Antitumor Efficacy of a Novel CLA-PTX Microemulsion Against Brain Tumors: In Vitro and in Vivo Findings.

Antitumor efficacy of a novel CLA-PTX microemulsion against brain tumors: in vitro and in vivo findings.

Filed under: Drug and Alcohol Rehabilitation

Int J Nanomedicine. 2012; 7: 6105-14
Li D, Yang K, Li JS, Ke XY, Duan Y, Du R, Song P, Yu KF, Ren W, Huang D, Li XH, Hu X, Zhang X, Zhang Q

Considering the observations that linoleic acid conjugated with paclitaxel (CLA-PTX) possesses antitumor activity against brain tumors, is able to cross the blood-brain barrier, but has poor water solubility, the purpose of this study was to prepare a novel CLA-PTX microemulsion and evaluate its activity against brain tumors in vitro and in vivo.The in vitro cytotoxicity of a CLA-PTX microemulsion was investigated in C6 glioma cells. The in vivo antitumor activity of the CLA-PTX microemulsion was evaluated in tumor-bearing nude mice and rats. The pharmacokinetics of the CLA-PTX microemulsion were investigated in rats, and its safety was also evaluated in mice.The average droplet size of the CLA-PTX microemulsion was approximately 176.3 ± 0.8 nm and the polydispersity index was 0.294 ± 0.024. In vitro cytotoxicity results showed that the IC(50) of the CLA-PTX microemulsion was 1.61 ± 0.83 ?M for a C6 glioma cell line, which was similar to that of free paclitaxel and CLA-PTX solution (P > 0.05). The antitumor activity of the CLA-PTX microemulsion against brain tumors was confirmed in our in vivo C6 glioma tumor-bearing nude mice as well as in a rat model. In contrast, Taxol(®) had almost no significant antitumor effect in C6 glioma tumor-bearing rats, but could markedly inhibit growth of C6 tumors in C6 glioma tumor-bearing nude mice. The pharmacokinetic results indicated that CLA-PTX in solution has a much longer circulation time and produces higher drug plasma concentrations compared with the CLA-PTX microemulsion. The results of the acute toxicity study showed that the LD(50) of CLA-PTX solution was 103.9 mg/kg. In contrast, the CLA-PTX microemulsion was well tolerated in mice when administered at doses up to 200 mg/kg.CLA-PTX microemulsion is a novel formulation with significant antitumor efficacy in the treatment of brain tumors, and is safer than CLA-PTX solution.
HubMed – drug

Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70.

Filed under: Drug and Alcohol Rehabilitation

Biologics. 2012; 6: 429-64
Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A

Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate.Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks’ follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data.The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-? inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results.Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-? inhibitor combination therapies are not equally effective.
HubMed – drug

Transmitted/Founder and Chronic HIV-1 Envelope Proteins are Distinguished by Differential Utilization of CCR5.

Filed under: Drug and Alcohol Rehabilitation

J Virol. 2012 Dec 26;
Parker ZF, Iyer SS, Wilen CB, Parrish NF, Chikere KC, Lee FH, Didigu CA, Berro R, Klasse PJ, Lee B, Moore JP, Shaw GM, Hahn BH, Doms RW

Infection by HIV-1 most often results from the successful transmission and propagation of a single virus variant, termed the transmitted/founder (T/F) virus. Here, we compared the attachment and entry properties of envelope (Env) glycoproteins from T/F and CC (CC) viruses. Using a panel of 40 T/F and 47 CC Envs, all derived by single genome amplification, we found that 52% of clade B and C CC Envs exhibited partial resistance to the CCR5 antagonist maraviroc (MVC) on cells expressing high levels of CCR5, while only 15% of T/F Envs exhibited this same property. Moreover, subtle differences in the magnitude with which MVC inhibited infection on cells expressing low levels of CCR5, including primary CD4+ T cells, was highly predictive of MVC-resistance when CCR5 expression levels were high. These results are consistent with previous observations showing a greater sensitivity of T/F Envs to MVC inhibition on cells expressing very high levels of CCR5 and indicate that CC Envs are often capable of recognizing MVC-bound CCR5, albeit inefficiently on cells expressing physiologic levels of CCR5. When CCR5 expression levels are high, this phenotype becomes readily detectable. The utilization of drug-bound CCR5 conformations by many CC Envs was seen with other CCR5 antagonists, with replication competent viruses, and did not obviously correlate with other phenotypic traits. The striking ability of clade B and C CC Envs to use MVC-bound CCR5 relative to T/F Envs argues that the more promiscuous use of CCR5 by these Env proteins is selected against at the level of virus transmission and is selected for during chronic infection.
HubMed – drug

Nationwide study of candidemia, antifungal use and antifungal drug resistance in Iceland, 2000-2011.

Filed under: Drug and Alcohol Rehabilitation

J Clin Microbiol. 2012 Dec 26;
Asmundsdottir LR, Erlendsdottir H, Gottfredsson M

Candidemia is often a life-threatening infection, with highly variable incidence between countries. We conducted a nationwide study of candidemia in Iceland 2000-2011, in order to determine recent trends in incidence rates, fungal species distribution, antifungal susceptibility patterns, and concurrent antifungal consumption. A total of 208 infection episodes in 199 patients were identified. The average incidence during the 12-years was 5.7 cases/100,000 population/year, which was significantly higher than during 1990-1999 (4.3/100,000/year; p=0.02). A significant reduction in the use of blood cultures was noted in the last three years of the study, coinciding with the economic crisis in the country (p<0.001). Age-specific incidence rates were highest among patients at the extremes of the age, 20.7/100,000 for %%T::68%%60 years, respectively, and varied by gender. Age-specific incidence among males >80 years was 28.6/100,000/year and 8.3/100,000/year for females in this age group (p=0.028). The 30-day survival rate among adult patients remained unchanged compared to 1990-1999 (70.4% vs 69.5%, p=0.97). Candida albicans was the predominant species (56%), followed by C. glabrata (16%), and C. tropicalis (13%). The species distribution remained stable compared to previous decades. Fluconazole use increased 2.4-fold from 2000 to 2011, with no increase in resistance. In summary, the incidence of candidemia in Iceland has continued to increase but may have reached a steady state, and no increase in antifungal drug resistance has been noted. Decreased use of blood cultures towards the end of the study may have influenced detection rates.
HubMed – drug

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