A Phase Ib/IIa Single Centre, Double-blind, Double-dummy, Placebo-controlled, Parallel-group Dose Ranging Trial in Adult Participants With Uncomplicated Dengue Fever in Singapore

Dengue fever is an acute febrile illness transmitted by mosquitoes, which affects half the world's population. There are 96 million symptomatic infections, 500,0000 hospitalisations and 25,000 deaths per year attributed to the disease. The economic burden is $12 billion. In Singapore, as elsewhere, the incidence of the disease continues to increase despite aggressive control measures. At present there are no approved medicines for treating dengue fever. Only supportive fluid replacement therapy is used to treat vascular leakage in patients with severe illness. Therefore there is an urgent need to find alternative treatments. Experiments in the laboratory have shown that Celgosivir and modipafant inhibit dengue virus and improve mouse survival. Both drugs have previously been used in humans with good safety records, so investigators are taking this one step further to find out how well it works in dengue patients. Investigators plan to enroll dengue patients within 48 hours of fever onset and assign them to one of four treatment groups over five days. Together with the support from the industry partner, 60°Pharmaceuticals PLC, the investigators will determine the safety and effectiveness of these drugs on acute dengue patients and pave the way forward for dengue antiviral medicines to reach patients.

开始日期2018-12-01

申办/合作机构

Singapore General Hospital Pte Ltd.

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100 项与莫地帕泛相关的转化医学

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2003-06-01·British Journal of Pharmacology2区 · 医学

Role of PAF receptors during intestinal ischemia and reperfusion injury. A comparative study between PAF receptor‐deficient mice and PAF receptor antagonist treatment

2区 · 医学

Article

作者: Takao Shimizu ; Mauro M Teixeira ; Adriana C Soares ; Danielle G Souza ; Vanessa Pinho ; Satoshi Ishii

The reperfusion of ischemic tissues may be associated with local and systemic inflammation that prevents the full benefit of blood flow restoration. The present study aimed to confirm a role for platelet‐activating factor receptor(s) (PAFR) during ischemia and reperfusion injury by using genetically modified mice deficient in the PAFR (PAFR−/− mice) and to evaluate comparatively the effectiveness of pharmacological treatment using the PAFR antagonist UK‐74,505 (modipafant).

The reperfusion of the ischemic superior mesenteric artery (SMA) induced marked local (intestine) and remote (lungs) tissue injury, as assessed by the increase in vascular permeability, neutrophil influx and intestinal hemorrhage and in the production of TNF‐α. There was also a systemic inflammatory response, as shown by the increase in serum TNF‐α concentrations and marked reperfusion‐associated lethality.

After reperfusion of the ischemic SMA, PAFR−/− mice had little tissue or systemic inflammation and lethality was delayed, but not prevented, in these mice. Interestingly, the reperfusion‐associated increases in tissue concentrations of IL‐10 were significantly greater in PAFR−/− than wild‐type mice.

Pretreatment with PAFR antagonist UK‐74,505 (1 mg kg−1) markedly prevented tissue injury, as assessed by the increase in vascular permeability, neutrophil accumulation, hemorrhage and TNF‐α concentrations in the intestine and lungs. In contrast, UK‐74,505 failed to affect reperfusion‐associated lethality and increases in serum TNF‐α when used at 1 mg kg−1.

Reperfusion‐associated lethality and increase in serum TNF‐α were only affected when a supra‐maximal dose of the antagonist was used (10 mg kg−1). At this dose, UK‐74,505 also induced a marked enhancement of reperfusion‐associated increases in tissue concentrations of IL‐10. However, at the same dose, UK‐74,505 failed to prevent reperfusion‐associated lethality in PAFR−/− mice any further.

The present studies using genetically modified animals and a receptor antagonist firmly establish a role of PAFR activation for the local, remote and systemic inflammatory injury and lethality which follows reperfusion of the ischemic SMA in mice. Moreover, it is suggested that high doses of PAFR antagonists need to be used if the real efficacy of these compounds is to be tested clinically.

