases Knowledge Portal (https://hugeamp.org) and the GWAS Catalog (www.ebi.ac.uk/gwas/, accession IDs: GCST90269867 to GCST90269899). [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]

Background: The comparative safety of sulfonylureas (SUs) in nursing home (NH) residents remains understudied despite widespread use. We compared the effects of three SU medications and initial SU doses on adverse glycemic and cardiovascular events among NH residents. Methods: This national retrospective cohort study linked Medicare claims with Minimum Data Set 2.0 assessments for long‐stay NH residents aged ≥65 years between January 2008 and September 2010. Exposures were the SU medication initiated (glimepiride, glipizide, or glyburide) and doses (standard or reduced). One‐year outcomes were hospitalizations or emergency department visits for severe hypoglycemia, heart failure (HF), stroke, and acute myocardial infarction (AMI). After the inverse probability of treatment and inverse probability of censoring by death weighting, we estimated hazard ratios (HR) using Cox regression models with robust 95% confidence intervals (CI). Results: The cohort (N = 6821) included 3698 new glipizide, 1754 glimepiride, and 1369 glyburide users. Overall, the mean (standard deviation) age was 81.4 (8.2) years, 4816 (70.6%) were female, and 5164 (75.7%) were White non‐Hispanic residents. The rates of severe hypoglycemia were 30.3 (95% CI 22.3–40.1), 49.0 (95% CI 34.5–67.5), and 35.9 (95% CI 22.2–54.9) events per 1000 person‐years among new glipizide, glimepiride, and glyburide users, respectively (glimepiride versus glipizide HR 1.6, 95% CI 1.0–2.4, p = 0.04; glyburide versus glipizide HR 1.2, 95% CI 0.7–1.9, p = 0.59). The rates of severe hypoglycemia were 27.1 (95% CI 18.6–38.0) and 42.8 (95% CI 33.6–53.8) events per 1000 person‐years among new users of reduced and standard SU doses, respectively (HR 2.2, 95% CI 1.4–3.5, p < 0.01). Rates of HF, stroke, and AMI were similar between medications and doses. Conclusions: Among long‐stay NH residents, new use of glimepiride and standard SU doses resulted in higher rates of severe hypoglycemic events. Cardiovascular outcomes may not be affected by the choice of SU medication or dose. [ABSTRACT FROM AUTHOR]

Nanocochleates (NCs) are amongst the nanoformulations gaining wide popularity owing to their ability to improve biopharmaceutical performance of drug molecules remarkably. However, biggest drawback of this nanocarrier is that it requires minimum two steps for synthesis which limits its industrial scalability. Considering the same, the present work was designed with an objective to assess suitability of electrospray technique in the preparation of biomaterial based NCs. Glipizide (GPZ) was chosen as a model drug for preparation of NCs. Briefly, GPZ, phosphatidylcholine and cholesterol were dissolved in methanol and co-axially sprayed into a pool of CaCl2 solution. Factorial design (2²) approach was used for batch optimization. The optimized batch was evaluated for surface morphology, FTIR, DSC, zeta potential, in-vitro drug release study and in-vivo evaluation in male wistar rats. FESEM images confirmed formation of NCs using electrospray technique. Negative zeta potential (-14.36 ± 0.55 mV) of optimized batch reflected high stability of the sample. GPZ was released in a controlled manner from the optimized GPZNC. In-vivo pharmacokinetic study demonstrated significant increase in Cmax (2-fold) and AUC (3-fold) upon entrapment of GPZ into NCs. Thus, the present work unfolded suitability of electrospray technology toward single step preparation of Phosphatidylcholine and Cholesterol biomaterial based nanocochleates over currently used two step preparation techniques. [ABSTRACT FROM AUTHOR]

