Investigation of Pharmacokinetic Parameters of Trelagliptin in Egyptian Volunteers Using Sensitive LC-MS/MS: A Comparative Study with a Japanese Population

Trelagliptin (TLN) is a novel once-weekly antidiabetic drug that enhanced the patient compliance in type 2 diabetes. TLN analysis and bioanalysis literature review showed many methods for TLN assay either in dosage form or as biological fluids (pharmacokinetic parameters), but all those methods did not consider the full details dealing with biological assay of TLN. Studies that included information about pharmacokinetic parameters did not mention the used analytical procedures for those determinations and parameters. Although some LC-MS/MS and UPLC-UV methods were reported for TLN bioassay in rats’ plasma, they used direct precipitation techniques, and the current described procedure showed lower LLOQ than all the reported methods in spite of that working on human plasma is more complicated than on rats’ plasma. In this study, LC-MS/MS bioanalysis of TLN in human plasma (4–1000 nM) was employed successfully with LLOQ of 4 nM which is lower than all reported methods in rats’ plasma followed by a preliminary pharmacokinetic study. Alogliptin was used as internal standard (IS) because of its structure similarity to TLN. Pharmacokinetic parameters of TLN were investigated in Egyptian volunteers, and they had been compared to Japanese. Liquid-liquid extraction showed more sensitive results than direct precipitation. The proposed method was successfully applied to a pharmacokinetic study conducted on Egyptian volunteers. No dose modification is required upon comparing the pharmacokinetic parameters of the current study and previous studies on non-Egyptian volunteers.

Incretins in the Therapy of Diabetic Kidney Disease

Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.

Metal-catalyzed organic reactions by Resonant Acoustic Mixing

We introduce catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as model reactions ruthenium-catalyzed ring-closing metathesis, ene-yne metathesis and copper-catalyzed sulfonamide-isocyanate coupling, we demonstrate RAM-based mechanochemical synthesis that is faster and operationally simpler than conventional ball milling. Moreover, the method can be readily scaled-up, as demonstrated by straightforward catalytic synthesis of the antidiabetic drug Tolbutamide from hundreds of milligrams to at least 10 grams, without any significant changes in reaction conditions.

Conjugated Linoleic Acid (CLA) co-treatment alleviates antidiabetic drug, rosiglitazone associated deterioration of bone remodeling

Diabetes mellitus (DM) is a chronic metabolic disease characterized by hyperglycemia due to decreased insulin secretion, defective action or both. The rosiglitazone (RSG) is one of the oral antidiabetic drug used in type 2 (T2) DM and has a unique insulin-sensitizing capacity. However, RSG has a negative side effect on the bone as it stimulates the differentiation of bone marrow-mesenchymal stromal cells (BM-MSCs) into adipocytes at the expense of osteoblasts in the bone marrow microenvironment, disturbing the normal balance of bone remodeling and causing BM adiposity. On the other hand, the trans-10,cis-12 conjugated linoleic acid (CLA), a fatty acid is known as anti-adipogenic, pro-osteogenic. Therefor, this study was designed to assess whether CLA can alleviate the negative effect of RSG on bone. We used adipose tissue derived-mesenchymal stem cells (AT-MSCs) as a human in vitro model to study the effect of CLA, RSG and combined treatment (RSG+CLA) on the osteoblastogenic and adipogenic differentiation of AT-MSCs. Osteoblastogenesis was assessed by Alizarin Red Staining and bone mineralization was assessed by 〖"OsteoImage" 〗^TMassays, whereas adipogenesis was assessed by Oil Red O Staining and LipidTOX assays. Besides, the level of expression of osteogenic and adipogenic markers was measured on treated osteo- and adipo-differentiated MSCs using real time RT-PCR, immunohistochemistry (IHC) and western blot analysis. Compared to RSG group, the combined treatment group stimulates osteoblastogenesis, as evidenced by increased mineralization and upregulation of osteogenic markers OPN and RUNX2 and inhibits adipogenesis in osteogenic media as showed by decreased lipid content and downregulation of adipogenic markers FABP4, LPL and adipsin. In conclusion, the use of CLA as an adjunctive treatment reversed the effects of RSG on osteogenesis and adipogenesis. Further preclinical and clinical studies will be undertaken to establish this treatment regimen for the successful treatment of diabetic patients with rosiglitazone without adverse side effects on bone.

In-silico discovery of antidiabetic drug potential of Balanites aegyptiaca leaf’s phenolic compounds

<i>Balanites aegyptiaca</i> leaf is very effective in managing diabetes and rich in phenolic compounds. However, the modes of action of the phytochemicals are mainly unknown. Thus, the present in silico drug discovery study on some phenolic compounds was designed to evaluate potential mechanisms of action of the antihyperglycemic phytochemicals of <i>B. aegyptiaca</i> leaf extract. The study deployed in silico drug-like studying techniques such as; predicted activity spectra of substances (PASS), molecular docking, prediction of adsorption, distribution, metabolism, excretion, and toxicity (ADMET), Lipinski’s rule of 5 (PLOP). The study reveals six compounds with good drug-like properties: cLogp, hydrogen bond donor/acceptor (<5/ < 10), and molar refractivity. In addition, ADMET and drug properties like kinase inhibitors, ion channel modulators, and nuclear receptors were positive for the compounds. Each phenolic compound showed one or more antidiabetic activities like insulin promoter, insulin sensitizer and inhibitors of α-amylase and α-glucosidase. Docking result predicted that the phenolic compounds inhibited either α-amylase or α-glucosidase while one of the compounds; 2-methoxy-4-(1-propenyl)-phenol inhibited both α-amylase and α-glucosidase with binding energies of -4.4 and -4.2 kcal/mol against -3.8 and -4.8 kcal/mol by Acarbose. The study revealed that phenolic compounds from <i>B. aegyptiaca</i> leaf possessed drug-like properties, including the ability to interact with α-amylase and α-glucosidase, a vital target protein in the management of diabetes mellitus. The data from the in silico study is a step toward the pharmaceutical discovery of the antidiabetic drug potential of <i>B. aegyptiaca</i> leaf.