Time-Action Profile of Technosphere Insulin in Children with Type 1 Diabetes.

INTRODUCTION: Technosphere insulin (TI) is an inhaled dry powder ultra-rapid-acting insulin. This report describes the results of the first study of TI in children with type 1 diabetes (T1D). METHODS: Pharmacokinetics (PK) of TI and the effect of TI on circulating glucose concentrations were evaluated in a single-arm study that enrolled children ages 8-17 years with T1D for more than 1 year, on a stable multiple daily insulin injection (MDI) regimen, and meeting pre-defined pulmonary function testing criteria (at least 70% predicted). To assess PK, subjects received an individualized single preprandial dose of TI (4-12 U, in 4-U increments) via oral inhalation, based on their usual meal-time subcutaneously injected rapid-acting insulin dose and meal content. Serum insulin and blood glucose were measured at - 30 to 250 min relative to dosing. RESULTS: Twenty-seven children with T1D participated in this single-dose PK study. Mean subject age was 13.3 years (59% female; 81.5% White). Mean serum insulin Cmax (maximum concentration) was 77.3, 119.15, and 207.7 µU/mL for doses of 4, 8, and 12 U, respectively. Tmax occurred at 10.5, 13.9, and 14.6 min post-dose for 4, 8, and 12 U. Glucose lowering 30-60 min post-dose was consistent with the PK profile. CONCLUSION: Serum insulin rapidly increased post-dose and returned to baseline by 120 min. The data suggests the PK of TI in youth with T1D ages 8-17 years was similar to that seen in previous adult studies. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02527265.

Reduction in Postprandial Peak Glucose With Increased Technosphere Insulin Dosage.

BACKGROUND: Technosphere Insulin (TI) is an ultra-rapid-acting inhaled insulin. This study assessed the mean peak two-hour postprandial glucose concentration with the initial TI dose (dose 1) calculated per the current label (United State Prescribing Information) compared with a ~2× higher dose (dose 2). Secondary objectives were to evaluate hypoglycemia within the two-hour postprandial period, evaluate change in forced expiratory volume in one second (FEV1) before and after the two-hour postprandial period, and monitor for other adverse events. METHODS: Twenty patients with diabetes, on basal-bolus insulin therapy, received an initial dose 1 of TI followed by the higher dose 2, one to three days later. Subjects received an identical meal for both visits, and TI doses were administered immediately prior to the meal. RESULTS: The higher dose 2 provided significant reductions in mean postprandial glucose excursion (PPGE) in the two-hour postprandial period starting from 45 minutes (P = .008) to 120 minutes (P < .0001). Mean peak glucose was reduced from 228.6 to 179.3 mg/dL (P < .001) at two hours. Two hypoglycemic events (one level 1, one level 2) were observed in a single subject during the two-hour postprandial period with dose 2. There were no significant changes in FEV1 after either dose of TI. CONCLUSIONS: The higher dose 2 reduced PPGE versus the current label recommended dose 1 within the two-hour postprandial timeframe without any new safety concerns. When confirmed with a larger study, this higher TI dosing recommendation may help patients and clinicians minimize immediate postprandial hyperglycemia when titrating TI for prandial glucose control.

R software package based statistical optimization of process components to simultaneously enhance the bacterial growth, laccase production and textile dye decolorization with cytotoxicity study.

The thermophilic bacterium, Bacillus licheniformis U1 is used for the optimization of bacterial growth (R1), laccase production (R2) and synthetic disperse blue DBR textile dye decolorization (R3) in the present study. Preliminary optimization has been performed by one variable at time (OVAT) approach using four media components viz., dye concentration, copper sulphate concentration, pH, and inoculum size. Based on OVAT result further statistical optimization of R1, R2 and R3 performed by Box-Behnken design (BBD) using response surface methodology (RSM) in R software with R Commander package. The total 29 experimental runs conducted in the experimental design study towards the construction of a quadratic model. The model indicated that dye concentration 110 ppm, copper sulphate 0.2 mM, pH 7.5 and inoculum size 6% v/v were found to be optimum to maximize the laccase production and bacterial growth. Whereas, maximum dye decolorization achieved in media containing dye concentration 110 ppm, copper sulphate 0.6 mM, pH 6 and inoculum size 6% v/v. R package predicted R2 of R1, R2 and R3 were 0.9917, 0.9831 and 0.9703 respectively; likened to Design-Expert (Stat-Ease) (DOE) predicted R2 of R1, R2, and R3 were 0.9893, 0.9822 and 0.8442 respectively. The values obtained by R software were more precise, reliable and reproducible, compared to the DOE model. The laccase production was 1.80 fold increased, and 2.24 fold enhancement in dye decolorization was achieved using optimized medium than initial experiments. Moreover, the laccase-treated sample demonstrated the less cytotoxic effect on L132 and MCF-7 cell lines compared to untreated sample using MTT assay. Higher cell viability and lower cytotoxicity observed in a laccase-treated sample suggest the impending application of bacterial laccase in the reduction of toxicity of dye to design rapid biodegradation process.

