AAPS PHARMSCITECH
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2025
·Vol. 26
·期 5
·1-18
·
IF 4
Yang Hongyu,Qin Jianpeng,Wang Yuou,Li Ji,Wang Dongkai
Pulmonary bacterial infections are a common disease, with erythromycin being a first-line treatment. However, conventional erythromycin tablets and injectables exhibit limited therapeutic efficacy and are associated with severe gastrointestinal side effects. Additionally, injectable formulations suffer from poor patient compliance. Dry powder inhaler (DPI) offers superior pulmonary targeting, circumvent first-pass metabolism, and are portable, enhancing patient adherence. In this study, we successfully developed a ternary inhalable erythromycin dry powder formulation (Ery-DPI). The Quality by Design (QbD) approach was employed to establish a design space for erythromycin micronization and to optimize the formulation. The physicochemical properties and fine particle fraction of the erythromycin DPI were evaluated through in vitro experiments. The final formulation, composed of α-lactose, mannitol, and erythromycin in a ratio of 1:0.2:2 (v/v/v), exhibited an FPF of 70 ± 3%. In vivo studies demonstrated that, compared to intravenous administration, Ery-DPI achieved higher and more stable local drug exposure in the lungs. Overall, our study provides new insights into pulmonary drug delivery strategies for treating bacterial infections. Graphical
研究领域:
药剂学
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呼吸病学
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药物化学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2022
·
IF 6.51
Xuejuan Zhang,Yue Zhou,Guanlin Wang,Ziyu Zhao,Zhongxiang Jiang,Yingtong Cui,Xiao Yue,Zhengwei Huang,Ying Huang,Xin Pan,Chuanbin Wu
Poly-L-lysine (PLL) is a promising candidate for the treatment of pulmonary infection with lower occurrence of drug-resistance due to its unique antibacterial mechanisms. Dry powder inhalations (DPIs) are considered as the first choice for formulating PLL to treat pulmonary infection on account of direct delivery and satisfactory stability. However, hygroscopicity of PLL limited its therapeutic effect on pulmonary infection when PLL developed into DPIs. The hygroscopicity caused two obstacles including the low drug deposition in the lower respiratory tract and undesirable aerosolization performance deterioration. In this study, PLL was co-spray-dried with L-leucine (LL) to achieve moisture-resistance and desirable aerosolization performance. The ratio of PLL and LL was optimized to obtain particles with different morphology, hygroscopicity and aerodynamic properties. The obtained PLL DPIs were suitable for inhalation with a corrugated surface formed by hydrophobic LL. The anti-hygroscopicity, aerosolization performance and rheological properties of P 2 DPIs were optimal when PLL:LL = 85:15. The DPIs particles were stable after being stored at high relative humidity (60 ± 5%), and their superiority in treating pulmonary infections was also proved by in vitro and in vivo experiments. The established PLL DPIs were proved to be a feasible and desirable approach to treat pulmonary infections.
研究领域:
药学
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呼吸医学
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材料科学
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DOI
PubMed
高影响因子
BMC Veterinary Research
·
2015
·Vol. 11
·期 1
·1-7
·
IF 1.777
Qu Ying,Qiu Zhenzhen,Cao Changfu,Lu Yan,Sun Meizhen,Liang Chaoping,Zeng Zhenling
Background Marbofloxacin is a third-generation fluoroquinolone developed solely for veterinary medicine with a broad spectrum of antibacterial activity against some Gram-positive and most Gram-negative bacteria, including the bovine respiratory tract pathogen, Pasteurella multocida. The objective of our study was to elucidate the pharmacokinetics and pharmacodynamics of marbofloxacin in a Pasteurella multocida infected murine lung model, and to estimate the magnitudes of pharmacokinetics-pharmacodynamics parameters associated with various effects.Results The pharmacokinetic studies revealed marbofloxacin kinetics in infected mice were linear over a dose ranging from 1.25 to 10 mg/kg of body weight. The protein binding in the plasma of neutropenic infected mice was 29.77 %. The magnitudes of the ratio of the free-drug area under the concentration-time curve over 24 h to MIC (fAUC0-24h/MIC) associated with static effect, a 2 log10 reduction and a 3 log10 reduction of bacterial counts were 40.84, 139.34, and 278.08 h, respectively.Conclusion sBased on the dose range study, marbofloxacin exhibited concentration-dependent killing and the fAUC/MIC was the PK/PD index that correlated best with efficacy (R2 = 83 %). On the basis of a bactericidal effect goal of fAUC0-24h/MIC of 278.08 h, if marbofloxacin is used for the treatment of P. multocida serious lung infection with an MIC90 of 0.12 μg/ml, the current dose (2 mg/kg) would fail to achieve a bactericidal effect. It would benefit from higher doses (4 ~ 6 mg/kg) than those commonly used in clinical practice.
