Search Results (12)

Diabetic patients have a two- to four-fold increase in the risk of heart failure (HF), and the co-existence of diabetes and HF is associated with poor prognosis. In randomized clinical trials (RCTs), compelling evidence has demonstrated the beneficial effects of sodium-glucose co-transporter-2 inhibitors on HF. The mechanism includes increased glucosuria, restored tubular glomerular feedback with attenuated renin–angiotensin II–aldosterone activation, improved energy utilization, decreased sympathetic tone, improved mitochondria calcium homeostasis, enhanced autophagy, and reduced cardiac inflammation, oxidative stress, and fibrosis. The RCTs demonstrated a neutral effect of the glucagon-like peptide receptor agonist on HF despite its weight-reducing effect, probably due to it possibly increasing the heart rate via increasing cyclic adenosine monophosphate (cAMP). Observational studies supported the markedly beneficial effects of bariatric and metabolic surgery on HF despite no current supporting evidence from RCTs. Bromocriptine can be used to treat peripartum cardiomyopathy by reducing the harmful cleaved prolactin fragments during late pregnancy. Preclinical studies suggest the possible beneficial effect of imeglimin on HF through improving mitochondrial function, but further clinical evidence is needed. Although abundant preclinical and observational studies support the beneficial effects of metformin on HF, there is limited evidence from RCTs. Thiazolidinediones increase the risk of hospitalized HF through increasing renal tubular sodium reabsorption mediated via both the genomic and non-genomic action of PPARγ. RCTs suggest that dipeptidyl peptidase-4 inhibitors, including saxagliptin and possibly alogliptin, may increase the risk of hospitalized HF, probably owing to increased circulating vasoactive peptides, which impair endothelial function, activate sympathetic tones, and cause cardiac remodeling. Observational studies and RCTs have demonstrated the neutral effects of insulin, sulfonylureas, an alpha-glucosidase inhibitor, and lifestyle interventions on HF in diabetic patients. Full article

Type 2 diabetes mellitus is one of the most common diseases of the 21st century, caused by a sedentary lifestyle, poor diet, high blood pressure, family history, and obesity. To date, there are no known complete cures for type 2 diabetes. To identify bioactive natural products (NPs) to manage type 2 diabetes, the NPs from the ZINC15 database (ZINC-NPs DB) were screened using a 3D shape similarity search, molecular docking approaches, and ADMETox approaches. Frequently, in silico studies result in asymmetric structures as “hit” molecules. Therefore, the asymmetrical FDA-approved diabetes drugs linagliptin (8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dione), sitagliptin ((3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one), and alogliptin (2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]benzonitrile) were used as queries to virtually screen the ZINC-NPs DB and detect novel potential dipeptidyl peptidase-4 (DPP-4) inhibitors. The most promising NPs, characterized by the best sets of similarity and ADMETox features, were used during the molecular docking stage. The results highlight that 11 asymmetrical NPs out of 224,205 NPs are potential DPP-4 candidates from natural sources and deserve consideration for further in vitro/in vivo tests. Full article

The aim of the study was to design injectable long-acting poly (lactide-co-glycolide) (PLGA)-based in situ gel implants (ISGI) loaded with the anti-diabetic alogliptin. Providing sustained therapeutic exposures and improving the pharmacological responses of alogliptin were targeted for achieving reduced dosing frequency and enhanced treatment outputs. In the preliminary study, physicochemical characteristics of different solvents utilized in ISGI preparation were studied to select a proper solvent possessing satisfactory solubilization capacity, viscosity, water miscibility, and affinity to PLGA. Further, an optimization technique using a 2³ factorial design was followed. The blood glucose levels of diabetic rats after a single injection with the optimized formulation were compared with those who received daily oral alogliptin. N-methyl-2-pyrrolidone (NMP) and dimethyl sulfoxide (DMSO), as highly water-miscible and low viscous solvents, demonstrated their effectiveness in successful ISGI preparation and controlling the burst alogliptin release. The impact of increasing lactide concentration and PLGA amount on reducing the burst and cumulative alogliptin release was represented. The optimized formulation comprising 312.5 mg of PLGA (65:35) and DMSO manifested a remarkable decrease in the rats’ blood glucose levels throughout the study period in comparison to that of oral alogliptin solution. Meanwhile, long-acting alogliptin-loaded ISGI systems demonstrated their feasibility for treating type 2 diabetes with frequent dosage reduction and patient compliance enhancement. Full article

