Population Pharmacokinetics of Atorvastatin in High-Altitude and Plain Patients with Hyperlipidemic.

The pharmacokinetic (PK) characteristics of drugs were altered under high-altitude hypoxia. We aim to describe the population PK of atorvastatin (ATV) to identify patient characteristics that are predictive of variability in the PK parameters of the ATV and investigate the effects of high-altitude hypoxia on the blood concentration of ATV in patients with hyperlipidemia. A total of 160 plasma concentrations were collected from 40 patients with hyperlipidemia in plateau areas and 40 in plain areas. The population pharmacokinetic model of patients with hyperlipidemia in plateau and plain areas of China was established by a nonlinear mixed-effects model. The PK of ATV were described by a 1-compartment model with first-order elimination. The main PK parameters of ATV were the first-order absorption rate (0.76 hour-1 fixed); clearance (174.22 L/h) and apparent volume of distribution (1119.62 L). The values of area and age were identified as significant covariates for the clearance, area, age, and urea for the volume of distribution. The steady-state peak concentration in the plateau area was higher than that in the plain area. This study may suggest dose reduction is necessary for patients with hyperlipidemia in high altitudes.

[The research progress of high altitude environment-associated chronic obstructive pulmonary disease and therapeutic drugs].

The plateau environment is characterized by low oxygen, low air pressure, low temperature, and strong ultraviolet rays, etc. Chronic obstructive pulmonary disease (COPD) is a preventable and treatable chronic lung disease. High altitude environment increases COPD prevalence, clinical manifestation and mortality. The therapeutic window of theophylline drugs for COPD is narrow, and the high altitude environment has an influence on the pharmacokinetics of the drugs. This review summarizes the differences in the prevalence, mortality, clinical manifestation and clinical symptoms of COPD in the plateau and plain, providing a basis for identifying the risk factors of COPD in the plateau areas. The effects of plateau hypoxic environment on the pharmacokinetics of COPD drugs were also discussed. It can provide a rationale for more effective prevention and treatment of COPD at high altitude.

Repurposing Sitafloxacin, Prulifloxacin, Tosufloxacin, and Sisomicin as Antimicrobials Against Biofilm and Persister Cells of Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a ubiquitous bacterium found in hospitals and the surrounding environment. The ability of P. aeruginosa to form biofilms confers high-level resistance to antibiotics, and the persister cells formed in the presence of high antibacterial drug concentrations make P. aeruginosa-related infections more refractory. Further, there rarely is an effective antimicrobial alternative when biofilm- and persister cell-targeting treatment fails. Using a high-throughput screening assay, we previously identified fluoroquinolones sitafloxacin, prulifloxacin, and tosufloxacin as well as aminoglycoside sisomicin among FDA-approved drugs with significant bactericidal activity against P. aeruginosa. In addition, in our current study, these antibiotics exhibited an effective time- and dose-dependent eradication effects against the preformed biofilms of P. aeruginosa at the concentrations of 2-4 µM. These agents also exhibited bactericidal efficacy against CCCP-induced P. aeruginosa persister cells with the viable cell count decreased from 9.14 log10 CFU/mL to 6.15 (sitafloxacin), 7.59 (prulifloxacin), 4.27 (tosufloxacin), and 6.17 (sisomicin) log10 CFU/mL, respectively, following 4 h of treatment. Furthermore, sisomicin was also effective against conventional antibiotics induced persister cells in a time-dependent manner within 24 h. In addition, we confirmed the in vivo anti-biofilm efficacy of the identified antibiotics in a subcutaneous implantation biofilm-related infection model. Tosufloxacin exhibited the greatest in vivo bactericidal activity against P. aeruginosa biofilms with a reduction of 4.54 ΔLog10 CFU/mL compared to the vehicle group, followed by prulifloxacin, sitafloxacin, and sisomicin. Taken together, our results indicate that sitafloxacin, prulifloxacin, tosufloxacin, and sisomicin have great potential as alternatives for the treatment of refractory infections caused by P. aeruginosa biofilms and persister cells.

Inhibitory effects of 1,3-diaminopropane on the biofilm formation of Pseudomonas aeruginosa via interaction with quorum sensing system. / 1,3-丙二胺通过群体密度感应系统对铜绿假单胞菌生物膜形成的抑制作用.

