Helical-Like Assembly of Nateglinide as Coating for Oral Delivery of Insulin and Their Synergistic Prevention of Diabetes Mellitus.

Oral delivery of antidiabetic active components promises to free millions of people from daily suffering who require routine injections. However, oral insulin (Ins) and other short-acting compounds such as nateglinide (NG) in harsh gastrointestinal tract still face great challenging, including low bioavailability, and rapid elimination. In this study, inspired by the self-assembly of phenylalanine-based peptides in nature, it is showed that NG a small phenylalanine derivative, assembles into left-handed helical nanofibers in the presence of Ca2+ . These helical NG nanofibers functioned as a coating layer on the surface of Ca2+ -linked alginate (Alg) microgels for the effective encapsulation of Ins. As expected, the sustained release and prolonged circulation of Ins and NG from the Ins-loading Alg/NG microgels (Ins@Alg/NG) in the intestinal tract synergistically maintain a relatively normal blood glucose level in streptozotocin-induced diabetic mice after oral administration of Ins@Alg/NG. This further confirms that Ins@Alg/NG ameliorated Ins resistance mainly through activating Insreceptor substrate 1 (IRS1), protein kinase B (AKT), and AMP-activated protein kinase (AMPK), as well as by repressing glycogen synthase kinase-3ß (GSK-3ß). The strategy of using the assembly of NG as a coating achieves the oral delivery of insulin and showcases a potential for the treatment of diabetes.

Development of pharmacogenomic algorithm to optimize nateglinide dose for the treatment of type 2 diabetes mellitus.

BACKGROUND: Nateglinide is a meglitinide used for the treatment of type 2 diabetes mellitus. Individual studies demonstrated the association of CYP2C9, SLCO1B1, and MTNR1B variants with the safety and efficacy of nateglinide. The current study aimed to develop a pharmacogenomic algorithm to optimize nateglinide therapy. METHODS: Multiple linear regression (MLR) and classification and regression tree (CART) were used to develop a pharmacogenomic algorithm for nateglinide dosing based on the published nateglinide pharmacokinetic data on the area under the curve data (AUC) and Cmax (n = 143). CYP2C9 metabolizer phenotype, SLCO1B1, MTNR1B genotypes, and CYP2C9 inhibitor usage were used as the input variables. The results and associations were further confirmed by meta-analysis and in silico studies. RESULTS: The MLR models of AUC and Cmax explain 87.4% and 59% variability in nateglinide pharmacokinetics. The Bland and Altman analysis of the nateglinide dose predicted by these two MLR models showed a bias of ± 26.28 mg/meal. The CART algorithm was proposed based on these findings. This model is further justified by the meta-analysis showing increased AUCs in CYP2C9 intermediate metabolizers and SLCOB1 TC and CC genotypes compared to the wild genotypes. The increased AUC in SLCO1B1 mutants is due to decreased binding affinity of nateglinide to the mutant affecting the influx of nateglinide into hepatocytes. MTNR1B rs10830963 G-allele-mediated poor response to nateglinide is attributed to increased transcriptional factor binding causing decreased insulin secretion. CONCLUSION: CYP2C9, SLCO1B1, and MTNR1B genotyping help in optimizing nateglinide therapy based on this algorithm and ensuring safety and efficacy.

Effect of Fatty Acids and Uremic Toxins on the Binding of Nateglinide, an Insulin Secretagogue, to Site II on Human Serum Albumin.

Nateglinide (NAT) is used to treat diabetes, stimulating pancreatic islet ß-cells with residual insulin secretory capacity to increase insulin secretion. NAT has been reported to bind to human serum albumin (HSA), but the detail is still unclear. In the current study, we investigated the location and the affinity for the binding of NAT to HSA. Quantitative analysis data from the ultrafiltration experiment indicated that NAT binds strongly to a primary site on HSA with a high affinity. The presence of diazepam (DZP) or ibuprofen (IB), the specific site II ligands of HSA, decreased the binding constants of NAT respectively, without the significant changes in the number of binding sites. Whereas warfarin (WF), a site I specific ligand, did not affect the binding of NAT. Fluorescent replacement experiment showed that NAT replaced dansylsarcosine (DNSS), a site II probe of HSA, but not WF. An increasing level of myristate and uremic toxins, indoxyl sulphate (IS), indoxyl acetate (IA) and p-cresyl sulphate (PCS), during renal disease significantly increased the concentration of unbound NAT. These findings suggest that NAT specifically binds to site II of HSA and the binding capacity and pharmacokinetics of NAT change in renal diseases.