British Journal of Pharmacology (2003) 139, 733–740. doi:10.1038/sj.bjp.0705296

2002-12-01·British Journal of Pharmacology2区 · 医学

Divergent mechanisms of action of the inflammatory cytokines interleukin 1‐β and tumour necrosis factor‐α in mouse cremasteric venules

2区 · 医学

Article

作者: R E Young ; S Nourshargh ; R D Thompson

Protein synthesis dependency and the role of endogenously generated platelet activating factor (PAF) and leukotriene B4 (LTB4) in leukocyte migration through interleukin‐1β (IL‐1β)‐ and tumour necrosis factor‐α (TNFα)‐stimulated mouse cremasteric venules was investigated using established pharmacological interventions and the technique of intravital microscopy.

Based on previously obtained dose‐response data, 30 ng rmIL‐1β and 300 ng rmTNFα were injected intrascrotally (4 h test period) to induce comparable levels of leukocyte firm adhesion and transmigration in mouse cremasteric venules.

Co‐injection of the mRNA synthesis inhibitor, actinomycin D (0.2 mg kg−1), with the cytokines significantly inhibited firm adhesion (49±13.6%) and transmigration (67.2±4.2%) induced by IL‐1β, but not TNFα.

In vitro, TNFα (1–100 ng ml−1), but not IL‐1β, stimulated L‐selectin shedding and increased β2 integrin expression on mouse neutrophils, as quantified by flow cytometry.

The PAF receptor antagonist, UK‐74,505 (modipafant, 0.5 mg kg−1, i.v.), had no effect on adhesion induced by either cytokine, but significantly inhibited transmigration induced by IL‐1β (66.5±4.5%).

The LTB4 receptor antagonist, CP‐105,696 (100 mg kg−1, p.o.), significantly inhibited both IL‐1β induced adhesion (81.4±15.2%) and transmigration (58.7±7.2%), but had no effect on responses elicited by TNFα. Combined administration of the two antagonists had no enhanced inhibitory effects on responses induced by either cytokine.

The data indicate that firm adhesion and transmigration in mouse cremasteric venules stimulated by IL‐1β, but not TNFα, is protein synthesis dependent and mediated by endogenous generation of PAF and LTB4. Additionally, TNFα but not IL‐1β, can directly stimulate mouse neutrophils in vitro. The findings provide further evidence to suggest divergent mechanisms of actions of IL‐1β and TNFα, two cytokines often considered to act via common molecular/cellular pathways.

British Journal of Pharmacology (2002) 137, 1237–1246. doi:10.1038/sj.bjp.0704981

2002-03-01·British Journal of Pharmacology2区 · 医学

Platelet‐activating factor drives eotaxin production in an allergic pleurisy in mice

2区 · 医学

Article

作者: Takao Shimizu ; Ana Letícia Alessandrini ; Mauro M Teixeira ; Vanessa Pinho ; André Klein ; Satoshi Ishii

The activation of eosinophils via G‐protein‐coupled seven transmembran receptors play a necessary role in the recruitment of these cells into tissue. The present study investigates a role for PAF in driving eotaxin production and eosinophil recruitment in an allergic pleurisy model in mice.

The intrapleural injection of increasing doses of PAF (10−11 to 10−9 moles per cavity) induced a dose‐ and PAF receptor‐dependent recruitment of eosinophils 48 h after stimulation.

Intrapleural injection of PAF induced the rapid (within 1 h) release of eotaxin into the pleural cavity of mice and an anti‐eotaxin antibody effectively inhibited PAF‐induced recruitment of eosinophils.

Eosinophil recruitment in the allergic pleurisy was markedly inhibited by the PAF receptor antagonist UK‐74,505 (modipafant, 1 mg kg−1). Moreover, recruitment of eosinophils in sensitized and challenged PAF receptor‐deficient animals was lower than that observed in wild‐type animals.

Blockade of PAF receptors with UK‐74,505 suppressed by 85% the release of eotaxin in the allergic pleurisy.

Finally, the injection of a sub‐threshold dose of PAF and eotaxin cooperated to induce eosinophil recruitment in vivo.

In conclusion, the production of PAF in an allergic reaction could function in multiple ways to facilitate the recruitment of eosinophils – by facilitating eotaxin release and by cooperating with eotaxin to induce greater recruitment of eosinophils.

British Journal of Pharmacology (2002) 135, 1213–1218; doi:10.1038/sj.bjp.0704570

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