Salivary Proteome and Intact N-Glycopeptides Analysis Reveal Specific Signatures in Periodontitis.

Periodontitis is a prevalent oral inflammatory disease that can result in tooth loss and is closely linked to type 2 diabetes (T2D). In this study, we analyzed the salivary proteome and intact N-glycopeptides (IGPs) of individuals with mild-moderate, severe, aggressive periodontitis, and periodontitis with T2D, including those treated with antidiabetic drugs, to identify specific signatures associated with the disease. Our results revealed that salivary proteins and glycoproteins were altered in all periodontitis groups (PRIDE ID: 1-20230612-72345), with fucose- and sialic acid-containing N-glycans showing the greatest increase. Additionally, differentially expressed proteins were classified into 9 clusters, including those that were increased in all periodontitis groups and those that were only altered in certain types of periodontitis. Interestingly, treatment with antidiabetic drugs reversed many of the changes observed in the salivary proteome and IGPs in T2D-related periodontitis, suggesting a potential therapeutic approach for managing periodontitis in patients with T2D. Consistent with MS/MS results, the expression of salivary IGHA2 and Fucα1-3/6GlcNAc (AAL) was significantly increased in MP. These findings provide new insights into the pathogenesis of periodontitis and highlight the potential of salivary biomarkers for diagnosis, prognosis, and monitoring of disease progression and treatment response.

Pramlintide an Adjunct to Insulin Therapy: Challenges and Recent Progress in Delivery.

Dysregulation of various glucoregulatory hormones lead to failure of insulin monotherapy in patients with diabetes mellitus due to various reasons, including severe hypoglycemia, glycemic hypervariability, and an increased risk of microvascular complications. However, pramlintide as an adjunct to insulin therapy enhances glucagon suppression and thereby offers improved glycemic control. Clinical studies have shown that pramlintide improves glycemic control, reduces postprandial glucose excursions, and promotes weight loss in patients with type 1 and type 2 diabetes. Although clinical benefits of pramlintide are well reported, there still exists a high patient resistance for the therapy, as separate injections for pramlintide and insulin must be administered. Although marketed insulin formulations generally demonstrate a peak action in 60-90 minutes, pramlintide elicits its peak concentration at around 20-30 minutes after administration. Thus, owing to the significant differences in pharmacokinetics of exogenously administered pramlintide and insulin, the therapy fails to elicit its action otherwise produced by the endogenous hormones. Hence, strategies such as delaying the release of pramlintide by using inorganic polymers like silica, synthetic polymers like polycaprolactone, and lipids have been employed. Also, approaches like noncovalent conjugation, polyelectrolyte complexation, and use of amphiphilic excipients for codelivery of insulin and pramlintide have been explored to address the issues with pramlintide delivery and improve patient adherence to the therapy. This approach may usher in a new era of diabetes management, offering patients multiple options to tailor their treatment and improve their quality of life. SIGNIFICANCE STATEMENT: To our knowledge, this is the first report that summarizes various challenges in insulin and pramlintide codelivery and strategies to overcome them. The paper also provides deeper insights into various novel formulation strategies for pramlintide that could further broaden the reader's understanding of peptide codelivery.

Zinc-Phthalocyanine Loaded PLGA-PVA-Chitosan Nanosystem for the Enhancement of Antidiabetic Activity.

Zinc, one of the most common nutraceutical agents, proved to be effective for diabetes as it regulates the blood glucose level by inhibiting glucagon secretion. However, the hepatotoxicity of zinc creates necrosis, hepatic glycogen depletion, and apoptosis of hepatocytes at the concentration of 10 µg/kg. Phthalocyanine, a blue-colored compound, is an aromatic macrocyclic compound with good antioxidant ability owing to its heterocyclic nitrogen conjugation. The conjugation of zinc with phthalocyanine aimed to reduce the toxicity associated with zinc and enhance the antidiabetic activity at a lower dose. Hence, the present research work possessed the insights of the synthetic aspect of zinc with phthalocyanine along with its entrapment in the poly(lactic-co-glycolic acid) (PLGA)-chitosan nanosystem via oral administration in the treatment of diabetes. A nanoprecipitation technique was implemented for the synthesis of PLGA chitosan nanoparticles, and formulation was further optimized using a central composite design. Twenty trials provided by the software selected optimum concentrations of PLGA, poly(vinyl alcohol) (PVA), and chitosan in consideration with particle size up to 335.6 nm, zeta potential 27.87 mV, and entrapment efficiency of 75.67 ± 8.13%. Addition of chitosan to the nanocarrier system for controlling the release of the drug for 3 days was accompanied by the improvement in the glucose level within 28 days. The delivery of the nanoparticles showed enhancement in the cholesterol, triglyceride, alkaline phosphatase (ALP), urine parameters, and pro-inflammatory cytokines. The application of DoE (design of experiments) for the optimization of the nanoparticles established a controlled release formulation for diabetes, which displayed safety and effectiveness in streptozotocin (STZ)-induced diabetic rats.

