Regulation of gluconeogenesis in type 2 diabetes mellitus: An investigation of the role of corticosteroids?

PhDType 2 diabetes mellitus (T2DM) is a complex disease involving various physiological factors, hormones and metabolites. Over expression of key gluconeogenic enzymes, such as PEPCK, cause features of T2DM including obesity and insulin resistance. Previous studies showed intravenous administration of corticotropin releasing factor (CRF) and sauvagine in rats cause marked hyperglycaemia, which is adrenal dependent. The 11-β hydroxylase inhibitor metyrapone augmented this hyperglycaemia raising important questions about the role of known and unknown corticosteroids in hepatic carbohydrate metabolism. The goal of this project was to identify and characterise the gluconeogenic activity of adrenal corticosteroids secreted under basal and stimulated conditions. This was accomplished by establishing a rapid, sensitive and robust multi-well assay for measurement of PEPCK activity in the hepatocyte cell line H4-II-E-C3. A sensitive fluorescent method for assay of glucose production by these cells was also developed. Extracts of media samples from adrenal glands incubated with sauvagine and metyrapone significantly increased hepatocyte glucose production (HGP) despite low corticosterone concentrations. HPLC characterisation of these extracts revealed increases in 11-deoxycorticosterone (DOC) and other unidentified peaks. However, none of these individual fractions significantly affected HGP in culture. Commercially available corticosterone, which contains DOC as an impurity, had greater gluconeogenic effect compared to purified corticosterone alone. Based on these observations and discrepancies in the literature, the effect of DOC on hepatic carbohydrate metabolism was characterised. Surprisingly, DOC suppressed the activity of gluconeogenic enzyme PEPCK in fed rat hepatocytes and enhanced insulin 4 stimulated glycogen stores in cultured hepatocytes at higher glucose concentrations (25 mM) over a 24 hour period. In serum-starved, fasted hepatocytes these effects were not significant, suggesting the need for a detailed investigation of the signalling pathways and regulatory control of DOC on GK, GS, G6Pase and PEPCK

DEVELOPMENT AND VALIDATION OF UV SPECTROPHOTOMETRIC METHOD AND RP-HPLC METHOD FOR ESTIMATION OF CAPECITABINE IN BULK AND TABLET DOSAGE FORMS

Objective: The objective of the present work is to develop and validate a novel, specific, precise and reliable method for estimation of Capecitabine in bulk and pharmaceutical dosage form using UV-visible spectroscopy and RP-HPLC method. Methods: UV-visible spectrophotometric determination was performed with Elico double beam SL 210 UV-visible spectrophotometer having deuterium lamp at λmax 304 nm using water as a medium. Linearity was noted over a concentration range of 2-20 µg/ml with a correlation coefficient of 0.99. HPLC analysis was performed using Eclipse XDB C18 column with 5 µm particle size having dimensions 4.6 X 250 mm column, Agilent 1260 infinity DAD detector, 1260 infinity quaternary pump using Ezchrome software at a flow rate of 1 ml/min and a run time pressure of 2140 psi. Methanol: acetonitrile: water in the ratio 30: 30: 40 was used as mobile phase and the effluents were analyzed at 304 nm. Both the proposed methods were validated for various parameters like linearity, precision, accuracy, robustness, ruggedness, selectivity, detection, quantification limits, formulation analysis as per International Conference on Harmonization (ICH) guidelines. Results: Linearity for UV and HPLC method was noted over a concentration range of 2-100 µg/ml with a correlation coefficient of 0.99. The retention time was considered to be 4.60 min. The % RSD for interday and intraday precision studies and recovery analysis of both UV and HPLC methods was found to be less than 1% which is less than the official RSD limit (2%). Recovery analysis performed using marketed formulation capeguard was considered to be greater than 99% for both the methods. Conclusion: Both the methods developed were validated according to the ICH guidelines. Hence it was evident that the developed methods were novel, sensitive, precise and reliable for estimation of Capecitabine in bulk and were successfully applied for estimation of pharmaceutical dosage forms. Keywords: Capecitabine, UV-visible spectroscopic method, HPLC method, Validatio

3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGR) Enzyme of the Sterol Biosynthetic Pathway: A Potential Target against Visceral Leishmaniasis

