New Chitosan-Based Co-Delivery Nanosystem for Diabetes Mellitus Therapy.

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders, with a major involvement of oxidative stress in its onset and progression. Pioglitazone (Pio) is an antidiabetic drug that mainly works by reducing insulin resistance, while curcumin (Cur) is a powerful antioxidant with an important hypoglycemic effect. Both drugs are associated with several drawbacks, such as reduced bioavailability and a short half-life time (Pio), as well as instability and poor water solubility (Cur), which limit their therapeutic use. In order to overcome these disadvantages, new co-delivery (Pio and Cur) chitosan-based nanoparticles (CS-Pio-Cur NPs) were developed and compared with simple NPs (CS-Pio/CS-Cur NPs). The NPs were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). In addition, the entrapment efficiency (EE) and loading capacity (LC), as well as the release profile, of the APIs (Pio and Cur) from the CS-APIs NPs in simulated fluids (SGF, SIF, and SCF) were also assessed. All the CS-APIs NPs presented a small particle size (PS) (211.6-337.4 nm), a proper polydispersity index (PI) (0.104 and 0.289), and a positive zeta potential (ZP) (21.83 mV-32.64 mV). Based on the TEM results, an amorphous state could be attributed to the CA-APIs NPs, and the TEM analysis showed a spherical shape with a nanometric size for the CS-Pio-Cur NPs. The FT-IR spectroscopy supported the successful loading of the APIs into the CS matrix and proved some interactions between the APIs and CS. The CS-Pio-Cur NPs presented increased or similar EE (85.76% ± 4.89 for Cur; 92.16% ± 3.79 for Pio) and LC% (23.40% ± 1.62 for Cur; 10.14% ± 0.98 for Pio) values in comparison with simple NPs, CS-Cur NPs (EE = 82.46% ± 1.74; LC = 22.31% ± 0.94), and CS-Pio NPs (EE = 93.67% ± 0.89; LC = 11.24% ± 0.17), respectively. Finally, based on the release profile results, it can be appreciated that the developed co-delivery nanosystem, CS-Pio-Cur NPs, assures a controlled and prolonged release of Pio and Cur from the polymer matrix along the GI tract.

Complexes of Ibuprofen Thiazolidin-4-One Derivatives with ß-Cyclodextrin: Characterization and In Vivo Release Profile and Biological Evaluation.

Generally, NSAIDs are weakly soluble in water and contain both hydrophilic and hydrophobic groups. One of the most widely used NSAIDs is ibuprofen, which has a poor solubility and high permeability profile. By creating dynamic, non-covalent, water-soluble inclusion complexes, cyclodextrins (CDs) can increase the dissolution rate of low aqueous solubility drugs, operating as a drug delivery vehicle, additionally contributing significantly to the chemical stability of pharmaceuticals and to reducing drug-related irritability. In order to improve the pharmacological and pharmacokinetics profile of ibuprofen, new thiazolidin-4-one derivatives of ibuprofen (4b, 4g, 4k, 4m) were complexed with ß-CD, using co-precipitation and freeze-drying. The new ß-CD complexes (ß-CD-4b, ß-CD-4g, ß-CD-4k, ß-CD-4m) were characterized using scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction and a phase solubility test. Using the AutoDock-VINA algorithm included in YASARA-structure software, we investigated the binding conformation of ibuprofen derivatives to ß-CD and measured the binding energies. We also performed an in vivo biological evaluation of the ibuprofen derivatives and corresponding ß-CD complexes, using analgesic/anti-inflammatory assays, as well as a release profile. The results support the theory that ß-CD complexes (ß-CD-4b, ß-CD-4g, ß-CD-4k, ß-CD-4m) have a similar effect to ibuprofen derivatives (4b, 4g, 4k, 4m). Moreover, the ß-CD complexes demonstrated a delayed release profile, which provides valuable insights into the drug-delivery area, focused on ibuprofen derivatives.

Modern Approaches in Wounds Management.

