It is well established that there is a link between type 2 diabetes mellitus and Parkinson's disease (PD) evidenced in faster progression and more severe phenotype in patients living with diabetes suggestive of shared cellular pathways; hence, antidiabetic drugs could be a possible treatment options for disease modification. This study evaluated the effect of glimepiride (GMP), a third generation sulphonylurea, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in mice. Sixty mice were divided randomly into six individual groups of 10 mice each and dose orally as follows: group 1: vehicle (10 ml/kg, p.o.); group 2: MPTP (20 mg/kg, i.p. × 4 at 2-h interval); groups 3-5: GMP (1, 2, or 4 mg/kg, p.o.) + MPTP (20 mg/kg, i.p. × 4 at 2-h interval); and group 6: GMP (4 mg/kg, p.o.). Effect of glimepiride on motor activities were appraised with the use of open-field test and rotarod performance while non-motor activity was evaluated using force swim test (FST; depression) and Y-maze test (working memory). MPTP induced significant decrease in latency to fall on rotarod, distance covered/rearing in open field, mean speed and climbing in FST, and percentage alternation behavior in Y-maze suggestive of motor and non-motor dysfunction. However, MPTP-induced motor and non-motor dysfunction were ameliorated with glimepiride post-treatment. In addition, MPTP-induced increase in oxidative stress parameters and cholinergic neurotransmission was attenuated by glimepiride. In addition, MPTP-induced nigral dopamine neuron loss (decrease in tyrosine hydroxylase-positive neuron (TH)) and neuroinflammation (activation of glial fibrillary acid protein (GFAP) and ionized calcium binding adaptor molecule 1 (iba-1)) were ameliorated by GMP administration. This study showed that glimepiride ameliorates MPTP-induced PD motor and non-motor deficits through enhancement of antioxidant defense signaling and attenuation of neuroinflammatory markers. Thus, this could be useful as a disease-modifying therapy in the management of PD.

Background and objectives: We aimed to describe medication-related incidents or medication errors (MEs) reported by community pharmacists and analyze the prevalent medications involved. Materials and Methods: We extracted ME reports from databases comprising patient safety incidents reported to the Korean Pharmaceutical Association between January 2013 and June 2021. Medications were analyzed according to the second (therapeutic subgroup) and fifth (chemical substance) levels of the Anatomical Therapeutic Chemical classification. Results: A total of 9046 MEs were identified, most of which were near miss reports (88.3%). Among the errors that reached the patients (521 cases), harmful incidents accounted for 76.8%. Most MEs occurred during prescription (89.5%), while harmful MEs occurred mainly during dispensing (73.3%). In the prescription step, wrong drugs (44.8%), dosing errors (27.0%), and wrong durations (14.0%) were common. Anti-inflammatory and anti-rheumatic products (M01), drugs for acid-related disorders (A02), and antihistamines for systemic use (R06) were the most frequently reported medication classes involved. Harmful incidents were most common for dosing errors (31.0%) and wrong drugs (26.8%) and were common with warfarin, levothyroxine, and glimepiride. Conclusions: The MEs reported by community pharmacists were mainly prescribing errors, most of which were rectified before reaching patients. The prevalent medications involved in harmful errors include anti-diabetic, anti-thrombotic, and anti-inflammatory agents.

A general strategy for the construction of dual-functional carbon-heteroatom bonds has been developed via a light-promoted nickel catalytic system. Employing a simple NiBr2 as the catalyst without any exogeneous ligands and photosensitizers, a variety of esters and sulfonamide N-arylation derivatives, including celecoxib- and glimepiride-derived sulfonamides, were readily accessed with high functional group tolerance and high efficiency. Moreover, the UV-vis absorption spectrum and free radical trapping experiments aimed at revealing the mechanism of the reaction are also presented.