Sterol biosynthetic pathway is explored for its therapeutic potential for Visceral Leishmaniasis. In Leishmania, this pathway produces ergosterol which is absent in host and therefore is a promising strategy to combat proliferation of both extracellular and intracellular forms of the parasite with minimal host toxicity. The present chapter focuses on 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) enzyme which is the rate-limiting enzyme of the ergosterol biosynthesis. HMGR gene of L. donovani was biochemically and biophysically characterized for the first time. HMGR over expressing transgenic parasites were generated to evaluate its role in parasite growth and infection ability. A series of statins like atorvastatin, simvastatin and mevastatin were evaluated for its therapeutic efficacy and mode of action elucidated. Atorvastatin and mevastatin were found to be killing both the promastigote and amastigote forms of the parasite without exhibiting host cytotoxicity. Besides, non-statin class of molecules like resveratrol and glycyrrhizic acid were also analyzed for antileishmanial potential. Two antidepressants, ketanserin and mianserin were found to kill both L. donovani promastigotes and intracellular amastigotes with no apparent toxicity to the host cells. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present work may have implications in treatment of Leishmaniasis

In vitro and in vivo evaluation of Quetiapine fumarate controlled gastroretentive floating drug delivery system

The aim of the present work was to develop and optimize gastroretentive floating system of Quetiapine fumarate (QF) for the effective treatment of Schizophrenia. The present study was carried out with an objective of preparation and in vivo evaluation of floating tablets of using QF as a model drug using HPMC polymers, Gelucire 43/01 and Polyox WSR 301 to improve oral bioavailability of QF floating tablets by increasing gastric residence time. The tablets were prepared by direct compression method. The effect of polymers concentration and viscosity grades of HPMC on drug release profile was evaluated. The result of in vitro dissolution study showed that the drug release profile could be sustained by increasing the concentration of HPMC K15M and Polyox WSR 301. The optimized formulation (F12) containing HPMC K15M and Polyox WSR301 showed 98.6% drug release at the end of 12h. Changing the viscosity grade of HPMC from K15M to K100M had no significant effect on drug release profile. The optimized formulations (F12) containing sodium bicarbonate 40mg per tablet showed desired buoyancy (floating lag time of about 32seconds and total floating time of >12h). Optimized formulation (F12) followed diffusion controlled zero order kinetics and non-fickian transport of the drug. FTIR and DSC studies revealed the absence of any chemical interaction between drug and polymers used. The best formulation (F12) was selected based on in vitro characteristics and was used in vivo radiographic studies by incorporating BaSO4. These studies revealed that the tablets remained in the stomach for 6h in fasting human volunteers and indicated that gastric retention time was increased by the floating principle, which was considered desirable for the absorption window drugs. Studies to evaluate the pharmacokinetics in vivo showed better bioavailability, area under the concentration–time curve, elimination rate constant and half-life than marketed product

Tensile and Wear Behavior of Calotropis Gigentea Fruit Fiber Reinforced Polyester Composites

AbstractAn experimental study has been carried out to investigate the tensile and wear characterization of polymer composites made by reinforcing Calotropis Gigentea fruit fiber as a new natural fiber into a polyester resin. The Calotropis Gigentea fibres extracted by manual processes have been used to fabricate the composites. The composites are fabricated up to a maximum volume fraction of fibre of 0.35. The tensile strength increased with increase in fiber content. Further, the wear behavior of the Calotropis Gigentea fruit fiber composite were studied with increase in fiber content

Design And Modeling Of Optical Structure Capacity Of Ten Megawatts Power Plants

This manages the parts design and simulates a PV life with MATLAB and Simulink programming. The power plant is made of photovoltaic panels connected in series and parallel, a DC-DC support transformer and a three-phase inverter interferes with a three-phase low voltage array of 0.4 kV and a medium voltage grid of 20 kV by phase methods Up to Transformers. The DCDC support transformer uses an MPPT controller and the inverter uses a d-q concession control strategy with the current PI controller. Some instances are recreated where the dynamic nature of an ordered photoelectric frame is intriguing. They treat solar radiation and temperature changes

