FORMULATION AND IN-VITRO EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF GLIPIZIDE

Diabetes mellitus is a metabolic disorder caused by insufficient production of endogenous insulin, with or without resistance to insulin action, resulting in hyperglycaemia. In type 1 diabetes mellitus, there is a failure in production of insulin as a result of destruction of the cells of the pancreas, and patients require treatment with insulin whereas type 2 diabetes can be characterised by defects in both insulin action (i.e. insulin resistance) and insulin secretion, and is associated with elevated basal hepatic glucose production.  Glipizide is a second-generation sulfonylurea that can acutely lower the blood glucose level in humans by stimulating the release of insulin from the pancreas and is typically prescribed to treat type II diabetes. Different formulations were prepared by varying the concentration of HPMC used as polymers. The effect of varying concentration of hydrophilic polymers (HPMC 5cps and 15 cps) was studied on the release pattern of glipizide. Sustained release glipizide matrix tablets were prepared by wet granulation and compression of hydroxypropylmethyl cellulose (5 cps and 15 cps), drug and other excipients mixture. The promising formulation was compared with the marketed sample of suatained release glynase in terms of release pattern. The release rate of a glipizide from matrix tablet was decreased with increasing the concentration as well as viscosity polymer. This might be probably due to increased swelling and reduced erosion rate of matrix tablet. The formulation 13 (F13) showed the similar result as marketed sample of sustained release glynase tablets in terms of release rate.Key Words: Glipizide, Hydroxy propyl methyl cellulose (HPMC), Viscosity grade

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Detection of Salmonella Typhi bacteriophages in surface waters as a scalable approach to environmental surveillance.

BackgroundEnvironmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. We sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays.MethodologyWe collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. We performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. We isolated and tested phages against multiple strains to assess their host range. We performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes.FindingsS. Typhi-specific bacteriophages were detected in 54.9% (198/361) of river and 6.3% (1/16) drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95) (p=0.005). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) river water samples contained phages. All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to the class Caudoviricetes and clustered in three distinct groups.ConclusionsS. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection. Screening small volumes of water with simple, low-cost (~$2) plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance

<i>S</i>. Typhi phage isolation from environmental samples collected in Nepal.

S. Typhi phage isolation from environmental samples collected in Nepal.</p

Host range activity of 10 <i>S</i>. Typhi phages isolated in our study.

S. Typhi phages (y-axis) were spotted on S. Typhi isolates (x-axis) belonging to different genotypes. Colored circles represent lytic activity, white circles represent no lytic activity.</p

Nucleotide-based intergenomic similarities of <i>S</i>. Typhi isolated from Nepal, using VIRIDIC.

A heatmap of hierarchical clustering of the intergenomic similarity values was generated and given as percentage values (right half, blue-green heatmap). Each genome pair is represented by three values (left half), where the top and bottom represent the aligned genome fraction for the genome in the row and column, respectively. The middle value represents the genome length ratio for each genome pair. (TIF)</p

Summary of phage genomics and protein clusters statistics generated by Virclust.

Summary of phage genomics and protein clusters statistics generated by Virclust.</p

VirClust hierarchical clustering of the <i>S</i>. Typhi isolated from Nepal, based on intergenomic distances calculated using the protein cluster content.

The genome clustering was performed based on PCs. The resulting tree was split into VGCs using a 0.9 intergenomic distance threshold. The visual components are described further. 1. Hierarchical tree calculated using PC-based intergenomic distances. 2. Silhouette width, color-coded in a range from −1 (red) to 1 (green). 3. VGC ID. 4. Heatmap representation of the PC distribution in the viral genomes. Rows are represented by individual viral genomes. Columns are represented by individual PCs. The ID of each PC can be read at the bottom of the heatmap. Colors encode the number of each PC per genome, with white signifying the PC absence, and the other colors signifying various degrees of replication. 5. Viral genome-specific statistics: genome length, the proportion of PC shared (dark grey) with any other genomes in the dataset, reported to the total PCs in the genome (light grey bar), the proportion of PC shared in its own VGC, the proportion of PCs shared only in its own VGC, the proportion of PCs shared also outside its own VGC, and the proportion of PC shared only outside own VGC. 6. S. Typhi phage name. (TIF)</p

Temporal variation in phage detection in Kathmandu, Nepal during the study period.

Temporal variation in phage detection in Kathmandu, Nepal during the study period.</p