A double-blind, randomized, placebo-controlled, single-dose study of the cyclooxygenase-2 inhibitor, GW406381, as a treatment for acute migraine

The objective of the present study was to explore the clinical efficacy and tolerability of GW406381, a cyclooxygenase-2 (COX-2) inhibitor with relatively high CNS penetration, in acute migraine. This was a double-blind, single-dose study of GW406381 compared with placebo and naproxen sodium compared with placebo (protocol number CXA20008). Three hundred and thirty-seven subjects were randomized 1:1:1 to GW406381 (70 mg), naproxen sodium (825 mg), or placebo for the treatment of one migraine headache of moderate or severe intensity in a potential 8-week period. The primary end-point was the proportion of subjects with headache relief [reduction in headache severity score from pre-dose 2 (moderate) or 3 (severe) to 0 (no pain) or 1 (mild)] at 2 h post-dose for GW406381 compared with placebo. Significantly higher proportions of subjects treated with GW406381 (50%, P  = 0.032) or naproxen sodium (56%, P  = 0.005) than with placebo (35%) reported headache relief at 2 h post-dose. Additional significant benefits were observed on many secondary outcomes, including proportions of subjects pain-free, for both GW406381 and naproxen sodium treatment compared with placebo. Both active treatments were well tolerated. Single-dose GW406381 (70 mg) and naproxen sodium (825 mg) were effective and well tolerated in the treatment of acute migraine.     

Identification of regions of the P2X(7) receptor that contribute to human and rat species differences in antagonist effects

Background and purpose:

Several P2X₇ receptor antagonists are allosteric inhibitors and exhibit species difference in potency. Furthermore, N²-(3,4-difluorophenyl)-N¹-(2-methyl-5-(1-piperazinylmethyl)phenyl)glycinamide dihydrochloride ({"type":"entrez-nucleotide","attrs":{"text":"GW791343","term_id":"293587509","term_text":"GW791343"}}GW791343) exhibits negative allosteric effects at the human P2X₇ receptor but is a positive allosteric modulator of the rat P2X₇ receptor. In this study we have identified several regions of the P2X₇ receptor that contribute to the species differences in antagonist effects.

Experimental approach:

Chimeric human-rat P2X₇ receptors were constructed with regions of the rat receptor being inserted into the human receptor. Antagonist effects at these receptors were measured in ethidium accumulation and radioligand binding studies.

Key results:

Exchanging regions of the P2X₇ receptor close to transmembrane domain 1 modified the effects of KN62, 4-(4-fluorophenyl)-2-(4-methylsulphinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and {"type":"entrez-nucleotide","attrs":{"text":"GW791343","term_id":"293587509","term_text":"GW791343"}}GW791343. Further studies, in which single amino acids were exchanged, identified amino acid 95 as being primarily responsible for the differential allosteric effects of {"type":"entrez-nucleotide","attrs":{"text":"GW791343","term_id":"293587509","term_text":"GW791343"}}GW791343 and, to varying degrees, the species differences in potency of SB203580 and KN62. The species selectivity of pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid was affected by multiple regions of the receptor, with potency being particularly affected by the amino acid 126 but not by amino acid 95. A further region of the rat receptor (amino acids 154–183) was identified that, when inserted into the corresponding position in the human receptor, increased ATP potency 10-fold.

Conclusions:

This study has identified several key residues responsible for the species differences in antagonist effects at the P2X₇ receptor and also identified a further region of the P2X₇ receptor that can significantly affect agonist potency at the P2X₇ receptor.     

Lapatinib: the evidence for its therapeutic value in metastatic breast cancer

INTRODUCTION: Breast cancer is the most common cancer affecting women. Many patients ultimately progress to metastatic disease and optimal management of this disease remains a significant therapeutic challenge. Lapatinib, a dual tyrosine kinase inhibitor, is in clinical development for treatment of this disease. AIMS: The objective of this article is to review the published evidence for the treatment of metastatic breast cancer with lapatinib, and assess its therapeutic potential. EVIDENCE REVIEW: Most evidence has appeared in meeting abstract reports of phase I and II studies in healthy volunteers and cancer patients. Four studies have included patients with exclusively breast cancer. Complete and partial responses and stable disease has been reported in some patients. Emerging evidence indicates that complete and partial responses can be achieved in some patients with metastatic breast cancer. Lapatinib appears to be well tolerated in cancer patients and the maximum tolerated dose is in the region of 1800 mg/day. In addition, it has been used in combination with other cancer treatments. Five ongoing or planned phase II monotherapy and three phase III combination-therapy studies with lapatinib have been identified. OUTCOMES SUMMARY: The phase I and II studies reported to date have provided safety data and preliminary indications regarding efficacy. There is preliminary evidence that lapatinib can achieve objective response rates of 10-38% in patients with metastatic breast cancer. Patients with tumors overexpressing ErbB1 and/or ErbB2 are likely to benefit from lapatinib treatment.     