The efficacy and safety of medications can be affected by alterations in gut microbiota in human beings. Among antidiabetic medications, incretin-based therapy such as dipeptidyl peptidase 4 inhibitors might affect gut microbiomes, which are related to glucose metabolism. This was a randomized, controlled, active-competitor study that aimed to compare the effects of combinations of gemigliptin-metformin vs. glimepiride-metformin as initial therapies on gut microbiota and glucose homeostasis in drug-naïve patients with type 2 diabetes. Seventy drug-naïve patients with type 2 diabetes (mean age, 52.2 years) with a glycated hemoglobin (HbA1c) level ≥7.5% were assigned to either gemigliptin-metformin or glimepiride-metformin combination therapies for 24 weeks. Changes in gut microbiota, biomarkers linked to glucose regulation, body composition, and amino acid blood levels were investigated. Although both treatments decreased the HbA1c levels significantly, the gemigliptin-metformin group achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain more effectively than did the glimepiride-metformin group (59% vs. 24%; p < 0.05). At the phylum level, the Firmicutes/Bacteroidetes ratio tended to decrease after gemigliptin-metformin therapy (p = 0.065), with a notable depletion of taxa belonging to Firmicutes, including Lactobacillus, Ruminococcus torques, and Streptococcus (all p < 0.05). However, regardless of the treatment modality, a distinct difference in the overall gut microbiome composition was noted between patients who reached the HbA1c target goal and those who did not (p < 0.001). Treatment with gemigliptin-metformin resulted in a higher achievement of the glycemic target without hypoglycemia or weight gain, better than with glimepiride-metformin; these improvements might be related to beneficial changes in gut microbiota.

GRADE Study Research Group; Nathan DM, Lachin JM, Buse JB, et al. Glycemia reduction in type 2 diabetes-microvascular and cardiovascular outcomes. N Engl J Med. 2022;387:1075-88. 36129997.

GRADE Study Research Group; Nathan DM, Lachin JM, Balasubramanyam A, et al. Glycemia reduction in type 2 diabetes-glycemic outcomes. N Engl J Med. 2022;387:1063-74. 36129996.

The pharmacologically privileged DHP derivatives were synthesized using the pragmatic multicomponent Hantzsch synthesis to screen the antidiabetic activity. Initially, the candidates were screened using an in vivo blood glucose test, where compound 8b showed the most prominent antidiabetic effect (% potency = 218%) compared to glimepiride. Then, a propositioned structure-activity relationship study was executed to reveal that longer side chains decreased the DHP's antidiabetic action. Mechanistically, compound 8b diminished ROS in β-cells and muscle cells simultaneously, which was proved by enhanced serum biochemical markers. Also, compound 8b decreased blood glucose by α-glucosidase inhibition (IC50 = 4.48 ± 0.32 μM), compared to acarbose (7.40 ± 0.41 μM), based selectively on the plasma window of 8b. Acarbose demonstrated auspicious inhibitor activity according to the binding affinity (ΔGbinding), which was slightly lower than that of compound 8b (-54.7 and -46.8 kcal/mol, respectively). During the 100 ns molecular dynamics simulations, the structural and energetic assessments exposed the high consistency of compound 8b to bind to the α-glucosidase.

The present study is regarding, Glimepiride is one derivatives of sulfonyl urea used in the treatment of Type II DM which classified as class-II (BCS) of high permeability and low degree of solubility. The endeavor is to improve its solubility by solvent vaporization method to enhance the rate of dissolution of glimepiride. Soluplus (Polyvinyl caprolactampolyvinyl acetate-polyethylene glycol graft co-polymer), PVP k40 (Polyvinylpyrrolidone) and PEG k5 are blended with the drug in various proportions (1:1,1:3) and prepared Soluplus1, Soluplus2, PEG1, PEG2, PVP1 and PVP2 as solid dispersion. The optimized formula of solid dispersion PVP1 is added to sodium starch glycolate and cross-carmellose. The disintegration profile will appear diminished in the drug release from the dosage form at a determined period of time. Differential scanning calorimetry appeared to a reduction in its crystallinity in solid dispersions. Scanning electron microscope and particle size analysis show a reduction in the drug particle size as solid dispersions. Fourier transform infrared spectroscopy does not show an interaction between them. Hence, that PVP1 batch will be considered from nine oral dissolving tablets dosage form. Finally, orally disintegrating tablets are estimated for various parameters; for instance, disintegration time, the content of the drug, wetting time, and in vitro release profile show a conventional result. The selected formula F6 shows a good result in disintegration time during 13-second and in-vitro drug release profile achieves 96% at the end of 40 minutes.