Response surface optimization of a vortex-assisted dispersive liquid-liquid microextraction method for highly sensitive determination of repaglinide in environmental water by HPLC/UV.

A vortex-assisted dispersive liquid-liquid microextraction (DLLME) method, mated to chemometrics and combined with HPLC/UV detection was optimized and validated for enrichment and determination of repaglinide in environmental samples using nateglinide as an internal standard (IS). A phosphate buffer (10 mM, pH 2.5): acetonitrile (45:55, v/v) was used as a mobile phase with a flow rate of 1 mL/min in an isocratic elution mode. Chemometrics-assisted optimization was performed using a quadratic integrated D-optimal design. The developed model assessed the statistical significance of the independent variables and their interactions to attain the optimum conditions revealing that extractant type, extractant volume and pH are the most influential factors. Optimization of the extraction procedures was performed with the aid of Design Expert 8® software, which suggested 58 different experiments. The optimal conditions were 30 µL of 1-octanol as extractant, 100 µL of acetonitrile as a disperser at pH 8. Under the optimized conditions, the method showed linearity over the range of 1-100 ng/mL with a limit of detection of 0.4 ng/mL. The accuracy, the intra- and inter-day precision were assessed, the %recoveries were found to be between 98.48 and 100.81% with %RSD lower than 1.3. Using chemometrics in method optimization helped achieve the maximum possible enrichment with the least effort, time, and reagents while considering all possible interactions between variables.

The Nitrated Form of Nateglinide Induces Apoptosis in Human Pancreatic Cancer Cells Through a Caspase-dependent Mechanism.

BACKGROUND/AIM: Nitric oxide (NO) has antitumor activity against various solid tumor cell types in addition to its vasodilatory effect. In the current study, we investigated the effect and mechanism of the synthetic nitrated form (NO2-NAT) of nateglinide, a hypoglycemic agent, on the induction of cell death in human pancreatic cancer cells. MATERIALS AND METHODS: NO production was evaluated by measuring nitrite (NO2) and nitrate (NO3) (NOx). Apoptotic cell numbers were determined using annexin V. RESULTS: NO2-NAT released nitrate and nitrite ions immediately upon dissolving in aqueous solution. NO2-NAT caused significant extracellular leakage of lactate dehydrogenase (LDH) in the human pancreatic cancer cell lines AsPC1 and BxPC3, and increased annexin-positive cells in a time- and concentration-dependent manner. NO2-NAT also significantly increased the activity of caspases 3 and 7. Exposure to Z-VAD-FMK, a caspase inhibitor, significantly suppressed NO2-NAT-induced cell death. CONCLUSION: These results indicated that NO2-NAT induces apoptosis in human pancreatic cancer cells and may serve as a new NO-based chemotherapeutic agent for the treatment of pancreatic cancer.

SUR1 As a New Therapeutic Target for Pulmonary Arterial Hypertension.