研究领域:
兽医学
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微生物学
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药物研究
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DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2018
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IF 4.019
Zeng Dongping,Sun Meizhen,Lin Zhoumeng,Li Miao,Gehring Ronette,Zeng Zhenling
Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle.
研究领域:
兽医学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY
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2019
·
IF 4.067
Jingjing Liu,Jie Meng,Liming Cao,Yuanyuan Li,Pengbo Deng,Pinhua Pan,Chengping Hu,Huaping Yang
Treatment of chronic lung infection becomes a great challenge due to the drug resistant bacteria. In this scenario, evolving a new drug based on lipid metal conjugation loaded with potential antibiotic provides better drug delivery. In this study, ciprofloxacin loaded selenium-lipid nanoparticle (CxLSENPs) is produced in a novel route and its antimicrobial properties were tested against clinically important Gram-negative P. aeruginosa . The synthesized CxLSENPs was characterized by biophysical techniques (UV, Fluorescence spectroscopy , Raman spectroscopy , FTIR , FESEM , HRTEM and Zeta potential). Raman spectra coupled with FTIR spectra confirmed the possible interaction of lipid components in the NPs. HRTEM analysis confirmed the spherical shape of NPs. CxLSENPs recorded greater antibacterial effects on P. aeruginosa . A drastic reduction in the count of P. aeruginosa was observed after treatment with CxLSENPs. In order to further confirm the antibacterial efficiency, the live/dead cell assay was carried out. Live/dead analysis helps us to investigate the viability of bacterial cells . The number of dead bacterial cells was significantly higher in CxLSENPs treated groups when compare to the control. Furthermore, CxLSENPs increased the antioxidant enzyme activities (SOD, GPx, CAT and LPO) in mouse and protected the liver damage from bacterial infection. This study concludes that the developed CxLSENPs might be employed as strong antimicrobial and antioxidant agents for treating lung infection or interstitial lung diseases .
研究领域:
药剂学
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微生物学
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纳米医学
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产品关联
DOI
PubMed
高影响因子
Evidence-based Complementary and Alternative Medicine
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2018
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IF 2.064
Peng Pang,Ke Zheng,Sizhi Wu,Huachong Xu,Li Deng,Yucong Shi,Xiaoyin Chen
The objective of this study is to investigate the effects of baicalin on controlling the pulmonary infection and improving the prognosis in influenza A virus (IAV) infection. PCR and western blot were used to measure the changes of some key factors in RLRs signaling pathway. MSD electrochemiluminescence was used to measure the expression of pulmonary inflammatory cytokines including IFN-γ, TNF-α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, and KC/GRO. Flow cytometry was used to detect the proportion of Th1, Th2, Th17, and Treg. The results showed that IAV infection led to low body weight and high viral load and high expression of RIG-I, IRF3, IRF7, and NF-κB mRNA, as well as RIG-I and NF-κB p65 protein. However, baicalin reduced the rate of body weight loss, inhibited virus replication, and downregulated the key factors of the RLRs signaling pathway. Besides, baicalin reduced the high expression inflammatory cytokines in lung and decreased the ratios of Th1/Th2 and Th17/Treg to arouse a brief but not overviolent inflammatory response. Therefore, baicalin activated a balanced host inflammatory response to limit immunopathologic injury, which was helpful to the improvement of clinical and survival outcomes.