Web Resources for Metagenomics Studies.

The development of next-generation sequencing (NGS) platforms spawned an enormous volume of data. This explosion in data has unearthed new scalability challenges for existing bioinformatics tools. The analysis of metagenomic sequences using bioinformatics pipelines is complicated by the substantial complexity of these data. In this article, we review several commonly-used online tools for metagenomics data analysis with respect to their quality and detail of analysis using simulated metagenomics data. There are at least a dozen such software tools presently available in the public domain. Among them, MGRAST, IMG/M, and METAVIR are the most well-known tools according to the number of citations by peer-reviewed scientific media up to mid-2015. Here, we describe 12 online tools with respect to their web link, annotation pipelines, clustering methods, online user support, and availability of data storage. We have also done the rating for each tool to screen more potential and preferential tools and evaluated five best tools using synthetic metagenome. The article comprehensively deals with the contemporary problems and the prospects of metagenomics from a bioinformatics viewpoint.

Metagenomic data of fungal internal transcribed Spacer and 18S rRNA gene sequences from Lonar lake sediment, India.

The data in this article contains the sequences of fungal Internal Transcribed Spacer (ITS) and 18S rRNA gene from a metagenome of Lonar soda lake, India. Sequences were amplified using fungal specific primers, which amplified the amplicon lined between the 18S and 28S rRNA genes. Data were obtained using Fungal tag-encoded FLX amplicon pyrosequencing (fTEFAP) technique and used to analyze fungal profile by the culture-independent method. Primary analysis using PlutoF 454 pipeline suggests the Lonar lake mycobiome contained the 29 different fungal species. The raw sequencing data used to perform this analysis along with FASTQ file are located in the NCBI Sequence Read Archive (SRA) under accession No. SRX889598 (http://www.ncbi.nlm.nih.gov/sra/SRX889598).

Evolution of exenatide as a diabetes therapeutic.

Type 2 diabetes (T2DM) is a disease of epidemic proportion associated with significant morbidity and excess mortality. Optimal glucose control reduces the risk of microvascular and possibly macrovascular complications due to diabetes. However, glycemic control is rarely optimal and several therapeutic interventions for the treatment of diabetes cause hypoglycemia and weight gain; some may exacerbate cardiovascular risk. Exenatide (synthetic exendin-4) is a glucagon- like peptide-1 receptor (GLP-1R) agonist developed as a first-in-class diabetes therapy. This review presents an overview of the evolution of exenatide as a T2DM treatment, beginning with the seminal preclinical discoveries and continuing through to clinical pharmacology investigations and phase 3 clinical trials. In patients with T2DM, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, and enhanced satiety. In controlled phase 3 clinical trials ranging from 12 to 52 weeks, 10-mcg exenatide twice daily (ExBID) reduced mean HbA1c by -0.8% to -1.7% as monotherapy or in combination with metformin (MET), sulfonylureas (SFU), and/or thiazolidinediones (TZD); with mean weight losses of -1.2 kg to -8.0 kg. In controlled phase 3 trials ranging from 24 to 30 weeks, a 2-mg once-weekly exenatide formulation (ExQW) reduced mean HbA1c by -1.3% to -1.9%, with mean weight reductions of -2.3 to -3.7 kg. Exenatide was generally well-tolerated. The most common side effects were gastrointestinal in nature, mild, and transient. Nausea was the most prevalent adverse event. The incidence of hypoglycemia was generally low. By building upon early observations exenatide was successfully developed into an effective diabetes therapy.

Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.

Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range. We investigated the pharmacokinetics of exenatide in normoglycemic rats and biological activity in diabetic db/db mice after delivery to various epithelial surfaces of the intestinal and respiratory tracts. In rats, elimination kinetics were similar for all routes of administration (median k(e) 0.017 min(-1)). Bioavailability (versus intravenous administration) and C(max) per unit dose differed markedly. For gastrointestinal administration, sublingual administration invoked the highest bioavailability (0.37%); in db/db mice, potentially therapeutic concentrations were obtainable. In contrast, intraduodenal bioavailability was low (0.0053%). In regard to respiratory surfaces, bioavailability of intratracheal exenatide was up to 13.6%, and for nasal administration, 1.68%. Both routes of administration produced therapeutic plasma concentrations and glucose-lowering in db/db mice. At high doses, aerosolized exenatide also achieved effective concentrations and glucose-lowering. In summary, the intestinal tract seems to have limited potential as a route of exenatide administration, with sublingual being most promising. In contrast, the respiratory tract appears to be more viable, comparing favorably with the clinically approved subcutaneous route. Despite little optimization of the delivery formulation, exenatide bioavailability compared favorable to that of several commercially available bioactive peptides.