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Cryptosporidiosis is considered a crucial zoonotic disease caused by widely distributing parasitic protozoa called Cryptosporidium spp. Nitazoxanide is the only FDA-approved drug but is only effective with a good immune response of the host. In addressing this unmet medical need, we previously identified a compound, namely, LN002, as a potent alternative oxidase inhibitor against cryptosporidiosis. To illustrate the pharmacokinetics, absolute bioavailability, and tissue distribution of LN002 in rats, rapid and sensitive high-performance liquid chromatography was developed and validated for the separation and detection of LN002 in plasma, tissue samples, and intestinal contents. In this study, a single dose of oral administration and intravenous injection of LN002 was used to determine the levels of LN002 in plasma, tissue samples, and intestinal contents by UHLC. Results of the study indicated that after intravenous administration of 1 mg/kg LN002, the AUC0-24 h, T1/2,Vd, and Cl were 7024.86 h·ng/mL, 10.91 h, 1.69 L/kg, and 0.11 L/h/kg, respectively. After oral administration of a single dosage of 100, 200, and 400 mg/kg LN002, the Tmax, Cmax, AUC0-24 h, T1/2, F, Vd, and Cl/F in plasma of rats were 1 h, 849.88-4033.21 ng/mL, 2280.41-7498.10 h·ng/mL, 17.96-18.83 h, 0.27%-0.32%, 581.54-869.21 L/kg, and 25.97-39.00 L/h/kg, respectively. After oral administration of 200 mg/kg, LN002 was extensively distributed in the main tissues of rats, and massive amounts of LN002 were distributed in the intestine and intestinal contents, indicating its potential as an effective anti-Cryptosporidium compound. After oral administration of a single dosage of 200 mg/kg, LN002 has a low bioavailability and high levels in the intestine, which is crucial for the safe and effective treatment of cryptosporidiosis. Overall, the results of this study provide valuable data support for the future study of LN002.
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The phenylpyrazole derivative 5-amino-3-[1-cyano-2-(3-phenyl-1H-pyrazol-4-yl) vinyl]-1-phenyl-1H-pyrazole-4-carbonitrile (LN002), which was screened out through high-throughput molecular docking for the AOX target, exhibits promising efficacy against Cryptosporidium. However, its poor water solubility limits its oral bioavailability and therapeutic utility. In this study, solid dispersion agents were prepared by using HP-ß-CD and Soluplus® and characterized through differential scanning calorimetry, Fourier transform infrared, powder X-ray diffraction, and scanning electron microscopy. Physical and chemical characterization showed that the crystal morphology of LN002 transformed into an amorphous state, thus forming a solid dispersion of LN002. The solid dispersion prepared with an LN002/HP-ß-CD/Soluplus® mass ratio of 1:3:9 (w/w/w) exhibited significantly increased solubility and cumulative dissolution. Meanwhile, LN002 SDs showed good preservation stability under accelerated conditions of 25 °C and 75% relative humidity. The complexation of LN002 with HP-ß-CD and Soluplus® significantly improved water solubility, pharmacological properties, absorption, and bioavailability.
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Disponibilidad Biológica , Cryptosporidium parvum , Solubilidad , Cryptosporidium parvum/efectos de los fármacos , Animales , Administración Oral , Polietilenglicoles/química , Pirazoles/química , Pirazoles/farmacocinética , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Simulación del Acoplamiento Molecular , Polivinilos/química , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos X , Rastreo Diferencial de Calorimetría , Ratas , Masculino , 2-Hidroxipropil-beta-Ciclodextrina/químicaRESUMEN
The economic impact of necrotizing enteritis (NE) resulting from Clostridium perfringens infection has been significant within the broiler industry. This study primarily investigated the antibacterial efficacy of hexahydrocolupulone against C. perfringens, and its pharmacokinetics within the ileal contents of broiler chickens. Additionally, a dosing regimen was developed based on the pharmacokinetic/pharmacodynamic (PK/PD) model specific to broiler chickens. Results of the study indicated that the minimum inhibitory concentration (MIC) of hexahydrocolupulone against C. perfringens ranged from 2 mg/L to 16 mg/L in MH broth. However, in ileal content, the MIC ranged from 8 mg/L to 64 mg/L. The mutation prevention concentration (MPC) in the culture medium was found to be 128 mg/L. After oral administration of hexahydrocolupulone at a single dosage of 10-40 mg/kg bodyweight, the peak concentration (Cmax), maximum concentration time (Tmax), and area under the concentration-time curve (AUC) in ileal content of broiler chickens were 291.42-3519.50 µg/g, 1-1.5 h, and 478.99-3121.41 µg h/g, respectively. By integrating the in vivo PK and ex vivo PD data, the AUC0-24h/MIC values required for achieving bacteriostatic, bactericidal, and bacterial eradication effects were determined to be 36.79, 52.67, and 62.71 h, respectively. A dosage regimen of 32.9 mg/kg at 24 h intervals for a duration of 3 days would yield therapeutic efficacy in broiler chickens against C. perfringens, provided that the MIC below 4 mg/L.