Molecular inhibition of prostaglandin E2 with GW627368X: Therapeutic potential and preclinical safety assessment in mouse sarcoma model

Prostaglandin E2, the major COX-2 product, acts via 4 functionally distinct prostanoid receptors, EP(1–4). PGE-2, through its receptors, feeds back to positively increase COX-2 expression augmenting its own synthesis thereby driving angiogenesis, while suppressing apoptosis and innate immunity. In addition to the well characterized PGE2/EP4/cAMP/PKA/CREB, EP4 activation increases GSK3 phosphorylation via PI3K and Akt consequently reducing β-catenin phosphorylation. EP4 induces angiogenesis by enhancing VEGF production via ERK activation. These effects of EP4 are asserted either directly or via EGFR transactivation depending on the type of cancer. In view of the safety concerns regarding long term use of COX-2 inhibitors and to find more effective alternatives, we evaluated the potential of EP4 prostanoid receptor as a target for treating cancer progression using a highly selective EP4 antagonist, 4-(4,9-diethoxy-1,3-dihydro-1-oxo-2H-benz[f]isoindol-2-yl)-N-(phenylsulfonyl)-benzeneacetamide. Oral administration of GW627368X showed significant tumor regression characterized by tumor reduction and induction of apoptosis. Reduction in prostaglandin E2 synthesis also led to reduced level of VEGF in plasma. Regulation of multiple pathways downstream of EP4 was evident by down regulation of COX-2, p-Akt, p-MAPK and p-EGFR. Considering wide distribution of the EP4 prostanoid receptor in major organs and the array of physiological processes it contributes to, the safety profile of the drug was analyzed. No major organ toxicity, immunosupression, behavioral change or change in blood parameters attributable to the drug was observed. The results assert the significance of EP4 prostanoid receptor as a therapeutic target as well as the safety of EP4 blockade by GW627368X.     

Combined Transradial and Transpedal Approach for Femoral Artery Interventions

Objectives

The purpose of this prospective study was to evaluate the acute success and complication rates of combined transradial and transpedal access for femoral artery intervention.

Single String Technique for Coronary Bifurcation Stenting: Detailed Technical Evaluation and Feasibility Analysis

ObjectivesThe study aimed to evaluate the adequacy and feasibility of the single string bifurcation stenting technique.BackgroundDouble-stent techniques may be required for complex bifurcations. Currently applied methods all have their morphological or structural limitations with respect to wall coverage, multiple strut layers, and apposition rate.MethodsSingle string is a novel method in which, first, the side branch (SB) stent is deployed with a single stent cell protruding into the main branch (MB). Second, the MB stent is deployed across this protruding stent cell. The procedure is completed by final kissing balloon dilation. The single string technique was first tested in vitro (n = 20) and next applied in patients (n = 11) with complex bifurcation stenoses.ResultsAll procedures were performed successfully, crossing a single stent cell in 100%. Procedure duration was 23.0 ± 7.9 min, and the fluoroscopy time was 9.4 ± 3.5 min. The results were evaluated by optical coherence tomography, showing fully apposed struts in 83.0 ± 9.2% in the bifurcation area. Residual area obstruction in the MB was 6.4 ± 5.6% and 25.0 ± 16.9% in the SB, as evaluated by micro computed tomography. All the human cases were performed successfully with excellent angiographic results: the residual area stenosis was 27 ± 8% and 29 ± 10% in the MB and in the SB, respectively, by 3-dimensional quantitative coronary angiography. No relevant periprocedural enzyme increase was observed. During follow-up (6 ± 4 months), no adverse clinical events (death, myocardial infarction, target vessel revascularization) were noted.ConclusionsThe single string technique for complex bifurcation dilation was shown to be adequate in vitro and feasible in humans, with favorable results in terms of stent overlap, malapposition rate, and low residual obstruction in both the MB and SB.     

PPARβ/δ及其配体在RAW264.7泡沫细胞模型中的作用

目的研究过氧化物酶体增殖物激活受体（Peroxisome Proliferators-activated Receptor,PPAR）-β/δ及其激动剂GW0742、抑制剂GSK0660在RAW264.7泡沫细胞模型中的作用。方法本研究选用RAW264.7细胞,共分为6组,分别是对照组、LPS组、ox-LDL组、模型组、激动剂组和抑制剂组。实时定量PCR（Real-time Quantitative PCR）用来检测PPARβ/δ和单核细胞趋化蛋白（monocyte chemoattractant protein,MCP）-1 m RNA的水平,蛋白质印迹法（Western Blotting,WB）检测PPARβ/δ和MCP-1蛋白的表达,酶联免疫吸附试验（Enzyme-linked Immunosorbent Assay,ELISA）测定细胞培养液上清中炎症因子肿瘤坏死因子（tumor necrosis factor,TNF）-α,白介素（interleukin,IL）-10和MCP-1的水平。结果对照组、LPS组、ox-LDL组、模型组、激动剂组的PPARβ/δ蛋白质和m RNA水平逐渐增加（P〈0.01）,而抑制剂组PPARβ/δ蛋白质和m RNA水平则明显低于模型组和激动剂组（P〈0.01）。MCP-1蛋白质和m RNA的水平在对照组、ox-LDL组、LPS组、模型组逐渐增加（P〈0.01）,而激动剂组明显降低（P〈0.01）,抑制剂组又有所增加（P〈0.01）。总之,MCP-1的蛋白质和m RNA水平在各组之间差异显著（P〈0.01）。细胞培养液中TNF-α、MCP-1的水平LPS组、ox-LDL组、模型组明显升高（P〈0.01）,而激动剂组明显降低（P〈0.01）,抑制剂组又有所增加（P〈0.01）。而IL-10在激动剂组和抑制剂组则表现出相反的趋势。结论 GW0742可以显著增加PPARβ/δ的表达,降低炎症因子MCP-1、TNF-α的水平,升高IL-10的水平;GSK0660则发挥完全相反的作用。     