Pioglitazone Phases and Metabolic Effects in Nanoparticle-Treated Cells Analyzed via Rapid Visualization of FLIM Images.

Fluorescence lifetime imaging microscopy (FLIM) has proven to be a useful method for analyzing various aspects of material science and biology, like the supramolecular organization of (slightly) fluorescent compounds or the metabolic activity in non-labeled cells; in particular, FLIM phasor analysis (phasor-FLIM) has the potential for an intuitive representation of complex fluorescence decays and therefore of the analyzed properties. Here we present and make available tools to fully exploit this potential, in particular by coding via hue, saturation, and intensity the phasor positions and their weights both in the phasor plot and in the microscope image. We apply these tools to analyze FLIM data acquired via two-photon microscopy to visualize: (i) different phases of the drug pioglitazone (PGZ) in solutions and/or crystals, (ii) the position in the phasor plot of non-labelled poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), and (iii) the effect of PGZ or PGZ-containing NPs on the metabolism of insulinoma (INS-1 E) model cells. PGZ is recognized for its efficacy in addressing insulin resistance and hyperglycemia in type 2 diabetes mellitus, and polymeric nanoparticles offer versatile platforms for drug delivery due to their biocompatibility and controlled release kinetics. This study lays the foundation for a better understanding via phasor-FLIM of the organization and effects of drugs, in particular, PGZ, within NPs, aiming at better control of encapsulation and pharmacokinetics, and potentially at novel anti-diabetics theragnostic nanotools.

Improvement of liraglutide release from PLGA microspheres by a porous microsphere-gel composite system.

In the current work, we aimed to prepare a liraglutide-loaded porous microsphere-gel composite system. By employing polyethylene glycol (PEG) as a porogenic agent and poly (lactic-co-glycolic acid) copolymer (PLGA) as a carrier, the liraglutide microspheres were prepared and dispersed in a temperature-sensitive gel made of poloxamer 407 (F-127) and poloxamer 188 (F-68), which served as the gel matrix, to construct the composite system. The porous microsphere-gel composite system demonstrated prolonged and steady drug release, with a reduction to 4.7% in the initial release within 1 d, according to data from in vitro release tests. The drug release from the porous microspheres decreased from 53% to 29% during the rapid release phase as the PEG concentration increased and the release rate slowed down. In vivo experiments in rats revealed that the composite system prolonged the release period by about 10 d. The pharmacokinetic parameter AUC0-1 was decreased by 24.78 ng/ml*h, the initial burst release was decreased, and the blood drug concentration fluctuation was lessened. The construction of a porous microsphere-gel composite matrix offers a novel approach to the systems with a sustained, long-lasting release that utilizes rational design.

Formulation of Saxagliptin Oral Films: Optimization, Physicochemical Characterization, In-Vivo Assessment, and In-Vitro Real-Time Release Monitoring via a Novel Polyaniline Nanoparticles-Based Solid-Contact Screen Printed Ion-Selective Electrode.