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Although carbapenems have not been approved for animal use, carbapenem-resistant Escherichia coli (CREC) strains are increasingly being detected in food-producing animals, posing a significant public health risk. However, the epidemiological characteristics of CREC isolates in yellow-feather broiler farms remain unclear. We comprehensively investigated the genetic features of carbapenem-resistance genes among E. coli isolates recovered from a yellow-feather broiler farm in Guangdong province, China. Among the 172 isolates, 88 (51.2%) were recovered from chicken feces (88.5%, 54/61), the farm environment (51.1%, 24/47), and specimens of dead chickens (15.6%, 41/64). All CREC isolates were positive for the blaNDM-5 gene and negative for other carbapenem-resistance genes. Among 40 randomly selected isolates subjected to whole-genome sequencing, 10 belonged to distinct sequence types (STs), with ST167 (n = 12) being the most prevalent across different sources, suggesting that the dissemination of blaNDM-5 was mainly due to horizontal and clonal transmission. Plasmid analysis indicated that IncX3, IncHI2, and IncR-X1-X3 hybrid plasmids were responsible for the rapid transmission of the blaNDM-5 gene, and the genetic surrounding of blaNDM-5 contained a common mobile element of the genetic fragment designated "IS5-â³ISAba125-blaNDM-5-bleMBL-trpF-dsbC". These findings demonstrate a critical role of multiple plasmid replicons in the dissemination of blaNDM-5 and carbapenem resistance.
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Introduction: Riemerella anatipestifer (R. anatipestifer) is an important pathogen in waterfowl, leading to substantial economic losses. In recent years, there has been a notable escalation in the drug resistance rate of R. anatipestifer. Consequently, there is an imperative need to expedite the development of novel antibacterial medications to effectively manage the infection caused by R. anatipestifer. Methods: This study investigated the in vitro and in vivo antibacterial activities of a novel substituted benzene guanidine analog, namely, isopropoxy benzene guanidine (IBG), against R. anatipestifer by using the microdilution method, time-killing curve, and a pericarditis model. The possible mechanisms of these activities were explored. Results and Discussion: The minimal inhibitory concentration (MIC) range of IBG for R. anatipestifer was 0.5-2 µg/mL. Time-killing curves showed a concentration-dependent antibacterial effect. IBG alone or in combination with gentamicin significantly reduced the bacterial load of R. anatipestifer in the pericarditis model. Serial-passage mutagenicity assays showed a low probability for developing IBG resistance. Mechanistic studies suggested that IBG induced membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to an imbalance in membrane potential and the transmembrane proton gradient, as well as the decreased of intracellular adenosine triphosphate. In summary, IBG is a potential antibacterial for controlling R. anatipestifer infections.