研究领域:
药理学
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免疫学
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病毒学
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DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
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2024
·
IF 5.4
Huan Sun,Shen Yan,Chaojie Wu,Jingye Ma,Kangwei Lu,Xi Cheng,Wenqi Yan,Shengyu Zhang,Xiao Dong Chen,Winston Duo Wu
Active pharmaceutical ingredient (API) embedded dry powder for inhalation (AeDPI) shows higher drug loading and delivery dose for directly treating various lung infections. Inspired by the dandelion, we propose a novel kind of AeDPI microparticle structure fabricated by spray freeze drying technology, which would potentially enhance the alveoli deposition efficiency. When inhaling, such microparticles are expected to be easily broken-up into fragments containing API that acts as ‘seed’ and could be delivered to alveoli aided by the low density ‘pappus’ composed of excipient. Herein, itraconazole (ITZ), a first-line drug for treating pulmonary aspergillosis, was selected as model API. TPGS, an amphiphilic surfactant, was used to achieve stable primary ITZ nanocrystal (INc) suspensions for spray freeze drying. A series of microparticles were prepared, and the dandelion-like structure was successfully achieved. The effects of feed liquid compositions and freezing parameters on the microparticle size, morphology, surface energy, crystal properties and in vitro aerosol performance were systematically investigated. The optimal sample (SF (-50) D-INc 7 Leu 3 -2) in one-way experiment showed the highest fine particle fraction of ~ 68.96% and extra fine particle fraction of ~ 36.87%, equivalently ~ 4.60 mg and ~ 2.46 mg could reach the lung and alveoli, respectively, when inhaling 10 mg dry powders. The response surface methodology (RSM) analysis provided the optimized design space for fabricating microparticles with higher deep lung deposition performance. This study demonstrates the advantages of AeDPI microparticle with dandelion-like structure on promoting the delivery efficiency of high-dose drug to the deep lung.
研究领域:
药学
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生物医学工程
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材料科学
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呼吸医学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2022
·
IF 16.744
Qianqian Guo,Yongjun Luo,Honglei Guo,Tianyu Lan,Shengquan Wang,Kedui Geng,Xin Lu,Ling Tao,Xiangchun Shen
Lung infection associated with drug-resistant P. aeruginosa and their wide spread have become a serious problem to public health. Effective antibacterial strategy without antibiotics must be developed for treatment of these infections. To combat pneumonia infected by multidrug-resistant P. aeruginosa (MRPA), a novel antibacterial nanocomoposite of [email protected] r PEGMA was prepared. [email protected] r PEGMA could bind with P. aeruginosa through the interaction betweeen PBA r PEGMA and bacteria proved by alizarin red assay. The nanocomposite could relieve inflammtory response in MRPA-infected macrophages by downregulating MAPK and NF κ B signal-transduction pathways. [email protected] r PEGMA showed well photo-thermal conversion capacity leading to the temperature increasing from 20 to 80 °C under near-infrared (NIR) irradiation for 5 min. The photo-thermal capacity endowed the nanocomposites efficient antibacterial activity against MRPA. Simultaneously, [email protected] r PEGMA with NIR irradiation could kill biofilm bacteria while traditional antibiotics were non-effetive. [email protected] r PEGMA with NIR irradiation could treat MRPA-related lung infection. The nanocomposite with NIR reduced the inflammatory cytokines of TNF-α, IL-1β, and IL-6 by downregulating the MAPK signal pathway in bronchoalveolar lavage fluids. The number of P. aeruginosa and expression of NF-κB p65 in lung also decreased. Above all, our study provides a non-antibiotic therapeutic strategy in clinical application and demonstrated that [email protected] r PEGMA with NIR irradiation showed a potential treatment for drug-resistant P. aeruginosa infection in Lung.
研究领域:
纳米技术
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微生物学
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药理学
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传染病学
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DOI
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Shihui Yu,Jieyi Pan,Mao Xu,Yujun Chen,Pengyu Li,Haiyan Hu
Multidrug-resistant P. aeruginosa (MDR- P. aeruginosa ), associated with elevated morbidity, mortality, and readmission rates, presents a formidable challenge to eradication due to its robust resistance to antimicrobial agents and biofilm formation. Herein, self-assembling nanoparticles (NO-PE/PLL NPs) comprised of NO donor-conjugated γ-polyglutamic acid (GSNO-PGA), epsilon-poly- l -lysine (PLL) and colistin were fabricated. The negatively charged NO-PE/PLL NPs exhibited effective penetration through airway mucus, reaching the infection site where GSNO-PGA released NO in response to glutathione within biofilm. PLL worked synergistically with colistin (fractional inhibitory concentration index: 0.281), reducing the minimum inhibitory concentration (MIC) of colistin from 2 to 0.5 μg/mL. Benefiting from this synergistic antibacterial action and NO-mediated biofilm disruption, NO-PE/PLL NPs achieved a 99.99 % eradication rate against MDR- P. aeruginosa biofilms. Additionally, NO-PE/PLL NPs efficiently inhibited endotoxins-stimulated inflammation response. In a chronic pulmonary infection model, NO-PE/PLL NPs displayed the highest eradication efficiency (99.78 %) to infected mice, while having no adverse effects on their major organs or pulmonary functions. These results highlight NO-PE/PLL NPs as a promising therapeutic strategy for treating recalcitrant infections caused by MDR- P. aeruginosa biofilms.