Mutations in ABCC8 have been identified in pulmonary arterial hypertension (PAH). ABCC8 encodes SUR1, a regulatory subunit of the ATP-sensitive potassium channel Kir6.2. However, the pathophysiological role of the SUR1/Kir6.2 channel in PAH is unknown. We hypothesized that activation of SUR1 could be a novel potential target for PAH. We analyzed the expression of SUR1/Kir6.2 in the lungs and pulmonary artery (PA) in human PAH or experimental pulmonary hypertension (PH). The contribution of SUR1 in human or rat PA tone was evaluated, and we measured the consequences of in vivo activation of SUR1 in control and PH rats. SUR1 and Kir6.2 protein expression was not reduced in the lungs or human pulmonary arterial endothelial cells and smooth muscle cells from PAH or experimentally induced PH. We showed that pharmacological activation of SUR1 by three different SUR1 activators (diazoxide, VU0071063, and NN414) leads to PA relaxation. Conversely, the inhibition of SUR1/Kir6.2 channels causes PA constriction. In vivo, long- and short-term activation of SUR1 with diazoxide reversed monocrotaline-induced PH in rats. In addition, in vivo diazoxide application (short protocol) reduced the severity of PH in chronic-hypoxia rats. Moreover, 3 weeks of diazoxide exposure in control rats had no cardiovascular effects. Finally, in vivo, activation of SUR1 with NN414 reduced monocrotaline-induced PH in rats. In PAH and experimental PH, the expression of SUR1/Kir6.2 was still present. In vivo pharmacological SUR1 activation by two different molecules alleviated experimental PH, providing proof of concept that SUR1 activation should be considered for PAH and evaluated more thoroughly.

Optimized Box-Behnken experimental design based response surface methodology and Youden's robustness test to develop and validate methods to determine nateglinide using kinetic spectrophotometry.

Selective and straightforward kinetic spectrophotometric methods were developed to quantify nateglinide (NTG) in pharmaceutical dosage forms. Fixed time (ΔA) and the equilibrium methods utilized the reaction of NTG with 1-chloro-2,4-dinitrobenzene (CDNB) in dimethyl sulfoxide (DMSO) with heating at 80 °C for 25 min to form a stable yellow-coloured Meisenheimer complex, which absorbs maximally at 421 nm. The optimization was achieved by utilizing the Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). In which three significant factors were studied, namely, CDNB volume (A), heating temperature (B) and heating time (C) against the absorbance as a response. Method validation presented the International Conference on Harmonisation (ICH) parameters such as specificity, selectivity, linearity, precision, accuracy, limit of detection (LOD), limit of quantitation (LOQ), robustness and solution stability. The LOD and LOQ values were 0.48, 1.46, and 0.21, 0.62 µg/ml, respectively, for a fixed time (ΔA) and equilibrium methods with the linear dynamic range of 1-15 µg/ml. Furthermore, Youden's robustness test using factorial combinations of the selected analytical parameters was performed and investigated its influence with alternative conditions. All results were reproducible and quickly adopted for routine analysis of NTG in pharmaceutical formulations and laboratory preparations.

PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms affect therapeutic efficacy of nateglinide in Chinese patients with type 2 diabetes mellitus.

BACKGROUND: Genetic polymorphisms in the PPARD and NOS1AP is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This study was designed to investigate a potential association of PPARD rs2016520 (T/C) and NOS1AP rs12742393 (A/C) polymorphisms with efficacy of nateglinide in newly diagnosed Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: Sixty patients with newly diagnosed T2DM were enrolled to identify PPARD rs2016520 and NOS1AP rs12742393 genotypes using the polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). All subjects were treated with nateglinide (360 mg/day) for 8 weeks. Anthropometric measurements, clinical laboratory tests were obtained at baseline and after 8 weeks of nateglinide treatment. RESULTS: After nateglinide treatment for 8 consecutive weeks, patients with at least one C allele of PPARD rs2016520 showed a smaller decrease in post plasma glucose (PPG), homeostasis model assessment for beta cell function (HOMA-B) than those with the TT genotype did (P < 0.05). In patients with the AA genotype of NOS1AP rs12742393, the drug showed better efficacy with respect to levels of fasting plasma glucose (FPG), fasting serum insulin (FINS), HOMA-B and homeostasis model assessment for insulin resistance (HOMA-IR) than in patients with the AC + CC genotype (P < 0.05). NOS1AP rs12742393 genotype distribution and allele frequency were associated with responsiveness of nateglinide treatment (P < 0.05). CONCLUSIONS: The PPARD rs2016520 and NOS1AP rs12742393 polymorphisms were associated with nateglinide monotherapy efficacy in Chinese patients with newly diagnosed T2DM. TRIAL REGISTRATION: Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

Design of experiment-based LC-MS/MS method development for simultaneous estimation of nateglinide and metformin hydrochloride in rat plasma.

