Nanoformulations of anticancer FGFR inhibitors with improved therapeutic index

Fibroblast growth factor receptor (FGFR) inhibitors like ponatinib and nintedanib are clinically approved for defined cancer patient cohorts but often exert dose-limiting adverse effects. Hence, we encapsulated the FGFR inhibitors ponatinib, PD173074, and nintedanib into polylactic acid nanoparticles and liposomes to enable increased tumor accumulation/specificity and reduce side effects. Different methods of drug loading were tested and the resulting formulations compared regarding average size distribution as well as encapsulation efficiency. Appropriate encapsulation levels were achieved for liposomal preparations only. Nanoencapsulation resulted in significantly decelerated uptake kinetics in vitro with clearly decreased short-term (up to 72?h) cytotoxicity at higher concentrations. However, in long-term clonogenic assays liposomal formations were equally or even more active as compared to the free drugs. Accordingly, in an FGFR inhibitor-sensitive murine osteosarcoma transplantation model (K7M2), only liposomal but not free ponatinib resulted in significant tumor growth inhibition (by 60.4%) at markedly reduced side effects.     

Lipid based nanocarriers: a translational perspective

Over the recent couple of decades, pharmaceutical field has embarked most phenomenal noteworthy achievements in the field of medications as well as drug delivery. The rise of Nanotechnology in this field has reformed the existing drug delivery for targeting, diagnostic, remedial applications and patient monitoring. The convincing usage of nanotechnology in the conveyance of medications that prompts an extension of novel lipid-based nanocarriers and non-liposomal systems has been discussed. Present review deals with the late advances and updates in lipidic nanocarriers, their formulation strategies, challenging aspects, stability profile, clinical applications alongside commercially available products and products under clinical trials. This exploration may give a complete idea viewing the lipid based nanocarriers as a promising choice for the formulation of pharmaceutical products, the challenges looked by the translational process of lipid-based nanocarriers and the combating methodologies to guarantee the headway of these nanocarriers from bench to bedside.     

Enhancing global vaccine pharmacovigilance: Proof-of-concept study on aseptic meningitis and immune thrombocytopenic purpura following measles-mumps containing vaccination

New vaccines designed to prevent diseases endemic in low and middle-income countries (LMICs) are now being introduced without prior record of utilization in countries with robust pharmacovigilance systems. To address this deficit, our objective was to demonstrate feasibility of an international hospital-based network for the assessment of potential epidemiological associations between serious and rare adverse events and vaccines in any setting. This was done through a proof-of-concept evaluation of the risk of immune thrombocytopenic purpura (ITP) and aseptic meningitis (AM) following administration of the first dose of measles-mumps-containing vaccines using the self-controlled risk interval method in the primary analysis. The World Health Organization (WHO) selected 26 sentinel sites (49 hospitals) distributed in 16 countries of the six WHO regions. Incidence rate ratios (IRR) of 5.0 (95% CI: 2.5–9.7) for ITP following first dose of measles-containing vaccinations, and of 10.9 (95% CI: 4.2–27.8) for AM following mumps-containing vaccinations were found. The strain-specific analyses showed significantly elevated ITP risk for measles vaccines containing Schwarz (IRR: 20.7; 95% CI: 2.7–157.6), Edmonston-Zagreb (IRR: 11.1; 95% CI: 1.4–90.3), and Enders’Edmonston (IRR: 8.5; 95% CI: 1.9–38.1) strains. A significantly elevated AM risk for vaccines containing the Leningrad-Zagreb mumps strain (IRR: 10.8; 95% CI: 1.3–87.4) was also found. This proof-of-concept study has shown, for the first time, that an international hospital-based network for the investigation of rare vaccine adverse events, using common standardized procedures and with high participation of LMICs, is feasible, can produce reliable results, and has the potential to characterize differences in risk between vaccine strains. The completion of this network by adding large reference hospitals, particularly from tropical countries, and the systematic WHO-led implementation of this approach, should permit the rapid post-marketing evaluation of safety signals for serious and rare adverse events for new and existing vaccines in all settings, including LMICs.     

The importance of microfluidics for the preparation of nanoparticles as advanced drug delivery systems

Introduction: Nanoparticles are anticipated to overcome persistent challenges in efficient drug delivery, but the limitations associated with conventional methods of preparation are resulting in slow translation from research to clinical applications. Due to their enormous potential, microfluidic technologies have emerged as an advanced approach for the development of drug delivery systems with well-defined physicochemical characteristics and in a reproducible manner.

Areas covered: This review provides an overview of microfluidic devices and materials used for their manufacturing, together with the flow patterns and regimes commonly used for nanoparticle preparation. Additionally, the different geometries used in droplet microfluidics are reviewed, with particular attention to the co-flow geometry used for the production of nanoparticles. Finally, this review summarizes the main and most recent nanoparticulate systems prepared using microfluidics, including drug nanosuspensions, polymeric, lipid, structured, and theranostic nanoparticles.