Oral dispersible films have received broad interest due to fast drug absorption and no first-path metabolism, leading to high bioavailability and better patient compliance. Saxagliptin (SXG) is an antidiabetic drug that undergoes first-path metabolism, resulting in a less active metabolite, so the development of SXG oral dispersible films (SXG-ODFs) improves SXG bioavailability. The formula optimisation included a response surface experimental design and the impact of three formulation factors, the type and concentration of polymer and plasticiser concentration on in-vitro disintegration time and folding endurance. Two optimised SXG-ODFs prepared using either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose were investigated. SXG-ODFs prepared with PVA demonstrated a superior rapid disintegration time, ranging from 17 to 890 s, with the fastest disintegration time recorded at 17 s. These short durations can be attributed to the hydrophilic nature of PVA, facilitating rapid hydration and disintegration upon contact with saliva. Additionally, PVA-based films displayed remarkable folding endurance, surpassing 200 folds without rupture, indicating flexibility and stability. The high tensile strength of PVA-based films further underscores their robust mechanical properties, with tensile strength values reaching up to 4.53 MPa. SXG exhibits a UV absorption wavelength of around 212 nm, posing challenges for traditional quantitative spectrophotometric analysis, so a polyaniline nanoparticles-based solid-contact screen-printed ion-selective electrode (SP-ISE) was employed for the determination of SXG release profile effectively in comparison to HPLC. SP-ISE showed a better real-time release profile of SXG-ODFs, and the optimised formula showed lower blood glucose levels than commercial tablets.

Repurposing Metformin for periodontal disease management as a form of oral-systemic preventive medicine.

BACKGROUND: Despite the improvements in treatment over the last decades, periodontal disease (PD) affects millions of people around the world and the only treatment available is based on controlling microbial load. Diabetes is known to increase the risk of PD establishment and progression, and recently, glucose metabolism modulation by pharmaceutical or dietarian means has been emphasised as a significant modulator of non-communicable disease development. METHODS: The impact of pharmaceutically controlling glucose metabolism in non-diabetic animals and humans (REBEC, UTN code: U1111-1276-1942) was investigated by repurposing Metformin, as a mean to manage periodontal disease and its associated systemic risk factors. RESULTS: We found that glucose metabolism control via use of Metformin aimed at PD management resulted in significant prevention of bone loss during induced periodontal disease and age-related bone loss in vivo. Metformin also influenced the bacterial species present in the oral environment and impacted the metabolic epithelial and stromal responses to bacterial dysbiosis at a single cell level. Systemically, Metformin controlled blood glucose levels and age-related weight gain when used long-term. Translationally, our pilot randomized control trial indicated that systemic Metformin was safe to use in non-diabetic patients and affected the periodontal tissues. During the medication window, patients showed stable levels of systemic blood glucose, lower circulating hsCRP and lower insulin levels after periodontal treatment when compared to placebo. Finally, patients treated with Metformin had improved periodontal parameters when compared to placebo treated patients. CONCLUSION: This is the first study to demonstrate that systemic interventions using Metformin in non-diabetic individuals aimed at PD prevention have oral-systemic effects constituting a possible novel form of preventive medicine for oral-systemic disease management.

Combined Experimental and Computational Study of V-Substituted Lindqvist Polyoxotungstate: Screening by Docking for Potential Antidiabetic Activity.

In the current work, a novel vanadotungstate compound, (C6H9N2)4[V2W4O19]·2H2O (1), is isolated by a simple stepwise synthesis method and characterized by a combined experimental and computational study. Molecular docking is conducted for the first time for this kind of substituted Lindqvist polyoxometalates to elucidate for potential antidiabetic activity. Hence, the modeling results revealed a significant docking score of the reported compound to bind to the active sites of α-glucosidase with the lowest binding energy of -5.7 kcal/mol, where the standard drug acarbose (ACB) had -4.6 kcal/mol binding energy. The stability of binding was enhanced by strong H-bonding, van der Waals, and electrostatic interactions occurring in the three-dimensional (3D) supramolecular network of polyanionic vanadotungstate subunits templated with organic moieties as shown by X-ray diffraction and Hirshfeld analyses. Furthermore, density functional theory (DFT) calculations supported with photophysical measurements are also discussed to predict the most chemical and biological reactivity. In this view, the complete description of electronic and biological features of (1) is enhanced by determination of the highest occupied molecular orbital (HOMO)/least unoccupied molecular orbital (LUMO) energy, electronic density, ionization potential, electron affinity, etc. These chemical descriptors, intermolecular interactions, docking score, and binding free energy estimation are essential in understanding the reactivity of this bioactive compound offering potential inhibition of the α-glucosidase enzyme.