This research aims to develop and validate a bioanalytical method for simultaneous estimation of an antidiabetic combination using LC-MS/MS in rat plasma. Nateglinide and metformin hydrochloride are commonly used combination for clinical management of Type 2 diabetes. Hence, simultaneous determination in plasma is essential for the rapid analysis of samples from the pharmacokinetic studies. Statistical optimization was carried out for liquid chromatography (LC) parameters and mass spectroscopic (MS) parameters by design of experiment (DoE) (Design Expert Version 11, Stat Ease Inc., USA) approach. A 33 full factorial design was used for optimization of LC parameters; %methanol, %formic acid, and flow rate were selected as independent variables, whereas peak area and tailing factor were considered as dependent variables for both drugs. Box-Behnken design was used to optimize MS parameters including drying gas flow rate, nebulizing gas flow rate, DL temperature, heat block temperature, and positive voltage as independent factors, and responses selected were [M + H]+ intensity of nateglinide and metformin hydrochloride. The [M + H]+ intensity of the optimized method for nateglinide and metformin hydrochloride were 2,462,838 and 11,873,826, respectively. The model was found significant for optimizing LC and MS parameters with p < 0.05 for both nateglinide and metformin hydrochloride. The optimized method was validated as per the ICH-M10 guideline, which was accurate, precise, and selective. The method was cost-effective and capable of quantitating concentrations in picogram levels for nateglinide and metformin hydrochloride simultaneously.

Evaluation of the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating type 2 diabetes among Chinese Han patients.

Genetic polymorphisms in the MTNR1B gene is associated with type 2 diabetes mellitus (T2DM); however, there is no evidence about its impact on the therapeutic efficacy of nateglinide. This prospective case-control study was designed to investigate the effect of MTNR1B rs10830963 gene variant on the therapeutic efficacy of nateglinide in treating T2DM. We genotyped untreated T2DM patients (N = 200) and healthy controls (N = 200) using the method of the high resolution of melting curve (HRM). Newly diagnosed T2DM patients (n = 60) with CYP2C9*1 and SLCO1B1 521TT genotypes were enrolled and given oral nateglinide (360 mg/d) for 8 weeks. The outcome was measured by collecting the venous blood samples before and at the 8th week of the treatment. The risk G allelic frequency of MTNR1B rs10830963 was higher in T2DM patients than the healthy subjects (P < 0.05). Post 8-week of treatment, newly diagnosed T2DM patients showed a less reduction in fasting plasma glucose levels and less increase in the carriers of genotype CG + GG at rs10830963 when compared with the CC genotype (P < 0.05). MTNR1B rs10830963 polymorphism was associated with the therapeutic efficacy of nateglinide in T2DM patients. Also, the CC homozygotes had a better effect than G allele carriers.Trial registration Chinese Clinical Trial Register ChiCTR13003536, date of registration: May 14, 2013.

High-Performance affinity chromatographic studies of repaglinide and nateglinide interactions with normal and glyoxal- or methylglyoxal-modified human albumin serum.

During diabetes human serum albumin (HSA), an important drug transport protein, can be modified by agents such as glyoxal (Go) and methylglyoxal (MGo) to form advanced glycation end-products. High-performance affinity microcolumns and zonal elution competition studies were used to compare interactions by the anti-diabetic drugs repaglinide and nateglinide with normal and Go- or MGo-modified HSA at Sudlow sites I and II of this protein. Both drugs had their strongest binding at Sudlow site II for the normal and modified forms of HSA. The association equilibrium constants at this site for repaglinide and nateglinide with normal HSA were 6.1 (± 0.2) × 104 M-1 and 7.1 (± 0.8) × 105 M-1, respectively, at pH 7.4 and 37°C; these values increased by up to 3.6-fold for repaglinide and decreased by up to 45-55 % for nateglinide when HSA was modified by Go or MGo at levels seen in prediabetes or diabetes. Both drugs were also found to bind at Sudlow site I, with association equilibrium constants at this site on normal HSA of 4.2 (± 0.3) × 104 M-1 for repaglinide and 5.0 (± 0.1) × 104 M-1 for nateglinide. The binding strength for repaglinide at Sudlow site I increased by 1.3- to 1.7-fold with the Go-modified HSA and decreased slightly (i.e., up to 19 %) for the MGo-modified HSA, while nateglinide showed only a small or insignificant change in binding with the same modified HSA samples. These results indicated that binding by repaglinide and nateglinide with HSA can be altered significantly by modification of this protein with Go or MGo, making these modifications of potential interest in the treatment of patients with these drugs during diabetes.