Increasing reports suggest insulin signalling pathway as a putative drug target against polyglutamine [poly(Q)] disorders, such as Huntington's disease (HD), Spinocerebellar ataxias (SCA) 1, 2, 3 etc. However, studies on drug-based stimulation of insulin signalling cascade to mitigate poly(Q) pathogenesis are lacking. In our study, we adopted an evidence-based approach to examine if some established insulin stimulating drug can be utilized to restrict poly(Q) aetiology in Drosophila disease models. For the first time, we report that glipizide, an FDA approved anti-diabetic drug upregulates insulin signalling in poly(Q) expressing tissues and restricts formation of inclusion bodies and neurodegeneration. Moreover, it reinstates the chromatin architecture by improving histone acetylation, which is otherwise abrogated due to poly(Q) toxicity. In view of the functional conservation of insulin signalling pathway in Drosophila and humans, our finding strongly suggests that glipizide can be repurposed as an effective treatment strategy against the neurodegenerative poly(Q) disorders. Also, with appropriate validation studies in mammalian disease models, glipizide could be subsequently considered for the clinical trials in human patients. • Glipizide upregulates insulin signalling in human poly(Q) expressing tissues in Drosophila. • Glipizide restricts formation of poly(Q) aggregates and neurodegeneration. • Glipizide improves histone acetylation and reinstate chromatin architecture in poly(Q) expressing cells. • Glipizide may be repurposed to restrict pathogenesis of human poly(Q) disorders. [ABSTRACT FROM AUTHOR]

Glipizide is an antidiabetic drug that belongs to a class of medication known as sulfonylureas. It is considered one of the highly prescribed antidiabetic drugs for the treatment of type II diabetes in patients following a kidney transplant. It lowers blood glucose levels by causing the release of insulin from β-cells in the pancreas. Its main metabolizing pathway is through the liver. It has several adverse effects, which range from an upset stomach to glipizide-induced haemolytic anaemia and hypoglycaemia. These adverse effects may be spontaneous, or they could have a genetic cause. The present study aimed to assess and document the incidence of glipizide-induced adverse reactions among patients prescribed the drug. The present retrospective case-control study used the electronic medical records of patients prescribed glipizide for the past 3 years. These records were reviewed to extract and document cases and/or signs of glipizide-induced adverse reactions. The results revealed that the incidence of adverse effects was higher among female patients (odds ratio, 2.40, P<0.001). Moreover, the results revealed that the likelihood of developing adverse drug reactions among patients <40 years of age was higher than in older patients (P>0.05). The outcomes of the present study are expected to prompt future studies to take sex and age into consideration, in an aim to improve treatment outcomes, reduce adverse events and decrease the burden of unnecessary costs for healthcare systems. Recommendations also include genetic screening prior to administering the medication, educating the patients and caregivers on the possibility of adverse drug reactions, and routine follow-up. This issue is of utmost importance to achieve the optimal outcomes with the minimal detrimental effects. [ABSTRACT FROM AUTHOR]

Sulfonylureas are oral antidiabetic medications that act by stimulating insulin release from pancreatic beta cells. Unintentional pediatric ingestions may result in hypoglycemia. While guidelines often recommend up to a 24-hour hospital observation period for any ingestion, the Oregon Poison Center has historically managed select patients at home. This study aimed to describe outcomes of home-managed pediatric sulfonylurea exposures and characteristics of ingestions that are appropriate for home monitoring. This is a retrospective chart review of pediatric (≤5 years) sulfonylurea ingestions in a single poison center over a 19-year period (2002–2020). We reviewed 491 individual cases for age, ingestion quantity, witnessed or unwitnessed ingestions, hypoglycemia (<60 mg/dL), disposition, and severe events (seizures or coma). We excluded cases in which missing pills were later found or another agent was identified. Of 474 patients meeting inclusion criteria, 135 (28%) were initially managed at home. Of these, 115 (85.3%) were ingestions of ≤1 tablet, where 68 (59%) were witnessed and 47 (41%) were unwitnessed. One hundred twenty five (92.6%) of these patients were successfully monitored at home, with 10 (7%) ultimately referred to a healthcare facility (HCF). Symptoms of hypoglycemia, measured glucose on home meter <60 mg/dL, fluctuations in monitored glucose, or parental concern were indications for HCF referral. Of those referred, 5 (4%) developed uncomplicated, asymptomatic hypoglycemia. Two of these received octreotide, at the discretion of the treating physician. No patients developed seizures or coma. We report 135 pediatric sulfonylurea ingestions managed with initial home monitoring, the majority of which were successfully monitored at home without any reported adverse events. Ten patients "failed home monitoring," as defined by referral to a healthcare facility. Of these, five developed hypoglycemia, though no patients developed symptoms or serious adverse events. Our findings support home observation for children ≤5 years with small ingestions of second-generation sulfonylureas. [ABSTRACT FROM AUTHOR]

