| Community-acquired pneumonia (CAP) is a common infectious disease with high morbidity and mortality, Serious threat to human health, especially the elderly and children. Streptococcus pneumoniae (Sp) is the most common pathogen in CAP all over the world. Despite many advances in medical science, the mortality rate from community-acquiredpneumonia (CAP) has changed little in the past four decades, especially in some countries were in the trend of increasing, these problems increase the difficulty of treatment, treatment costs and patient mortality. At present, fluoroquinolones have been recommended as one of the preferred antibiotics in the guidelines for the management of CAP. In America, guidelines for CAP suggests that the plasma concentration of fluoroquinolones must exceed the mutant prevention concentration (MPC) for Streptococcus pneumoniae for as long as possible, to avoid drug-resistant mutants and ensure the success of the treatment. Clinical studies for moxifloxacin have evidenced that it has good clinical efficacy in CAP. In vitro experiments showed that MIC of moxifloxacin for Streptococcus pneumonia is lower than levofloxacin, which can eliminate the bacteria and improve the clinical symptoms more rapidly.The dosage of moxifloxacin for Streptococcus pneumonia is recommended at 400mg once a day in many guidelines of different countries, and the efficacy of moxifloxacin have no significant difference of oral and intravenous administration. Ambroxol is a common expectorant used in a variety of respiratory tract infections. Several studies reported that the Pharmacodynamic of ambroxol in vivo are closely related to the dosage of ambroxol, when its concentration reaches a certain concentration it has anti-inflammatory effects, and synergy with antimicrobial agents. There is a certain controversy for ambroxol about the selection of clinical dosage, and which is ambroxol’s best dosage is not clear. Small sample clinical studies showed that large dosage of ambroxol combined with antibiotics was significantly better than antibiotics alone, or small dosage. However, there is no report about whether ambroxol would affect the pharmacokinetic characteristics of moxifloxacin in lung tissue, if so, which is the optimal dosage of ambroxol.In the past, Pharmacokinetic studies of antimicrobial drugs most often rely on data from plasma or whole tissue homogenates. However, since most infections take place in tissues extra cellular fluids, free antimicrobial concentrations in the interstitial space at the infection site are responsible for the antibacterial effect. The microdialysis (MD) technique, a reliable method of studying drug tissue distribution and penetration and monitoring drug active ingredients, allows a real-time and online continuous sampling with no interference with normal metabolic processes in vivo. Unfortunately, very few studies have reported the use of microdialysis in lung tissue, and even fewer antimicrobial classes have been studied.Objective:The sample of blood and lung tissue in a rat model of pneumococcal pneumonia is collected by microdialysis simultaneously and the concentration of the moxifloxacin is tested by HPLC-MS. and exploring the pharmacokinetic characteristics of moxifloxacin in the lung tissue with Streptococcus pneumoniae pneumonia and the influence of different dosage of ambroxol, providing evidence for clinical medication.Materials and Methods:1. Twenty-four specific pathogen-free male WISTAR rats, weighing 220g-250g, were assigned to 4 groups randomly.2. The model of pneumococcal pneumonia of rat were set up by intratracheal injection of pneumococcal suspension (1.8x108CFU/rat).3. Mimicking the usual dose of moxifloxacin 400mg/day for an adult, the administered dose in rats was 40mg/kg converted by the body surface area. All rats of four groups received a dose of moxifloxacin via gastric canal (40mg/kg), and Group A received normal saline 1ml, other three groups received different dosage of ambroxol (Group B, 6mg/kg、Group C,12mg/kg and Group D,60mg/kg) via gastric canal.4. The disposition of