Bioequivalence of a Generic Nateglinide Formulation in Healthy Chinese Volunteers under Fasting and Fed Conditions: A Randomized, Open-Label, Double-Cycle, Double-Crossover Study.

INTRODUCTION: Nateglinide or N-(trans-4-isopropylcyclohexyl-1-carbonyl)-D-phenylalanine is a drug with a rapid hypoglycemic effect that is mainly used in the treatment of type 2 diabetes. Very few studies have assessed bioequivalence based on feeding status. This study aimed to assess the pharmacokinetic bioequivalence and safety of nateglinide-containing tablets (0.12 g) in healthy Chinese volunteers under fasting and fed conditions. METHODS: The studies were performed in 2017-2018 in the Phase I Clinical Trial Ward of the Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, China. Eligible Chinese volunteers received a single 0.12-g dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. Blood samples were collected at various time intervals, and plasma nateglinide concentrations were analyzed by liquid chromatography-tandem mass spectrometry. Then, the adverse events, laboratory test results, vital signs, and physical exam findings were compared between the 2 groups. RESULTS: The ratios of the geometric means of Cmax, AUC0-t, and AUC0-inf of the tested to reference preparations under fasting conditions were 105.03% (90% confidence interval [CI]: 99.53-110.83%), 104.02% (90% CI: 101.37-106.74%), and 104.04% (90% CI: 101.38-106.77%), respectively. The same ratios under fed conditions were 96.55% (90% CI: 85.80-108.65%), 103.08% (90% CI: 100.07-106.18%), and 103.07% (90% CI: 100.21-106.01%), respectively. The 90% CI values for Cmax, AUC0-t, and AUC0-inf fell within the accepted range of bioequivalence (80.00-125.0%). Common adverse events included hypoglycemia, heart rate increase, palpitation, sweating, dizziness, and diarrhea. CONCLUSIONS: The test formulation (0.12 g) met the CFDA's regulatory definition for bioequivalence to the reference formulation. Both formulations were well tolerated by healthy Chinese subjects. TRIAL REGISTRATION: This trial has been registered in the Chinese Clinical trial registry (ChiCTR2000030694), March 10, 2020.

Acute Peripheral Inflammation Increases Plasma Concentration of Hypoglycemic Agent Nateglinide with Decreased Hepatic Drug-Metabolizing Activity in Rats.

The effects of inflammation on hypoglycemic agents were evaluated in male rats with acute peripheral inflammation (API). Nateglinide (NTG) was utilized as a model compound, since it is a hepatically-metabolized compound and its metabolism is mainly mediated by CYP 2C11 enzyme. In the experiments, rats were subjected to carrageenan injection into their hind paws for API induction, and the plasma concentration profiles of NTG were then examined. In addition, pooled liver microsomes were prepared from control and API rats, and the hepatic drug-metabolizing activity toward NTG and the hepatic expression of CYP2C11 protein were evaluated. It was shown that the plasma concentration of NTG following its intravenous administration decreases at a slower rate in API rats than that in control rats. It was also indicated in the incubation study with the liver microsomes that the hepatic drug-metabolizing activity toward NTG decreases in API rats. Additionally, it was revealed in Western immunoblotting that the hepatic expression of CYP2C11 protein decreases in API rats. These findings suggest that inflammation occurring in peripheral tissues brings about a decrease in hepatic NTG metabolism by suppressing the hepatic expression of CYP2C11 protein, causing an alteration of the plasma concentration profile of NTG with its impaired elimination.

Efficacy and Cardiovascular Safety of Meglitinides.