Orthogonal Reversed-Phase C18 and Pentafluorophenyl HPLC Separation for Phytochemical Profiling of Serrulatanes in Eremophila denticulata.

Serrulatanes constitute a class of unique diterpenoids derived from all-Z nerylneryl diphosphate rather than the conventional all-E diterpenoid precursor geranylgeranyl diphosphate and thus provide an intriguing expansion of the chemical space of plant specialized metabolites. Plants of the Australian Eremophila genus are rich sources of structurally diverse serrulatanes. Here, we report the identification of 15 hitherto undescribed serrulatanes (eremoculatanes A-N), together with 16 previously reported compounds, from the EtOAc extract of Eremophila denticulata leaves. Isolation was performed by a combined use of systematic HPLC-PDA-HRMS-based phytochemical profiling and orthogonal reversed-phase C18 and pentafluorophenyl separations. Among the new compounds isolated, eremoculatane A contains a C12 backbone, for which the configuration was established by comparison of experimentally measured and theoretically calculated ECD spectra. The antihyperglycemic and antibacterial activities of the E. denticulata extract were investigated by high-resolution inhibition profiling, and they indicated that major constituents, mainly serrulatanes and flavonoids, contributed to the observed activity of the extract. One flavonoid, eupafolin (4), displayed moderate α-glucosidase inhibitory activity with an IC50 value of 41.3 µM, and four serrulatanes (8, 9, 19g, and 19j) showed more than 50% PTP1B inhibition at 200 µM.

A Novel Drug Delivery System: Hyodeoxycholic Acid-Modified Metformin Liposomes for Type 2 Diabetes Treatment.

Metformin is a first-line drug for the clinical treatment of type 2 diabetes; however, it always leads to gastrointestinal tolerance, low bioavailability, short half-life, etc. Liposome acts as an excellent delivery system that could reduce drug side effects and promote bioavailability. Hyodeoxycholic acid, a cholesterol-like structure, can regulate glucose homeostasis and reduce the blood glucose levels. As an anti-diabetic active ingredient, hyodeoxycholic acid modifies liposomes to make it overcome the disadvantages of metformin as well as enhance the hypoglycemic effect. By adapting the thin-film dispersion method, three types of liposomes with different proportions of hyodeoxycholic acid and metformin were prepared (HDCA:ME-(0.5:1)-Lips, HDCA:ME-(1:1)-Lips, and HDCA:ME-(2:1)-Lips). Further, the liposomes were characterized, and the anti-type 2 diabetes activity of liposomes was evaluated. The results from this study indicated that three types of liposomes exhibited different characteristics-Excessive hyodeoxycholic acid decreased encapsulation efficiency and drug loading. In the in vivo experiments, liposomes could reduce the fasting blood glucose levels, improve glucose tolerance, regulate oxidative stress markers and protect liver tissue in type 2 diabetic mice. These results indicated that HDCA:ME-(1:1)-Lips was the most effective among the three types of liposomes prepared and showed better effects than metformin. Hyodeoxycholic acid can enhance the hypoglycemic effect of metformin and play a suitable role as an excipient in the liposome.

Green polymer altered in-situ gel oral liquid sustainable release preparation of vildagliptin suitable for dysphagic diabetic patients: assessment in-vitro & in-vivo.

PURPOSE: This work aimed to fabricate alginate based in-situ gelling matrix of vildagliptin improved by calcium and carboxy methyl cellulose (CMC) for appropriate adjustment of the onset and duration of action. This easy-to-swallow thickened liquid preparation aimed to improve compliance for dysphagic or elderly diabetic patients. METHODS: Vildagliptin dispersions containing alginate were fabricated in the presence or absence of calcium chloride to assess the effect of calcium ion, then a matrix containing 1.5% w/v of sodium alginate with calcium was further examined after the addition of CMC with different concentrations ranging from 0.1% to 0.3%. The viscosity, gelling forming property, Differential scanning calorimetry, and in-vitro drug release were assessed before monitoring the hypoglycemic effect of the selected formulation. RESULTS: In-situ gel matrixes were fabricated at gastric pH with and without calcium ions. The best formula concerning viscosity and the gel-forming property was achieved with higher CMC concentrations, which in turn decreased the rate of vildagliptin release in stimulated gastric pH. In-vivo results confirmed the extended hypoglycemic effect of the vildagliptin in-situ gelling matrix compared to the vildagliptin aqueous solution. CONCLUSION: This study represents a green polymeric-based in-situ gel as a liquid oral retarded release preparation intended for reducing dose frequency, easier administration of vildagliptin, and improving compliance in geriatric and dysphagic diabetic patients.

