Comparative Pharmacokinetics and Preliminary Pharmacodynamics Evaluation of Piscidin 1 Against PRV and PEDV in Rats

Abstract

Antimicrobial peptide (Piscidin-1) is an effective natural polypeptide, which has great influence and potential on porcine epidemic diarrhea virus (PEDV) and pseudorabies virus (PRV). As an alternative antibiotic substitute, Piscidin-1 was subjected for pharmacokinetics study with three administration routes (i.v, i.m, and p.o) after a single dose of 2 mg/kg in rats and preliminary pharmacodynamics including antiviral activity in cell against PEDV and PRV. Based on 50 percent tissue culture infective dose (TCID50), there were about 2 and 10% virus survived ratios for Piscidin-1 against PRV and PEDV, respectively. The plaque test showed 1 and 2 μg/ml Piscidin-1 could eliminate 95% PRV and 85% PEDV, respectively. The main pharmacokinetics parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in plasma were not applicable value, 25.9 μg*h/ml, 0.041 h−1, 16.97 h, not available value, 22.77 h, 0.067 L/h*kg after i.v administration, 2.37 μg/ml, 18.95 μg*h/ml, 0.029 h−1, 23.50 h, 0.33 h, 30.12 h, 0.095 L/h*kg after i.m administration and 0.73 μg/ml, 9.63 μg*h/ml, 0.036 h−1, 19.46 h, 0.50 h, 26.76 h, 0.171 L/h*kg after p.o administration. The bioavailability values after i.m and p.o administrations were calculated as 73.17 and 37.18%, respectively. The i.m administration was selected for pharmacokinetics study in ileum content against PEDV. The main pharmacokinetic parameters of Cmax, AUC0−∞, Ke, t1/2, Tmax, MRT, and Clb in ileum content were 1.67 μg/ml, 78.40 μg*h/ml, 0.034 h−1, 20.16 h, 8.12 h, 36.45 h, 0.026 L/h*kg. The Cmax values in plasma (2.37 μg/ml) and ileum content (1.67 μg/ml) were higher than the effective inhibitory concentration determined in the plaque test, and this indicates that Piscidin-1 might have effective inhibition effect against PRV and PEDV after administration of 2 mg/kg i.m. The results of this study represent the first investigations toward the pharmacokinetic characteristics of piscidin-1 in plasma upon three different administration routes, among which i.m. resulted in the highest bioavailability (73.17%). Furthermore, the pharmacokinetics study of ileum content indicated Piscidin-1 might have good effect against PEDV and could be regarded as an alternative antibiotic in clinical veterinary in the future study.

Resistant cutoff values and optimal scheme establishments for florfenicol against Escherichia coli with PK‐PD modeling analysis in pigs

“…Proverbially, FF is the structural analog relative to the thiamphenicol and has the wide‐spectrum antibacterial activities against either gram‐positive ( Staphylococcus aureus , Streptococcus suis ) or gram‐negative bacteria ( E. coli , Pasteurella multocida ) (Lei, Liu, Qi, et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Yang, et al., ; Lei, Liu, Zhu, et al., ). As a kind of excellent broad‐spectrum antibiotics, FF is applied in the treatment of E. coli infections.…”

“…Furthermore, based on its low toxicity, high bioavailability (near to 100%), and the therapeutic effect equal to or better than other chloramphenicol analogs, FF is recommended to treat for intestinal tract and respiratory infectious diseases in livestock (Kim et al., ; Liu, Fung, Chen, Zeng, & Zhang, ; Ueda, Ohtsuki, & Narukawa, ). There are several previously published reports on the pharmacokinetics (PK) and pharmacodynamics (PD) of FF in the serum in vitro in the chicken, pigs, dogs, and so on (Burch & Klein, ; Dorey, Pelligand, Cheng, & Lees, ; Haritova & Fink‐Gremmels, ; Koc et al., ; Lei, Liu, Qi, et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Yang, et al., ; Lei, Liu, Zhu, et al., ; Maaland, Mo, Schwarz, & Guardabassi, ; Poźniak et al., ; Sidhu, Illambas, Potter, Rycroft, & Lees, ; Wang et al., ). However, it is insufficient to assay the practical effect and predict the dosage accordingly with serum and in vitro PK‐PD data.…”

“…The susceptibility breakpoint for FF against E. coli has not been provided at present. Therefore, it should be essential to establish such a criterion to monitor the development of resistance (Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Cao, & Qiu, ; Lei et al., 2017a; Lei et al., 2017b; Lei, Liu, Yang, Xiong, et al., ; Lei, Liu, Qi, et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Yang, et al., ; Lei, Liu, Zhu, et al., ). Furthermore, it would be better to set the susceptibility of target bacteria to the antibiotics in order to reduce the development of bacterial resistance and strengthen the management of antibiotic use.…”

“…With the development of bacterial resistance, the reasonable and reappraisal dosages are imperative for old antibiotics in veterinary clinic application (De la Fuente‐Núñez, Reffuveille, Fernández, & Hancock, ; Freiremoran et al., ; Tacconelli et al., ; Yoneyama & Katsumata, ). As a classical approach, PK‐PD integration model is performed for dosage prediction (Ijaz et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Cao, & Qiu, ; Lei et al., 2017a; Lei et al., 2017b; Lei, Liu, Yang, Xiong, et al., ;; Lei, Liu, Qi, et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Yang, et al., ; Lei, Liu, Zhu, et al., ; Peng et al., ). As an effective tool, PK‐PD analysis has been approved to assay the optimal dosage according to the development content of new antibiotic agents by the Food and Drug Administration and European Medicines Agency (Lei, Liu, Qi, et al., ; Lei, Liu, Yang, Ahmed, et al., ; Lei, Liu, Yang, Yang, et al., ; Lei, Liu, Zhu, et al., ; Yan et al., ).…”

Caerin1.1 Suppresses the Growth of Porcine Epidemic Diarrhea Virus In Vitro via Direct Binding to the Virus

“…Antiviral activities of Caerin1.1 is expected to be improved through the combination usages with other different AMPs or other antiviral agents like graphene oxide (GO), which could make Caerin1.1 a good weapon to deal with the diseases caused by viruses including PEDV [ 33 ]. As a matter of fact, we did a combination treatment with Piscidin which was also proved to be effective against PEDV [ 34 ], but the results were not as good as expected based on our unpublished work. The mechanisms still remain to be further investigated.…”