We apply a heterogeneous graph convolution network (GCN) combined with a multi-layer perceptron (MLP) denoted by GCNMLP to explore the potential side effects of drugs. Here the SIDER, OFFSIDERS, and FAERS are used as the datasets. We integrate the drug information with similar characteristics from the datasets of known drugs and side effect networks. The heterogeneous graph networks explore the potential side effects of drugs by inferring the relationship between similar drugs and related side effects. This novel in silico method will shorten the time spent in uncovering the unseen side effects within routine drug prescriptions while highlighting the relevance of exploring drug mechanisms from well-documented drugs. In our experiments, we inquire about the drugs Vancomycin, Amlodipine, Cisplatin, and Glimepiride from a trained model, where the parameters are acquired from the dataset SIDER after training. Our results show that the performance of the GCNMLP on these three datasets is superior to the non-negative matrix factorization method (NMF) and some well-known machine learning methods with respect to various evaluation scales. Moreover, new side effects of drugs can be obtained using the GCNMLP.

[This retracts the article DOI: 10.2147/IJN.S210548.].

Microvascular pathology in the brain is one of the suggested mechanisms underlying the increased incidence and progression of neurodegenerative diseases in people with type 2 diabetes (T2D). While accumulating data suggest a neuroprotective effect of antidiabetics, the underlying mechanisms are unclear. Here, we investigated whether two clinically used antidiabetics, the dipeptidyl peptidase-4 inhibitors (DPP-4i) linagliptin and the sulfonylurea glimepiride, restore T2D-induced brain vascular pathology. Microvascular pathology was examined in the striatum of mice fed for 12 months with either normal chow diet or a high-fat diet (HFD) to induce T2D. A subgroup of HFD-fed mice was treated with either linagliptin or glimepiride for 3 months before the sacrifice. We demonstrate that T2D caused leakage of the blood-brain barrier (BBB), induced angiogenesis and reduced pericyte coverage of microvessels. However, linagliptin and glimepiride recovered the BBB integrity and restored the pericyte coverage differentially. Linagliptin normalised T2D-induced angiogenesis and restored pericyte coverage. In contrast, glimepiride enhanced T2D-induced angiogenesis and increased pericyte density, resulting in proper vascular coverage. Interestingly, glimepiride reduced microglial activation, increased microglial-vascular interaction, and increased collagen IV density. This study provides evidence that both DPP-4 inhibition and sulfonylurea reverse T2D-induced BBB leakage which may contribute to the antidiabetic neurorestorative effects.

The development of an oral anti-diabetic medication characterized by enhanced hypoglycemic activity is in high demand. The goal was to study the hypoglycemic activity and pancreatic histopathology after the black-seed-based self-nanoemulsifying drug delivery system (SNEDDS) loaded with glimepiride liquisolid tablets to diabetic rats. The solubility of glimepiride in various vehicles was investigated. An optimization SNEDDS formulation was developed using a mixture of the experimental design approach. Box-Behnken design (BBD) was used to develop glimepiride liquisolid tablets utilizing Avicel PH 101 and Neusilin as a carrier mixture and FujiSil as a coating material. The quality attributes of the prepared tablets were assessed. Following the administration of the optimized tablets to diabetic rats, the pharmacodynamics and histopathological changes were investigated and compared to a commercial drug product. Results revealed that the optimized SNEDDS formulation that contains 15.43% w/w black seed oil, 40% w/w Tween 80, and 44.57% w/w Polyethylene glycol 400 showed an average droplet size of 34.64 ± 2.01 nm and a drug load of 36.67 ± 3.13 mg/mL. The optimized tablet formulation contained 0.31% Avicel in the carrier mixture, a 14.99 excipient ratio, and 8% superdisintegrant. Pre- and post-compression properties were satisfactory, and the optimized glimepiride liquisolid tablet showed a two-fold increase in dissolution. The optimized tablet demonstrated superior pharmacodynamics. The pancreatic tissues of the group treated with the optimized tablet displayed normal histological structure. The obtained data offered a commercially viable alternative for manufacturing solid dosage forms containing water-insoluble drugs, but additional clinical research is required.

