Pharmacokinetics Evaluation of Nimotuzumab in Combination with Doxorubicin and Cyclophosphamide in Patients with Advanced Breast Cancer

EGFr （Epidermal growth factor receptor） overexpression has been detected in many tumors of epithelial origin, specifically in breast cancer and it is often associated with tumor growth advantages and poor prognosis. The nimotuzumab is a genetically engineered humanized MAb （monoclonal antibody） that recognizes an epitope located in the extracellular domain of human EGFr. The aim of this study was to assess the pharmacokinetics of nimotuzumab in patients with locally advanced breast cancer who are receiving neoadyuvant therapy combined with the AC chemotherapy regimen （i.e., 60 mg/m2 of Doxorubicin and 600 mg/m2 of Cyclophosphamide in 4 cycles every 21 days）. A single center, non-controlled, open Phase I clinical trial, with histopathological diagnosis of locally advanced stage III breast cancer, was conducted in 12 female patients. Three patients were enrolled at each of the following fixed dose levels： 50, 100, 200 and 400 mg/week. Multiple intermittent short-term intravenous infusions of nimotuzumab were administered weekly, except on weeks 1 and 10, when blood samples were drawn for pharmacokinetic assessments. Nimotuzumab showed dose-dependent kinetics. No anti-idiotypic response against nimotuzumab was detected in blood samples of participants. There was not interaction between the administration of nimotuzumab and chemotherapy at the dose levels studied. The optimal biological doses ranging were estimated to be 200 mg/weekly to 400 mg/weekly.

Emerging pathways of communication between the heart and non-cardiac organs

The breakthrough discovery of cardiac natriuretic peptides provided the first direct demonstration of the connection between the heart and the kidneys for the maintenance of sodium and volume homeostasis in health and disease. Yet,little is still known about how the heart and other organs cross-talk. Here, we review three physiological mechanisms of communication linking the heart to other organs through: i) cardiac natriuretic peptides, ii) the microRNA-208 a/mediator complex subunit-13 axis and iii) the matrix metalloproteinase-2(MMP-2)/C-C motif chemokine ligand-7/cardiac secreted phospholipase A2(sPLA2) axis-a pathway which likely applies to the many cytokines, which are cleaved and regulated by MMP-2. We also suggest experimental strategies to answer still open questions on the latter pathway. In short, we review evidence showing how the cardiac secretome influences the metabolic and inflammatory status of non-cardiac organs as well as the heart.

Topical Calendula officinalis L.inhibits inflammatory pain through antioxidant,anti-inflammatory and peripheral opioid mechanisms

Objective The present study evaluated the antinociceptive activity of Calendula officinalis L.(Ca)cream on inflammatory hypernociception.Methods Creams with different Ca concentrations were tested for their ability to ameliorate pain-related behavior and edema in rats using formalin test,carrageenan(Cg)-induced acute inflammation model,bradykinin(BK)-induced acute inflammation model,and complete Freund’s adjuvant(CFA)-induced chronic inflammation model.Using the formalin test,we also examined the implication of peripheral opioid receptors in the antinociceptive mechanisms of Ca cream,by means of Q-naloxone,a peripherally acting nonselective opioid antagonist.Furthermore,the effects of Ca cream compared with diclofenac on BK-induced edema were examined when the kininase II in tissue was preserved or inhibited by captopril.The local production of redox biomarkers in formalin model,tumor necrosis factor-α(TNF-α)in Cg model and histopathological changes in CFA model were also evaluated.Results A single application of Ca cream at a dose of 10%or 30%(w/w)decreased the formalin-induced licking/biting behavior during both phases of this test in a Q-naloxone-sensitive manner.This effect was associated with the reduction of oxidative stress in the injured paw and the edema associated with the later phase of formalin-induced pain.A single application of Ca cream(10%or 30%)reduced paw edema and thermal hypernociception in Cg-induced acute inflammation,corresponding with a local decrease in TNF-α.Ca cream also inhibited BK-induced spontaneous nociceptive behavior and paw inflammation in both paradigms studied.Repeated applications of Ca cream also decreased CFA-induced chronic inflammation,mechanical hypernociception and histopathological changes in the paw.Conclusion These results reveal the topical antinociceptive and antiedematogenic effects of Ca cream.A modulatory action on peripheral opioid receptors associated with its antioxidant mechanism may be involved,at least in part,in its analgesic effects.These findings may have an impact on the clinical management of painful inflammatory diseases.