VPC 23019

VPC 23019, phosphoric acid mono-[2-amino-2-(3-octyl-phenylcarbamoyl)-ethyl] ester, is an S1P1/S1P3 receptor antagonist. S1P is short for sphingosine-1-phosphate [1]. VPC 23019 abolished S1P-induced, cell migration, Gi-dependent Rac stimulation and tube formation [2]. VPC 23019 inhibited SIP1 activity with an IC50 value of 8 nM [3].

S1P can act on specific G protein-coupled receptors. 5 subtypes of these receptors have been found and termed S1P1–5. These receptors couple to intracellular second messenger systems including intracellular Ca2+, phospholipase C, adenylyl cyclase, phosphatidylinositol 3 (PI3)-kinase, mitogen-activated protein kinases, protein kinase Akt, and Ras- and Rho-dependent pathways [1].

In the bEnd.3 cell line, VPC 23019 did not affect basal NO production. Preincubation with 10 µmol/L VPC 23019 made Ang II–induced NO production decrease to approximately basal level [1]. S1P, in a dose-dependent manner, stimulated trans-well migration of mouse vascular endothelial cells with a peak response at 10-7M. VPC 23019 was able to abolish this stimulatory effect of S1P [2]. Preincubation with 10 µM of VPC 23019 partially inhibited S1P-induced calcium increase in L2071 cells [4].

In rat, VPC 23019 significantly increased the S1P-induced vasoconstriction in preparation with intact endothelium (P< 0.01), but did not change it in preparation without endothelium. In intact mouse basilar artery (relaxation to ACh, 45.6±7.2%, n= 16), VPC 23019 left-shifted the concentration-contraction curve to S1P by a half log. VPC 23019 did not modify contractile responses to 5-HT, KCl or U46619 [5].

References:
[1].  Arthur C.M. Mulders, Mariëlle C. Hendriks-Balk, Marie-Jeanne Mathy, et al. Sphingosine Kinase-dependent Activation of Endothelial Nitric Oxide Synthase by Angiotensin II. Arterioscler Thromb Vasc Biol., 2006, 26:2043-2048.
[2].  Isao Inoki, Noriko Takuwa, Naotoshi Sugimoto, et al. Negative regulation of endothelial morphogenesis and angiogenesis by S1P2 receptor. Biochemical and Biophysical Research Communications, 2006, 346: 293-300.
[3].  Ju Wang, Zi-Qi Shi, Xiaojun Xu, et al. Triptolide Inhibits Amyloid-β Production and Protects Neural Cells by Inhibiting CXCR2 Activity. Journal of Alzheimer’s Disease, 2013, 33:1-2.
[4].  Mi-Kyoung Kim, Kyoung Sun Park, Hyuck Lee, et al. Phytosphingosine-1-phosphate stimulates chemotactic migration of L2071 mouse fibroblasts via pertussis toxin-sensitive G-proteins. Exp. Mol. Med., 2007, 39(2):185-194.
[5].  S Salomone, EM Potts, S Tyndall, et al. Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools. British Journal of Pharmacology, 2008, 153:140-147.

Validity of auditory perceptual assessment of velopharyngeal function and dysfunction - the VPC-Sum and the VPC-Rate.[Pubmed:28362219]

Clin Linguist Phon. 2017;31(7-9):589-597.

Overall weighted or composite variables for perceptual auditory estimation of velopharyngeal closure or competence have been used in several studies for evaluation of velopharyngeal function during speech. The aim of the present study was to investigate the validity of a composite score (VPC-Sum) and of auditory perceptual ratings of velopharyngeal competence (VPC-Rate). Available VPC-Sum scores and judgments of associated variables (hypernasality, audible nasal air leakage, weak pressure consonants, and non-oral articulation) from 391 5-year olds with repaired cleft palate (the Scandcleft project) were used to investigate content validity, and 339 of these were compared with an overall judgment of velopharyngeal competence (VPC-Rate) on the same patients by the same listeners. Significant positive correlations were found between the VPC-Sum and each of the associated variables (Cronbachs alpha 0.55-0.87, P < 0.001), and a moderately significant positive correlation between VPC-Sum and VPC-Rate (Rho 0.698, P < 0.01). The latter classified cases well when VPC-Sum was dichotomized with 67% predicted velopharyngeal competence and 90% velopharyngeal incompetence. The validity of the VPC-Sum was good and the VPC-Rate a good predictor, suggesting possible use of both measures depending on the objective.