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Bovine mastitis caused by infectious pathogens can lead to a decline in production performance and an increase in elimination rate, resulting in huge losses to the dairy industry. This study aims to prepare a novel dairy cow teat disinfectant with polyhexamethylene biguanide (PHMB) as the main bactericidal component and to evaluate its bactericidal activity in vitro and its disinfection effect in dairy cow teats. PHMB disinfectant with a concentration of 3 g/L was prepared with PVA-1788, propylene glycol and glycerol as excipients. When the dilution ratio is 1:4800 and the action time is 5 min, the PHMB teat disinfectant can reduce the four types of bacteria (S. agalactiae ATCC 12386, S. dysgalactiae ATCC 35666, S. aureus ATCC 6538, and E. coli ATCC 8099) by 99.99%. PHMB teat disinfectant applied on the skin of rabbits with four bacteria types achieved an average log10 reduction greater than 4. After 30 s of PHMB teat disinfectant dipping, the bacteria of cow teats were counted prior to disinfection. The mean log10 reduction in bacteria on the skin surface of 12 cows ranged from 0.99 to 3.52 after applying the PHMB teat disinfectant for 10 min. After 12 h, the PHMB teat disinfectant achieved an average log10 reduction in bacteria from 0.27 to 0.68 (compared with that prior to disinfection). These results suggested that PHMB teat disinfection has the potential to prevent and treat mastitis-causing bacteria in dairy herds.
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Desinfectantes , Mastitis Bovina , Femenino , Animales , Bovinos , Conejos , Desinfectantes/farmacología , Staphylococcus aureus , Escherichia coli , Bacterias , Glándulas Mamarias Animales/microbiología , Mastitis Bovina/prevención & control , Mastitis Bovina/microbiologíaRESUMEN
Introduction: Milbemycin oxime (MBO) and praziquantel (PZQ) have a broad spectrum of biological activity and are commonly used to treat the parasitic infection in the veterinary clinic. In this study, a fast and efficient LC-MS/MS method was established and validated for the simultaneous determination of MBO, PZQ, cis-4-hydroxylated-PZQ (C-4-OH-PZQ) and trans-4-hydroxylated-PZQ (T-4-OH-PZQ) and in cat plasma. Methods: Extraction of analytes and internal standards from cat plasma by acetonitrile protein precipitation, allows rapid processing of large batches of samples. MBO, PZQ, C-4-OH-PZQ, T-4-OH-PZQ, and internal standard (IS) were eluted for 13.5 min on a C18 column with a 0.1% formic acid water/acetonitrile mixture as the mobile phase. Results: Results showed that the method had good precision, accuracy, recovery, and linearity. The linearity range was 2.5-250 ng/mL for MBO, and 10-1000 ng/mL for PZQ, C-4-OH-PZQ, and T-4-OH-PZQ. The intra-day and inter-day precision CV values of the tested components were within 15%. The extraction recoveries of the four components ranged from 98.09% to 107.46%. The analytes in plasma remained stable for 6 h at room temperature, 26 h in the autosampler (4 °C), after freeze-thaw (-20°C) cycles, and 60 days in a -20°C freezer. Method sensitivity sufficed for assessing pharmacokinetic parameters of MBO, PZQ, C-4-OH-PZQ, and T-4-OH-PZQ in plasma samples with LLOQ of 2.5 ng/mL for MBO and 10 ng/mL for PZQ, C-4-OH-PZQ, and T-4-OH-PZQ. Conclusion: In this study, a selective and sensitive LC-MS/MS method for the simultaneous quantification of MBO, PZQ, C-4-OH-PZQ, and T-4-OH-PZQ in cat plasma was developed and validated.This method had been successfully applied to evaluate the pharmacokinetics of MBO, PZQ, C-4-OH-PZQ, and T-4-OH-PZQ after a single oral administration of 8 mg MBO and 20 mg PZQ in cats.
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Jet injection technology has become the alternative drug delivery method of conventional needle-based injection due to its obvious advantages. In order to meet the demand for larger volume injection, the pneumatic jet injection systems have efficiently administrated vaccine up to 1 mL in human. Our recent study has also demonstrated that controlling the driving pressure enabled the pneumatic jet injection system to deliver larger volumes of drugs to target sites at desired rates and times. This work continues to explore the optimal two-phase driving pressure combination with better injection efficiency for typical larger-volume (1.0 mL) jet injection with controllable pneumatic jet injection system. Under the combination of a first phase driving pressure of 1.00 MPa and a second phase driving pressure ranging from 0.25 to 0.90 MPa, dynamic characteristics, dispersion characteristics and pharmacokinetic characteristics of this controllable jet injection system were quantitatively analyzed. In all experiments, it was confirmed that the optimal driving pressure combination of 1.0 mL ejection volume was close to (1.00-0.50) MPa. That is, the injection velocities of 151.85 m/s and 102.01 m/s for the first and second phase respectively facilitated better injection performance with a controlled release of 1.0 mL ejection volume. This strategy is practical for facilitating the clinical application of large-volume controllable jet injection systems.