Wound management represents a well-known continuous challenge and concern of the global healthcare systems worldwide. The challenge is on the one hand related to the accurate diagnosis, and on the other hand to establishing an effective treatment plan and choosing appropriate wound care products in order to maximize the healing outcome and minimize the financial cost. The market of wound dressings is a dynamic field which grows and evolves continuously as a result of extensive research on developing versatile formulations with innovative properties. Hydrogels are one of the most attractive wound care products which, in many aspects, are considered ideal for wound treatment and are widely exploited for extension of their advantages in healing process. Smart hydrogels (SHs) offer the opportunities of the modulation physico-chemical properties of hydrogels in response to external stimuli (light, pressure, pH variations, magnetic/electric field, etc.) in order to achieve innovative behavior of their three-dimensional matrix (gel-sol transitions, self-healing and self-adapting abilities, controlled release of drugs). The SHs response to different triggers depends on their composition, cross-linking method, and manufacturing process approach. Both native or functionalized natural and synthetic polymers may be used to develop stimuli-responsive matrices, while the mandatory characteristics of hydrogels (biocompatibility, water permeability, bioadhesion) are preserved. In this review, we briefly present the physiopathology and healing mechanisms of chronic wounds, as well as current therapeutic approaches. The rational of using traditional hydrogels and SHs in wound healing, as well as the current research directions for developing SHs with innovative features, are addressed and discussed along with their limitations and perspectives in industrial-scale manufacturing.

New Smart Bioactive and Biomimetic Chitosan-Based Hydrogels for Wounds Care Management.

Wound management represents a continuous challenge for health systems worldwide, considering the growing incidence of wound-related comorbidities, such as diabetes, high blood pressure, obesity, and autoimmune diseases. In this context, hydrogels are considered viable options since they mimic the skin structure and promote autolysis and growth factor synthesis. Unfortunately, hydrogels are associated with several drawbacks, such as low mechanical strength and the potential toxicity of byproducts released after crosslinking reactions. To overcome these aspects, in this study new smart chitosan (CS)-based hydrogels were developed, using oxidized chitosan (oxCS) and hyaluronic acid (oxHA) as nontoxic crosslinkers. Three active product ingredients (APIs) (fusidic acid, allantoin, and coenzyme Q10), with proven biological effects, were considered for inclusion in the 3D polymer matrix. Therefore, six API-CS-oxCS/oxHA hydrogels were obtained. The presence of dynamic imino bonds in the hydrogels' structure, which supports their self-healing and self-adapting properties, was confirmed by spectral methods. The hydrogels were characterized by SEM, swelling degree, pH, and the internal organization of the 3D matrix was studied by rheological behavior. Moreover, the cytotoxicity degree and the antimicrobial effects were also investigated. In conclusion, the developed API-CS-oxCS/oxHA hydrogels have real potential as smart materials in wound management, based on their self-healing and self-adapting properties, as well as on the benefits of APIs.

A Sustainable Approach to a Cleaner Production of Antimicrobial and Biocompatible Protein Fibers.

This study presents the production, characterization, and application of celandine (Chelidonium majus L.) extracts (aqueous, acidic, alcoholic, and ultrasound) on wool fibers and their characterization. The study aims to obtain an ecologically dyed wool support that possesses biocompatible and antimicrobial activities. The plant extracts were characterized based on pH, total polyphenol content, and berberine content. Ecologically dyed wool supports were characterized based on scanning electron microscopy, levelness index, color measurements, contact angle indirect biocompatibility, and antibacterial analysis. According to the obtained results, celandine extract can be considered a potential candidate for the sustainable dyeing and functionalization of wool fibers.

Recent Biomedical Approaches for Chitosan Based Materials as Drug Delivery Nanocarriers.

In recent decades, drug delivery systems (DDSs) based on nanotechnology have been attracting substantial interest in the pharmaceutical field, especially those developed based on natural polymers such as chitosan, cellulose, starch, collagen, gelatin, alginate and elastin. Nanomaterials based on chitosan (CS) or chitosan derivatives are broadly investigated as promising nanocarriers due to their biodegradability, good biocompatibility, non-toxicity, low immunogenicity, great versatility and beneficial biological effects. CS, either alone or as composites, are suitable substrates in the fabrication of different types of products like hydrogels, membranes, beads, porous foams, nanoparticles, in-situ gel, microparticles, sponges and nanofibers/scaffolds. Currently, the CS based nanocarriers are intensely studied as controlled and targeted drug release systems for different drugs (anti-inflammatory, antibiotic, anticancer etc.) as well as for proteins/peptides, growth factors, vaccines, small DNA (DNAs) and short interfering RNA (siRNA). This review targets the latest biomedical approaches for CS based nanocarriers such as nanoparticles (NPs) nanofibers (NFs), nanogels (NGs) and chitosan coated liposomes (LPs) and their potential applications for medical and pharmaceutical fields. The advantages and challenges of reviewed CS based nanocarriers for different routes of administration (oral, transmucosal, pulmonary and transdermal) with reference to classical formulations are also emphasized.

