Hy-Line (United States)

Background: Olaparib (OLA) and regorafenib (REG) are metabolized by the CYP3A4 isoenzyme of cytochrome P450. Both drugs are also substrates and inhibitors of the membrane transporters P-glycoprotein and BCRP. Therefore, the potential concomitant use of OLA and REG may result in clinically relevant drug–drug interactions. Knowledge of the influence of membrane transporters and cytochrome P450 enzymes on the pharmacokinetics of drugs makes it possible to assess their impact on the efficacy and safety of therapy. Purpose: The study aimed to evaluate the bilateral pharmacokinetic interactions of OLA and REG and its active metabolites after a single administration in healthy rats. Methods: The study was performed in male Wistar rats (n = 24) randomly divided into three groups: one study group, IREG+OLA (n = 8), received REG with OLA, and two control groups, IIREG (n = 8) and IIIOLA (n = 8), received REG and OLA, respectively. The concentrations of OLA, REG, REG-N-oxide (M-2), and N-desmethyl-REG-N-oxide (M-5) were determined by ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). The values of the pharmacokinetic parameters of OLA, REG, M-2, and M-5 were determined by non-compartmental analysis with linear interpolation. Results: After OLA administration, the pharmacokinetic parameters of REG (AUC0–∞, tmax, and t0.5) increased significantly by 3.38-, 2.66-, and 1.82-fold, respectively. On the other hand, REG elimination parameters, i.e., kel and Cl/F, were significantly reduced in the study group by 1.77- and 1.70-fold, respectively. In the study group, Cmax and AUC0–t values were also 7.22- and 8.86-fold higher for M-2 and 16.32- and 17.83-fold higher for M-5, respectively. The Metabolite M-2/Parent and Metabolite M-5/Parent ratios for Cmax and AUC0–t increased by 6.52-, 10.74-, 28-, and 13-fold, respectively. After administration of OLA with REG, the Cmax, AUC0–t, and AUC0–∞ of OLA increased by 2.0-, 3.4-, and 3.4-fold, respectively, compared to the control group. Meanwhile, Cl/F and Vd/F of OLA were significantly decreased in the presence of REG. Conclusions: OLA was shown to significantly affect the pharmacokinetics of REG and its active metabolites M-2 and M-5 in rats after co-administration of both drugs. There was also a significant effect of REG on the pharmacokinetics of OLA, which may have clinical relevance. The AUC ratios (study group/control group) were 3.41 and 3.39 for REG and OLA, respectively, indicating that REG and OLA were moderate inhibitors in this preclinical study. The results obtained need to be confirmed in clinical studies. This study may provide guidance on the safety of using both drugs in clinical practice.

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M-5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.

Highly pathogenic strains of avian influenza (HPAI) devastate poultry flocks and result in significant economic losses for farmers due to high mortality, reduced egg production, and mandated euthanization of infected flocks. Within recent years, HPAI outbreaks have affected egg production flocks across the world. The H5N2 outbreak in the US in 2015 resulted in over 99% mortality. Here, we analyze sequence data from chickens that survived (42 cases) along with uninfected controls (28 samples) to find genomic regions that differ between these two groups and that, therefore, may encompass prime candidates that are resistant to HPAI. Blood samples were obtained from survivors of the 2015 HPAI outbreak plus age and genetics-matched non-affected controls. A whole-genome sequence was obtained, and genetic variants were characterized and used in a genome-wide association study to identify regions showing significant association with survival. Regions associated with HPAI resistance were observed on chromosomes 1, 2, 5, 8, 10, 11, 15, 20, and 28, with a number of candidate genes identified. We did not detect a specific locus which could fully explain the difference between survivors and controls. Influenza virus replication depends on multiple components of the host cellular machinery, with many genes involved in the host response.

BackgroundThere are 13 known chicken blood systems, which were originally detected by agglutination of red blood cells by specific alloantisera. The genomic region or specific gene responsible has been identified for four of these systems (A, B, D and E). We determined the identity of the gene responsible for the chicken blood system I, using DNA from multiple birds with known chicken I blood system serology, 600K and 54K single nucleotide polymorphism (SNP) data, and lowpass sequence information.ResultsThe gene responsible for the chicken I blood system was identified as RHCE, which is also one of the genes responsible for the highly polymorphic human Rh blood group locus, for which maternal/fetal antigenic differences can result in fetal hemolytic anemia with fetal mortality. We identified 17 unique RHCE haplotypes in the chicken, with six haplotypes corresponding to known I system serological alleles. We also detected deletions in the RHCE gene that encompass more than 6000 bp and that are predicted to remove its last seven exons.ConclusionsRHCE is the gene responsible for the chicken I blood system. This is the fifth chicken blood system for which the responsible gene and gene variants are known. With rapid DNA-based testing now available, the impact of I blood system variation on response against disease, general immune function, and animal production can be investigated in greater detail.

