| Objective:①To study a model of ceftiofur resistance in APP in vitro in order to investigate the pharmacodynamics of ceftiofur and heartleaf houttuynia herb united in vitro.②Compound ceftiofur hydrochloride suspension was made according to the purpose of drug combination in veterinary surgeon clinical.③To inspect the characteristic delayed release of compound ceftiofur hydrochloride suspension baseding on pharmacokinetics.Methods:①Studied in vitro: The strains of APP-0 that was susceptible to ceftiofur was induced to produce resistant filial generation APP-Y100 by the method of MIC times to times increase. Comparisons of the biological phenotype variation were done on MIC, morphology, drug resistance maintainability, growth kinetics and in vivo test between susceptible and resistant strains.②Studied of preparation: The study on this preparation included orthogonal design, screening of accessories medicine, preparative method, then to inspect all programs such as subsidence ratio, content, character appearance, particle diameter, excitation organism and so on.③Studied of pharmacodynamics: 36 SPF rat were divided 3 groups trabant equally.A group was given a single injection dose of compound ceftiofur hydrochloride suspension 50mg/(kg·b·w) ; B group was given a single injection dose of ceftiofur hydrochloride suspension 50mg/(kg·b·w); C group was given a single injection dose of ceftiofur sodium 50mg/(kg·b·w) .The ceftiofur concentrations in plasma were detemined reversed-phase by HPLC, with a limit of detection of 0.1μg /ml in plasma. The pharmacokinetic variables were calculated by DAS2.0 PK program and SPSS(11.0) program.Results:①The MIC of the resistant filial generation APP-Y100 had improved 128 times and the resistant filial generation APP-Y100 maintained 64 times for 30 passages when it grew on drug-free medium. The thalluses of the resistant filial generation become to bigger rod shape. The parent strains had a nearly similar doubling-time to their filial generation on drug-free medium, but it was significant difference on drug medium. In vivo test, the survival rate of low , low and high-dose group respectively for 80% , 100% and 0 , 80%.②The best prescription of preparation is A2B2C3, the volume ratio of preparation is 90.4%, the grain size of 2.0-10.0μm is 74.5%, the relative amount kept 98% in 6 monthes. The preparation was stabilization to high temperature and wet, and injected succeed.(3)The study of pharmacokinetics showed that the model of A,B and C groups was fitted a two-compartment Model with 1st Order Absorption(weight= 1/cc). The main pharmacokinetics parameters and calculated-equations in chickens were as follows, respectively:Group A:T1/2Ka=(1.253±0.100) h,T1/2α=(1.532±0.191) h,T1/2β=(15.321±3.755) h,T peak=(2.000±0.000) h,C max=(35.203±5.732) mg/L, AUC=(229.51±18.278)(mg/L·h),Ka为(0.556±0.046)(1/h),MRT0→48(h)=(8.049±0.274) h, C = 313.754e-0.458t+ 4.249e-0.047t -318.003e-0.556t. GroupB:T1/2Ka=(0.341±0.090) h,T1/2α=(1.734±0.300) h, T1/2β=(10.186±1.842) h, Tpeak= (1.000±0.000)h, C max=(43.919±1.51) mg/L , AUC=(188.488±9.611) (mg/L·h), Ka=(2.154±0.673) (1/h) ,MRT0→48(h)= (6.872±0.449) h,C = 52.917e-0.407t+5.651e0.069t-58.568e-2.154t. Group C : T1/2Ka=(0.044±0.012) h,T1/2a=(0.456±0.079) h, T1/2p=(0.983±0.010) h,Tpeak=(0.167±0.000) h , C max=(159.091±19.971) mg/L, AUC=(128.554±6.625)(mg/L·h),Ka=(16.340±3.844) (1/h) ,MRT0→48(h)= (0.911±0.059) h,C = 123.222e-1.550t+ 5.651e-0.705t- 128.873e-16.340t.ConcIusions:(1)The new strains of ceftiofur resistant were successfully induced andproved by in vivo and invitro tests.②Heartleaf Houttuynia Herb with ceftiofur showed synergistic effect against APP of ceftiofur resistance ,but they showed addition effect against origin APP.③The physical stability of compound ceftiofur hydrochloride suspension which were manufactured by prescription of A2B2C3 were good and injected succeed.④The Compound ceftiofur hydrochloride suspension was more slowly absorbed with in plasma, decreased the speed of absorption, but enhanced the degree of absorption, retarded the speed of elimination,increased the time of drug action; increased the bioavailability of ceftiofur.It suggested that the dose of compound ceftiofur hydrochloride suspension was once daily by intramuscular injection for 3 to 5 d, and it can keep utility haemoconcentration. |
