Failures in trials for Alzheimer's disease (AD) may be attributable to inadequate dosing, population selection, drug inefficacy, or insufficient design optimization. The Coalition Against Major Diseases (CAMD) was formed in 2008 to develop drug development tools (DDT) to expedite drug development for AD and Parkinson's disease. CAMD led a process that successfully advanced a clinical trial simulation (CTS) tool for AD through the formal regulatory review process at the US Food and Drug Administration (FDA) and European Medicines Agency (EMA).
FTY720 (also called fingolimod) is recognized as an immunosuppressant and has been approved by the Food and Drug Administration to treat refractory multiple sclerosis. However, long-term administration of FTY720 potentially increases the risk for cancer in recipients. The underlying mechanisms remain poorly understood. Herein, we provided evidence that FTY720 administration potentiated tumor growth. Mechanistically, FTY720 enhanced extramedullary hematopoiesis and massive accumulation of myeloid-derived suppressor cells (MDSCs), which actively suppressed antitumor immune responses. Granulocyte-macrophage colony-stimulating factor (GM-CSF), mainly produced by MDSCs, was identified as a key factor to mediate these effects of FTY720 in tumor microenvironment. Furthermore, we showed that FTY720 triggers MDSCs to release GM-CSF via S1P receptor 3 (S1pr3) through Rho kinase and extracellular signal-regulated kinase-dependent pathway. Thus, our findings provide mechanistic explanation for the protumorigenic potentials of FTY720 and suggest that targeting S1pr3 simultaneously may be beneficial for the patients receiving FTY720 treatment.
Fingolimod 0.5 mg q.d. (once daily) has been approved for the treatment of patients with relapsing and remitting forms of multiple sclerosis (RRMS). Fingolimod at two doses (0.5 and 1.25 mg) showed superior effectiveness in the frequency of relapse with little difference between the two dose groups. At the same time, fingolimod manifests a number of dose-dependent adverse events. Given the safety concerns and similar effect size at both dose groups, it was reasonable to raise the question whether doses even lower than 0.5 mg would produce sufficient effectiveness. Therefore, our analysis focused on estimating the effect size of the primary endpoint at doses lower than 0.5 mg via exposure–response analysis. Specifically, we aim to show how biomarker data can be used as a bridge in exposure–response analysis to estimate the clinical endpoint response at certain doses when the direct relationship between exposure and the clinical endpoint can not be quantified reliably.
The mission of the International Society of Pharmacometrics (ISoP) Standards and Best Practices Committee is to provide best practices and recommendations for standard pharmacometric analyses-e.g., population pharmacokinetics/pharmacodynamics (PK/PD), exposure-response, disease models-with the goal of increasing consistency, productivity, quality, communication, and impact of pharmacometrics on decision making. We present the progress and plans of the committee and call for volunteers to start new initiatives.
Sphingosine-1-phosphate (S1P) is a bioactive lipid that distributed in a wide variety of body tissues, especially inflammatory tissues. We observed that S1P plays an important role in the pathogenesis of Experimental allergic encephalomyelitis (EAE), the animal model of Multiple sclerosis (MS). Additionally, Vitamin D is observed to be a key determinant in the regulation of S1P. We monitored the effects of Vitamin D on Sphingosine kinase type 1 (SPHK1), an important synthetase associated with S1P. The associated results suggest a reduction in SPHK1 in the spinal cords of EAE rats whose diets supplement with Vitamin D. Many of the biological functions that are traditionally associated with Vitamin D is mediated through the Vitamin D receptor (VDR). Indeed, these interactions play a major role in the regulation of transcription of many target genes. As part of this analysis, we revealed the relationship between VDR and SPHK1. This is performed using over-expression experiments and observations relating to the interference effects of VDR on SPHK1. Our results verify that expression of the factor S1P, which is associated with EAE, is caused by alterations in SPHK1 levels. This relationship is regulated by VDR. Consequently, immune regulatory mechanisms associate with Vitamin D adjuvant therapy, used for the treatment of MS, may be involved in the regulation of SPHK1. This regulatory role may ultimately modulate the levels of S1P in cells. This report focuses on the relationship between SPHK-S1P and Vitamin D and provides a potentially novel approach for the treatment of MS.
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