Idiopathic VPC: Distribution Of FOCI And Tips Of Ablation.[Pubmed:27909491]

J Atr Fibrillation. 2016 Apr 30;8(6):1342.

Idiopathic Ventricular Premature Contraction (VPC) is currently more routinely referred for electrophysiology evaluation. Usually it carries a good prognosis but, when symptomatic or suspected to produce ventricular dysfunction, will require treatment. Nowadays, RF ablation has great advantages over antiarrhythmic drugs. Classically the outflow tract (right or left), with the typical inferior axis with left (eventually right) bundle brunch block like ECG morphology, is considered the most frequent site of origin for idiopathic VPC, but with the widespread of EP procedures and advancement of technology making possible to map and ablate difficult locations, it is possible to see a growing and changing population referred for idiopathic VPC ablation, displaying that, almost any region of the heart may be source of this kind of arrhythmia that can be successfully treated. A well-planned procedure, with the presumed region of origin settled and employing the current technology and knowledge (tips), will have a high chance of cure.

[VPC regimen combined with whole-brain radiotherapy in the treatment of small cell lung cancer with brain metastasis].[Pubmed:21189183]

Zhongguo Fei Ai Za Zhi. 2005 Apr 20;8(2):136-8.

BACKGROUND: The main treatment strategy of cancer patients with brain meta- stasis is irradiation, while so far there is few research concerning chemotherapy combined with radiotherapy for these patients. The aim of this study is to evaluate the therapeutic effect and toxicity of chemotherapy with VPC regimen combined with whole-brain radiotherapy (WBRT) in small cell lung cancer (SCLC) with brain metastasis. METHODS: A total of 60 SCLC patients with brain metastasis received a cycle of VPC regimen (teniposide 60mg/m(2) iv on days 1-5, cisplatin 35mg/m(2) iv on days 1-3, semustine 80mg/m(2) PO on day 1) every 3-4 weeks. WBRT was administered on day 6 of the first cycle of chemotherapy at a dose of 2Gy given in 5 fractions per week. Patients with less than 3 brain lesions received WBRT at a dose of 30Gy and then small field radiotherapy up to total dose of 50Gy, otherwise they received WBRT at a total dose of 40Gy. Response was evaluated by brain and chest CT or MRI after WBRT and at least 2 cycles of chemotherapy were completed. RESULTS: All the patients completed WBRT combined with chemotherapy. Total response rate of primary pulmonary tumor was 46.7%, with 4 cases of CR. The objective brain response rate was 60.0%, with 11 cases of CR and 25 cases of PR. Symptom relief was observed in all 48 patients with neurological symptoms. Main adverse effects were myelotoxicity, nausea/vomiting, constipation and alopecia. The follow-up rate was 93.3% with a median survival duration of 11.3 months. The 1-, 2- and 5-year survival rate was 43.3%, 35.0% and 6.7%, respectively. CONCLUSIONS: Chemotherapy combined with WBRT can be safely performed for SCLC with brain metastasis and its short-term response is quite satisfactory. It may be worthy of further clinical investigation.

Using wavelet transform and fuzzy neural network for VPC detection from the Holter ECG.[Pubmed:15248543]

IEEE Trans Biomed Eng. 2004 Jul;51(7):1269-73.

A novel method for detecting ventricular premature contraction (VPC) from the Holter system is proposed using wavelet transform (WT) and fuzzy neural network (FNN). The basic ideal and major advantage of this method is to reuse information that is used during QRS detection, a necessary step for most ECG classification algorithm, for VPC detection. To reduce the influence of different artifacts, the filter bank property of quadratic spline WT is explored. The QRS duration in scale three and the area under the QRS complex in scale four are selected as the characteristic features. It is found that the R wave amplitude has a marked influence on the computation of proposed characteristic features. Thus, it is necessary to normalize these features. This normalization process can reduce the effect of alternating R wave amplitude and achieve reliable VPC detection. After normalization and excluding the left bundle branch block beats, the accuracies for VPC classification using FNN is 99.79%. Features that are extracted using quadratic spline wavelet were used successfully by previous investigators for QRS detection. In this study, using the same wavelet, it is demonstrated that the proposed feature extraction method from different WT scales can effectively eliminate the influence of high and low-frequency noise and achieve reliable VPC classification. The two primary advantages of using same wavelet for QRS detection and VPC classification are less computation and less complexity during actual implementation.

The suppressive effect of sphingosine 1-phosphate on monocyte-endothelium adhesion may be mediated by the rearrangement of the endothelial integrins alpha(5)beta(1) and alpha(v)beta(3).[Pubmed:17403093]

J Thromb Haemost. 2007 Jun;5(6):1292-301.