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Sistemas de Liberación de Medicamentos , Agujas , Humanos , Inyecciones a ChorroRESUMEN
Isopropoxy benzene guanidine (IBG) is a guanidine derivative with antibacterial activity against multidrug-resistant bacteria. A few studies have revealed the metabolism of IBG in animals. The aim of the current study was to identify potential metabolic pathways and metabolites of IBG. The detection and characterization of metabolites were performed with high-performance liquid chromatography tandem mass spectrometry (UHPLC-Q-TOF-MS/MS). Seven metabolites were identified from the microsomal incubated samples by using the UHPLC-Q-TOF-MS/MS system. The metabolic pathways of IBG in the rat liver microsomes involved O-dealkylation, oxygenation, cyclization, and hydrolysis. Hydroxylation was the main metabolic pathway of IBG in the liver microsomes. This research investigated the in vitro metabolism of IBG to provide a basis for the further pharmacology and toxicology of this compound.
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Microsomas Hepáticos , Espectrometría de Masas en Tándem , Ratas , Animales , Espectrometría de Masas en Tándem/métodos , Microsomas Hepáticos/metabolismo , Benceno , Guanidina/farmacología , Cromatografía Líquida de Alta Presión/métodosRESUMEN
Streptococcus suis, an encapsulated zoonotic pathogen, has been reported to cause a variety of infectious diseases, such as meningitis and streptococcal-toxic-shock-like syndrome. Increasing antimicrobial resistance has triggered the need for new treatments. In the present study, we found that isopropoxy benzene guanidine (IBG) significantly attenuated the effects caused by S. suis infection, in vivo and in vitro, by killing S. suis and reducing S. suis pathogenicity. Further studies showed that IBG disrupted the integrity of S. suis cell membranes and increased the permeability of S. suis cell membranes, leading to an imbalance in proton motive force and the accumulation of intracellular ATP. Meanwhile, IBG antagonized the hemolysis activity of suilysin and decreased the expression of Sly gene. In vivo, IBG improved the viability of S. suis SS3-infected mice by reducing tissue bacterial load. In conclusion, IBG is a promising compound for the treatment of S. suis infections, given its antibacterial and anti-hemolysis activity.
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Infecciones Estreptocócicas , Streptococcus suis , Animales , Ratones , Streptococcus suis/genética , Benceno , Guanidina , Infecciones Estreptocócicas/tratamiento farmacológico , Infecciones Estreptocócicas/microbiología , Guanidinas/farmacología , Guanidinas/uso terapéutico , Guanidinas/metabolismo , Proteínas Hemolisinas/metabolismoRESUMEN
This study aimed to investigate the transmission and molecular epidemiological characteristics of the rmtB gene in Escherichia coli (E. coli) strains isolated from duck farms in Guangdong Province of China from 2018 to 2021. A total of 164 (19.4%, 164/844) rmtB-positive E. coli strains were recovered from feces, viscera, and environment. We performed antibiotic susceptibility tests, pulsed-field gel electrophoresis (PFGE), and conjugation experiments. We obtained the genetic context of 46 rmtB-carrying E. coli isolates and constructed a phylogenetic tree via whole genome sequencing (WGS) and bioinformatic analysis. The isolation rate of rmtB-carrying E. coli isolates in duck farms increased yearly from 2018 to 2020 but decreased in 2021. All rmtB-harboring E. coli strains were multidrug resistant (MDR), and 99.4% of the strains were resistant to more than 10 drugs. Surprisingly, duck- and environment-associated strains similarly showed high MDR. Conjugation experiments revealed that the rmtB gene horizontally cocarried blaCTX-M and blaTEM gene dissemination via IncFII plasmids. Insertion sequences IS26, ISCR1, and ISCR3 were closely associated with the spread of rmtB-harboring E. coli isolates. WGS analysis indicated that ST48 was the most prevalent sequence type. The results of single nucleotide polymorphism (SNP) differences revealed potential clonal transmission between ducks and the environment. Based on One Health principles, we need to strictly use veterinary antibiotics, monitor the distribution of MDR strains, and evaluate the impact of plasmid-mediated rmtB gene on human, animal, and environmental health.
