Guiyang Liu

Drug nanocrystals: In vivo performances.

Over the past few decades, there has been a considerable research interest in drug nanocrystal system as a pharmaceutical approach for poorly soluble drugs. At the beginning lots of works have been done to study various technologies associated with production of drug nanocrystals and their in vitro physical and chemical properties, such as morphology, formulation composition, stabilities, crystalline structure and enhanced solubility and dissolution velocity. Recently, in vivo behaviors of the nanocrystals have been generally studied in animals (including human), and the results proved that drug nanocrystals could be used as a versatile formulation to alter and improve the pharmacokinetic, pharmacodynamic and targeting properties of poorly soluble drugs. In this paper, in vivo performances of drug nanocrystals exhibited in animals in different administration route were reviewed, and the advantages of drug nanocrystals in the aspect of safety, pharmacodynamics, pharmacokinetics and targeting delivery were discussed in detail.

Preparation of a chemically stable quercetin formulation using nanosuspension technology.

In the present study the evaporative precipitation into aqueous solution (EPAS) process and the high homogenization press (HPH) process were compared to evaluate their feasibility to form a chemically stable quercetin nanosuspension. The particle size and Zeta potential of the EPAS nanosuspension were similar to those of the HPH nanosuspension. Differences in results of differential scanning calorimetery and X-ray measures were observed between the two processes. The crystalline-to-amorphous phase transition was shown in the profile of EPAS dried powder. On the contrary the initial crystalline state of drug was maintained throughout the HPH process. Dissolution test results indicated that the EPAS process showed a higher improvement in the drug solubility and dissolution rate than the HPH process. At last the high performance liquid chromatography (HPLC) analysis proved the superiority of both nanosuspensions over QCT solution formulation for the chemical and photo-stability. As a result, it can be concluded that the EPAS and HPH techniques were feasible to prepare a chemically stable QCT nanosuspension with significantly enhanced dissolution rate.

Application of Drug Nanocrystal Technologies on Oral Drug Delivery of Poorly Soluble Drugs

The limited solubility and dissolution rate exhibited by poorly soluble drugs is major challenges in the pharmaceutical process. Following oral administration, the poorly soluble drugs generally show a low and erratic bioavailability which may lead to therapeutic failure. Pure drug nanocrystals, generated by “bottom up” or “top down” technologies, facilitate a significant improvement on dissolution behavior of poorly soluble drugs due to their enormous surface area, which in turn lead to substantial improvement in oral absorption. This is the most distinguished achievement of drug nanocrystals among their performances in various administration routes, reflected by the fact that most of the marketed products based on the nanocrystals technology are for oral application. After detailed investigations on various technologies associated with production of drug nanocrystals and their in vitro physicochemical properties, during the last decade more attentions have been paid into their in vivo behaviors. This review mainly describes the in vivo performances of oral drug nanocrystals exhibited in animals related to the pharmacokinetic, efficacy and safety characteristics. The technologies and evaluation associated with the solidification process of the drug nanocrystals suspensions were also discussed in detail.

Paclitaxel nanosuspension coated with P-gp inhibitory surfactants: II. Ability to reverse the drug-resistance of H460 human lung cancer cells

PURPOSE The present studies evaluated the ability of paclitaxel (PTX) nanosuspension coated with TPGS to reverse drug-resistance of P-glycoprotein (P-gp)-overexpressing H460 human lung cancer cells. METHOD P-gp expression level of H460 cells was detected by western blot method. MTT assay was used to investigate in vitro cytotoxicity of PTX formulations and the resistance index (RI) of H460/RT cells. At last the antitumor efficacy of PTX nanosuspension was evaluated in resistant H460 cells xenograft Balb/c mice. RESULTS The P-gp expression level of H460/RT cells was four times more than that of sensitive H460 cells. TPGS could reduce the P-gp expression by 25.41% at a concentration of 100 μg/ml after 24h exposure. Both PTX solution and nanosuspension exhibited obvious cytotoxicity against sensitive H460 cells. When H460/RT cells were treated, PTX nanosuspension showed significantly higher cytotoxicity compared with PTX solution, with much lower IC50 value and RI at each time point. After intravenous administration PTX nanosuspension exhibited about 5-fold increase in the inhibition rate of tumor growth compared with the mixed solution of PTX and TPGS. CONCLUSIONS PTX nanosuspension coated with TPGS could effectively reverse drug resistance of H460/RT cells. The usage of TPGS as stabilizers on the surface of nanocrystals of insoluble anticancer drugs may be an effective approach to overcome the multi-drug resistances (MDR).