Heat stress results in significant economic losses to the poultry industry. Genetics plays an important role in chickens adapting to the warming environment. Physiological parameters, including hematochemical parameters, change in response to heat stress in chickens. To explore the genetics of heat stress resilience in chickens, a genome-wide association study (GWAS) was conducted using Hy-Line Brown (HLB) layer chicks treated with either high ambient temperature or combined high temperature and Newcastle disease virus (NDV) infection. Hematochemical parameters were measured during three treatment phases: acute heat stress, chronic heat stress, and chronic heat stress combined with NDV infection. Significant changes in blood parameters were recorded for 11 parameters across the three treatments. The GWAS revealed 39 significant SNPs (P < 0.05) for 7 parameters, located on Gallus gallus chromosomes (GGA) 1, 3, 4, 6, 11, and 12. The significant genomic regions were further investigated to examine if the genes within the regions were associated with the corresponding traits under heat stress. A candidate gene list including genes in the identified genomic regions that were also differentially expressed in chicken tissues under heat stress was generated. Understanding the correlation between genetic variants and resilience to heat stress is an important step in improving heat tolerance in poultry.

The yolk sac is a multifunctional organ, which not only participates in nutrient absorption, but also plays an important role in immune function. The objective of this study was to compare the mRNA abundance of avian β-defensin 10 (AvBD10) and 3 cathelicidins (CATH1, CATH2, and CATH3) in the yolk sac tissue (YST) of commercial broilers and white egg and brown egg commercial layers. AvBD10 and CATH mRNA abundance was analyzed using two-way ANOVA and Tukey's test, with P < 0.05 being considered significant. AvBD10 and CATH mRNA showed similar temporal expression patterns in the YST of both broiler and layers, with an increase from embryonic day (E) 7 to E9 through E13 followed by a decrease to day of hatch. AvBD10 mRNA showed a breed × age interaction with greater expression in the YST of both layers compared to broilers at E9 and E11. CATH1 mRNA was greater in the YST of brown egg layers than broilers. CATH2 mRNA showed a breed × age interaction, with greater expression in the YST of brown egg layers than broilers at E11. CATH3 mRNA showed no difference in the YST between layers and broilers. Because broilers and brown egg layers are genetically related, these results show that selection for production parameters (broiler vs. layer) and not genetic relatedness (white egg layer vs. brown egg layer and broilers) is the basis for the differences in AvBD10, CATH1, and CATH2 mRNA in the YST of broilers and layers. The yolk-free body weights of broiler embryos were greater than that of both brown and white egg layers from E9 to 17. One possible explanation is that the reduced expression of AvBD10, CATH1 and CATH2 mRNA in the YST of broilers compared to layers at E9 and 11 may be due to faster embryonic growth at the expense of host defense peptide expression in broilers compared to layers.

Background:Parkinson disease (PD), the second most common neurodegenerative disease, has no cure or applicable disease-modifying approach, only symptomatic therapy. Oxidative stress and mitochondrial dysfunction play key roles in PD pathophysiology. Animal studies have demonstrated that photobiomodulation (PBM) may enhance mitochondrial function and boost adenosine triphosphate production, thus alleviating PD symptoms; however, this process can cause increased reactive oxygen species (ROS) production. Molecular hydrogen (H2) is a potent and possibly therapeutic antioxidant that can mitigate the effect of ROS. PBM targeting the brainstem may facilitate neuronal activity, and the concomitant H2 may clear additional ROS produced by PBM. Therefore, this study aimed to determine the safety and effectiveness of PBM + H2 in patients with PD.Methods:We included 18 patients with PD (age 30–80 years) who were at Hoehn and Yahr stages II-III. All the participants received daily PBM + H2 therapy for 2 weeks. The adverse event and the Unified Parkinson Disease Rating Scale (UPDRS) scores were recorded.Results:We noted that the UPDRS scores began significantly decreasing from the first week, and this improvement persisted until the end of therapy. Moreover, no adverse event was recorded. After 1 week of therapy cessation, UPDRS scores slightly increased but the improvement remained significant compared with the baseline.Conclusion:This novel, proof-of-concept study demonstrated that PBM+H2 therapy is safe and reduces disease severity. A larger-scaled clinical trial is warranted to completely investigate the effects of PBM + H2 therapy on PD.

Marek’s disease (MD) represents a significant global economic and animal welfare issue. Marek’s disease virus (MDV) is a highly contagious oncogenic and highly immune-suppressive α-herpes virus, which infects chickens, causing neurological effects and tumour formation. Though partially controlled by vaccination, MD continues to have a profound impact on animal health and on the poultry industry. Genetic selection provides an alternative and complementary method to vaccination. However, even after years of study, the genetic mechanisms underlying resistance to MDV remain poorly understood. The Major Histocompatability Complex (MHC) is known to play a role in disease resistance, along with a handful of other non-MHC genes. In this study, one of the largest to date, we used a multi-facetted approach to identify quantitative trait locus regions (QTLR) influencing resistance to MDV, including an F6 population from a full-sib advanced intercross line (FSIL) between two elite commercial layer lines differing in resistance to MDV, RNA-seq information from virus challenged chicks, and genome wide association study (GWAS) from multiple commercial lines. Candidate genomic elements residing in the QTLR were further tested for association with offspring mortality in the face of MDV challenge in eight pure lines of elite egg-layer birds. Thirty-eight QTLR were found on 19 chicken chromosomes. Candidate genes, microRNAs, long non-coding RNAs and potentially functional mutations were identified in these regions. Association tests were carried out in 26 of the QTLR, using eight pure lines of elite egg-layer birds. Numerous candidate genomic elements were strongly associated with MD resistance. Genomic regions significantly associated with resistance to MDV were mapped and candidate genes identified. Various QTLR elements were shown to have a strong genetic association with resistance. These results provide a large number of significant targets for mitigating the effects of MDV infection on both poultry health and the economy, whether by means of selective breeding, improved vaccine design, or gene-editing technologies.