ABSTRACT
Abstract Objectives Pain is associated with many circumstances, including inflammatory reactions, which arise from modification of the features of signaling pathways. α2-adrenergic receptor antagonists are widely utilized in narcosis. Here, the authors focused on the narcotic effect of A-80426 (A8) on Complete Freund's Adjuvant (CFA) injections-triggered chronic inflammation pain in WT and TRPV1-/- mice and explored whether its antinociceptive impact was modulated via Transient Receptor Potential Vanilloid 1 (TRPV1). Method CFA with or without A8 was co-administered to the mice, which were categorized randomly into four groups: CFA, A8, control, and vehicle. Pain behaviors underwent evaluation through mechanical withdrawal threshold, abdominal withdrawal reflex, and thermal withdrawal latency of WT animals. Results Quantitative polymerase chain reaction revealed that inflammation-promoting cytokines (IL-1β, IL-6, and TNF-α) were upregulated in Dorsal Root Ganglion (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT animals. A8 administration reduced the pain behaviors and production of pro-inflammatory cytokines; however, this effect was significantly reduced in TRPV1-/- mice. Further analysis showed that CFA treatment reduced the TRPV1 expression in WT mice and A8 administration increased its expression and activity. The co-administration of SB-705498, a TRPV1 blocker, did not influence the pain behaviors and inflammation cytokines in CFA WT mice; however, SB-705498 the effect of A8 in WT mice. In addition, the TRPV1 block decreased the NFκB and PI3K activation in the Dorsal Root Ganglia (DRG) and Spinal Cord Dorsal Horn (SCDH) tissues of WT mice. Conclusions Together, A8 exerted a narcotic impact on CFA-supplemented mice via the TRPV1-modulated NFκB and PI3K pathway.
ABSTRACT
Alzheimer's disease(AD)represents the main form of dementia;however,valid diagnosis and treatment measures are lacking.The discovery of valuable biomarkers through omics technologies can help solve this problem.For this reason,metabolomic analysis using ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS)was carried out on plasma,hippocampus,and cortex samples of an AD rat model.Based on the metabolomic data,we report a multi-factor combined biomarker screening strategy to rapidly and accurately identify potential bio-markers.Compared with the usual procedure,our strategy can identify fewer biomarkers with higher diagnostic specificity and sensitivity.In addition to diagnosis,the potential biomarkers identified using our strategy were also beneficial for drug evaluation.Multi-factor combined biomarker screening strategy was used to identify differential metabolites from a rat model of amyloid beta peptide 1-40(Aβ1-40)plus ibotenic acid-induced AD(compared with the controls)for the first time;lysophosphati-dylcholine(LysoPC)and intermediates of sphingolipid metabolism were screened as potential bio-markers.Subsequently,the effects of donepezil and pine nut were successfully reflected by regulating the levels of the abovementioned biomarkers and metabolic profile distribution in partial least squares-discriminant analysis(PLS-DA).This novel biomarker screening strategy can be used to analyze other metabolomic data to simultaneously enable disease diagnosis and drug evaluation.
ABSTRACT
From a regulatory perspective,drug quality consistency evaluation must concern different processes used for the same drug.In this study,an assessment strategy based on quality by design(QbD)was developed for population pharmaceutical quality evaluation.A descriptive analysis method based on QbD concept was first established to characterize the process by critical evaluation attributes(CEAs).Then quantitative analysis method based on an improved statistical process control(SPC)method was established to investigate the process indicators(PIs)in the process population,such as mean distri-bution,batch-to-batch difference and abnormal quality probability.After that rules for risk assessment were established based on the SPC limitations and parameters.Both the SPC parameters of the CEAs and the risk of PIs were visualized according to the interaction test results to obtain a better understanding of the population pharmaceutical quality.Finally,an assessment strategy was built and applied to generic drug consistency assessment,process risk assessment and quality trend tracking.The strategy demon-strated in this study could help reveal quality consistency from the perspective of process control and process risk,and further show the recent development status of domestic pharmaceutical production processes.In addition,a process risk assessment and population quality trend tracking provide data-based information for approval.Not only can this information serve as a further basis for decision-making by the regulatory authority regarding early warnings,but it can also reduce some avoidable adverse reactions.With continuous addition of data,dynamic population pharmaceutical quality is meaningful for emergencies and decision-making regarding drug regulation.