moxifloxacin in rat lung and blood was collected simultaneously by the technique of microdialysis. The concentration of the moxifloxacin is tested by HPLC-MS. The individual set of data of Pharmacokinetic is calculated by the software of DSA3.0 according to the atrioventricular model.Results:1. Group A(moxifloxacin single group):The time to peak (tmax) of moxifloxacin in blood was 1.00±0.00h and the maximum free moxifloxacin concentrations (Cmax) was 4.84±0.05μg/mL. The time to peak (tmax) of moxifloxacin in lung tissue was 0.95±0.10h and the maximum free moxifloxacin concentrations (Cmax) was 4.84±0.02ug/mL. The elimination half-life (ti/2) is 2.16±0.12h in blood, and 3.27±0.48h in lung. The area under curve (AUC(0-t)) in blood and lung were 12.85±1.46h·μg/mL and 13.22±0.62h·μg/mL, respectively. The lung tissue distribution(AUCiung/AUCbiood) of free moxifloxacin was 1.10±0.04.2. Group B (low doses of ambroxol combined with moxifloxacin):The time to peak (tmax) of moxifloxacin in blood was 0.83±0.17h and the maximum free moxifloxacin concentrations (Cmax) was 5.13±1.20μg/mL. The time to peak (tmax) of moxifloxacin in lung tissue was 0.83±0.17h and the maximum free moxifloxacin concentrations (Cmax) was 5.58±0.17μg/mL. The elimination half-life (t1/2) is 3.78±3.02h in blood, and 3.16±1.39h in lung. The area under curve (AUC(0-t)) in blood and lung were 12.66±1.20h μg/mL and 13.78±3.30hμg/ml, respectively. The lung tissue distribution (AUClung/AUCblood) of free moxifloxacin was 1.14±0.47.3. Group C (middle doses of ambroxol combined with moxifloxacin):The time to peak (tmax) of moxifloxacin in blood was1.00±0.00h and the maximum free moxifloxacin concentrations (Cmax) was 4.76±0.43μg/mL. The time to peak (tmax) of moxifloxacin in lung tissue was 0.89±0.10h and the maximum free moxifloxacin concentrations (Cmax) was 7.26±1.69μg/mL. The elimination half-life (t1/2) is 4.98±1.81h in blood, and 4.47±3.38 h in lung. The area under curve (AUC(0-t)) in blood and lung were 15.54±3.2662h·μg/mL and 18.64±3.2662h·μg/mL, respectively. The lung tissue distribution (AUCiung/AUCblood) of free moxifloxacin was 1.15±0.88.4. Group D (high doses of ambroxol combined with moxifloxacin):The time to peak (tmax) of moxifloxacin in blood was 0.94±0.10h and the maximum free moxifloxacin concentrations (Cmax) was 4.68±0.18μg/mL. The time to peak (tmax) of moxifloxacin in lung tissue was 0.89±0.19h and the maximum free moxifloxacin concentrations (Cmax) was 7.84±2.34μg/mL. The elimination half-life (t1/2) is4.12±1.83h in blood, and 3.90±1.19h in lung. The area under curve (AUC(0-t)) in blood and lung were 16.46±1.31h·μg/mL and 22.00±4.78h·μg/mL , respectively. The lung tissue distribution (AUClung/AUCblood) of free moxifloxacin was 1.29±0.34.5. The Cmax (7.84±2.34μg/mL) and AUC(0-t) (22±4.78hμg/mL) of lung tissue in group D were higher than that of group A and group B. (P<0.05).Conclusion:1. In the rat model of Streptococcus pneumonia after oral administration of moxifloxacin, the drug is absorbed rapidly and eliminated slowly. The synchronization of moxifloxacin concentration in blood and lung tissue is good, which suggests that the drug has a strong penetrative ability through lung tissue and its index of tissue distribution is high, and its bioavailability is good.2. In the rat model of Streptococcus pneumonia, when combined with different dosage of ambroxol, moxifloxacin has a strong penetrative power、higher distribution index in lung tissue and the scale of the area below curve (AUC(0-t)) in lung tissue reaches or exceeds the scale of the area under the curve in the blood.3. When moxifloxacin is combined with ambroxol, there is a positive correlation between the concentration of free moxifloxacin in lung tissue and the dosage of ambroxol whereas the concentration of free moxifloxacin in blood has no significant correlation with the dosage of ambroxol.4. It is suggested that high dosage of ambroxol could increase the concentration and bioavailability of moxifloxacin in the lung tissue of rats significantly. |
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