Acetaminophen, an analgesic and antipyretic drug, has been used clinically for more than a century. Previous studies showed that acetaminophen undergoes metabolic transformations to form an analgesic compound, N-(4-hydroxyphenyl) arachidonamide (AM404), in the rodent brain. However, these studies were performed with higher concentrations of acetaminophen than are used in humans.
The aim of the present study was to examine the metabolism of AM404 from acetaminophen in the rat brain at a concentration of 20 mg/kg, which is used in therapeutic practice in humans, and to compare the pharmacokinetics between them.
We used rat brains to investigate the metabolism of AM404 from acetaminophen at concentrations (20 mg/kg) used in humans. In addition, we determined the mean pharmacokinetic parameters for acetaminophen and its metabolites, including AM404.
The maximum plasma concentrations of acetaminophen and AM404 in the rat brain were 15.8 µg/g and 150 pg/g, respectively, with corresponding AUC0-2h values of 8.96 μg hour/g and 117 pg hour/g. The tmax for both acetaminophen and AM404 was 0.25 hour.
These data suggest that AM404’s concentration-time profile in the brain is similar to those of acetaminophen and its other metabolites. Measurement of blood acetaminophen concentration seems to reflect the concentration of the prospective bioactive substance, AM404.

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The interaction between vascular endothelial growth factor and its receptor is an important therapeutic target due to the importance of this pathway in carcinogenesis. In particular, this pathway promotes and regulates angiogenesis as well as increases endothelial cell proliferation, permeability, and survival. Ramucirumab is a fully human monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2, the key receptor implicated in angiogenesis. Currently, ramucirumab is approved for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC) in combination with docetaxel. In a Phase III clinical trial, ramucirumab was shown to improve the overall survival in patients with disease progression, despite platinum-based chemotherapy for advanced NSCLC. This review describes the pharmacology, pharmacokinetics and dynamics, adverse event profile, and the clinical activity of ramucirumab observed in Phase II and III trials in NSCLC.

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Mucin 1 (MUC1 [CD227]) is a high-molecular weight (>400 kDa), type I membrane-tethered glycoprotein that is expressed on epithelial cells and extends far above the glycocalyx. MUC1 is overexpressed and aberrantly glycosylated in adenocarcinomas and in hematological malignancies. As a result, MUC1 has been a target for tumor immunotherapeutic studies in mice and in humans. MUC1 has been shown to have anti-adhesive and immunosuppressive properties, protects against infections, and is involved in the oncogenic process as well as in cell signaling. In addition, MUC1 plays a key role in the reproductive tract, in the immune system (affecting dendritic cells, monocytes, T cells, and B cells), and in chronic inflammatory diseases. Evidence for all of these roles for MUC1 is discussed herein and demonstrates that MUC1 is truly a multitasked molecule.

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Polymeric micelles, self-assembling nano-constructs of amphiphilic copolymers, are widely considered as convenient nano-carriers for a variety of applications, such as diagnostic imaging, and drug and gene delivery. They have demonstrated a variety of favorable properties including biocompatibility, longevity, high stability in vitro and in vivo, capacity to effectively solubilize a variety of poorly soluble drugs, changing the release profile of the incorporated pharmaceutical agents, and the ability to accumulate in the target zone based on the enhanced permeability and retention effect. Moreover, additional functions can be imparted to the micelle-based delivery systems by engineering their surface for specific applications. Various targeting ligands can be attached for cell or intracellular accumulation at a site of interest. Also, the chelation or incorporation of imaging moieties into the micelle structure enables in vivo biodistribution studies. Moreover, pH-, thermo-, ultrasound-, enzyme- and light-sensitive block-copolymers allow for controlled micelle dissociation and triggered drug release in response to the pathological environment-specific stimuli and/or externally applied signals. The combination of these approaches can further improve specificity and efficacy of micelle-based drug delivery to promote the development of smart multifunctional micelles.
© 2015 Wiley Periodicals, Inc.

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Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) secrete various beneficial molecules, which have anti-apoptotic activity and cell proliferation. However, the effect of hUCB-MSCs in melanogenesis is largely unclear. In this study, we show that conditioned media (CM) derived from hUCB-MSCs inhibit melanogenesis by regulating microphthalmia-associated transcription factor (MITF) expression via the ERK signalling pathway. Treatment of hUCB-MSC-CM strongly inhibited the alpha-melanocyte stimulating hormone-induced hyperpigmentation in melanoma cells as well as melanocytes. Treatment of hUCB-MSC-CM induced ERK1/2 activation in melanocytes. In addition, inhibition of ERK1/2 suppressed the anti-pigmentation activity of the hUCB-MSC-CM in melanocytes and in vitro artificial skin models. We also found that the expression of MITF was appreciably diminished while expression of phosphorylated MITF, which leads to its proteasomal degradation, was increased in cells treated with hUCB-MSC-CM. These results suggested that hUCB-MSC-CM significantly suppresses melanin synthesis via MITF degradation by the ERK pathway activation.

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