Meglitinides are a group of oral hypoglycemic medications currently approved for the treatment of type 2 diabetes mellitus (T2DM). Two meglitinide molecules, Repaglinide and Nateglinide, are presently in use. Repaglinide is preferred because of its superior glycemic efficacy. They have modest efficacy with a mean decrement of glycosylated haemoglobin (HbA1c) ranging between -0.2 to -1.50% with individual therapy. Additional HbA1c reduction can occur with combination therapy with other oral hypoglycemics. This class of drugs is effective in controlling postprandial hyperglycemia with minimal risk of hypoglycemia. It is also useful in patients with variable meal timings, especially in the elderly, and in patients with renal failure. There are a dearth of long-term studies on meglitinides to assess cardiovascular outcomes or mortality in T2DM, although the Nateglinide and Valsartan in Impaired Glucose ToleranceOutcomes Research (NAVIGATOR) study showed no difference between Nateglinide and placebo with regard to the core composite cardiovascular outcomes. Based on a PubMed literature search using key words: 'meglitinides', 'repaglinide', 'nateglinide', 'HbA1c', 'glycated haemoglobin', 'cardiovascular safety', 'cardiovascular events', 'cardiovascular outcome trials', 'type 2 diabetes mellitus' and heart failure, and combining the search terms using Boolean operators 'AND', 'OR' and 'NOT' as needed we compiled current evidence for use of these oral hypoglycemic agents in clinical use. This article is an attempt to review the efficacy and cardiovascular (CV) safety of Meglitinides to help clinicians to use this class of oral hypoglycaemic agents prudently.

Co-processing of nateglinide with meglumine for enhanced dissolution rate: in vitro and in vivo evaluation.

OBJECTIVE: The aim of this work was to investigate dry co-grinding of nateglinide with meglumine for enhanced dissolution rate of nateglinide. The study was extended to investigate the effect of this dissolution enhancement on the hypoglycemic effect of the drug in diabetic rats. METHODS: Nateglinide was subjected to dry co-grinding with increasing proportions of meglumine to prepare products containing the drug with meglumine at 1:1, 1:2, and 1:3 molar ratios. These products were evaluated using combined instrumental analysis which employed Fourier transform infrared spectroscopy (FTIR), differential thermal analysis (DTA), and X-ray diffraction (XRD). Drug dissolution was also monitored before and after processing with and without meglumine. The optimum ratio was used to assess the effect of dissolution enhancement on the hypoglycemic effect of nateglinide on diabetic rats. The unprocessed nateglinide was used as control. RESULTS: Co-grinding of nateglinide resulted in changes in the FTIR spectral patterns of nateglinide and meglumine. The changes suggested the formation of amide bond between both compounds at 1:1 molar ratio. The new species was confirmed by DTA and XRD. This species exhibited fast dissolution of nateglinide after incorporation of higher proportions of meglumine. Co-grinding was essential as indicated from slower dissolution from physical mixture containing the highest proportion of meglumine. Enhanced dissolution was reflected in vivo as improved rate and extent of hypoglycemia. CONCLUSION: Dry co-grinding of nateglinide with meglumine developed new species which liberated nateglinide rapidly and enhanced the rate and extent of hypoglycemia of nateglinide.

Nateglinide Exerts Neuroprotective Effects via Downregulation of HIF-1α/TIM-3 Inflammatory Pathway and Promotion of Caveolin-1 Expression in the Rat's Hippocampus Subjected to Focal Cerebral Ischemia/Reperfusion Injury.