研究领域:
药学
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纳米技术
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微生物学
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传染病学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
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2023
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IF 5
Yanchao Liu,Yingying Ma,Linying Xue,Wenhao Guan,Yancai Wang
To better address the etiology of lung infections and the delivery limitations that exist, the development of a pulmonary inhalation formulation with antibacterial and mucolytic effects is necessary. This study was conducted using multidrug dry powder in one step to treat pulmonary infections. The optimal ratio of drugs for antibacterial activity was determined by the checkerboard method. The appearance of the dry powder for inhalation was yellow, and SEM images revealed that the powder was sphere-like, with a controlled particle size of 6 μm or less, good dispersion and a wrinkled and depressed surface. Confocal laser scanning microscopy (CLSM) images revealed that curcumin nanoparticles were uniformly distributed in the dry powder inhalation. Both the twin stage impinger (TSI) and Next Generation Impactor (NGI) showed that the multidrug powder has excellent aerosol performance, with a fine particle fraction (FPF) ranging from 68.93% to 77.75%. The multidrug powder presented satisfactory antibacterial effects at low doses, thereby reducing systemic toxicity due to high-dose delivery. In vitro drug release experiments also demonstrated that the powder had great release properties. In conclusion, a multidrug codelivery system of curcumin nanosuspensions and ciprofloxacin with N-acetylcysteine dry powder was prepared that was suitable for lung infection therapy.
研究领域:
药学
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肺科学
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纳米技术
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药物递送系统
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产品关联
DOI
高影响因子
Advanced Science
·
2023
·Vol. 11
·期 9
·2307173
·
IF 15.1
Jingzhi Yang,Yami Ran,Shaopeng Liu,Chenhao Ren,Yuntian Lou,Pengfei Ju,Guoliang Li,Xiaogang Li,Dawei Zhang
Antimicrobial resistance (AMR) from pathogenic bacterial biofilms has become a global health issue while developing novel antimicrobials is inefficient and costly. Combining existing multiple drugs with enhanced efficacy and/or reduced toxicity may be a promising approach to treat AMR. D-amino acids mixtures coupled with antibiotics can provide new therapies for drug-resistance infection with reduced toxicity by lower drug dosage requirements. However, iterative trial-and-error experiments are not tenable to prioritize credible drug formulations, owing to the extremely large number of possible combinations. Herein, a new avenue is provide to accelerate the exploration of desirable antimicrobial formulations via high-throughput screening and machine learning optimization. Such an intelligent method can navigate the large search space and rapidly identify the D-amino acid mixtures with the highest anti-biofilm efficiency and also the synergisms between D-amino acid mixtures and antibiotics. The optimized drug cocktails exhibit high antimicrobial efficacy while remaining non-toxic, which is demonstrated not only from in vitro assessments but also the first in vivo study using a lung infection mouse model.
研究领域:
药理学
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微生物学
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机器学习
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生物技术
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
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2024
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IF 12.8
Jian He,Xiuhui Lin,Dongxiao Zhang,Huiqun Hu,Xiaoyuan Chen,Feng Xu,Min Zhou
The hypometabolic and nutrient-limiting condition of dormant bacteria inside biofilms reduces their susceptibility to antibacterial agents, making the treatment of biofilm-dominating chronic infections difficult. Herein, we demonstrate an intratracheal aerosolized maltohexaose-modified catalase-gallium integrated nanosystem that can ‘wake up’ dormant Pseudomonas aeruginosa biofilm to increase the metabolism and nutritional iron demand by reconciling the oxygen gradient. The activated bacteria then enhance suicidal gallium uptake since gallium acts as a 'Trojan horse' to mimic iron. The internalized gallium ions disrupt biofilms by interfering with the physiological processes of iron ion acquisition and utilization, biofilm formation, and quorum sensing. Furthermore, aerosol microsprayer administration and bacteria-specific maltohexaose modification enable accumulation at biofilm-infected lung and targeted release of gallium into bacteria to improve the therapeutic effect. This work provides a potential strategy for treating infection by reversing the dormant biofilm's resistance condition.
研究领域:
微生物学
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药学
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纳米技术
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传染病学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）