Effects of Nonsurgical Periodontal Therapy on Glycemic Control in Diabetic Patients under Systemic Administration of Antidiabetic Ayurvedic Drug.

AIM: This study aimed to monitor the metabolic response of nonsurgical periodontal therapy in type-2 diabetic patients with chronic periodontitis under systemic administration of antidiabetic ayurvedic drug. MATERIALS AND METHODS: About 90 newly diagnosed mild-to-moderate forms of type-2 diabetes mellitus (DM) subjects with generalized chronic periodontitis were selected according to the inclusion and exclusion criteria and were randomly divided into group A and group B with 45 patients in each group. Clinical parameters, including plaque index, probing pocket depth, clinical attachment level, and glycemic status, were assessed at baseline. Following initial periodontal clinical examination, the drug Nishamalaki (NA) 2 gm twice daily for 3 months was prescribed after food by an Ayurvedic physician to all the patients enrolled in group A and group B, and scaling and root planing were completed only for group B patients. Patients were recalled for review, and all the parameters were reassessed at the end of the 1st, 2nd, and 3rd months following interventions. RESULTS: Regarding clinical and metabolic parameters at baseline, no statistically significant differences were displayed between the two groups. However, at the 3-months follow-up period, the patients in group B demonstrated significantly better clinical and metabolic outcomes than patients in group A. CONCLUSION: Periodontal therapy improved glycemic control in patients with type-2 DM in both groups; however, the reduction in FBS values reached statistical significance only in the group receiving scaling and root planing alone. CLINICAL SIGNIFICANCE: Nonsurgical periodontal therapy may have a beneficial effect on the periodontal clinical and glycemic levels in type-2 diabetic patients with chronic periodontitis.

Surface Adsorption-Mediated Ultrahigh Efficient Peptide Encapsulation with a Precise Ratiometric Control for Type 1 and 2 Diabetic Therapy.

A surface adsorption strategy is developed to enable the engineering of microcomposites featured with ultrahigh loading capacity and precise ratiometric control of co-encapsulated peptides. In this strategy, peptide molecules (insulin, exenatide, and bivalirudin) are formulated into nanoparticles and their surface is decorated with carrier polymers. This polymer layer blocks the phase transfer of peptide nanoparticles from oil to water and, consequently, realizes ultrahigh peptide loading degree (up to 78.9%). After surface decoration, all three nanoparticles are expected to exhibit the properties of adsorbed polymer materials, which enables the co-encapsulation of insulin, exenatide, and bivalirudin with a precise ratiometric control. After solidification of this adsorbed polymer layer, the release of peptides is synchronously prolonged. With the help of encapsulation, insulin achieves 8 days of glycemic control in type 1 diabetic rats with one single injection. The co-delivery of insulin and exenatide (1:1) efficiently controls the glycemic level in type 2 diabetic rats for 8 days. Weekly administration of insulin and exenatide co-encapsulated microcomposite effectively reduces the weight gain and glycosylated hemoglobin level in type 2 diabetic rats. The surface adsorption strategy sets a new paradigm to improve the pharmacokinetic and pharmacological performance of peptides, especially for the combination of peptides.

Weight-Based Insulin During and After Intravenous Insulin Infusion Reduces Rates of Rebound Hyperglycemia When Transitioning to Subcutaneous Insulin in the Medical Intensive Care Unit.

