Prostaglandin D2 Receptor Antagonist Research Articles

AMG853, A Bispecific Prostaglandin D2 Receptor 1 and 2 Antagonist, Dampens Basophil Activation and Related Lupus-Like Nephritis Activity in Lyn-Deficient Mice.

Systemic lupus erythematosus is a complex autoimmune disease during which patients develop autoantibodies raised against nuclear antigens. During the course of the disease, by accumulating in secondary lymphoid organs (SLOs), basophils support autoreactive plasma cells to amplify autoantibody production. We have recently shown that murine lupus-like disease could be controlled by 10 days of oral treatment with a combination of prostaglandin D2 (PGD2) receptor (PTGDR) antagonists through the inhibition of basophil activation and recruitment to SLOs. Importantly, inhibiting solely PTGDR-1 or PTGDR-2 was ineffective, and the development of lupus-like disease could only be dampened by using antagonists for both PTGDR-1 and PTGDR-2. Here, we aimed at establishing a proof of concept that a clinically relevant bispecific antagonist of PTGDR-1 and PTGDR-2 could be efficient to treat murine lupus-like nephritis. Diseased Lyn-deficient female mice received treatment with AMG853 (vidupiprant, a bispecific PTGDR-1/PTGDR-2 antagonist) for 10 days. This led to the dampening of basophil activation and recruitment in SLOs and was associated with a decrease in plasmablast expansion and immunoglobulin E (IgE) production. Ten days of treatment with AMG853 was consequently sufficient in reducing the dsDNA-specific IgG titers, circulating immune complex glomerular deposition, and renal inflammation, which are hallmarks of lupus-like disease. Thus, bispecific PTGDR-1 and PTGDR-2 antagonists, such as AMG853, are a promising class of drugs for the treatment or prevention of organ damage in systemic lupus erythematosus.

Eicosanoid signalling blockade protects middle-aged mice from severe COVID-19.

Coronavirus disease 2019 (COVID-19) is especially severe in aged populations1. Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective, but vaccine efficacy is partly compromised by the emergence of SARS-CoV-2 variants with enhanced transmissibility2. The emergence of these variants emphasizes the need for further development of anti-SARS-CoV-2 therapies, especially for aged populations. Here we describe the isolation of highly virulent mouse-adapted viruses and use them to test a new therapeutic drug in infected aged animals. Many of the alterations observed in SARS-CoV-2 during mouse adaptation (positions 417, 484, 493, 498 and 501 of the spike protein) also arise in humans in variants of concern2. Their appearance during mouse adaptation indicates that immune pressure is not required for selection. For murine SARS, for which severity is also age dependent, elevated levels of an eicosanoid (prostaglandin D2 (PGD2)) and a phospholipase (phospholipase A2 group 2D (PLA2G2D)) contributed to poor outcomes in aged mice3,4. mRNA expression of PLA2G2D and prostaglandin D2 receptor (PTGDR), and production of PGD2 also increase with ageing and after SARS-CoV-2 infection in dendritic cells derived from human peripheral blood mononuclear cells. Using our mouse-adapted SARS-CoV-2, we show that middle-aged mice lacking expression of PTGDR or PLA2G2D are protected from severe disease. Furthermore, treatment with a PTGDR antagonist, asapiprant, protected aged mice from lethal infection. PTGDR antagonism is one of the first interventions in SARS-CoV-2-infected animals that specifically protects aged animals, suggesting that the PLA2G2D-PGD2/PTGDR pathway is a useful target for therapeutic interventions.

Enantioselective Desymmetrization of 3-Substituted Oxetanes: An Efficient Access to Chiral 3,4-Dihydro-2H-1,4-benzoxazines.

Herein, we describe a versatile transition metal/oxidant free synthesis of the chiral 2H-1,4-benzoxazines through chiral phosphoric acid (CPA) catalyzed enantioselective desymmetrization of prochiral oxetanes (30 examples) in up to 99% yield and 99% enantioselectivity under mild reaction conditions. The reported strategy not only complements the conventional 2H-1,4-benzoxazine synthetic strategies but also provides access to key intermediates of therapeutic candidates, i.e., prostaglandin D2 receptor antagonist and M1 positive allosteric modulator (PAM) compound VU0486846.