Diabetes mellitus is a major global health concern in the current scenario which is chiefly characterized by the rise in blood sugar levels or hyperglycemia. In the context, DPP4 enzyme plays a critical role in glucose homeostasis. DPP4 targets and inactivates incretin hormones such as glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) as physiological substrates, which are essential to regulate the amount of insulin that is secreted after eating. Since the inactivation of incretins occurs, the hyperglycemic conditions continue to rise, and result in adverse physiological conditions linked with diabetes mellitus. Hence, inhibition of DPP4 has been the center of focus in the present antidiabetic studies. Although few DPP4 inhibitor drugs, such as alogliptin, saxagliptin, linagliptin, and sitagliptin, are available, their adverse effects on human metabolism are undeniable. Therefore, it becomes essential for the phytochemical intervention of the disease using computational methods prior to performing in vitro and in vivo studies. In this regard, we used an in-silico approach involving molecular docking, molecular dynamics simulations, and binding free energy calculations to investigate the inhibitory potential of Ocimum tenuiflorum phytocompounds against DPP4. In this regard, three phytocompounds (1S-α-pinene, β-pinene, and dehydro-p-cymene) from O. tenuiflorum have been discovered as the potential inhibitors of the DPP4 protein. To summarize, from our in-silico experiment outcomes, we propose dehydro-p-cymene as the potential lead inhibitor of DPP4 protein, thereby discovering new a phytocompound for the effective management of hyperglycemia and diabetes mellitus. The reported compound can be taken for in vitro and in vivo analyses in near future. Full article

The nano-drug delivery system has gained greater acceptability for poorly soluble drugs. Alogliptin (ALG) is a FDA-approved oral anti-hyperglycemic drug that inhibits dipeptidyl peptidase-4. The present study is designed to prepare polymeric ALG nanoparticles (NPs) for the management of diabetes. ALG-NPs were prepared using the nanoprecipitation method and further optimized by Box–Behnken experimental design (BBD). The formulation was optimized by varying the independent variables Eudragit RSPO (A), Tween 20 (B), and sonication time (C), and the effects on the hydrodynamic diameter (Y1) and entrapment efficiency (Y2) were evaluated. The optimized ALG-NPs were further evaluated for in vitro release, intestinal permeation, and pharmacokinetic and anti-diabetic activity. The prepared ALG-NPs show a hydrodynamic diameter of between 272.34 nm and 482.87 nm, and an entrapment efficiency of between 64.43 and 95.21%. The in vitro release data of ALG-NPs reveals a prolonged release pattern (84.52 ± 4.1%) in 24 h. The permeation study results show a 2.35-fold higher permeation flux than pure ALG. ALG-NPs exhibit a significantly (p < 0.05) higher pharmacokinetic profile than pure ALG. They also significantly (p < 0.05) reduce the blood sugar levels as compared to pure ALG. The findings of the study support the application of ALG-entrapped Eudragit RSPO nanoparticles as an alternative carrier for the improvement of therapeutic activity. Full article