The safety profile of new antidiabetic xanthine derivatives and their chitosan based formulations.

The safety profile of new antidiabetic xanthine derivatives with thiazolidine­4­one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7), administrated to diabetic rats, have been evaluated in terms of biochemical markers of liver and kidney function as well as of hematological markers. The effect on lipid profile and clinic parameters (body weight, food and water intake) has been also evaluated. The treatment of diabetic rats with xanthine derivatives (6, 7) and chitosan based formulations (CS-6, CS-7) was associated with lower liver enzymes (AST, ALT, LDH) and bilirubin (direct, total) values compared to the non-treated diabetic rats, that means the tested derivatives/formulations have improved the liver function injured in diabetes mellitus conditions. Also the kidney biochemical markers (creatinine, uric acid, urea) were significantly decreased in diabetic rats treated with 6, 7 and chitosan microparticles (CS-6, CS-7). The values of biochemical markers of liver and kidney functions were even better than the values recorded for pioglitazone, used as standard antidiabetic drug. The improving effect on kidney function was proved by the histopathological study. Moreover, the xanthine derivatives and their chitosan based formulation were associated with improved hematological markers compared to the non-treated diabetic rats which mean the improving of the hemorheological state. These results support the safety profile of new xanthine derivatives with thiazolidine­4­one scaffold (6, 7) and their new chitosan based formulations (CS-6, CS-7) and their potential applications for the treatment of diabetes mellitus syndrome.

Synthesis and biological evaluation of the new 1,3-dimethylxanthine derivatives with thiazolidine-4-one scaffold.

BACKGROUND: The xanthine structure has proved to be an important scaffold in the process of developing a wide variety of biologically active molecules such as bronchodilator, hypoglycemiant, anticancer and anti-inflammatory agents. It is known that hyperglycemia generates reactive oxygen species which are involved in the progression of diabetes mellitus and its complications. Therefore, the development of new compounds with antioxidant activity could be an important therapeutic strategy against this metabolic syndrome. RESULTS: New thiazolidine-4-one derivatives with xanthine structure have been synthetized as potential antidiabetic drugs. The structure of the synthesized compounds was confirmed by using spectral methods (FT-IR, 1H-NMR, 13C-NMR, 19F-NMR, HRMS). Their antioxidant activity was evaluated using in vitro assays: DPPH and ABTS radical scavenging ability and phosphomolybdenum reducing antioxidant power assay. The developed compounds showed improved antioxidant effects in comparison to the parent compound, theophylline. In the case of both series, the intermediate (5a-k) and final compounds (6a-k), the aromatic substitution, especially in para position with halogens (fluoro, chloro), methyl and methoxy groups, was associated with an increase of the antioxidant effects. CONCLUSIONS: For several thiazolidine-4-one derivatives the antioxidant effect of was superior to that of their corresponding hydrazone derivatives. The most active compound was 6f which registered the highest radical scavenging activity.Graphical abstractDesign and synthesis of new thiazolidine-4-one derivatives.

EVALUATION OF ANTIOXIDANT ACTIVITY OF SOME IMINES DERIVATIVES OF L-ARGININE.

UNLABELLED: L-Arginine is an a-amino acid which plays important roles in different diseases or processes, such as Alzheimer disease, inflammatory process, healing and tissue regeneration and it also could be useful as an anti-atherosclerotic agent. AIM: Considering the large amount of studies on the beneficial effects of different antioxidants, this paper is focused on the evaluation of the antioxidant potential of some imine derivatives, synthesized by the authors and described in a previous article. MATERIAL AND METHODS: The evaluation of the antioxidant power was performed using phosphomolydenum-reducing antioxidant power (PRAP) and ferric reducing antioxidant power (FRAP) assays, tests described in the literature and which are used with some minor modifications. RESULTS: It was found that most of the imine derivatives are more active than the L-Arginine in the PPAP and FRAP assays. The most active derivative was the compound obtained by condensation of L-arginine with 2,3-dihydroxybenzaldehyde (2k) and 2-nitrobenzaldehyde (2g). CONCLUSIONS: Following the described protocol, some imine derivatives of L-arginine were evaluated in terms of antioxidant potential using in vitro methods. The most favorable influence was obtained by the aromatic substitution with nitro and hydroxyl, the corresponding derivatives being the most active derivatives compared to L-arginine.