Ischemic stroke is a major cause of death and motor disabilities all over the world. It is a muti-factorial disorder associated with inflammatory, apoptotic, and oxidative responses. Nateglinide (NAT), an insulinotropic agent used for the treatment of type 2 diabetes mellitus, recently showed potential anti-inflammatory and anti-apoptotic effects. The aim of our study was to elucidate the unique neuroprotective role of NAT in the middle cerebral artery occlusion (MCAO)-induced stroke in rats. Fifty-six male rats were divided to 4 groups (n = 14 in each group): the sham-operated group, sham receiving NAT (50 mg/kg/day, p.o) group, ischemia/reperfusion (IR) group, and IR receiving NAT group (50 mg/kg/day, p.o). MCAO caused potent deficits in motor and behavioral functions of the rats. Significant increase in inflammatory and apoptotic biomarkers has been observed in rats' hippocampi. Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway was significantly stimulated causing activation of series inflammatory biomarkers ending up neuro-inflammatory milieu. Pretreatment with NAT preserved rats' normal behavioral and motor functions. Moreover, NAT opposed the expression of hypoxia-inducible factor-1α (HIF-1α) resulting in downregulation of more inflammatory mediators namely, NF-κB, tumor necrosis factor-ß (TNF-ß), and the anti-survival gene PMAIP-1. NAT stimulated caveolin-1 (Cav-1) which prevented expression of oxidative biomarkers, nitric oxide (NO), and myeloperoxidase (MPO) and hamper the activation of apoptotic biomarker caspase-3. In conclusion, our work postulated that NAT exhibited its neuroprotective effects in rats with ischemic stroke via attenuation of different unique oxidative, apoptotic, and inflammatory pathways.

Mini Health Technology Assessment of Repaglinide and Naglinide / 中国药房

OBJECTIVE：To provid e reference for hospital decision-maker to select and use repaglinide and naglinide reasonably. METHODS ：Through reviewing literautre ，guideline and instruction ，full score system was estalished for comunni- cation between pharmacists and physicians ；from the aspects of clinical necessity ，effectiveness，safety，economy，medical insu- rance attribute ，essential medicine attribute ，original research attribute ，drug packaging attribute ，drug market and enterprise attributes，the Mini health technology assessment （Mini HTA ）was carried out for repaglinide and nateglinide ，and scored on the basis of weight value. RESULTS ：Repaglinide and naglinide ’s final score were 77 and 74，respectively. For type 2 diabetes，both of them could reduce postprandial blood glucose ，and had less side effect and good safety. They were both included in the medical insurance list. Both of them were original varieties ，easy to store and had a long period of validity. Although they were expensive in the treatment of type 2 diabetes，their manufacturers had a good reputation and were widely used in the world ，which was a good choice for patients with type 2 diabetes. But they were different to certain extent ；repaglinide could be used in patients with poor renal function [eGFR ＜30 mL/min] without dose adjustment ；nateglinide should be adjusted according to eGFR for renal excretion. Repaglinide was essential medicine but nateglinide wasn ’t；repaglinide didn ’t need shading storage but nateglinide did. In addition ， a variety of liver drug enzyme inducers or inhibitors may interact with the two drugs ，and special groups should be used with. CONCLUSIONS ：Mini HTA provide reference for the selection and rational use of repaglinide and nateglinide ；patients with type 2 diabetes can select suitable drug according to their own conditions and needs. When combined with other drugs ，blood glucose should be closely monitored to prevent the occurrence of hypoglycemia.

Development and Characterization of Microstructured, Spray-Dried Co-Amorphous Mixture of Antidiabetic Agents Stabilized by Silicate.

In the present work, co-amorphous mixture (COAM) of poorly soluble nateglinide (NT) and highly soluble Metformin hydrochloride (MT) was prepared by spray drying method to improve the dissolution rate of NT and the processability of COAM. Binary spray-dried COAM of NT and MT (120 mg: 500 mg) was prepared in its clinical dose ratio whereas 20% Neusilin®US2 (NS) was added to prepare non-sticky, free flowing ternary COAM. Solubility studies of binary and ternary COAM exhibited sevenfold and tenfold rise in the solubility of NT. Complete amorphization of NT was revealed in XRPD and DSC studies of both COAM and hydrogen-bonding interactions were reflected in FTIR-spectra. SEM microphotographs illustrated round-shaped microparticles in ternary COAM against the irregular particles in binary COAM. In vitro dissolution of NT was significantly improved in ternary COAM > binary COAM > NT irrespective of dissolution medium. On contrary, MT has partially transformed to the amorphous form in COAM without altering the solubility. In accelerated stability studies, NT and MT devitrification was not observed in XRPD of ternary COAM in contrast to binary COAM. Therefore, enhanced dissolution of NT, stabilization of spray-dried dispersion, and its improved processability can be achieved by preparing ternary COAM of NT:MT:NS.