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as anti-hyperglycemic agents that improve glycemic control in type 2 diabetic patients, either as monotherapy or in combination with other antidiabetic drugs. Methods: A novel series of dihydropyrimidine phthalimide hybrids was synthesized and evaluated for their in vitro and in vivo DPP-4 inhibition activity and selectivity using alogliptin as reference. Oral glucose tolerance test was assessed in type 2 diabetic rats after chronic treatment with the synthesized hybrids ± metformin. Cytotoxicity and antioxidant assays were performed. Additionally, molecular docking study with DPP-4 and structure activity relationship of the novel hybrids were also studied. Results: Among the synthesized hybrids, 10g, 10i, 10e, 10d and 10b had stronger in vitro DPP-4 inhibitory activity than alogliptin. Moreover, an in vivo DPP-4 inhibition assay revealed that 10g and 10i have the strongest and the most extended blood DPP-4 inhibitory activity compared to alogliptin. In type 2 diabetic rats, hybrids 10g, 10i and 10e exhibited better glycemic control than alogliptin, an effect that further supported by metformin combination. Finally, 10j, 10e, 10h and 10d had the highest radical scavenging activity in DPPH assay. Conclusions: Hybrids 10g, 10i and 10e are potent DPP-4 inhibitors which may be beneficial for T2DM treatment. Full article

The authors in the current work suggested the potential repurposing of omarigliptin (OMR) for neurodegenerative diseases based on three new findings that support the preliminary finding of crossing BBB after a single dose study in the literature. The first finding is the positive results of the docking study with the crystal structures of A_2A adenosine (A2AAR) and acetylcholine esterase (AChE) receptors. A2AAR is a member of non-dopaminergic GPCR superfamily receptor proteins and has essential role in regulation of glutamate and dopamine release in Parkinson’s disease while AChE plays a major role in Alzheimer’s disease as the primary enzyme responsible for the hydrolytic metabolism of the neurotransmitter acetylcholine into choline and acetate. Docking showed that OMR perfectly fits into A2AAR binding pocket forming a distinctive hydrogen bond with Threonine 256. Besides other non-polar interactions inside the pocket suggesting the future of the marketed anti-diabetic drug (that cross BBB) as a potential antiparkinsonian agent while OMR showed perfect fit inside AChE receptor binding site smoothly because of its optimum length and the two fluorine atoms that enables quite lean fitting. Moreover, a computational comparative study of OMR docking, other 12 DPP-4 inhibitors and 11 SGLT-2 inhibitors was carried out. Secondly, glucagon-like peptide-1 (GLP-1) concentration in rats’ brain tissue was determined by the authors using sandwich GLP-1 ELISA kit bio-analysis to ensure the effect of OMR after the multiple doses’ study. Brain GLP-1 concentration was elevated by 1.9-fold following oral multiple doses of OMR (5 mg/kg/day, p.o. for 28 days) as compared to the control group. The third finding is the enhanced BBB crossing of OMR after 28 days of multiple doses that had been studied using LC-MS/MS method with enhanced liquid–liquid extraction. A modified LC-MS/MS method was established for bioassay of OMR in rats’ plasma (10–3100 ng/mL) and rats’ brain tissue (15–2900 ng/mL) using liquid–liquid extraction. Alogliptin (ALP) was chosen as an internal standard (IS) due to its LogP value of 1.1, which is very close to the LogP of OMR. Extraction of OMR from samples of both rats’ plasma and rats’ brain tissue was effectively achieved with ethyl acetate as the extracting solvent after adding 1N sodium carbonate to enhance the drug migration, while choosing acetonitrile to be the diluent solvent for the IS to effectively decrease any emulsion between the layers in the stated method of extraction. Validation results were all pleasing including good stability studies with bias of value below 20%. Concentration of OMR in rats’ plasma were determined after 2 h of the latest dose from 28 days multiple doses, p.o, 5 mg/kg/day. It was found to be 1295.66 ± 684.63 ng/mL estimated from the bio-analysis regression equation. OMR passed through the BBB following oral administration and exhibited concentration of 543.56 ± 344.15 ng/g in brain tissue, taking in consideration the dilution factor of 10. The brain/plasma concentration ratio of 0.42 (543.56/1295.66) was used to illustrate the penetration power through the BBB after the multiple doses for 28 days. Results showed that OMR passed through the BBB more effectively in the multiple dose study as compared to the previously published single dose study by the authors. Thus, the present study suggests potential repositioning of OMR as antiparkinsonian agent that will be of interest for researchers interested in neurodegenerative diseases. Full article