New antimicrobial chitosan derivatives for wound dressing applications.

Chitosan is a non-toxic, biocompatible, biodegradable natural cationic polymer known for its low imunogenicity, antimicrobial, antioxidant effects and wound-healing activity. To improve its therapeutic potential, new chitosan-sulfonamide derivatives have been designed to develop new wound dressing biomaterials. The structural, morphological and physico-chemical properties of synthesized chitosan derivatives were analyzed by FT-IR, (1)H NMR spectroscopy, scanning electron microscopy, swelling ability and porosity. Antimicrobial, in vivo testing and biodegradation behavior have been also performed. The chitosan derivative membranes showed improved swelling and biodegradation rate, which are important characteristics required for the wound healing process. The antimicrobial assay evidenced that chitosan-based sulfadiazine, sulfadimethoxine and sulfamethoxazole derivatives were the most active. The MTT assay showed that some of chitosan derivatives are nontoxic. Furthermore, the in vivo study on burn wound model induced in Wistar rats demonstrated an improved healing effect and enhanced epithelialization of chitosan-sulfonamide derivatives compared to neat chitosan. The obtained results strongly recommend the use of some of the newly developed chitosan derivatives as antimicrobial wound dressing biomaterials.

Development and Characterization of Novel Films Based on Sulfonamide-Chitosan Derivatives for Potential Wound Dressing.

The objective of this study was to develop new films based on chitosan functionalized with sulfonamide drugs (sulfametoxydiazine, sulfadiazine, sulfadimetho-xine, sulfamethoxazol, sulfamerazine, sulfizoxazol) in order to enhance the biological effects of chitosan. The morphology and physical properties of functionalized chitosan films as well the antioxidant effects of sulfonamide-chitosan derivatives were investigated. The chitosan-derivative films showed a rough surface and hydrophilic properties, which are very important features for their use as a wound dressing. The film based on chitosan-sulfisoxazol (CS-S6) showed the highest swelling ratio (197%) and the highest biodegradation rate (63.04%) in comparison to chitosan film for which the swelling ratio was 190% and biodegradation rate was only 10%. Referring to the antioxidant effects the most active was chitosan-sulfamerazine (CS-S5) which was 8.3 times more active than chitosan related to DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging ability. This compound showed also a good ferric reducing power and improved total antioxidant capacity.

HYPOGLYCEMIA INDUCED BY ANTIDIABETIC SULFONYLUREAS.

Diabetes mellitus is a major health problem due to its increasing prevalence and life-threatening complications. Antidiabetic sulfonylureas represent the first-line drugs in type 2 diabetes even though the most common associated risk is pharmacologically-induced hypoglycemia. In the development of this side effect are involved several factors including the pharmacokinetic and pharmacodynamic profile of the drug, patient age and behavior, hepatic or renal dysfunctions, or other drugs associated with a high risk of interactions. If all these are controlled, the risk-benefit balance can be equal to other oral antidiabetic drugs.

Development, optimization and biological evaluation of chitosan scaffold formulations of new xanthine derivatives for treatment of type-2 diabetes mellitus.

New xanthine derivatives as antidiabetic agents were synthesized and new chitosan formulations have been developed in order to improve their biological and pharmacokinetic profile. Their physicochemical properties in terms of particle size, morphology, swelling degree, crystalline state, the loading efficiency as well as in vitro release and biodegradation rate were evaluated. According to the results the optimized formulations have a high drug loading efficiency (more than 70%), small particle size, a good release profile in the simulated biological fluids (the percentage of cumulative release being more than 55%) and improved biodegradation rate in reference with chitosan microparticles. The presence of xanthine derivatives (6, 7) in chitosan microparticles was demonstrated by means of FTIR analysis. The X-ray diffraction (XRD) proved that xanthine derivatives present a crystalline state. The biological evaluation assays confirmed the antioxidant and antidiabetic effects of the xanthine derivatives (6, 7) and their chitosan formulations (CS-6, CS-7). Xanthine derivative 6 showed a high antiradical scavenging effect (DPPH remaining=41.78%). It also reduced the glucose blood level with 59.30% and recorded level of glycosylated hemoglobin was 4.53%. The effect of its chitosan formulation (CS-6) on the level of blood glucose (114.5mg/dl) was even more intense than the one recorded by pioglitazone (148.5mg/dl) when used as standard antidiabetic drug. These results demonstrated the potential application of xanthine derivative 6 and its chitosan formulation (CS-6) in the treatment of the diabetes mellitus syndrome.

