Formulation and evaluation of fast disintegrating tablets of Granisetron HCl using natural polymers

The present research work is to formulate and evaluate fast disintegrating tablets of Ganisetron HCl using natural polymers. Tablets were prepared by direct compression method using different drug polymer concentration. Fourier Transform Infrared Spectroscopy (FT-IR) study revealed no chemical interaction between drug and polymers used. Precompression and postcompression parameters were within the limits for the tablets. Disintegration and dissolution data of tablets were directly proportional to the superdisintegrants concentration. Selected fast dissolving tablet F8 containing plantago ovate 5%w/w has released 99.66 % within 3min

Formulation and evaluation of controlled release matrix tablets of antihypertensive drug using natural and synthetic hydrophilic polymers

The present study is to prepare and evaluate controlled release matrix tablets of Losartan potassium using natural and synthetic polymers. Tablets were prepared by direct compression method using different drug: polymer concentration. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) study revealed no chemical interaction between drug and polymers used. Precompression and postcompression parameters complied with pharmacopoeial limit for the tablets. In-vitro release studies was performed and the results indicates that matrix tablet  (F9) containing 50% w/w blend of natural and synthetic polymer has better controlled release for a period of 24 h

Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3-TACE dyad in type 2 diabetes mellitus : a randomised, double-blind, placebo-controlled, mechanistic study

Aims/hypothesis: Pioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)γ agonist insulin-sensitiser with anti-inflammatory and anti-atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes. Methods: A randomised, double-blind, placebo-controlled, mechanistic trial was conducted on 29 patients with type 2 diabetes treated with metformin and/or sulfonylurea. They were randomised to receive PIO or placebo (PLC) for 6 months, in a 1:1 ratio. Participants were allocated to interventions by central office. All study participants, investigators and personnel performing measurements were blinded to group assignment. At baseline and after 6 months patients underwent: (1) OGTT; (2) muscle biopsy to evaluate expression of TNF-α, tissue inhibitor of metalloproteases 3 (TIMP-3) levels, TNF-α converting enzyme (TACE) expression and enzymatic activity; (3) euglycaemic-hyperinsulinaemic clamp; (4) measurement of plasma high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor type-1 (PAI-1), TNF-α, IL-6, monocyte chemotactic protein-1 (MCP-1), adiponectin and fractalkine (FRK). The interventions were PIO 15 mg/day vs placebo and the main outcomes measured were absolute changes in whole-body insulin sensitivity, insulin secretion and inflammatory state. Results: Fifteen participants were randomized to receive PIO and 14 participants were randomized to receive PLC. Eleven participants completed the study in the PIO group and nine participants completed the study in the PLC group and were analysed. Fasting plasma glucose and HbA1c decreased modestly (p < 0.05) after PIO and did not change after PLC. M/I (insulin-stimulated whole-body glucose disposal), adipose tissue insulin resistance (IR) index, insulin secretion/IR (disposition) index and insulinogenic index improved significantly after PIO, but not after PLC. Circulating MCP-1, IL-6, FRK, hsCRP and PAI-1 levels decreased in PIO- as compared with PLC-treated patients, while TNF-α did not change. TNF-α protein expression and TACE enzymatic activity in muscle were significantly reduced by PIO but not PLC. Adiponectin levels increased significantly after PIO as compared with PLC treatment. Given that the mean TACE enzymatic activity level at baseline in the PIO group was 0.29 ± 0.07 (fluorescence units [FU]), and at end of study decreased to 0.05 vs 0.14 in the PLC group, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.80. Given that M/I was 2.41 ± 0.35 μmol kg-1 min-1 (pmol/l)-1 at baseline and increased by 0.55 in the PIO and 0.17 in the PLC groups, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.85. The type I error probability associated with this test of this null hypothesis is 0.05. No serious adverse events occurred in either group. Conclusions/interpretation: Low-dose PIO (15 mg/day) improves glycaemic control, beta cell function and inflammatory state in obese patients with type 2 diabetes. Trial registration: Clinical.Trial.gov NCT01223196 Funding: This study was funded by TAKEDA

Membranous Nephropathy And Cerebellar Degeneration With Anti-gad Antibodies In Type 2 Diabetes Mellitus.