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Proteínas de Escherichia coli , Escherichia coli , Animales , Humanos , Patos/genética , Proteínas de Escherichia coli/genética , Epidemiología Molecular , Filogenia , Pollos/genética , Antibacterianos/farmacología , China , Pruebas de Sensibilidad Microbiana/veterinaria , Metiltransferasas/genéticaRESUMEN
This study aimed to evaluate the antibacterial activity of isopropoxy benzene guanidine (IBG) against C. perfringens based on pharmacokinetics/pharmacodynamics (PK/PD) modeling in broilers. The PK parameters of IBG in the plasma and ileal content of C. perfringens-infected broilers following oral administration at 2, 30, and 60 mg/kg body weight were investigated. in vivo PD studies were conducted over oral administration ranging from 2 to 60 mg/kg and repeated every 12 h for 3 days. The inhibitory I max model was used for PK/PD modeling. Results showed that the MIC of IBG against C. perfringens was 0.5-32 mg/L. After oral administration of IBG, the peak concentration (C max ), maximum concentration time (T max ), and area under the concentration-time curve (AUC) in ileal content of broilers were 10.97-1,036.64 mg/L, 2.39-4.27 h, and 38.31-4,266.77 mg·h/L, respectively. After integrating the PK and PD data, the AUC0 - 24h /MIC ratios needed for the bacteriostasis, bactericidal activity, and bacterial eradication were 4.00, 240.74, and 476.98 h, respectively. For dosage calculation, a dosage regimen of 12.98 mg/kg repeated every 12 h for 3 days was be therapeutically effective in broilers against C. perfringens with MIC ≤ 2 mg/L. In addition, IBG showed potent activity against C. perfringens, which may be responsible for cell membrane destruction. These results can facilitate the evaluation of the use of IBG in the treatment of intestinal diseases in broilers caused by C. perfringens.
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Isopropoxy benzene guanidine (IBG) is a novel substituted benzene guanidine analogue with antibacterial activity against multidrug-resistant bacteria. However, the bioavailability of IBG is not optimal due to its finite aqueous solubility, thus hampering its potential therapeutic exploitation. In this study, we prepared IBG/hydroxypropyl-ß-CD (IBG/HP-ß-CD) complex, and characterized it by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffraction, and scanning electron microscopy. Physicochemical characterization indicated that the crystal morphology of IBG transformed into an amorphous state, thus forming IBG/HP-ß-CD inclusion complexes. Complexation with HP-ß-CD significantly improve the aqueous solubility, pharmaceutical properties, absorption, and bioavailability of IBG.
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Benceno , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Disponibilidad Biológica , Guanidina , Guanidinas , Agua , beta-Ciclodextrinas/químicaRESUMEN
Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect I max model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0-24h /MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0-24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.
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Recombinant lysostaphin has been used for the treatment of cow endometritis and mastitis in China. To our knowledge, no scientific effort has been made to evaluate the efficacy of lysostaphin in sows with clinical endometritis. Lysostaphin, loaded in effervescent tablets that were completely foamed and dissolved within 30 min in the presence of water or body fluids and released active lysostaphin, were administered vaginally on endometritis sows in this study. The clinical recovery, bacterial clearance and reproductive performance of sows with endometritis were investigated. We found that the 400U dosage (400U lysostaphin/pill/time, repeat once on the third day, a total of two times, with 10% oxytetracycline uterine injection as a control) is the most effective treatment. Staphylococcus aureus was the most prevalent finding (34%, n = 188), followed by Streptococcus (32%, n = 181), Escherichia coli (19%, n = 104) and other bacilli (15%, n = 83) before treatment by drugs. Administration of lysostaphin resulted in an extremely significant (p < .01) reduction in S. aureus (0.18 ± 0.25 from 4.57 ± 0.33) and Streptococcus (0.11 ± 0.14 from 3.88 ± 0.29), as well as a significant (p < .05) reduction in E. coli (0.55 ± 0.42 from 3.11 ± 0.14). Mixed infections (83%) were predominant before treatment, in contrast to single infections (61%) after treatment. Large-scale trials were conducted to verify the clinical efficacy of lysostaphin on sow endometritis. The average cure rate of 400u lysostaphin on sow endometritis(82.5%) was higher than the antibiotic group(72.17%). In addition, our results revealed that intravaginal administration of lysostaphin had no adverse effect on the reproductive performance of sows. Thus, this lysostaphin has potential application value as a new method alternative to antibiotics to treat endometritis in sows.