Curcumin attenuates cardiac fibrosis in spontaneously hypertensive rats through PPAR-γ activation

Aim:

To investigate the effects of curcumin (Cur) on cardiac fibrosis in spontaneously hypertensive rats (SHRs) and the mechanisms underlying the anti-fibrotic effect of Cur in rat cardiac fibroblasts (CFs) in vitro.

Methods:

SHRs were orally treated with Cur (100 mg·kg⁻¹·d⁻¹) or Cur (100 mg·kg⁻¹·d⁻¹) plus the PPAR-γ antagonist GW9662 (1 mg·kg⁻¹·d⁻¹) for 12 weeks. Cultured CFs were treated with angiotensin II (Ang II, 0.1 μmol/L) in vitro. The expression of relevant proteins and mRNAs was analyzed using Western blotting and real-time PCR, respectively. The expression and activity of peroxisome proliferator-activated receptor-γ (PPAR-γ) were detected using Western blotting and a DNA-binding assay, respectively.

Results:

Treatment of SHRs with Cur significantly decreased systolic blood pressure, blood Ang II concentration, heart weight/body weight ratio and left ventricle weight/body weight ratio, with concurrently decreased expression of connective tissue growth factor (CTGF), plasminogen activator inhibitor (PAI)-1, collagen III (Col III) and fibronectin (FN), and increased expression and activity of PPAR-γ in the left ventricle. Co-treatment with GW9662 partially abrogated the anti-fibrotic effects of Cur in SHRs. Pretreatment of CFs with Cur (5, 10, 20 μmol/L) dose-dependently inhibited Ang II-induced expression of CTGF, PAI-1, Col III and FN, and increased the expression and binding activity of PPAR-γ. Pretreatment with GW9662 partially reversed anti-fibrotic effects of Cur in vitro. Furthermore, pretreatment of CFs with Cur inhibited Ang II-induced expression of transforming growth factor-β1 (TGF-β1) and phosphorylation of Smad2/3, which were reversed by GW9662.

Conclusion:

Cur attenuates cardiac fibrosis in SHRs and inhibits Ang II-induced production of CTGF, PAI-1 and ECM in CFs in vitro. The crosstalk between PPAR-γ and TGF-β1/Smad2/3 signaling is involved in the anti-fibrotic and anti-proliferative effects of Cur.     

阿托伐他汀缓解百草枯中毒大鼠肺纤维化机制的研究

目的：观察阿托伐他汀对百草枯中毒所致肺纤维化疗效,并探讨其可能的作用机制。方法取健康成年 SD 大鼠120只,随机分为生理盐水组和百草枯组,每组10只,百草枯+阿托伐他汀10、20、40 mg 组(实验1、2、3组),百草枯+阿托伐他汀40 mg +吡格列酮组(PLZ 组)和百枯草+阿托伐他汀40 mg + GW9662组(GW9662组),每组20只。百草枯肺间质纤维化模型以百草枯溶液3.5 mg/ kg 的剂量腹腔注射制备,生理盐水组则以等体积的生理盐水腹腔注射,其余各药物干预组均在建立百草枯模型的基础上给予相应的药物,连续给药14 d 后处死大鼠,比较各组大鼠肺泡灌洗液中炎性细胞数目、肺组织中羟脯氨酸、血清中转化生长因子(TGF)-β1的含量。结果肺泡灌洗液中炎性细胞数目、肺组织中羟脯氨酸、血清中 TGF-β1的含量百草枯组均高于生理盐水组,实验2、3组均低于百草枯组(P <0．05,P <0．01)。 GW9662组肺泡灌洗液中炎性细胞数目和肺组织中羟脯氨酸低于实验3组,PLZ 组高于实验3组(P <0．05,P <0．01)。 GW9662组和 PLZ 组血清中 TGF-β1的含量均高于实验3组,但 PLZ 组升高更明显(P <0．05,P <0．01)。结论阿托伐他汀可缓解百草枯中毒所致的肺纤维化,且呈剂量依赖的方式,其作用机制可能是通过 PPARγ途径而实现。