To study the potential pathogenic significance of the coexistence of membranous nephropathy, cerebellar degeneration and anti-glutamic acid decarboxylase (GAD) autoantibodies in patients with diabetes. We performed a direct immunocytochemistry on human kidney slides, electron microscopy on human kidney biopsy, direct immunofluorescence on human kidney biopsy. Baboon and rat kidney cell lines were fractionated and subjected to western blotting with antibodies to GAD. In this patient we demonstrate the presence of autoantibodies to GAD, which is highly enriched in podocytes plasma membrane and tubular cells of the kidney as well as sub-endothelial IgG and complement C3 deposits in the glomerular basement membrane (GBM). We hypothesize the existence in this patient of a common autoimmune pathogenic mechanism with GAD as the autoantigenic determinant, underlying cerebellar degeneration and membranous nephropathy.52897-90

A Recombinant Protein Biomarker DDA Library Increases DIA Coverage of Low Abundance Plasma Proteins

AbstractCredible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). Here, we employed a mixture of recombinant proteins in DDA libraries to subsequently detect cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 human recombinant proteins that had been previously implicated as possible cancer biomarkers in both our own and other studies. The rPSL was then used to identify proteins from non-depleted colorectal cancer (CRC) plasmas by SWATH-MS. Most (32/36) of the proteins in the rPSL were reliably identified in plasma samples, including 8 proteins (BTC, CXCL10, IL1B, IL6, ITGB6, TGFα, TNF, TP53) not previously detected using high-stringency MS in human plasmas according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and post-digestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 were identified using DDA-MS. The 20 additional proteins exclusively identified by using the rPSL approach with SWATH were mostly lower abundance (i.e., &lt;10ng/ml) plasma proteins. To mitigate FDR concerns, and replicating a more typical approach, the DDA rPSL was also merged into a human plasma DDA library. When SWATH identification was repeated using this merged library, the majority (33/36) of low abundance plasma proteins from the rPSL could still be identified using high-stringency HPP Guidelines v3.0 protein inference criteria.</jats:p

Altered CD8+ T cell frequency and function in tuberculous lymphadenitis

CD8(+) T cells secreting Type1 and Type 17 cytokines and cytotoxic molecules play a major role in immunity and protection against pulmonary tuberculosis (PTB), although their role in tuberculous lymphadenitis (TBL) is not well known. To identify the distribution and function of CD8(+) T cells expressing Type1, Type 2 and Type 17 cytokines and cytotoxic molecules in TBL, we examined baseline and mycobacterial–antigen specific immune responses in the whole blood of individuals with PTB and compared them with TBL. TBL is characterized by elevated frequencies of baseline and mycobacterial-antigen stimulated CD8(+) T cells expressing Type 1 (IL-2 and TNFα) and Type 17 (IL-17A and IL-17F) cytokines in comparison to PTB individuals. In contrast, TBL individuals exhibited diminished frequency of CD8(+) T cells expressing perforin, granzyme B and CD107a. The blockade of IL-1R and IL-6R during antigenic stimulation resulted in significantly diminished frequencies of CD8(+) T cells expressing Type 1 and Type 17 cytokines in TBL. Therefore, our data suggest that TBL is characterized by an IL-1 and IL-6 dependent expansion of CD8(+) T cells expressing Type 1 and Type 17 cytokines as well as altered frequencies of cytotoxic molecules, reflecting an important association of these cells with the pathogenesis of TBL

Membranous nephropathy and cerebellar degeneration with anti-GAD antibodies in type 2 diabetes mellitus

Aims: To study the potential pathogenic significance of the coexistence of membranous nephropathy, cerebellar degeneration and anti-glutamic acid decarboxylase (GAD) autoantibodies in patients with diabetes. Methods: We performed a direct immunocytochemistry on human kidney slides, electron microscopy on human kidney biopsy, direct immunofluorescence on human kidney biopsy. Baboon and rat kidney cell lines were fractionated and subjected to western blotting with antibodies to GAD. Results: In this patient we demonstrate the presence of autoantibodies to GAD, which is highly enriched in podocytes plasma membrane and tubular cells of the kidney as well as sub-endothelial IgG and complement C3 deposits in the glomerular basement membrane (GBM). Conclusions: We hypothesize the existence in this patient of a common autoimmune pathogenic mechanism with GAD as the autoantigenic determinant, underlying cerebellar degeneration and membranous nephropathy