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Antiinfecciosos Locales/uso terapéutico , Endometritis/veterinaria , Lisostafina/uso terapéutico , Administración Intravaginal , Animales , China , Relación Dosis-Respuesta a Droga , Endometritis/tratamiento farmacológico , Femenino , Distribución Aleatoria , Proteínas Recombinantes/uso terapéutico , Sus scrofa , Comprimidos , Resultado del TratamientoRESUMEN
Diclazuril (DIC) is widely used as a racemic mixture to prevent and treat coccidiosis in farm animals, while the pharmacokinetics, bioactivity, and toxicity of DIC enantiomers are not known at all. This study first established a simple, sensitive, and reliable liquid chromatography tandem mass spectrometry method for separation of R-DIC and S-DIC and their analyses. Then, it was applied to investigate the stereoselective pharmacokinetics and residual elimination of individual enantiomers, and their anticoccidial activity was also evaluated in broiler chickens. The results indicated that the area under the concentration-time curve (AUC) and elimination half-life (t1/2ß) were significantly different (p < 0.05) for two enantiomers in chicken plasma. The AUC and t1/2ß of S-DIC were approximately 2 and 1.4 times those of R-DIC, respectively. The residual elimination of DIC enantiomers in chicken tissues was also stereoselective. The concentrations of S-DIC in chicken muscle and liver were greater than those of R-DIC, and it is the opposite in the kidney. There was no significant difference (p > 0.05) in the anticoccidial activity of racemate and enantiomers when a single enantiomer in feed was added above 0.5 mg kg-1. However, the anticoccidial activity of R-DIC (0.25 mg kg-1) was significantly higher (p < 0.05) than that of S-DIC (0.25 mg kg-1) in the diet. It should be mentioned that in chicken small intestine and cecum, the enantiomerization rate of each enantiomer in the infection group was faster than that in the uninfected group.
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Pollos/sangre , Coccidiostáticos/farmacología , Residuos de Medicamentos/farmacocinética , Nitrilos/farmacocinética , Triazinas/farmacocinética , Animales , Coccidiostáticos/sangre , Coccidiostáticos/química , Residuos de Medicamentos/química , Nitrilos/sangre , Nitrilos/química , Estereoisomerismo , Triazinas/sangre , Triazinas/químicaRESUMEN
Hypodermic needles and syringes are currently the main route of the transdermal administration. Many complaints associated with needle-stick injuries, needle phobia, and needle abuse have motivated the development of alternative drug delivery strategies. Pneumatic needle-free injections stand out from various alternative strategies because of the convenience in adjusting the driving pressure and the injection volume. This study proposed a novel control method of the pneumatic needle-free injection for delivering larger volume drugs to the target sites at desired rates and time by controlling the driving pressure. The dynamic characteristics of this injection mode were evaluated in the impact experiments and the results confirmed the reliability of this controllable system in controlling the outlet pressure and jet velocity. The injection performances of it were compared with that of other injection modes through in vivo and in vitro experiments. This controllable system was able to control the injection depth and it was more conducive to the lateral diffusion of the liquid jets in gelatin. Moreover, it could not only enlarge the diffusion of diclofenac solution in rats, but also accelerate the metabolism of diclofenac solution in rats. All experimental results confirmed the reliability of this controllable injection system.
