Target organ profiles in toxicity studies supporting human dosing: An assessment of recovery and chronic dosing

We have previously reported the profile of toxic effects with respect to target organs (defined as organs showing histopathological changes) observed in rodent and non-rodent toxicity studies conducted prior to first time in man (FTIM) for 77 AstraZeneca candidate drugs (CDs) across a range of therapy areas. The main objectives of the current study were twofold; to determine which target organs observed in the FTIM studies recovered after a dose free recovery period and to determine which additional target organs were observed in subsequent chronic (?3 month) studies required to support longer term clinical dosing. The analysis showed that ?86% of findings in studies supporting FTIM either fully or partially resolved at the end of the recovery period, with profiles of recovery that were similar whether the CD progressed into man or not and across different therapy areas. Compared to observations in FTIM studies, chronic studies identified toxicities in an additional 39% of target organs. Overall these data demonstrate that chronic studies in both rodents and non-rodents provide valuable information for the risk assessment for longer term dosing in humans. In addition, the high levels of recovery demonstrated in this analysis suggest that inclusion of recovery assessments on FTIM studies should be on a case-by-case basis driven by a positive indication of need. This is in line with ICH non-clinical guidance that states that reversibility of severe nonclinical toxicities of potential clinic relevance should be assessed ‘when appropriate’, but that the evaluation can be based on a study of reversibility or on a scientific assessment.     

Formulation and optimization of quinoa starch nanoparticles: Quality by design approach for solubility enhancement of piroxicam

In the present study piroxicam loaded starch nanoparticles were prepared to enhance the solubility of piroxicam by nanoprecipitation technique. The preparation of nanoparticles was carried out as per central composite experimental design protocol, having concentration of starch and drug as independent variables and particle size and polydispersity index (PdI) as dependent variables. The particle size and PdI of piroxicam loaded starch nanoparticles was found to be between 282–870 nm and 0.339–0.772, respectively. After the characterization by FT-IR, TGA, XRD and SEM studies, the optimized batch was evaluated for in-vitro release study, anti-inflammatory activity and anti-oxidant activity. The in-vitro anti-inflammatory activity of piroxicam loaded starch nanoparticles was found to be more than the pure drug piroxicam whereas the anti-oxidant activity of starch is found greater than starch nanoparticles. In-vitro release study showed 98.8% release in 2 h dissolution study following supercase II transport mechanism of drug release.     

An assessment of the impact of multi‐route co‐exposures on human variability in toxicokinetics: A case study with binary and quaternary mixtures of volatile drinking water contaminants

This study aimed to assess the impact of multi‐route co‐exposures to chemicals on interindividual variability in toxicokinetics. Probabilistic physiologically based pharmacokinetic multi‐route interaction models were developed for adults and four younger subpopulations. Drinking water‐mediated multi‐route exposures were simulated for benzene alone or in co‐exposure with toluene, ethylbenzene and m‐xylene, for trichloroethylene or vinyl chloride (VC), alone and in mixture. These simulations were performed for “low” and “high” exposure scenarios, involving respectively the US EPA's short‐term drinking water health advisories, and 10 times these advisory values. Distributions of relevant internal dose metrics for benzene, trichloroethylene and VC were obtained using Monte Carlo simulations. Intergroup variability indexes (VI) were computed for the “low” (VI_L) and “high” (VI_H) exposure scenarios, as the ratio between the 95th percentile in each subpopulation over the median in adults. Thus, for benzene, parent compound's area under the curve‐based VI_L for single exposures vs. co‐exposures correspondingly varied between 1.7 (teenagers) and 2.8 (infants) vs. 1.9 and 3.1 respectively. VI_H varied between 2.5 and 3.5 vs. 2.9 and 4.1. Inversely, VI_L and VI_H for the amount of benzene metabolized via CYP2E1 pathway decreased in co‐exposure compared to single exposure. For VC and trichloroethylene, similar results were obtained for the “high” exposure, but “low” co‐exposures did not impact the toxicokinetics of individual substances. In conclusion, multi‐route co‐exposures can have an impact on the toxicokinetics of individual substances, but to an extent, that does not seem to challenge the default values attributed to the factors deemed at reflecting interindividual or child/adult differences in toxicokinetics.     

Kinetic and isotherm studies on adsorptive removal of sulfates by cotton shell derived biochar: Recovery of sulfates from marcasite soil

This work illustrates the potential applications of the raw cotton shell (RCS) and cotton shell biochar (CSB) in the remediation of sulfate contaminants from aqueous solvents. Comprehensively, optimal batch and adsorption kinetics of sulfate by RCS and CSB were intensively analyzed and determined by varying the adsorption parameters. For RCS, the optimal series of parameters were at (pH-7, sulfate conc-150 mgL^?1, adsorbent dose- 0.5 g and time-150 min). While for CSB optimum conditions were at (pH-9.8, sulfate conc-100 mgL^?1, dosage- 0.1 g and time-90 min). The maximum adsorption efficiency for both RCS and CSB was achieved at 86.47% and 90.77%, respectively. Sulfate adsorption by RCS and CSB was examined by isotherm models and kinetic studies. The data are best suited to the Langmuir isotherm model with the highest RCS and CSB sulfate adsorption capability of 61.35 and 153.85 mg g^?1 and followed pseudo-second-order kinetics. Box-Behnken design (BBD) based response surface methodology (RSM) model-based analysis of variance test has demonstrated optimum conditions and sulfate adsorption by both RCS and CSB. The recovery studies on sulfates from marcasite soil were evaluated at different doses of RCS and CSB. This study provides insights into the usage of the developed process towards the circular economy of the sulfates.