BACKGROUND: Sphingosine 1-phosphate (S1P), known to play important roles in vascular biology, is a bioactive lysophospholipid mediator that maintains endothelial integrity via its cell-surface receptors (S1Ps). In this in vitro study, we aimed to examine the role of S1P in monocyte-endothelium adhesion, which is an important event in the pathophysiology of atherosclerosis. METHODS AND RESULTS: S1P pretreatment of human umbilical vein endothelial cells (ECs), but not U937 cells, effectively suppressed U937-EC adhesion independently from the expression of adhesion molecules, namely ICAM-1, VCAM-1, and E-selectin. This S1P-induced suppressive effect was inhibited by the blockage of S1P(1) and S1P(3) receptors and the specific inhibitors of G(i) protein, Src family proteins, phosphatidylinositol 3-kinase, and Rac1, indicating involvement of these key downstream pathways. Moreover, the RGD peptide and antibodies, which neutralize adhesion via alpha(5)beta(1) and alpha(v)beta(3), effectively inhibited U937-EC adhesion with a degree similar to S1P pretreatment. Both an adhesion assay and flow-cytometric analysis demonstrated that U937 cells adhered through integrins alpha(5)beta(1) and alpha(v)beta(3) expressed on the apical surface of monolayer ECs, and S1P shifted the localization of these integrins from the apical surface to the basal surface. CONCLUSIONS: From the present results, we propose that S1P may contribute to the maintenance of vascular integrity and the regulation of atherogenesis through the rearrangement of endothelial integrins.

High-fat/high-cholesterol diet promotes a S1P receptor-mediated antiapoptotic activity for VLDL.[Pubmed:17264352]

J Lipid Res. 2007 Apr;48(4):806-15.

Withdrawing growth factors or serum from endothelial cells leads to the activation of effector caspases 3 and 7, resulting in apoptotic cell death. HDL protects against caspase induction through sphingosine-1-phosphate (S1P) receptors. This anti-caspase activity of HDL is antagonized by VLDL from apolipoprotein E4 (apoE4) (genotype, APOE4/4; apolipoprotein, apoE) targeted replacement (TR) mice, but not by VLDL from TR APOE3/3 mice, and requires the binding of apoE4-VLDL to an LDL receptor family member. In the absence of HDL, apoE4-VLDL and apoE3-VLDL from TR mice have limited antiapoptotic activity. In contrast, we show here that a high-fat/high-cholesterol/cholate diet (HFD) radically alters this biological activity of VLDL. On HFD, both apoE3-VLDL and apoE4-VLDL (HFD VLDL) inhibit caspase 3/7 activation initiated by serum withdrawal. This activity of HFD VLDL is independent of an LDL receptor family member but requires the activation of S1P(3) receptors, as shown by the ability of pharmacological block of S1P receptors by VPC 23019 and by small interfering RNA-mediated downregulation of S1P(3) receptors to inhibit HFD VLDL anticaspase activity.

Sphingosine 1-phosphate analogs as receptor antagonists.[Pubmed:15590668]

J Biol Chem. 2005 Mar 18;280(11):9833-41.

Sphingosine 1-phosphate (S1P) is a lysophospholipid mediator that evokes a variety of cell and tissue responses via a set of cell surface receptors. The recent development of S1P receptor agonists, led by the immunomodulatory pro-drug FTY720, has revealed that S1P signaling is an important regulator of lymphocyte trafficking. With the twin goals of understanding structure-activity relationships of S1P ligands and developing tool compounds to explore S1P biology, we synthesized and tested numerous S1P analogs. We report herein that a subset of our aryl amide-containing compounds are antagonists at the S1P(1) and S1P(3) receptors. The lead compound in series, VPC23019, was found in broken cell and whole cell assays to behave as a competitive antagonist at the S1P(1) and S1P(3) receptors. The structure-activity relationship of this series is steep; for example, a slight modification of the lead compound resulted in VPC25239, which was one log order more potent at the S1P(3) receptor. These new chemical entities will enable further understanding of S1P signaling and provide leads for further S1P receptor antagonist development.

VPC 23019, an aryl amide-containing Sphingosine 1-phosphate (S1P) analog, is a competitive antagonist at the S1P1 and S1P3 receptors (pKi= 7.86 and 5.93, respectively) and an agonist at the S1P4 and S1P5 receptors (pEC50= 6.58 and 7.07, respectively).

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