Paclitaxel nanosuspensions coated with P-gp inhibitory surfactants: I. Acute toxicity and pharmacokinetics studies.

PURPOSE The aim of the present study was to evaluate the acute toxicity and pharmacokinetics of paclitaxel nanosuspensions stabilized with TPGS in mice. METHOD The paclitaxel nanosuspensions were prepared by evaporative precipitation into aqueous solution (EPAS) method, and freeze-dried powders of the nanosuspensions were obtained through lyophilization process. The morphology and particle size of nanosuspensions were determined by transmission electron microscope and Zetasizer, respectively. The acute toxicity and pharmacokinetics of paclitaxel nanosuspensions after intravenous administration to Kunming mice were studied. A marketed paclitaxel injectable solution was studied parallelly. RESULTS The paclitaxel nanoparticles were in rod shape under transmission electron microscope, and their mean particle size was 135.4 ± 5.7 nm. Results of acute toxicity showed the LD50 of paclitaxel nanosuspensions was 98.63 mg/kg, twice more than that of the marketed injection (41.46 mg/kg). After intravenous injection paclitaxel nanosuspensions displayed different pharmacokinetic properties in comparison with the marketed injectable solution, including a decreased initial drug concentration, increased plasma half-life, AUC and MRT. CONCLUSIONS The paclitaxel nanosuspensions prepared in this study could markedly enhance the tolerance dosage in mice, and manifest different pharmacokinetic properties compared with the solution.

Evaluation of TPGS-modified thermo-sensitive Pluronic PF127 hydrogel as a potential carrier to reverse the resistance of P-gp-overexpressing SMMC-7721 cell lines.

In the present studies locally injectable docetaxel nanocrystals loaded d-alpha tocopheryl polyethylene glycol 1000 succinate-modified Pluronic F127 (DOC-NCs-TPGS-PF127) thermo-sensitive hydrogels were prepared to reverse drug resistance of P-glycoprotein (P-gp)-overexpressing human liver cancer SMMC-7721 tumors. Firstly, DOC nanosuspensions with mean particle size of 196nm were prepared and dispersed into series of mixed solutions containing PF127 and TPGS of different ratios to obtain DOC-NCs-TPGS-PF127 hydrogels. DOC NCs, exhibiting a uniform distribution and very good physical stability during three sol-gel cycles in the hydrogel network, did not influence the gelation temperature. Swelling-dependent release pattern was found for DOC NCs from hydrogels and release profiles could be well fitted by the Peppas equation. MTT test showed that hydrogels containing 0% or 0.1% TPGS had no cytotoxicity against L929 fibroblasts. Both DOC solution and DOC-NCs-TPGS-PF127 hydrogels exhibited obvious cytotoxicity against sensitive SMMC-7721 cells. When resistant SMMC7721 cells were treated, DOC-NCs-TPGS-PF127 hydrogels showed significantly higher cytotoxicity compared with DOC solution and hydrogels containing no TPGS (DOC-NCs-PF127), with markedly lower IC50 and resistant index (RI). After intratumoral injection in SMMC-7721/RT tumor xenograft Balb/c mice model, DOC-NCs-TPGS-PF127 hydrogels exhibited about 5-fold increase and 1.8-fold increase in the inhibition rate of tumor growth compared with intravenous and intratumoral injection of DOC solution, respectively. It could be concluded that TPGS-modified PF127 thermo-sensitive hydrogel was an excellent locally injectable carrier to reverse P-gp overexpression associated multi-drug resistance.