New hydrazones with pyrazolone structure: synthesis, characterization and biological evaluation.

AIM: To design new hydrazones with pyrazolone structure with improved biological properties. MATERIAL AND METHODS: New hydrazones of antipyrine have been prepared by reaction of 4-aminophenazone (4-aminoantipyrine) with chloracetylchoride and hydrazine hydrate and then condensation with various aromatic aldehydes. RESULTS: The synthesized compounds were screened for their antibacterial activity against Gram positive (Staphylococcus aureus ATCC 25923, Sarcinalutea ATCC 9341, Bacillus cereus ATCC 14579, Bacillus subtilis) and Gram negative bacterial strains (Escherichia coli ATCC 25922) and pathogenic yeasts (Candida albicans ATCC 10231, Candida sake, Candidaglabrata). Some of them were found to have good antibacterial and antifungal activity. The antioxidant activity of these compounds was also evaluated using the total antioxidant capacity test. CONCLUSIONS: The chemical modulations performed on antipyrine structure have a good influence on the biological activity of the synthesized compounds.

The synthesis and the biological evaluation of new thiazolidin-4-one derivatives containing a xanthine moiety.

Starting from theophylline (1,3-dimethylxanthine) new thiazolidin-4-one derivatives 7a1₋7, 7b1₋7 have been synthesized as potential antidiabetic drugs. The structure of the new derivatives was confirmed using spectral methods (FT-IR, ¹H-NMR, ¹³C-NMR). The in vitro antioxidant potential of the synthesized compounds was evaluated according to the ferric reducing power, the total antioxidant activity and the DPPH and ABTS radical scavenging assays. Reactive oxygen species (ROS) and free radicals are considered to be implicated in a variety of pathological events, such as diabetes mellitus and its micro- and macrovascular complications. The results of chemical modulation of the thiazolidin-4-one intermediaries 6a, 6b through condensation with several aromatic aldehydes is the improvement of the antioxidant effect. All benzylidenethiazolidin-4-one derivatives 7a1₋7, 7b1₋7 are more active than their parent thiazolidin-4-ones. The most active compounds are the ones obtained by reaction of condensation with 4-hydroxybenzaldehyde (compounds 7a5, 7a6), 4-dimethylaminobenzaldehyde (compounds 7a6, 7b6) and 2-nitrobenzaldehyde (compounds 7a7, 7b7).

Synthesis and biological evaluation of new 2-azetidinones with sulfonamide structures.

New series of N-(arylidene)hydrazinoacetyl sulfonamides 4a1-6, 4b1-6 and N-(4-aryl-3-chloro-2-oxoazetidin-1-yl)aminoacetyl sulfonamides 5a1-6, 5b1-6 were synthesized. The structures of the new derivatives was confirmed using spectral methods (FT-IR, 1H-NMR, 13C-NMR). The antibacterial activities of these compounds against Gram positive (Staphylococcus aureus ATCC 6583, Staphylococcus epidermidis ATCC 12228, Enterococcus faecalis ATCC 25912) and Gram negative (Klebsiella pneumoniae CIP 53153, Proteus vulgaris CIP 104989, Citrobacter freundii CIP 5732, Enterobacter cloacae CIP 103475, Escherichia coli ATCC 25922, Pseudomonas aeruginosa CIP 82118) bacterial strains were evaluated using the broth micro-dilution method. Compound 4a2 displayed the highest antibacterial activity, especially against Staphylococcus epidermidis, Enterococcus faecalis and Pseudomonas aeruginosa. The antioxidant potential of the synthesized compounds was also investigated according to ferric reducing power, total antioxidant activity and DPPH radical scavenging assays. All tested compounds showed excellent antioxidant activity in comparison with sulfadiazine and sulfisoxazole which were used as parent sulfonamides. Moreover, some of them showed an antioxidant activity comparable with that of ascorbic acid. In general, the compounds designed based on a sulfadiazine skeleton (compounds 4a1-6, 5a1-6) are more active than those obtained from sulfisoxazole (compounds 4b1-6, 5b1-6), and the N-(arylidene)hydrazinoacetyl sulfonamide derivatives 4a1-6, 4b1-6 are more active than their azetidionone analogues 5a1-6, 5b1-6.

