DOSE OPTIMIZATION OF CEFTRIAXONE-SULBACTAM COMBINATION IN ADULTS USING IN VITRO SYSTEMS, PK/PD MODELING AND STOCHASTIC SIMULATIONS APPROACHES

Objective: To optimize the dosage regimen of fixed-dose combination (FDC) of ceftriaxone/sulbactam (2/1 w/w) using in vitro system, pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte-Carlo simulations (MCS).Methods: One compartment in vitro system was used for identification of PK/PD driver that best correlates with therapeutic potential of FDC against ESBL positive E. coli infection. Using in vitro approach, the best exposure from dose escalation study was fractionated twice-a-day (BID) and thrice-a-day (TID) to determine a best dosage regimen of the FDC. In second approach i.e. in silico PK/PD modeling, dose response curve was constructed to estimate curve parameters (EC50, γ, and Emax), which were then used to develop PK/PD model for the FDC. In the third approach, MCS were employed to evaluate the impact of different dosage regimen against mild-to-severe infections. Lastly, the recommendation of dose adjustments for patients with renal impairment was also presented.Results: Based on all three approaches, the best antibacterial effect was obtained from the exposure of 20 x MICcomb, which when fractioned to twice-daily dosing showed a maximum reduction in bacterial densities for severe infections. Dose reduction was recommended for patients with several renal impairments.Conclusion: FDC dosage regimen of 1.5g BD or 3g OD was recommended for mild to moderate infections; whereas 3g BD was required for severely infected patients.Keywords: PK/PD modeling, Monte-carlo simulations, Ceftriaxone, Sulbactam, Dose optimizatio

Hmrbase: a database of hormones and their receptors

<p>Abstract</p> <p>Background</p> <p>Hormones are signaling molecules that play vital roles in various life processes, like growth and differentiation, physiology, and reproduction. These molecules are mostly secreted by endocrine glands, and transported to target organs through the bloodstream. Deficient, or excessive, levels of hormones are associated with several diseases such as cancer, osteoporosis, diabetes etc. Thus, it is important to collect and compile information about hormones and their receptors.</p> <p>Description</p> <p>This manuscript describes a database called Hmrbase which has been developed for managing information about hormones and their receptors. It is a highly curated database for which information has been collected from the literature and the public databases. The current version of Hmrbase contains comprehensive information about ~2000 hormones, e.g., about their function, source organism, receptors, mature sequences, structures etc. Hmrbase also contains information about ~3000 hormone receptors, in terms of amino acid sequences, subcellular localizations, ligands, and post-translational modifications etc. One of the major features of this database is that it provides data about ~4100 hormone-receptor pairs. A number of online tools have been integrated into the database, to provide the facilities like keyword search, structure-based search, mapping of a given peptide(s) on the hormone/receptor sequence, sequence similarity search. This database also provides a number of external links to other resources/databases in order to help in the retrieving of further related information.</p> <p>Conclusion</p> <p>Owing to the high impact of endocrine research in the biomedical sciences, the Hmrbase could become a leading data portal for researchers. The salient features of Hmrbase are hormone-receptor pair-related information, mapping of peptide stretches on the protein sequences of hormones and receptors, Pfam domain annotations, categorical browsing options, online data submission, DrugPedia linkage etc. Hmrbase is available online for public from <url>http://crdd.osdd.net/raghava/hmrbase/</url>.</p

Curie temperature engineering in a novel 2D analog of iron ore (hematene) via strain

As a newly exfoliated magnetic 2D material from hematite, hematene is the most far-reaching ultrathin magnetic indirect bandgap semiconductor. We have carried out a detailed structural analysis of hematene via prefacing strain by means of first-principles calculations based on density functional theory (DFT). Hematene in the pristine form emerges out to be a magnetic semiconductor with a bandgap of 1.0/2.0 eV for the majority/minority spin channel. The dependence of magnetic anisotropy energy (MAE), TC, and the bandgap on compressive and tensile strains has been scanned exclusively. It is examined that TC depends firmly on the compressive strain and increases up to 21.1% at a compressive strain of 6% whereas it decreases significantly for tensile strain. The MAE is negatively correlated with the tensile and compressive strain. The value of MAE for all compressive strain cases is more than that of the pristine hematene. These results summarize that the studied 2D hematene has broad application prospects in spintronics, memory-based devices, and valleytronics

Efficacy and safety of tadalafil in ureteric stent related symptoms: a double blind, prospective, randomised study

Background: Is tadalafil effective and safe in ureteric stent related symptoms? The objective of this trial is to study the efficacy and safety of tadalafil and compare it with tamsulosin in relieving ureteric stent related symptoms by using ureteral stent symptom questionnaire.Methods: Total 144 patients with dj stent symptoms were randomized into two groups with 72 patients in each. Group A patients were given tadalafil 5mg and Group B, tamsulosin 0.4mg for 2 weeks. Ureteral stent symptom questionnaire was filled on 7th day and on 21st day after stent insertion. Statistically significant difference between groups was determined by the t-test, Mann-Whitney U-test, Pearson Chi-square test or Fisher's exact test. Comparison between quantitative time related variables was done by Wilcoxon Signed Rank test. All the statistical tests were two-sided and were performed at a significance level of α=.05.Results: Tamsulosin was found more effective then tadalafil in decreasing mean urinary index (p=0.004). Tadalafil caused significant decrease in body pain (p=0.006) and improvement in general health index score, work performance and sex score (P value= 0.041, <0.001 and <0.015 respectively) as compared to tamsulosin. Additional problems score improvement and analgesic use were found comparable in 2 groups (p value =0.193, 0.070 respectively). Adverse effect with both the drugs were minimal, mild to moderate and self-limiting.Conclusions: Tadalafil found more effective then Tamsulosin in relieving body pain, sexual symptoms and improving general health and work performance but less effective in improvement of urinary symptoms