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Preparaciones Farmacéuticas , Piel , Animales , Sistemas de Liberación de Medicamentos , Diseño de Equipo , Inyecciones a Chorro , Agujas , Ratas , Reproducibilidad de los ResultadosRESUMEN
Penicillin G is widely used in food-producing animals at extralabel doses and is one of the most frequently identified violative drug residues in animal-derived food products. In this study, the plasma pharmacokinetics and tissue residue depletion of penicillin G in heavy sows after repeated intramuscular administrations at label (6.5 mg/kg) and 5 × label (32.5 mg/kg) doses were determined. Plasma, urine, and environmental samples were tested as potential antemortem markers for penicillin G residues. The collected new data and other available data from the literature were used to develop a population physiologically based pharmacokinetic (PBPK) model for penicillin G in heavy sows. The results showed that antemortem testing of urine provided potential correlation with tissue residue levels. Based on the United States Department of Agriculture Food Safety and Inspection Service action limit of 25 ng/g, the model estimated a withdrawal interval of 38 days for penicillin G in heavy sows after 3 repeated intramuscular injections at 5 × label dose. This study improves our understanding of penicillin G pharmacokinetics and tissue residue depletion in heavy sows and provides a tool to predict proper withdrawal intervals after extralabel use of penicillin G in heavy sows, thereby helping safety assessment of sow-derived meat products.
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Antibacterianos/farmacocinética , Peso Corporal , Modelos Biológicos , Penicilina G/farmacocinética , Porcinos/sangre , Animales , Antibacterianos/administración & dosificación , Simulación por Computador , Relación Dosis-Respuesta a Droga , Residuos de Medicamentos , Femenino , Penicilina G/administración & dosificación , Porcinos/metabolismo , Porcinos/orinaRESUMEN
Residue depletion of T-2 toxin in chickens after oral gavage at 2.0 mg/kg twice daily for 2 days was determined in this study. A flow-limited physiologically based pharmacokinetic (PBPK) model was developed for lifetime exposure assessment in chickens. The model was calibrated with data from the residue depletion study and then validated with independent data. A local sensitivity analysis was performed, and 16 sensitive parameters were subjected to Monte Carlo analysis. The population PBPK model was applied to estimate daily intake values of T-2 toxin in different countries based on reported consumption factors and the guidance value of 0.25 mg/kg in feed for chickens by the European Food Safety Authority (EFSA). The predicted daily intakes in different countries were all lower than the EFSA's total daily intake, suggesting that the EFSA's guidance value has minimal risk. This model provides a foundation for scaling to other mycotoxins and other food animal species.
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Carne/análisis , Toxina T-2/metabolismo , Toxina T-2/farmacocinética , Animales , Pollos , Seguridad de Productos para el Consumidor , Inocuidad de los Alimentos , Humanos , Método de Montecarlo , Toxina T-2/toxicidadRESUMEN
Bayesian population pharmacokinetic models of florfenicol in healthy pigs were developed based on retrospective data in pigs either via intravenous (i.v.) or intramuscular (i.m.) administration. Following i.v. administration, the disposition of florfenicol was best described by a two-compartment open model with the typical values of half-life at α phase (t1/2α ), half-life at ß phase (t1/2ß ), total body clearance (Cl), and volume of distribution (Vd ) were 0.132 ± 0.0289, 2.78 ± 0.166 hr, 0.215 ± 0.0102, and 0.841 ± 0.0289 L kg-1 , respectively. The disposition of florfenicol after i.m. administration was best described by a one-compartment open model. The typical values of maximum concentration of drug in serum (Cmax ), elimination half-life (t1/2Kel ), Cl, and Volume (V) were 5.52 ± 0.605 µg/ml, 9.96 ± 1.12 hr, 0.228 ± 0.0154 L hr-1 kg-1 , and 3.28 ± 0.402 L/kg, respectively. The between-subject variabilities of all the parameters after i.m. administration were between 25.1%-92.1%. Florfenicol was well absorbed (94.1%) after i.m. administration. According to Monte Carlo simulation, 8.5 and 6 mg/kg were adequate to exert 90% bactericidal effect against Actinobacillus pleuropneumoniae after i.v. and i.m. administration.