New hydrazines with sulphonamidic structure: synthesis,characterization and biological activity.

UNLABELLED: Infections caused by bacterial species are common in immunocompromised patients and carry significant treatment costs and mortality. The emerging resistance of microorganisms to some synthetic antimicrobial agents makes it necessary to continue the research for new antimicrobial drugs. AIM: To design new sulphonamide compounds with potential antibacterial and antioxidant activity. MATERIAL AND METHODS: New N-hydrazino acetyl-sulphonamides were prepared by condensation of some sulphonamides with chloroacetyl chloride and amination of intermediate compounds with hydrazine hydrate. RESULTS: The synthesized compounds were screened for their antibacterial activity against Gram positive (Klebsiellapneumoniae. Proteus vulgaris, Citrobacter freundii, Enterobacter cloacae, Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis) and Gram negative bacterial strains (Pseudomonas aeruginosa, Escherichia coli). Some of them were found to have good antibacterial activity. The antioxidant activity of these compounds was also tested using different methods: total antioxidant capacity, reducing power, and DPPH radical scavenging activity. CONCLUSIONS: Chemical modulations performed on sulphonamide structure have a good influence on the biological activity of the synthesized compounds, especially on their antioxidant effects.

Synthesis and evaluation of antioxidant activity of some new benzylidene-thiazolidine-xanthine derivatives.

UNLABELLED: The International Diabetes Federation reported that 246 million adults worldwide had diabetes mellitus and the prevalence of this syndrome was expected to increase continuously. AIM: To design new compound with potential antidiabetic and antioxidant activity. MATERIAL AND METHODS: New benzylidene-thiazolidine derivatives (BT2a-2e) were obtained by condensation of xanthine-thiazolidine-4-one (TZ-4-one) with aromatic aldehydes. The synthesized compounds were characterized by spectral method (IR, 1H-NMR, 13C-NMR) and their antioxidant potential has been also evaluated. RESULTS: The synthesized compounds have important antioxidant effects as compared to xanthine-thiazolidine derivatives. The most active compounds were those obtained by condensation with 4-dimethylaminobenzaldehyde (BT2c) and 4-nitro-benzaldehyde (BT2e). CONCLUSIONS: The chemical modulations performed on the structure of TZD-4-one have a good influence on their antioxidant potential.

[Incretin modulators, a new perspective in diabetes mellitus treatment]. / Modulatorii incretinelor, o noua perspectiva în tratamentul diabetului zaharat.

AIM: The study was designed to present the modern therapy used for the treatment of type 2 diabetes mellitus (T2DM). MATERIAL AND METHODS: Diabetes mellitus and the pharmacological and the pharmacokinetic characteristics of the incretins and of the incretin modulators are presented. RESULTS: Diabetes mellitus is a chronic metabolic disorder, which is considered to be a major health issue all over the world. World Health Organization indicates that world-wide almost 3 million deaths per year are caused by diabetes and 1,5 million new cases are diagnosed annually, T2DM representing approximately 90-95% of the diagnosed cases. This form of diabetes mellitus is characterized by several path physiological defects including insulin resistance at peripheral target tissues, excess hepatic glucose production and progressive pancreatic beta cell dysfunction. The newest direction in the treatment of T2DM mellitus is the incretin modulators. The incretins (GLP-1--glucagon-like-peptide-1 and GIP--glucose-dependent insulin tropic peptide), are natural hormones that contribute to glucose homeostasis by acting on the pancreas, gastrointestinal tract, muscle and brain tissue. After secretion, GLP-1 and GIP are immediately metabolized by dipeptidyl peptidase IV enzyme (DPP IV), which limits their therapeutic use. CONCLUSIONS: In order to achieve optimal glycemic control, by using the therapeutic effects of incretins, research has been directed to the development of synthetic analogues of GLP-1 resistant to DPP IV enzyme inactivation and DPP IV inhibitors.