Enhancing drug extraction from human plasma is a challenging approach that critically affects pharmacokinetic and any further clinical studies based on the drug C_min and C_max values. It also has a serious impact on the sensitivity and the lower limit of quantification (LLOQ) value of the bio-analytical methods. An advanced liquid chromatography tandem mass spectrometry (LC-MS/MS) bio-analytical method of omarigliptin (25–1000 nM) was established in human plasma using one-step liquid-liquid extraction. Alogliptin was used as an internal standard (IS) to attain good recovery and reproducibility while reducing the effects of the matrix. Enhanced plasma extraction of omarigliptin was successfully achieved with tertiary butyl methyl ether—diethyl ether (TBME-DEE) mixture as the extracting solvent, while using acetonitrile as the diluent solvent for the IS to effectively decrease the formed emulsion. Multiple Reaction Monitoring (MRM) of the transition pairs of m/z 399.2 to 153.0 for omarigliptin and m/z 340.2 to 116.0 for alogliptin was employed in positive Electro Spray Ionization (ESI) mode. Human plasma samples were collected after 1.5 h (t_max) of Marizev^® (12.5 mg) tablets administration to healthy human volunteers showing average concentration of 292.18 nM. Validation results were all satisfactory including successful stability studies with bias below 12%. The proposed study will be valuable for ethnicity comparison studies that will be commenced on omarigliptin in Egypt by the authors in prospective study, following the FDA recommends, to evaluate possible sub-group dissimilarities that include pharmacokinetic parameters. Full article

Despite a similar mechanism of action underlying their glucose-lowering effects in type 2 diabetes, dipeptidyl peptidase-4 (DPP-4) inhibitors have diverse molecular structures, raising the prospect of agent-specific, glucose-independent actions. To explore the issue of possible DPP-4 inhibitor cardiac heterogeneity, we perfused different DPP-4 inhibitors to beating mouse hearts ex vivo, at concentrations equivalent to peak plasma levels achieved in humans with standard dosing. We studied male and female mice, young non-diabetic mice, and aged diabetic high fat diet-fed mice and observed that linagliptin enhanced recovery after ischemia-reperfusion, whereas sitagliptin, alogliptin, and saxagliptin did not. DPP-4 transcripts were not detected in adult mouse cardiomyocytes by RNA sequencing and the addition of linagliptin caused ≤0.2% of cardiomyocyte genes to be differentially expressed. In contrast, incubation of C166 endothelial cells with linagliptin induced cell signaling characterized by phosphorylation of Akt and endothelial nitric oxide synthase, whereas the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine increased serine 16 phosphorylation of the calcium regulatory protein, phospholamban in cardiomyocytes. Furthermore, linagliptin increased cardiomyocyte cGMP when cells were co-cultured with C166 endothelial cells, but not when cardiomyocytes were cultured alone. Thus, at a concentration comparable to that achieved in patients, linagliptin has direct effects on mouse hearts. The effects of linagliptin on cardiomyocytes are likely to be either off-target or indirect, mediated through NO generation by the adjacent cardiac endothelium. Full article