Risk of congenital anomalies associated with antithyroid treatment during pregnancy: a meta-analysis

To evaluate the association of either propylthiouracil or methimazole treatment for hyperthyroidism during pregnancy with congenital malformations, relevant studies were identified by searching Medline, PubMed, the Cochrane Library and EMBASE. We intended to include randomized controlled trials, but no such trials were identified. Thus, we included cohort studies and case-control studies in this meta-analysis. A total of 7 studies were included in the meta-analyses. The results revealed an increased risk of birth defects among the group of pregnant women with hyperthyroidism treated with methimazole compared with the control group (odds ratio 1.76, 95% confidence interval 1.47–2.10) or the non-exposed group (odds ratio 1.71, 95% confidence interval 1.39–2.10). A maternal shift between methimazole and propylthiouracil was associated with an increased odds ratio of birth defects (odds ratio 1.88, 95% confidence interval 1.27–2.77). An equal risk of birth defects was observed between the group of pregnant women with hyperthyroidism treated with propylthiouracil and the non-exposed group (odds ratio 1.18, 95% confidence interval 0.97–1.42). There was only a slight trend towards an increased risk of congenital malformations in infants whose mothers were treated with propylthiouracil compared with in infants whose mothers were healthy controls (odds ratio 1.29, 95% confidence interval 1.07–1.55). The children of women receiving methimazole treatment showed an increased risk of adverse fetal outcomes relative to those of mothers receiving propylthiouracil treatment. We found that propylthiouracil was a safer choice for treating pregnant women with hyperthyroidism according to the risk of birth defects but that a shift between methimazole and propylthiouracil failed to provide protection against birth defects.

Dual VEGF/EGFR inhibition versus single targeted agent treatment in patients with metastatic colorectal cancer: a meta-analysis of randomized trials

Dear Editor: Colorectal cancer is one of the most common cancers and the second leading cause of cancer worldwide. Development and introduction of antibodies targeting the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR) in treatment algorithms have significantly improved the overall survival of patients with metastatic colorectal cancer. Bevacizumab is a humanized antibody against VEGF. Panitumumab and cetuximab are antibodies against EGFR. When in combination with chemotherapy, blocking either VEGF or EGFR pathway could increase the antitumor activity. Since VEGF and EGFR share downstream signaling components, there may be potential for synergic therapeutic efficacy with therapies targeting both pathways. In preclinical studies, the combination of bevacizumab and cetuximab demonstrated complete inhibition of VEGF expression and angiogenesis in vitro. Given encouraging preclinical and clinical rationale for use of dual VEGF-EGFR blockage, several randomized clinical trials were conducted to evaluate the effectiveness of this combination. However, their results were not consistent. Some studies demonstrated excessive toxicity and decreased efficacy in the panitumumab/cetuximab and bevacizumab group when compared with bevacizumab group. While others showed that the combination of two target agents in the first-line treatment of advanced colorectal cancer appeared to be safe and feasible, thus, we conducted this metaanalysis to evaluate the efficacy and safety of panitumumab/ cetuximab and chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer. For this purpose, we searched three electronic databases (Medline, the Cochrane Central Register of Controlled Trials, and Embase) for articles reporting the therapeutic effects and adverse effects of dual EGFR/VEGF inhibition in patients with colorectal cancer as compared with one targeted agent group. A total of five randomized controlled trials (RCT) were included in this meta-analysis. Among them, three studies evaluated the combination of chemotherapy plus bevacizumab with or without cetuximab. One study evaluated the combination of chemotherapy plus cetuximab with or without bevacizumab. The remaining study reported the efficacy and safety of chemotherapy combined with bevacizumab and panitumumab as compared to outcomes of chemotherapy and bevacizumab alone. When compared with those receiving chemotherapy and cetuximab/bevacizumab, all included studies did not show any difference in overall response rate in patients receiving the combination of chemotherapy and dual EGFR/VEGF inhibition. Meta-analysis of these four studies resulted in a pooled odds ratio (OR) of 0.95, 95 % CI 0.80–1.14, indicating no benefit of dual EGFR/VEGF inhibition in the treatment of mCRC. In addition, complete response rate (CR) and partial response rate (PR) did not differ between the two treatment arms. The pooled OR for CR and PR were 0.43 (95 % CI 0.09–1.97) and 0.89 (95 % CI 0.72– 1.11), respectively. As for disease control rate (DCR) in patients receiving the combination of chemotherapy and targeted therapies, there was a significant reduction in the DCR in those treated with chemotherapy, bevacizumab, Xiang Li and Min Wang contributed equally to this work.