Co-administered medicinal herbs can modify a drug's pharmacokinetics (PK), effectiveness, and toxicity. Andrographis paniculata (Burm. f.) ethanolic extract (APE) and andrographolide (AND) (a potent CYP2C9 inducer/inhibitor) can alter the pharmacokinetic parameters of glipizide (GLZ). This study aimed to determine the potential pharmacokinetics of herb–drug interactions between GLZ and APE/AND in the plasma of normal and diabetic rats using the HPLC bioanalysis method. The glipizide bioanalytical method established with RP-HPLC/UV instrument was validated following the EMA guidelines. GLZ was administered alone and in combination with APE or AND to normal and diabetic rats. The GLZ pharmacokinetic parameters were estimated according to the correlation between concentration and sampling time using the PK solver program. A simple and rapid GLZ bioanalysis technique with a lower limit of quantitation of 25 ng/mL was developed and presented the following parameters: accuracy (error ≤ 15%), precision (CV ≤ 15%), selectivity, stability, and linearity (R2 = 0.998) at concentrations ranging 25–1500 ng/mL. APE administration significantly improved the Cmax and AUC0–t/AUC0–∞ GLZ values in normal and diabetic rats (p < 0.05). AND significantly reduced the bioavailability of GLZ in diabetic rats with small values of T 1/2, Cmax, and AUC0–t/AUC0–∞ (p < 0.05). This combination can be considered in administering medications because it can influence the pharmacological effects of GLZ. [ABSTRACT FROM AUTHOR]

Abstract The co‐crystallization approach has been used to enhance specific desirable properties of active pharmaceutical ingredients (APIs) such as solubility, dissolution rate, and stability. Solubility is a fundamental property that affects the bioavailability and dosage of the API. The co‐crystal approach is one of the emerging methods with the potential for improving the solubility of these drugs. This paper reviews the latest progress on improving the solubility of some antidiabetic drug molecules using the co‐crystal approach.

Background: Oral hypoglycemic agents are a frequent cause of hypoglycemia in nondiabetic people. Here, we report a case of recurrent hypoglycemia caused by glipizide, in which diagnosis was delayed because of a combination of delayed hypoglycemic agent screening and low sensitivity of the hypoglycemic agent screening panel used. Case Report: A 66-year-old woman repeatedly presented with symptomatic hypoglycemia. At the first presentation, the serum glucose level was 40 mg/dL (2.2 mmol/L), C-peptide level was 13.1 ng/mL (0.8-3.1 ng/mL), proinsulin level was 96.9 pmol/L (

A RP-HPLC method has been developed for the estimation of glipizide (GLP). The proposed method is based on the separation of the drug in reversed-phase mode using BDS HYPERSIL C18 (4.6 mmox250 mm) analytical column, mobile phase methanol:water 70:30 V/V, at the flow rate of 1.0 mL min-1 and detection wavelength 222 nm. GLP was well resolved and retained at t = 3.86 minutes. This RP-HPLC method was validated as per the recommendations of ICH Revised Q2(R1) guidelines of analytical method validation, in order to prove that the new analytical method meets the reliability characteristics. The method characteristics showed the capacity of an analytical method to keep, all over the time, the basic standards for validation: selectivity, linearity, precision, accuracy and sensitivity. The method was found linear over the range 1-7 µg mL-1. The LOD and LOQ were 0.5281 and 1.761 µg mL-1 for GLP. The validated method was successfully used for quantitative estimation(assay) of GLP from in-house formulation and marketed formulations. [ABSTRACT FROM AUTHOR]