OBJECTIVE: Hyperglycemia often occurs after the transition from intravenous insulin infusion (IVII) to subcutaneous insulin. Weight-based basal insulin initiated earlier in the course of IVII in the medical intensive care unit (MICU), and a weight-based basal-bolus regimen after IVII, can potentially improve post-IVII glycemic control by 48 hours. METHODS: This prospective study included 69 patients in MICU who were on IVII for ≥24 hours. Exclusions were end-stage renal disease, type 1 diabetes mellitus, and the active use of vasopressors. The intervention group received weight-based basal insulin (0.2-0.25 units/kg) with IVII and weight-based bolus insulin after IVII. The control group received current care. The primary end points were glucose levels at specific time intervals up to 48 hours after IVII. RESULTS: There were 25 patients in the intervention group and 44 in the control group. The mean age of the patients was 59 ± 15 years, 32 (47%) were men, and 52 (78%) had prior diabetes mellitus. The 2 groups were not different (acute kidney injury/chronic kidney disease, pre-existing diabetes mellitus, illness severity, or nothing by mouth status after IVII), except for the steroid use, which was higher in the control group than in the intervention group (34% vs 12%, respectively). Glucose levels were not lower until 36 to 48 hours after IVII (166.8 ± 39.1 mg/dL vs 220.0 ± 82.9 mg/dL, P < .001). When controlling for body mass index, nutritional status, hemoglobin A1C, and steroid use, glucose level was lower starting at 12 to 24 hours out (166.87 mg/dL vs 207.50 mg/dL, P = .015). The frequency of hypoglycemia was similar between the 2 groups (5.0% vs 7.1%). The study did not reach target enrollment. CONCLUSION: The addition of weight-based basal insulin during, and basal-bolus insulin immediately after, IVII in MICU results in better glycemic control at 24 hours after IVII with no increased hypoglycemia.

Preparation, in vitro and in vivo evaluation of pinocembrin-loaded TPGS modified liposomes with enhanced bioavailability and antihyperglycemic activity.

PURPOSE: To prepare polyethylene glycol succinate-vitamin E modified pinocembrin (PCB)-loaded liposomes (PCBT-liposomes) and evaluate PCBT-liposomal pharmacokinetics and antihyperglycemic activity. SIGNIFICANCE: The novel PCBT-liposomes demonstrated a promising application prospect as a nano drug carrier for future research. METHODS: Thin film dispersion was used to prepare PCBT-liposomes. We measured a series of characterization, followed by in vitro cumulative release, in vivo pharmacokinetic study, and antihyperglycemic activity evaluation. RESULTS: PCBT-liposomes displayed spherical and bilayered nanoparticles with mean particle size (roughly 92 nm), negative zeta potential (about -26.650 mV), high drug encapsulation efficiency (87.32 ± 1.34%) and good storage (at 4 or 25 °C) stability during 48 h after hydration. The cumulative release rate of PCBT-liposomes was markedly higher than free PCB in four different pH media. In vivo investigation showed that PCBT-liposomes could obviously improve oral bioavailability of PCB by 1.96 times, whereas the Cmax, MRT0-t, and T1/2 of PCBT-liposomes were roughly 1.700 ± 0.139 µg·mL-1, 12.695 ± 1.647 h, and 14.244 h, respectively. In terms of biochemical analysis, aspartate amino-transferase (AST), alanine amino-transferase (ALT), interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α) concentrations in serum of diabetic mice were respectively decreased 28.28%, 17.23%, 17.77%, and 8.08% after PCBT-liposomal treatment. CONCLUSION: These results show PCBT-liposomal preparation as an excellent nano-carrier which has the potential to improve water solubility, bioavailability, and antihyperglycemic activity of PCB, amid broadening the application of PCB in the clinical settings.

Novel strategies to oral delivery of insulin: Current progress of nanocarriers for diabetes management.

Diabetes mellitus is one of the most serious public health problems in the world. Repeated daily injections of subcutaneous insulin is the standard treatment for patients with type 1 diabetes mellitus; however, subcutaneous insulin injections can potentially cause local discomfort, patient noncompliance, hypoglycemia, failure to regulate glucose homeostasis, infections, and fat deposits at the injection sites. In recent years, numerous attempts have been made to produce safe and efficient nanoparticles for oral insulin delivery. Oral administration is considered the most effective alternative route to insulin injection, but it is accompanied by several challenges related to enzymatic proteolysis, digestive breakdown, and absorption barriers. A number of natural and synthetic polymeric, lipid-based, and inorganic nanoparticles have been investigated for use. Although improvements have recently been made in potential oral insulin delivery systems, these require further investigation before clinical trials are conducted. In this review, new approaches to oral insulin delivery for diabetes treatment are discussed, including polymeric, lipid-based, and inorganic nanoparticles, as well as the clinical trials performed for this purpose.