Lack of IL-6 increases blood-brain barrier permeability in fungal meningitis

The pathogenesis of increased blood–brain barrier permeability during Cryptococcus meningitis is still largely unknown. Interleukin (IL-6) is a multifunctional cytokine, and numerous studies have shown that IL‐6 influences the integrity of the blood–brain barrier. In this study we investigated the role of IL-6 in Cryptococcus meningitis. First, wild-type or IL-6−/− mice were injected with Cryptococcus neoformans (C. neoformans) and the survival time in both groups was recorded. Second, the number of fungi was measured in the brains of IL-6−/− wild-type mice. Finally, the blood–brain barrier permeability index was detected in infected IL-6−/− mice treated with recombinant human IL-6. The blood–brain barrier permeability index was measured in infected wild-type mice treated with anti-IL-6 antibodies as well. The survival of IL-6−/− mice injected with C. neoformans was significantly lower than that of identically challenged wild-type mice. The infected IL-6−/− mice had significantly larger brain fungal burdens than wild-type mice. Furthermore, increased blood–brain barrier index was found in infected IL-6−/− mice when compared with that in infected control mice. Similar results were obtained when mice challenged with C. neoformans were treated systemically with neutralizing anti-IL-6 antibodies, resulting in an elevation of vascular permeability. Our data revealed that IL-6 reduced the blood–brain barrier permeability during Cryptococcus meningitis, and it might provide an explanation for the significantly lower survival of infected IL-6−/− mice.

Association of macrolides with overall mortality and cardiac death among patients with various infections: A meta-analysis

BACKGROUND A large body of evidences suggested that macrolide therapy could improve the survival of patients with various infections. While in the same time, macrolides are known to increase fatal arrhythmogenic risks and cause cardiac death. To assess the risks and benefits of macrolide therapy, we systematically reviewed all studies of macrolide use, cardiac death and mortality among patients with various infections. METHODS We searched Pubmed, Embase and Cochrane library and reviewed reference lists from 1980 through April 2015. Studies were included if they compared macrolides to other antibiotics in adults with various infections. The outcome measures were the overall mortality and the risk of cardiac death. RESULTS Overall, macrolide use was associated with a statistically significant mortality reduction compared with nonmacrolide use (OR: 0.65, 95% CI: 0.46-0.92). There was no difference in the risk of cardiac death between macrolide and nonmacrolide regimes (OR: 1.43, 95% CI: 0.86-2.40). In subgroup analyses, macrolide use was found to be associated with the decreased risk of mortality in a population of older individuals (age>48 years, OR: 0.69; 95% CI: 0.66-0.72). While in a general population of young and middle-aged adults, the use of macrolide-based regimens could not decrease the risk of death from any cause (age<48 years, OR: 0.42; 95% CI: 0.02-11.01). As for cardiac death, macrolide use was found to be associated with increased risk of cardiac death in a population of older individuals (age>48 years, OR: 1.99; 95% CI: 1.53-2.59). CONCLUSION Despite the potential cardiotoxic effects, there is a net benefit associated with macrolide use in older patients with various infections and macrolide use except roxithromycin was found to be associated with increased risk of cardiac death in a population of adults aged > 48 years.