Drug-drug interactions (DDIs) may adversely affect the prevention and cure of diseases. The effects of three polyether ionophore antibiotics, salinomycin (SAL), monensin (MON), and maduramycin (MAD) on the pharmacokinetics of florfenicol (FFC) were investigated in broilers. The chickens were fed rations with or without SAL (60 mg/kg feeds), MON (120 mg/kg feeds), or MAD (5 mg/kg feeds) for 14 consecutive days. FFC was given to the chickens either intravenously (i.v.) or orally (p.o.) at a single dose of 30 mg/kg body weight. Blood samples were taken from each chicken at 0-24 h postadministration of FFC. The plasma concentration of FFC was detected by high-performance liquid chromatography. The plasma concentration of FFC decreased with i.v. or p.o. co-administration of SAL, MON, or MAD in broilers, implying occurrence of DDIs during the co-administration of FFC with these ionophores. Our findings suggest that more attention should be given to the use of FFC to treat bacterial infections in chickens supplemented with polyether ionophore antibiotics.
The pharmacokinetics and oral bioavailability of tylosin tartrate and tylosin phosphate were carried out in broiler chickens according to a principle of single dose, random, parallel design. The two formulations of tylosin were given orally and intravenously at a dose level of 10 mg/kg b.w to chicken after an overnight fasting (n = 10 chickens/group). Serial blood samples were collected at different time points up to 24 h postdrug administration. A high performance liquid chromatography method was used for the determination of tylosin concentrations in chicken plasma. The tylosin plasma concentration's time plot of each chicken was analyzed by the 3P97 software. The pharmacokinetics of tylosin was best described by a one-compartmental open model 1st absorption after oral administration. After intravenous administration the pharmacokinetics of tylosin was best described by a two-compartmental open model, and there were no significant differences between tylosin tartrate and tylosin phosphate. After oral administration, there were significant differences in the Cmax (0.18 ± 0.01, 0.44 ± 0.09) and AUC (0.82 ± 0.05, 1.57 ± 0.25)between tylosin phosphate and tylosin tartrate. The calculated oral bioavailability (F) of tylosin tartrate and tylosin phosphate were 25.78% and 13.73%, respectively. Above all, we can reasonably conclude that, the absorption of tylosin tartrate is better than tylosin phosphate after oral administration.
Maduramicin, a polyether ionophore antibiotic derived from the bacterium Actinomadura yumaensis, is currently used as a feed additive against coccidiosis in poultry worldwide. It has been clinically observed that maduramicin can cause skeletal muscle and heart cell damage, resulting in skeletal muscle degeneration, heart failure, and even death in animals and humans, if improperly used. However, the mechanism of its toxic action in myoblasts is not well understood. Using mouse myoblasts (C2C12) and human rhabdomyosarcoma (RD and Rh30) cells as an experimental model for myoblasts, here we found that maduramicin inhibited cell proliferation and induced cell death in a concentration-dependent manner. Further studies revealed that maduramicin induced accumulation of the cells at G0/G1 phase of the cell cycle, and induced apoptosis in the cells. Concurrently, maduramicin downregulated protein expression of cyclin D1, cyclin-dependent kinases (CDK4 and CDK6), and CDC25A, and upregulated expression of the CDK inhibitors (p21Cip1 and p27Kip1), resulting in decreased phosphorylation of Rb. Maduramicin also induced expression of BAK, BAD, DR4, TRADD and TRAIL, leading to activation of caspases 8, 9 and 3 as well as cleavage of poly ADP ribose polymerase (PARP). Taken together, our results suggest that maduramicin executes its toxicity in myoblasts at least by inhibiting cell proliferation and inducing apoptotic cell death.
Background
Halofuginone hydrobromide (HF) is a synthetic analogue of the naturally occurring quinazolinone alkaloid febrifugine, which has potential therapeutic effects against breast cancer, however, its poor water solubility greatly limits its pharmaceutical application. D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) is a water-soluble derivative of vitamin E, which can self-assemble to form polymeric micelles (PMs) for encapsulating insoluble anti-tumor drugs, thereby effectively enhancing their anti-cancer effects.
Methods
HF-loaded TPGS PMs (HTPMs) were manufactured using a thin-film hydration technique, followed by a series of characterizations, including the hydrodynamic diameter (HD), zeta potential (ZP), stability, drug loading (DL), encapsulation efficiency (EE), and in vitro drug release. The anti-cancer effects and potential mechanism of HTPMs were investigated in the breast cell lines MDA-MB-231 and MCF-7, and normal breast epithelial cell line Eph-ev. The breast cancer-bearing BALB/c nude mouse model was successfully established by subcutaneous injection of MDA-MB-231 cells and used to evaluate the in vivo therapeutic effect and safety of the HTPMs.
Results
The optimized HTPMs had an HD of 17.8±0.5 nm and ZP of 14.40±0.1 mV. These PMs exhibited DL of 12.94 ± 0.46% and EE of 90.6 ± 0.85%, along with excellent storage stability, dilution tolerance and sustained drug release in pH-dependent manner within 24 h compared to free HF. Additionally, the HTPMs had stronger inhibitory effects than free HF and paclitaxel against MDA-MB-231 triple-negative breast cancer cells, and little toxicity in normal breast epithelial Eph-ev cells. The HTPMs induced cell cycle arrest and apoptosis of MDA-MB-231 by disrupting the mitochondrial membrane potential and enhancing reactive oxygen species formation. Evaluation of in vivo anti-tumor efficacy demonstrated that HTPMs exerted a stronger tumor inhibition rate (68.17%) than free HF, and exhibited excellent biocompatibility.
Conclusion
The findings from this study indicate that HTPMs holds great clinical potential for treating triple-negative breast cancer.
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