OBJECTIVES: To study the inhibitory effects of 1,3-diaminopropane on the biofilm formation of Pseudomonas aeruginosa and the underlying mechanisms. METHODS: The experiment was divided into an experimental group and a control group. Crystal violet staining was used to examine the inhibitory effects of 1,3-diaminopropane on the biofilm formation of Pseudomonas aeruginosa, and the biofilm formation was compared between the 2 groups.Initial adherence inhibition assay and swimming plate assay were used to determine the inhibitory effects of 1,3-diaminopropane on the initial adherence and swimming motility of Pseudomonas aeruginosa,and the quantification of adhered cells and swimming diameter were compared between the 2 groups. Meanwhile, Western blotting was used to detect the Flagellin production of Pseudomonas aeruginosa; real-time RT-PCR was used to detect the quorum sensing system relative genes and flagellum regulative related genes expression in the 2 groups. Finally, molecular docking assay was used to calculate the interaction between 1,3-diaminopropane and LasI. RESULTS: Compared with the control group, the biofilm formation of Pseudomonas aeruginosa was significantly inhibited in the experimental group in a dose-dependent manner (t=6.07, P<0.01).Compared with the control group, the initial adherence of Pseudomonas aeruginosa could significantly inhibit from (0.890±0.389)×106 to (0.245±0.076)×106 CFU/mL (t=3.257, P<0.05) in the experimental group (2.0 mmol/L).Compared with the control group, the swimming motility of Pseudomonas aeruginosa flagellar mediation could also inhibit in the experimental group (2.0 mmol/L). The swimming motility diameter was from (1.840±0.144) to (0.756±0.222) cm (t=7.099, P<0.01). Compared with the control group, the Flagellin production was inhibited in the experimental group. Finally, the molecular docking assay showed that the potential target of 1,3-diaminopropane was LasI. CONCLUSIONS: 1,3-diaminopropane can significantly inhibit the biofilm formation of Pseudomonas aeruginosa, which potentially targets LasI protein.

Drug Repurposing: In vitro and in vivo Antimicrobial and Antibiofilm Effects of Bithionol Against Enterococcus faecalis and Enterococcus faecium.

Widespread antibiotic resistance has been reported in enterococcal pathogens that cause life-threatening infections. Enterococci species rapidly acquire resistance and the pace of new antibiotic development is slow. Drug repurposing is a promising approach in solving this problem. Bithionol (BT) is a clinically approved anthelminthic drug. In this study, we found that BT showed significant antimicrobial and antibiofilm effects against Enterococcus faecalis and vancomycin-resistant Entercococcus faecium in vitro, in a dose-dependent manner, by disrupting the integrity of the bacterial cell membranes. Moreover, BT effectively reduced the bacterial load in mouse organs when combined with conventional antibiotics in a peritonitis infection model. Thus, BT has shown potential as a therapeutic agent against E. faecalis- and vancomycin-resistant E. faecium-related infections.

Drug repurposing: Antimicrobial and antibiofilm effects of penfluridol against Enterococcus faecalis.

The bacterium Enterococcus faecalis has increasingly attracted global attention as an important opportunistic pathogen due to its ability to form biofilms that are known to increase drug resistance. However, there are still no effective antibiofilm drugs in clinical settings. Here, by drug repurposing, we investigated the antibacterial activity of penfluridol (PF), an oral long-acting antipsychotic approved by the FDA, against E. faecalis type strain and its clinical isolates. It was found that PF inhibited the growth of E. faecalis planktonic cells with the MIC and MBC of 7.81 µg/ml and 15.63 ~ 62.50 µg/ml, respectively. Moreover, PF could significantly prevent the biofilm formation of E. faecalis at the concentration of 1 × MIC. Furthermore, PF significantly eradicated 24 h pre-formed biofilms of E. faecalis in a dose-dependent manner, with a concentration range of 1 × MIC to 8 × MIC. Here, through the checkerboard method with other tested conventional antibiotics, we also determined that gentamycin, penicillin G, and amikacin showed partial synergistic antibacterial effects with PF. Also, PF showed almost no hemolysis on human erythrocytes. In a mouse peritonitis model, a single dose of 20 mg/kg of PF treatment could significantly reduce the bacterial colonization in the liver (~5-fold reduction) and spleen (~3-fold reduction). In conclusion, these findings indicated that after structural optimization, PF has the potential as a new antibacterial agent against E. faecalis.

High-Throughput Identification of Antibacterials Against Pseudomonas aeruginosa.

Antibiotic resistance is a growing public health concern, though the constant development of new antibiotics. The combination of high-throughput screening and drug repurposing is an effective way to develop new therapeutic uses of drugs. In this study, we screened a drug library consisting of 1,573 drugs already approved by the Food and Drug Administration and 903 drugs from the natural product library, to identify antimicrobials against Pseudomonas aeruginosa. A high-throughput screening assay based on microtiter plate was used to screen 39 drugs that inhibit the planktonic or biofilm formation of P. aeruginosa while most of them are antibiotics. The antimicrobial activities of these drugs were evaluated by phenotypic analysis. Further studies showed the combined therapy of tetracycline antibiotics demeclocycline hydrochloride (DMCT) and the novel antimicrobial peptide SAAP-148 has an effective synergistic antibacterial effect on P. aeruginosa PAO1 and P. aeruginosa ATCC27853. Moreover, the time-kill curve assay and murine model of cutaneous abscesses further confirmed the synergistic effect. In addition, the combination of DMCT and SAAP-148 has the potential to combat clinically isolated multidrug-resistant (MDR) P. aeruginosa strains. Our results clearly indicate that DMCT and SAAP-148 combined therapy could be an effective method to combat MDR P. aeruginosa-related infections.

Repurposing Antispasmodic Agent Otilonium Bromide for Treatment of Staphylococcus aureus Infections.

Recently, the problem of bacterial resistance has been brought into focus, which makes the development of new antibiotics become a necessity. Compared with traditional development approaches, drug repurposing provides a faster and more effective approach to find new antimicrobial agents. In this study, we found that antispasmodic agent otilonium bromide had strong antibacterial ability and bactericidal activity against Staphylococcus aureus, with minimal inhibitory concentrations (MICs) of 4-8 µg/ml, and bacteria could be killed completely after treatment with 2× MIC of otilonium bromide for 5 h. Furthermore, it had a potent effect on eradicating biofilm at concentrations ranging from 16 to 64 µg/ml. At the same time, it had low tendency to develop resistance and possessed limited cytotoxicity. In the methicillin-resistant S. aureus-infected mouse peritonitis model, it was also effective to cure mice and improve their survival rate. In addition, we observed that otilonium bromide changed the permeability of bacterial membrane and caused membrane damage, and it is probably the antibacterial mechanism of otilonium bromide. Taken together, our results indicated that otilonium bromide could be a new antimicrobial agent to treat S. aureus infections more safely and efficiently.

Insights into idarubicin antimicrobial activity against methicillin-resistant Staphylococcus aureus.

BACKGROUND: MRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem. OBJECTIVE: Idarubicin was profiled to assess its antimicrobial effects in vitro and in vivo, and the underlying mechanisms. METHODS: We investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection in vivo. RESULTS: Idarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects. CONCLUSIONS: Idarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.

Neuroprotection against Aß25-35-induced apoptosis by Salvia miltiorrhiza extract in SH-SY5Y cells.

The neurotoxicity of ß-amyloid protein (Aß) contributes significantly to the pathogenesis of Alzheimer's disease (AD), and hence the attractive therapeutic strategies focusing on the modulation of Aß-induced neurotoxicity are warranted. The present study aims to investigate the neuroprotection and underlying mechanisms by which Salvia miltiorrhiza Bunge (Lamiaceae) extract (SME) protects against Aß25-35-induced apoptosis in SH-SY5Y cells. 2h Pre-treatment of SH-SY5Y cells with SME (0.01, 0.1 or 0.2mg raw herb/ml) concentration-dependently attenuated Aß25-35-induced cell death, as evidenced by the increase in cell viability and decrease in neuronal apoptosis. In addition, SME suppressed the increased intracellular reactive oxygen species levels, decreased the protein expression of cleaved caspase-3, cytosolic cytochrome c, and Bax/Bcl-2 ratio. These findings taken together suggest that SME provides substantial neuroprotection against Aß25-35-induced neurotoxicity in SH-SY5Y cells, at least in part, via inhibiting oxidative stress and attenuating the mitochondria-dependent apoptotic pathway. The approach used in this study may also be useful for the screening of therapeutic agents for AD and other related neurodegenerative disease.