Expert opinion: The production of nanoparticles at industrial scale is still a challenge, but the microfluidic technologies bring exciting opportunities to develop drug delivery systems that can be engineered in an easy, cost-effective and reproducible manner. As a highly interdisciplinary research field, more efforts and general acceptance are needed to allow for the translation of nanoparticulate drug delivery systems from academic research to the clinical practice.     

Developmental regulation of kidney and liver solute carrier and ATP-binding cassette drug transporters and drug metabolizing enzymes: the role of remote organ communication

Introduction: The ontogeny of drug transport and metabolism is generally studied independently in tissues, yet in the immediate postnatal period the developmental regulation of SLC and ABC transporters and metabolizing enzymes must be coordinated. Using the Remote Sensing and Signaling Hypothesis as a framework, we describe how a systems physiology view helps to make sense of how inter-organ communication via hepatic, renal, and intestinal transporters and drug metabolizing enzymes (DMEs) is regulated from the immediate postnatal period through adulthood.

Areas covered: This review examines patterns of developmental expression and function of transporters and DMEs with a focus on how cross-talk between these proteins in the kidney, liver and other organs (e.g., intestine) may be coordinated postnatally to optimize levels of metabolites and endogenous signaling molecules as well as gut-microbiome products.

Expert opinion/commentary: Developmental expression is considered in terms of the Remote Sensing and Signaling Hypothesis, which addresses how transporters and DMEs participate in inter-organ and inter-organism small molecule communication in health, development, and disease. This hypothesis, for which there is growing support, is particularly relevant to the ‘birth transition’ and post-natal developmental physiology when organs must deal with critical physiological tasks distinct from the fetal period and where remote inter-organ and possibly inter-organismal (e.g. infant-gut microbiome) communication is likely to be critical to maintain homeostasis.     

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

Introduction: Scientific interest in the gut microbiota is increasing due to improved understanding of its implications in human health and disease. In patients with kidney disease, gut microbiota-derived uremic toxins directly contribute to altered nonrenal drug clearance. Microbial imbalances, known as dysbiosis, potentially increase formation of microbiota-derived toxins, and diminished renal clearance leads to toxin accumulation. High concentrations of microbiota-derived toxins such as indoxyl sulfate and p-cresol sulfate perpetrate interactions with drug metabolizing enzymes and transporters, which provides a mechanistic link between increases in drug-related adverse events and dysbiosis in kidney disease.

Areas covered: This review summarizes the effects of microbiota-derived uremic toxins on hepatic phase I and phase II drug metabolizing enzymes and drug transporters. Research articles that tested individual toxins were included. Therapeutic strategies to target microbial toxins are also discussed.

Expert commentary: Large interindividual variability in toxin concentrations may explain some differences in nonrenal clearance of medications. Advances in human microbiome research provide unique opportunities to systematically evaluate the impact of individual and combined microbial toxins on drug metabolism and transport, and to explore microbiota-derived uremic toxins as potential therapeutic targets.     

药物临床试验机构备案制发生的变化和影响

我国药物临床试验机构经历了30多年的发展历程。在临床试验实施中起着重要的作用。2017年10月27日,国家食品药品监督管理总局（CFDA）,发布了新的《药物临床试验机构管理规定（征求意见稿）》。较由原国家食品药品监督管理局和卫生部共同颁布《药物临床试验机构资格认定办法（试行）》,在药物临床试验机构资质申请认定和管理方面都发生了很大变化,在申请资质与途径、流程和时限、申请基本条件、违法惩处力度等方面有了新的表述。本文旨在比较前法规与新法规的相关变化并分析其发生的影响。     

复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果研究

目的 验证复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果。方法 选用琼脂扩散法,比较复方氟康唑凝胶与氟康唑凝胶对耐氟康唑假丝酵母菌的体外抑菌效果;通过感染耐氟康唑假丝酵母菌大鼠治疗试验,比较复方氟康唑凝胶与氟康唑凝胶治疗效果。结果 复方氟康唑凝胶抑菌圈直径(18.55±0.03)mm（n=20）,氟康唑凝胶抑菌圈直径(7.12±0.01)mm（n=20）,差异具有统计学意义（P<0.05）;复方氟康唑凝胶治疗感染耐氟康唑假丝酵母菌大鼠15d的转阴率为80%,氟康唑凝胶为40%,差异具有统计学意义（P<0.05,n=15）;复方氟康唑凝胶抑制阴道灌洗液炎性细胞因子水平能力、减轻病变损伤程度明显高于氟康唑凝胶（P<0.05,n=15）。结论 复方氟康唑凝胶对耐氟康唑假丝酵母菌的抗菌效果肯定,较氟康唑凝胶具有优势。