DEVELOPMENT AND IN VIVO EVALUATION OF GASTRORETENTIVE FLOATING TABLETS OF ANTIPSYCHOTIC DRUG RISPERIDONE

Objective: The objective of this research work was to formulate and evaluate the floating drug delivery system containing Risperidone, to improve oral bioavailability by increasing gastric residence time.Methods: Total fifteen formulations of Risperidone floating tablets were prepared by direct compression method using different grades of HPMC polymers, Gelucire, Polyox and NaHCO3. In vivo radiographic studies were performed in human volunteers by incorporating barium sulphate.Results: The prepared tablets were characterized and found to exhibit satisfactory physicochemical characteristics. All the prepared batches showed good in vitro buoyancy with low floating lag time. It was observed that the tablets remained buoyant for more than 12h. Optimized formulation (F15) consisting of HPMC K100M, WSR 301, Gelucire 50/13 and NaHCO3, followed diffusion controlled zero-order kinetics and non-fickian transport of the drug. FTIR and DSC studies revealed the absence of any chemical interaction between drug and polymers used. The in vivo radiographic studies revealed that the tablets remained in the stomach for 6h in fasting human volunteers. In vivo bioavailability studies performed in healthy human volunteers and Tmax, Cmax, AUC was calculated and confirmed significant improvement in bioavailability when compared with marketed formulation Respidon 2.Conclusion: The data obtained thus suggests that floating delivery system of Risperidone can be successfully designed to give controlled drug delivery and improved oral bioavailability

The Effect of Taxpayers Attitudes towards the Legal System and Government on Tax Morale (With Reference to Selected Assesses in Addis Ababa, Ethiopia)

The overall purpose of this study was to assess the effect of taxpayers’ attitudes towards the legal system and government on tax morale. The researchers used survey method for the study. Data for the survey study were collected from the target populations by means of self administered questionnaire. From the populations the sample was select by using stratified sampling to obtain a representative sample from taxpayers of business organization. An ordered probit model is employed to analyze the effect of taxpayers’ attitudes towards the legal system and government on tax morale. The results showed that tax morale (dependent variable) is correlated at 0.4982 with attitude of taxpayers towards government and legal system at 5 percent significance level and there is a significant relationship between taxpayer attitude towards the legal system and government, and tax morale at a p value of 0.001 and 0.000 and has a significant positive effect on tax morale, with higher marginal effects. They have a statistically significant positive effect on tax morale. Therefore, governance quality seems to be a key component in the understanding of tax morale. Hence, governments are called to create confidence in their credibility and their capacity to deliver promised returns for taxes. The government should build trustworthy institutions; much weight should be put on developing a trustworthy ground so that taxpayers feel comfortable with paying taxes. Keywords: Tax morale, Legal System, Governmen

Pharmacological studies of zinc oxide nanoparticles

500-505In this paper, we focused on the synthesis and characterization of zinc oxide nanoparticles by using a chemical method. The characterization of Zinc oxide Nanoparticles are determined by different spectroscopic techniques such as UV-Visible, DRS, FTIR, FESEM, and EDX. Further, the antimicrobial activity and cytotoxic studies also performed towards different bacterial species like Bacillus subtilis, Escherichia coli, fungi like Aspergillus niger and MCF-7 Breast Cancer cell line

DEVELOPMENT AND VALIDATION OF A GAS CHROMATOGRAPHY-MASS SPECTROMETRY WITH SELECTED ION MONITORING METHOD FOR THE DETERMINATION OF TRACE LEVELS OF METHANE SULFONYL CHLORIDE AS AN IMPURITY IN ITRACONAZOLE ACTIVE PHARMACEUTICAL INGREDIENT

ABSTRACTObjective: To develop an accurate, precise, and linear gas chromatographic-mass spectrometry selective ion monitoring (SIM) method for quantitativeestimation of methane sulfonyl chloride (MSC) as an impurity in itraconazole (ICR) active pharmaceutical ingredient (API) at ppm level and validatedas per International Council of Harmonization (ICH) guidelines. Methods: This method used in SIM mode mass selective detection was developed and validated for the trace level analysis of an impurity.Chromatographic separation of MSC was achieved in 5.45 minutes and m/z value was 79 on SIM mode, ZB-5 ms 30 m × 0.25 mm × 0.25 µm column,using helium carrier gas with 1.0 ml/min.Results: The method was linear for MSC in ICR 1.90-7.5 µg/ml, respectively. The coefficient of correlation (r) for the MSC was better than 0.999. Thelimit of detection and limit of quantification (LOQ) obtained were 0.44 and 1.32 µg/ml. The method was fully validated, complying Food and DrugAdministration, ICH, and European Medicines Agency guidelines. Furthermore, verified precision, accuracy, LOQ precision, LOQ accuracy, ruggedness,and robustness.2Conclusion: The methods were successfully validated to determination and quantification of MSC in ICR API. Hence, the method holds good for theroutine trace analysis of MSC in ICR and various pharmaceutical industries as well as academics.Keywords: Methane sulfonyl chloride, Itraconazole, Gas chromatography-mass spectrometry, Method development, Method validation