Diabetes mellitus is a severe health problem in Mexico, and its prevalence is increasing exponentially every year. Recently, DPP-4 (dipeptidyl peptidase-4) inhibitors have become attractive oral anti-hyperglycemic agents to reduce the pathology of diabetes. Gliptin’s family, such as sitagliptin, vildagliptin, and alogliptin, are in clinical use to treat diabetes mellitus but possess side effects. Therefore, there is a specific need to look for new therapeutic scaffolds (biomolecules). Garlic bulb is widely used as a traditional remedy for the treatment of diabetes. The garlic extracts are scientifically proven to control glucose levels in patients with diabetes, despite the unknown mechanism of action. The aim of the study is to investigate the antidiabetic effects of ultrasonication assisted garlic bulb extract. To achieve this, in-vitro assays such as DPP-4 inhibitory and antioxidant activities were investigated. Further, functional group analysis using FTIR and identification of phytochemicals using mass spectrometry analysis was performed. The results showed that 70.9 µg/mL of garlic bulb extract inhibited 50% DPP-4 activity. On top of that, the garlic extract exhibited a 20% scavenging activity, equivalent to 10 µg/mL of ascorbic acid. Molecular docking simulations on identified phytochemicals using mass spectrometry revealed their potential binding at the DPP-4 druggable region, and therefore the possible DPP-4 inhibition mechanism. These results suggest that prepared garlic extract contains phytochemicals that inhibit DPP-4 and have antioxidant activity. Also, the prepared extract induces skeletal muscle cell proliferation that demonstrates the antidiabetic effect and its possible mechanism of action. Full article

A drug repurposing strategy could be a potential approach to overcoming the economic costs for diabetes mellitus (DM) treatment incurred by most countries. DM has emerged as a global epidemic, and an increase in the outbreak has led developing countries like Mexico, India, and China to recommend a prevention method as an alternative proposed by their respective healthcare sectors. Incretin-based therapy has been successful in treating diabetes mellitus, and inhibitors like sitagliptin, vildagliptin, saxagliptin, and alogliptin belong to this category. As of now, drug repurposing strategies have not been used to identify existing therapeutics that can become dipeptidyl peptidase-4 (DPP-4) inhibitors. Hence, this work presents the use of bioinformatics tools like the Activity Atlas model, flexible molecular docking simulations, and three-dimensional reference interaction site model (3D-RISM) calculations to assist in repurposing Food and Drug Administration (FDA)-approved drugs into specific nonsteroidal anti-inflammatory medications such as DPP-4 inhibitors. Initially, the Activity Atlas model was constructed based on the top scoring DPP-4 inhibitors, and then the model was used to understand features of nonsteroidal anti-inflammatory drugs (NSAIDs) as a function of electrostatic, hydrophobic, and active shape features of DPP-4 inhibition. The FlexX algorithm was used to infer protein–ligand interacting residues, and binding energy, to predict potential draggability towards the DPP-4 mechanism of action. 3D-RISM calculations on piroxicam-bound DPP-4 were used to understand the stability of water molecules at the active site. Finally, piroxicam was chosen as the repurposing drug to become a new DPP-4 inhibitor and validated experimentally using fluorescence spectroscopy assay. These findings are novel and provide new insights into the role of piroxicam as a new lead to inhibit DPP-4 and, taking into consideration the biological half-life of piroxicam, it can be proposed as a possible therapeutic strategy for treating diabetes mellitus. Full article

Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes mellitus and accounts for about 95% of all diabetes cases. Many newer oral as well as parenteral antidiabetic drugs have been introduced in to the market in recent years to control hyperglycemic conditions in diabetes patients and many of these drugs produce potential side effects in diabetes patients. Hence, this systematic review was aimed to analyze and compare the efficacy and safety of oral antidiabetic agents in controlling HbA1c in T2DM patients, that were approved by the United States-Food and Drug Administration (US-FDA) from 2013 to 2017. All randomized controlled, double-blind trials published in English during the search period involving the newer antidiabetic agents were selected. In the outcome assessment comparison, semaglutide demonstrated the highest efficacy in lowering HbA1c, with a 1.6% reduction (p < 0.0001) when given at a dose of 1.0 mg. The safety profile of all the agents as compared to placebo or control were similar, with no or slight increase in the occurrence of adverse events (AEs) but no fatal reaction was reported. The most common AEs of all the antidiabetic agents were gastrointestinal in nature, with several cases of hypoglycemic events. However, among all these agents, semaglutide seems to be the most efficacious drug to improve glycemic control in terms of HbA1c. Alogliptin has the least overall frequency of AEs compared to other treatment groups. Full article