Formulation, Characterization, and Evaluation of Eudragit-Coated Saxagliptin Nanoparticles Using 3 Factorial Design Modules.

Background and Introduction: Saxagliptin is a hypoglycemic drug that acts as a dipeptidyl peptidase-4 (DPP-4) inhibitor and is preferably used in the treatment of Type 2 Diabetes Mellitus (T2DM). It is safe and tolerable; however, the major disadvantage associated with it is its low bioavailability. Aim: The present research aimed to enhance the bioavailability of the drug by enteric coating with a polymer that controls the rate of drug delivery, and it was prepared as Solid Lipid Nanoparticles (SLNs). Methodology: In the current study, various SLN formulations were developed using a central composite design (CCD) module using Design Expert-11 software. A modified solvent injection technique was used to prepare Saxagliptin nanoparticles coated with Eudragit RS100. The CCD was used to determine the independent variables and their effect on dependent variables at varied levels. Evaluation studies such as particle size analysis, Zeta potential, polydispersity index (PDI), drug loading, entrapment efficiency, in-vitro drug release studies, and in vivo pharmacokinetic studies were performed for the optimized SLN formulation. The reversed-phase HPLC method was developed and validated for the estimation of the pharmacokinetic parameters of the pure drug and prepared SLNs. Results: The effect of independent variables (A1: amount of lipid, A2: amount of polymer, A3: surfactant concentration, and A4: homogenization speed) on dependent variables (R1: particle size, and R2: entrapment efficiency) was established in great detail. Observed responses of the prepared and optimized Saxagliptin SLN were close to the predicted values by the CCD. The prepared SLNs depicted particle sizes in the range of 212-442 nm. The particle size analysis results showed that an increase in the lipid concentration led to an increase in particle size. The developed bioanalytical method was noted to be very specific and robust. The method accuracy varied from 99.16% to 101.95% for intraday, and 96.08% to 103.12% for inter day operation at low (5 mcg/mL), moderate (10 mcg/mL), and higher (15 mcg/mL) drug concentrations. The observed Zeta potential values for the prepared SLNs were in the range of -41.09 ± 0.11 to 30.86 ± 0.63 mV suggesting quite good stability of the SLNs without any aggregation. Moreover, the polydispersity indices were in the range of 0.26 ± 0.051 to 0.45 ± 0.017, indicative of uniformity of sizes among the prepared SLNs. In vivo study outcomes proved that Saxagliptin oral bioavailability significantly enhanced in male Albino Wistar Rats via SLN formulation and Eudragit RS100 coating approach. Conclusions: The developed and optimized Saxagliptin SLNs revealed enhanced Saxagliptin bioavailability in comparison to the native drug. Thus, this formulation strategy can be of great importance and can be implied as a promising approach to enhance the Saxagliptin bioavailability for facilitated T2DM therapy.

Revisiting the Nutritional, Chemical and Biological Potential of Cajanus cajan (L.) Millsp.

The genus Cajanus (Family: Fabaceae) consists of approximately 37 species, and Cajanus cajan (C. cajan) is a significant member of the genus. It is a commercial legume crop widely grown in sub-tropical and semi-arid tropical areas of the world. C. cajan is well known for its folk medicinal uses to treat various disorders, such as toothache, dizziness, diabetes, stomachache, female ailments and chronic infections. These properties have been linked to the presence of several value-added nutritional and bioactive components. Different solvent extracts from C.cajan (leaves, root, stem and seeds) have been evaluated for their phytochemical and biological activities, namely antioxidant, antimicrobial, antidiabetic, neuroprotective, and anti-inflammatory effects. Taken together, and considering the prominent nutraceutical and therapeutic properties of C. cajan, this review article focuses on the important details including ethnomedicinal uses, chemical composition, biological applications and some other medicinal aspects related to C.cajan nutraceutical and pharmacological applications.

mPEG2k-PCLx Polymeric Micelles Influence Pharmacokinetics and Hypoglycemic Efficacy of Metformin through Inhibition of Organic Cation Transporters in Rats.