Dose optimization of ceftriaxone-vancomycin combination using fractional inhibitory concentration kinetics in resistant bacteria

The notorious Staphylococcus aureus resistant strains with ever changing resistance patterns have limited treatment options and have led to substantial number of deaths. Almost dried antibiotic pipeline has led us to look into combinations of already approved antibiotics for tackling rising incidence of antibacterial resistance. Recommended use of vancomycin and ceftriaxone together for treating severe infections involving resistant S. aureus is limited by dose adjustments and different dose frequencies. We have developed a pharmacodynamically synergistic fixed dose combination (FDC) of ceftriaxone and vancomycin (2:1), for eliminating individual component dose adjustments and frequencies. For identification of optimum exposure-response of FDC, one compartment in vitro system was used for dose escalation, fractionation and dose-response studies. The in-silico pharmacokinetic/pharmacodynamic (PK/PD) modeling, simulations and validations were done. The results suggested % T>MICcomb (percentage of time fractional inhibitory concentrations of the drugs combined remained above the MICcomb [minimum inhibitory concentration for FDC]) followed by AUCcomb/MICcomb (ratio of area under fractional inhibitory curves to MICcomb) can predict the exposure (dose of FDC)-response (reduction in bacterial load) relationships effectively (r2 >0.9). Total exposure of 6 g in two divided doses (3 g each) was identified to be optimum. Monte Carlo simulations were performed to evaluate the effect of increasing doses against different MICs. Clinical breakpoint of the FDC was identified to be 4 µg/mL, which was 2 fold higher than that of vancomycin suggesting better antibacterial coverage

Mesenchymal Stromal Cell-Derived Tailored Exosomes Treat Bacteria-Associated Diabetes Foot Ulcers: A Customized Approach From Bench to Bed

Exosomes are nano-vesicles of endosomal origin inherited with characteristics of drug delivery and cargo loading. Exosomes offer a diverse range of opportunities that can be exploited in the treatment of various diseases post-functionalization. This membrane engineering is recently being used in the management of bacteria-associated diabetic foot ulcers (DFUs). Diabetes mellitus (DM) is among the most crippling disease of society with a large share of its imposing economic burden. DM in a chronic state is associated with the development of micro- and macrovascular complications. DFU is among the diabetic microvascular complications with the consequent occurrence of diabetic peripheral neuropathy. Mesenchymal stromal cell (MSC)-derived exosomes post-tailoring hold promise to accelerate the diabetic wound repair in DFU associated with bacterial inhabitant. These exosomes promote the antibacterial properties with regenerative activity by loading bioactive molecules like growth factors, nucleic acids, and proteins, and non-bioactive substances like antibiotics. Functionalization of MSC-derived exosomes is mediated by various physical, chemical, and biological processes that effectively load the desired cargo into the exosomes for targeted delivery at specific bacterial DFUs and wound. The present study focused on the application of the cargo-loaded exosomes in the treatment of DFU and also emphasizes the different approaches for loading the desired cargo/drug inside exosomes. However, more studies and clinical trials are needed in the domain to explore this membrane engineering

Effectiveness of pegylated erythropoietin in renal anaemia patients on dialysis-a multicentre, cross-sectional, observational outcome study

Background: Low dose of pegylated erythropoietin (PegEPO) is better than conventional erythropoietin stimulating agents (ESAs) in improving hyporesponsiveness and maintaining stable haemoglobin (Hb) levels in renal anaemic patients undergoing hemodialysis. This real-world study aimed to assess effectiveness and safety of low-dose PegEPO (30 µg/0.3 mL), administered at different time-points in renal anaemia patients on dialysis. Methods: HEMEPEG (HEMoglobin outcomE with PegEPO) was a multicentre, retrospective, cross-sectional, observational study of renal anaemia patients receiving PegEPO up to 3 months. The study assessed an increase in Hb, patients achieving Hb 10-12 g/dl, and Hb increase by ≥1 and ≥2 g/dl. Results: Data from 223 out of 273 patients from 19 Indian centers were analyzed. PegEPO was administered weekly to 132 patients (59.19%), with 38.64% being diabetic and 77.27% previously treated with ESAs. Ten day dosing was given to 91 patients (40.81%), including 46.15% diabetic patients and 72.53% previously treated with ESAs. A Significant (p&lt;0.0001) increase in mean Hb levels from baseline to day 30, 60 and 90 were observed for both studied groups, with a target Hb of 10-12 g/dl achieved in 51.08% and 52.85% of patients in the respective groups after 3 months. An increase in Hb by ≥1 and ≥2 g/dl were observed in weekly (68.67% and 45.78%) and 10-day group (77.14% and 50.00%) patients, respectively. Conclusions: PegEPO (30 µg/0.3 mL) was effective treatment of renal anaemia and diabetic chronic kidney disease (CKD) patients on dialysis when administered weekly or every 10 days over a 3-month treatment period

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR