Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Recent Advance of Nanomaterial-Mediated Tumor Therapies in the Past Five Years.

Cancer has posed a major threat to human life and health with a rapidly increasing number of patients. The complexity and refractory of tumors have brought great challenges to tumor treatment. In recent years, nanomaterials and nanotechnology have attracted more attention and greatly improved the efficiency of tumor therapies and significantly prolonged the survival period, whether for traditional tumor treatment methods such as radiotherapy, or emerging methods, such as phototherapy and immunotherapy, sonodynamic therapy, chemodynamic therapy and RNA interference therapeutics. Various monotherapies have obtained positive results, while combination therapies are further proposed to prevent incomplete eradication and recurrence of tumors, strengthen tumor killing efficacy with minimal side effects. In view of the complementary promotion effects between different therapies, it is vital to utilize nanomaterials as the link between monotherapies to achieve synergistic performance. Further development of nanomaterials with efficient tumor-killing effect and better biosafety is more in line with the needs of clinical treatment. In a word, the development of nanomaterials provides a promising way for tumor treatment, and here we will review the emerging nanomaterials towards radiotherapy, phototherapy and immunotherapy, and summarized the developed nanocarriers applied for the tumor combination therapies in the past 5 years, besides, the advances of some other novel therapies such as sonodynamic therapy, chemodynamic therapy, and RNA interference therapeutics have also been mentioned.

Bushen-Tiansui Formula Improves Cognitive Functions in an Aß 1-42 Fibril-Infused Rat Model of Alzheimer's Disease.

Bushen-Tiansui Formula (BTF) was empirically updated from a classical prescription named Kong-Sheng-Zhen-Zhong pill. It is based on the traditional Chinese medicine theory of the mutual relationship between the brain and the kidney and is intended to treat neurodegenerative diseases. This formulation has been used for several years to treat patients with Alzheimer's disease- (AD-) like symptoms in our clinical department. However, the medicinal ingredients and the mechanisms by which BTF improves cognition and memory functions have not been characterized. In this study, we used UPLC-MS to generate a chromatographic fingerprinting of BTF and identified five possible active ingredients, including stilbene glycoside; epimedin A1, B, and C; and icariin. We also showed that oral administration of BTF reversed the cognitive defects in an Aß 1-42 fibril-infused rat model of AD, protected synaptic ultrastructure in the CA1 region, and restored the expression of BDNF, synaptotagmin (Syt), and PSD95. These effects likely occurred through the BDNF-activated receptor tyrosine kinase B (TrkB)/Akt/CREB signaling pathway. Furthermore, BTF exhibited no short-term or chronic toxicity in rats. Together, these results provided a scientific support for the clinical use of BTF to improve learning and memory in patients with AD.

Topical treatments for diabetic neuropathic pain.

Diabetic neuropathic pain (DNP) has a huge impact on quality of life and can be difficult to treat. Oral treatment is the most frequently used method for DNP, but its use is often limited by systemic side effects. Topical use of drugs as an alternative option for DNP treatment is currently gaining interest. In the present review, a summary is provided of the available agents for topical use in patients with DNP, including lidocaine plasters or patches, capsaicin cream, gel or patches, amitriptyline cream, clonidine gel, ketamine cream, extracts from medicinal plants including nutmeg extracts and Citrullus colocynthis extract oil, and certain compounded topical analgesics. Furthermore, the potential efficacy of these treatments is addressed according to the available clinical research literature. It has been indicated that these topical drugs have the potential to be valuable additional options for the management of DNP, with adequate safety and continuous long-term treatment efficacy. Compounded topical agents are also effective and safe for patients with DNP and could be another area worthy of further investigation based on the strategy of using low-dose, complementary therapies for DNP. The findings indicate that developing topical drugs acting on different targets in the process of DNP is a valuable area of future research.

Supplement intervention associated with nutritional deficiencies in autism spectrum disorders: a systematic review.

PURPOSE: Nutritional supplements have been used for correction of deficiencies that may occur in patient with autism spectrum disorder (ASD) and to improve core symptoms. We aim to provide current best evidence about supplements for nutritional deficiencies and core symptoms in children with ASD and to evaluate the effectiveness and safety. METHODS: A systematic literature search of scientific databases was performed to retrieve relevant randomized controlled trials. Risk of bias was assessed for each study. RESULTS: 18 randomized controlled trials of five supplements were included. B6/Mg was not helpful for improving ASD symptoms (seven RCTs). Two RCTs of methyl B12 reported some improvement in ASD severity but the effects on the correction of deficiencies were inconclusive. Two RCTs of vitamin D3 both reported increased levels of mean 25(OH)D in serum but inconsistent results in behavioral outcomes. Omega-3 fatty acid supplementation did not affect ASD behaviors but may correct deficiencies (six RCTs). One RCT of folinic acid reported positive results in improving ASD symptoms measured by various behavioral scales. CONCLUSIONS: Current evidence for the use of supplements for correcting nutritional deficiencies in children with ASD and to improve the symptoms is little. More studies are needed.

The Ethanol Extract of Licorice (Glycyrrhiza uralensis) Protects against Triptolide-Induced Oxidative Stress through Activation of Nrf2.

To investigate the potential role of nuclear factor erythroid 2-related factor 2 (Nrf2) in licorice ethanol extract (LEE) against triptolide- (TP-) induced hepatotoxicity, HepG2 cells were exposed to LEE (30, 60, and 90 mg·L-1) for 12 h and then treated with TP (50 nM) for 24 h. Besides, an acute liver injury model was established in ICR mice by a single dose of TP (1.0 mg·kg-1, i.p.). Relevant oxidant and antioxidant mediators were analyzed. TP led to an obvious oxidative stress as evidenced by increasing levels of ROS and decreasing GSH contents in HepG2 cells. In vitro results were likely to hold true in in vivo experiments. LEE protected against TP-induced oxidative stress in both in vitro and in vivo conditions. Furthermore, the decreased level of Nrf2 in the TP-treated group was observed. The mRNA levels of downstream genes decreased as well in ICR mice liver, whereas they increased in HepG2 cells. In contrast, LEE pretreatment significantly increased the level of Nrf2 and its downstream genes. LEE protects against TP-induced oxidative stress partly via the activation of Nrf2 pathway.

The anti-inflammatory effect of Andrographis paniculata (Burm. f.) Nees on pelvic inflammatory disease in rats through down-regulation of the NF-κB pathway.

BACKGROUND: Andrographis paniculata (Burm. f.) Nees (APN), a principal constituent of a famous traditional Chinese medicine Fukeqianjin tablet which is used for the treatment of pelvic inflammatory disease (PID), has been reported to have anti-inflammatory effect in vitro. However, whether it has pharmacological effect on PID in vivo is unclear. Therefore, the aim of this study is to test the anti-inflammatory effect of APN and illuminate a potential mechanism. METHODS: Thirty-six female specific pathogen-free SD rats were randomly divided into control group, PID group, APN1 group, APN2 group, APN3 group and prednisone group. Pathogen-induced PID rats were constructed. The APN1, APN2 and APN3 group rats were orally administrated with APN extract at different levels. The prednisone group rats were administrated with prednisone. Eight days after the first infection, the histological examination of upper genital tract was carried out, and enzyme-linked immunosorbent assay (ELISA) was carried out using homogenate of the uterus and fallopian tube. Furthermore, immunohistochemical evaluations of NF-κB p65 and IκB-α in uterus was conducted. RESULTS: APN obviously suppressed the infiltrations of neutrophils and lymphocytes, and it could significantly reduce the excessive production of cytokines and chemokines including IL-1ß, IL-6, CXCL-1, MCP-1 and RANTES in a dose-dependent manner. Furthermore, APN could block the pathogen-induced activation of NF-κB pathway. CONCLUSION: APN showed potent anti-inflammatory effect on pathogen-induced PID in rats, with a potential mechanism of inhibiting the NF-κB signal pathway.

Preparation, characterization, and evaluation of antitumor effect of Brucea javanica oil cationic nanoemulsions.

The purpose of this study was to prepare Brucea javanica oil cationic nanoemulsions (BJO-CN) with BJO as drug as well as oil phase and chitosan as cationic inducer, to explore the practical suitability of using cationic nanoemulsions for oral delivery of mixed oil, and to test its bioavailability and antitumor effect. BJO-CN was prepared by chitosan solution stirring method and then characterized physicochemically. The obtained BJO-CN had a spherical morphology with a positive zeta potential of 18.9 mV and an average particle size of 42.36 nm, showing high colloidal stability. The drug loading of BJO-CN was 91.83 mg·mL(-1), determined by high-performance liquid chromatography with precolumn derivatization. Pharmacokinetic studies revealed that, compared with BJO emulsion (BJO-E) (the dosage of BJO-CN and BJO-E was equal to 505 mg·kg(-1), calculated by oleic acid), BJO-CN exhibited a significant increase in the area under the plasma drug concentration-time curve over the period of 24 hours and relative bioavailability was 1.6-fold. Furthermore, the antitumor effect of BJO-CN in the orthotopic mouse model of lung cancer was evaluated by recording the median survival time and the weight of lung tissue with tumor, hematoxylin and eosin staining, and immunohistochemical technique. Results of anticancer experiments illustrated that, even though the administrated dosage in the BJO-CN group was half of that in the BJO-E group, BJO-CN exhibited similar antitumor effect to BJO-E. Moreover, BJO-CN had good synergistic effect in combination therapy with vinorelbine. These results suggested that cationic nanoemulsions are an effective and promising delivery system to enhance the oral bioavailability and anticancer effect of BJO.

Metabolomic Study on the Preventive Effect of Patrinia scabiosaefolia Fisch on Multipathogen Induced Pelvic Inflammatory Disease in Rats.

Patrinia scabiosaefolia Fisch (PSF), a well-known traditional Chinese medicine (TCM), has been used as a "heat-clearing and detoxifying" agent. The present study was to illustrate the preventive effect of PSF on pelvic inflammatory disease (PID) in rats. The PID model was constructed by multipathogen infection of the upper genital tract with reference to the method previously reported. Urine metabolomic analysis was conducted with a GC-MS coupled with derivatization method. In this study, PID rats showed obvious infiltration of inflammatory cells and elevated expression of cytokines (IL-1ß and IL-6) in upper genital tract, compared with control rats. Sixteen differentiating metabolites contributed to the alteration of metabolic profile in PID rats, including two amino acids, three fat acids, nine organic acids, and two types of sugars. The rats, infected by multipathogen and administered with PSF, showed decreased infiltration of inflammatory cells and lowered expression of cytokines in upper genital tract, compared with PID rats. Meanwhile, PSF intervened in the PID-associated alterations in TCA cycle, sugar metabolism, amino acid metabolism, and other uncertain metabolic pathways. These results indicate that PSF has preventive effect on multipathogen induced PID and holistic interventional effect on disease-associated metabolomic change.

Puerarin attenuates calcification of vascular smooth muscle cells.

Several studies demonstrate that estradiol can prevent arterial calcification. However, little is known regarding the effect of puerarin, a phytoestrogen extracted from Radix Puerariae, on arterial calcification. The aim of the present study was to determine whether puerarin reduced osteoblastic differentiation of calcifying vascular smooth muscle cells (CVSMCs). The CVSMCs were isolated from mice aorta and treated with different concentrations of puerarin. The alkaline phosphatase (ALP) activity, osteocalcin secretion and Runx2 expression were determined. To examine whether estrogen receptors (ERs) PI3K and Akt play a role in this effect, ICI182789, phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, or the Akt inhibitor, 1L-6-hydroxymethyl-chiro-inositol 2-(R)-2-O-methyl-3-O-octadecylcarbonate (HIMO) was used. Our results showed puerarin could inhibit ALP activity, osteocalcin secretion and Runx2 expression in CVSMCs. Puerarin could induce the activation of Akt. Furthermore, pretreatment of ICI182780, LY294002, HIMO could abolish the effect of puerarin on ALP activity in CVSMCs. Our experiment demonstrated that puerain could attenuate the osteoblastic differentiation of VSMCs through the ER/PI3K-Akt signal pathway.

[Protective effect of yixinshu capsule on myocardial ischemia reperfusion injury in rats].

OBJECTIVE: To observe the protective effect of Yixinshu capsule on myocardial ischemia reperfusion injury (MIRI) in SD rats. METHOD: Sixty healthy SD rats were randomized into six groups: sham group, MIRI model group, Xinsuning capsule group, low, middle or high dose Yixinshu capsule. Acute MIRI rat models were created by reperfusion for 120 min after anterior interventricular branch of the left coronary artery for 30 min. The serum creatine kinase (CK), lactic dehydrogenase (LDH), aspartate aminotransferase (AST) and malondialdehyde(MDA), blood viscosity, and infarction area of myocardium were determined. RESULT: Yixinshu capsule could reduce serum CK, LDH, AST and LDH activity, improve the blood viscosity, and reduced the myocardial infarct size. CONCLUSION: Yixinshu capsule can protect against MIRI in rats.

[Stability of PEGylated puerarin under different storage conditions].

OBJECTIVE: To detect the stability of PEGylated puerarin (PEG-PUE), in order to provide experimental basis for storage conditions of PEGylated puerarin. METHOD: First, a method for determining the content of PEG-PUE was established. Next, a system study was conducted for the stability of PEG-PUE affected by different factors such as temperature, humidity, light and light avoidance. RESULT: PEG-PUE was severely degraded under the conditions of high temperature, high humidity and light. It was also seriously degraded under high temperature. CONCLUSION: PEG-PUE shall be stored under low temperature and in a dark and dry environment.

[In vitro dissolution of forsythin in Forsythia suspensa powder of different particle diameter].

OBJECTIVE: To examine the in vitro dissolution of forsythin in Forsythia suspensa powder of different particle diameter, in order to give guidance to the grinding process. METHOD: HPLC was used to determine the in vitro dissolution quantity and dissolution velocity of forsythin coarse powder, fine powder and ultramicroscopic powder. RESULT: The dissolution curves of Forsythia suspensa coarse powder, fine powder and ultramicroscopic powder were basically inconformity to Weibull distribution. Specifically, T50 was 11.8, 10.5 and 6.8 min, respectively, and Q45 was 78.22%, 81.91% and 90.76%, respectively. CONCLUSION: The superfine milling process can significantly increase the dissolution quantity and dissolution velocity of forsythin.