Increasing evidence has shown that nanocarriers have effects on several efflux drug transporters. To date, little is known about whether influx transporters are also modulated. Herein, we investigated the impact of amphiphilic polymer micelles on the uptake function of organic cation transporters (OCTs) and the influence on the pharmacokinetics and pharmacodynamics of metformin, a well-characterized substrate of OCTs. Five types of polymeric micelles (mPEG2k-PCL2k, mPEG2k-PCL3.5k, mPEG2k-PCL5k, mPEG2k-PCL7.5k, and mPEG2k-PCL10k) were prepared to evaluate the inhibition of hOCT1-3-overexpressing Madin-Darby canine kidney cells. The mPEG2k-PCLx micelles played an inhibitory role above the critical micelle concentration. The inhibitory potency could be ranked as mPEG2k-PCL2k > mPEG2k-PCL3.5k > mPEG2k-PCL5k > mPEG2k-PCL7.5k > mPEG2k-PCL10k, which negatively declined with the increase of molecular weight of the hydrophobic segment. The inhibitory effects of polymeric micelles on the hOCT1 isoform were the most pronounced, with the lowest IC50 values ranging from 0.106 to 0.280 mg/mL. The mPEG2k-PCL2k micelles distinctly increased the plasma concentration of metformin and significantly decreased Vss by 35.6% (p < 0.05) after seven consecutive treatments in rats, which was interrelated with the restrained metformin distribution in the liver and kidney. The uptake inhibition of micelles on hepatic and renal rOcts also diminished the glucose-lowering effect of metformin and fasting insulin levels in the oral glucose tolerance test. Consistent with the inhibitory effects, the mRNA and protein levels of rOct1 and rOct2 were decreased in the liver, kidney, and small intestine. The present study demonstrated that mPEG2k-PCLx micelles could inhibit the transport function of OCTs, indicating a potential risk of drug-drug interactions during concomitant medication of nanomedicine with organic cationic drugs.

Efficacy and safety of polyethylene glycol loxenatide monotherapy in type 2 diabetes patients: A multicentre, randomized, double-blind, placebo-controlled phase 3a clinical trial.

AIM: To evaluate the efficacy and safety of polyethylene glycol loxenatide (PEX168) monotherapy in type 2 diabetes (T2D) patients in China. MATERIALS AND METHODS: In a multicentred, randomized, double-blinded, placebo-controlled phase 3a clinical trial, 361 patients with inadequate glycaemic control (HbA1c 7.0%-10.5%, fasting plasma glucose <13.9 mmol/L) were randomized (1:1:1) for weekly subcutaneous injections: placebo, PEX168/100 µg or PEX168/200 µg. The 24-week treatment was followed by a 28-week extension, during which placebo-treated patients were randomly assigned to PEX168/100 µg or PEX168/200 µg. The primary efficacy endpoint was the HbA1c change from baseline to week 24. RESULTS: The three groups had similar demographics and baseline characteristics. The HbA1c least-square mean (95% CI) change from baseline to week 24 was greater for PEX168/100 µg (-1.02% [-1.21%, -0.83%]) and PEX168/200 µg (-1.34% [-1.54%, -1.15%]) than for placebo (-0.17% [-0.36%, 0.02%]); (superiority: P < .0001). The proportions of patients with less than 7% HbA1c in the placebo, PEX168/100 µg and PEX168/200 µg groups were 15.7%, 34.7% and 46.6%, respectively. Common gastrointestinal adverse events (AEs) were nausea (5.6%, 10.0% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively) and vomiting (2.4%, 8.3% and 0% for PEX168/100 µg, PEX168/200 µg and placebo, respectively). Six (1.6%) patients (PEX168/100 µg: N = 2 [1.6%], PEX168/200 µg: N = 3 [2.5%] and placebo: N = 1 [0.8%]) discontinued treatment because of AEs. Four (1.2%) patients (PEX168/100 µg: N = 3 [2.5%] and PEX168/200 µg: N = 1 [0.9%]) developed PEX168 antidrug antibodies. CONCLUSION: PEX168 monotherapy significantly improved glycaemic control in T2D patients with a safety profile resembling that of other glucagon-like peptide-1 receptor agonists.