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) reduce the risk of heart failure progression and mortality rates. Moreover, osmotic diuresis induced by SGLT2 inhibition may result in an improved heart failure prognosis. Independent of conventional diuretics in patients with type 2 diabetes (T2D) and chronic heart failure, especially in patients with heart failure with preserved ejection fraction (HFpEF), it is unclear whether SGLT2i chronically reduces estimated plasma volume (ePV). As a subanalysis of the CANDLE trial, which assessed the effect of canagliflozin on N-terminal pro-brain natriuretic peptide (NT-proBNP), we examined the change (%) in ePV over 24 weeks of treatment based on the baseline level associated with diuretic usage. In the CANDLE trial, nearly all patients were clinically stable (NYHA class I-II), with approximately 70% of participants presenting a baseline phenotype of HFpEF. A total of 99 (42.5%) patients were taking diuretics (mostly furosemide) at baseline, while 134 (57.5%) were not. Relative to glimepiride, canagliflozin significantly reduced ePV without worsening renal function in patients in both groups: -4.00% vs. 1.46% (p = 0.020) for the diuretic group and -6.14% vs. 1.28% (p < 0.001) for the nondiuretic group. Furthermore, canagliflozin significantly reduced serum uric acid without causing major electrolyte abnormalities in patients in both subgroups. The long-term beneficial effect of SGLT2i on intravascular congestion could be independent of conventional diuretic therapy without worsening renal function in patients with T2D and HF (HFpEF predominantly). In addition, the beneficial effects of canagliflozin are accompanied by improved hyperuricemia without causing major electrolyte abnormalities.

(1) Insulin resistance, a symptom of type 2 diabetes mellitus (T2DM), is caused by the inactivation of the insulin signaling pathway, which includes IRS-PI3K-IRS-1-PKC-AKT2 and GLUT4. Metformin (biguanide) and glimepiride (sulfonylurea) are both drugs that are derivatives of urea, and they are widely used as first-line drugs for the treatment of type 2 diabetes mellitus. Palmatine has been previously reported to possess antidiabetic and antioxidant properties. (2) The current study compared palmatine to metformin and glimepiride in a type 2 diabetes model for ADME and insulin resistance via the PI3K/Akt/GLUT4 signaling pathway: in vitro, in vivo, ex vivo, and in silico molecular docking. (3) Methods: Differentiated L6 skeletal muscle cells and soleus muscle tissue were incubated in standard tissue culture media supplemented with high insulin and high glucose as a cellular model of insulin resistance, whilst streptozotocin (STZ)-induced Sprague Dawley rats were used as the diabetic model. The cells/tissue/animals were treated with palmatine, while glimepiride and metformin were used as standard drugs. The differential gene expression of PI3K, IRS-1, PKC-α, AKT2, and GLUT4 was evaluated using qPCR. (4) Results: The results revealed that the genes IRS-PI3K-IRS-1-PKC-AKT2 were significantly down-regulated, whilst PKC-α was upregulated significantly in both insulin-resistant cells and tissue animals. Interestingly, palmatine-treated cells/tissue/animals were able to reverse these effects. (5) Conclusions: Palmatine appears to have rejuvenated the impaired insulin signaling pathway through upregulation of the gene expression of IRS-1, PI3K, AKT2, and GLUT4 and downregulation of PKC-expression, according to in vitro, in vivo, and ex vivo studies.