Current perspective on eicosanoids in asthma and allergic diseases: EAACI Task Force consensus report, part I.

Eicosanoids are biologically active lipid mediators, comprising prostaglandins, leukotrienes, thromboxanes, and lipoxins, involved in several pathophysiological processes relevant to asthma, allergies, and allied diseases. Prostaglandins and leukotrienes are the most studied eicosanoids and established inducers of airway pathophysiology including bronchoconstriction and airway inflammation. Drugs inhibiting the synthesis of lipid mediators or their effects, such as leukotriene synthesis inhibitors, leukotriene receptors antagonists, and more recently prostaglandin D2 receptor antagonists, have been shown to modulate features of asthma and allergic diseases. This review, produced by an European Academy of Allergy and Clinical Immunology (EAACI) task force, highlights our current understanding of eicosanoid biology and its role in mediating human pathology, with a focus on new findings relevant for clinical practice, development of novel therapeutics, and future research opportunities.

Lipocalin-type prostaglandin D2 synthase deletion induces dyslipidemia and non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D2 synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D2 receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment.

A CRTH2 antagonist, CT-133, suppresses NF-κB signalling to relieve lipopolysaccharide-induced acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions that still have no definite pharmacotherapy. Hence, we investigate the potential effectiveness and underlying mechanism of CT-133, a newly developed selective antagonist of prostaglandin D2 receptor 2 (DP2) or of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), against lipopolysaccharide (LPS)-induced ALI. CT-133 (10 or 30 mg/kg) or dexamethasone (1 mg/kg, positive control) were intragastrically administered 1 h before and 12 h after intratracheal LPS instillation, and primary neutrophils and macrophages and RAW264.7 macrophages were used to investigate the role of CT-133 in regulation of their functions. LPS induced a significant secretion of PGD2 from primary macrophages, however, CT-133 dose-dependently and markedly decreased the infiltration of neutrophils and macrophages into lungs, reduced the IL-1β, TNF-α, IL-6, and KC levels in broncho-alveolar lavage (BAL) fluids, decreased the wet weight and myeloperoxidase activity of lungs, reduced Evans blue and albumin exudation into lungs, and improved the lung histopathological changes and hypoxemia. Moreover, CT-133 significantly suppressed the primary neutrophil migration toward the PGD2 and robustly inhibited the mRNA and protein expression of IL-1β, TNF-α, IL-6, and KC in primary and RAW264.7 macrophages in response to either LPS- or PGD2 stimulation. Finally, CT-133 significantly blocked the LPS-induced P65 activation in both RAW264.7 macrophages and mouse lungs. Thus, This is the first report that a CRTH2 antagonist, CT-133, is capable of significantly alleviating LPS-induced lung injury by probably down-regulating the NF-κB signalling.

Genetically engineered drugs for treatment of bronchial asthma: recent achievements

Current population of patients with asthma is characterized by increasing resistance to standard pharmacotherapeutic agents such as inhaled corticosteroids, antileukotriene agents and anti-IgE antibodies. These findings were confirmed by international statistic data and indicate insufficient efficacy of the treatment. Asthma phenotyping encompassing a role of certain biomarkers for bronchial inflammation could contribute to achieving better response to treatment. Genetically engineered drugs could directly impact on mediators and modulators involved in the inflammation and bronchoconstriction. This is one of the most promising directions of the modern pharmacotherapy, particularly considering severe and difficult-to-treat asthma. A comparative analysis of efficacy and safety of currently available genetically engineered drug groups (monoclonal anti-IgE antibodies, monoclonal antibodies against interleukin (IL)-4/IL-13 and IL-5, and prostaglandin D2 receptor antagonists) was performed by the authors of this article on the basis of results of randomized controlled clinical trials (RCT). According to RCT results, omalizumab is still the leading genetically engineered drug. Moreover, evidence of efficacy and safety of novel agents has been published that allowed implementation these drugs in the routine clinical practice for treatment of severe eosinophilic asthma.

Prostaglandin D2 receptor antagonists in allergic disorders: safety, efficacy, and future perspectives

ABSTRACTIntroduction: Prostaglandin D2 (PGD2) is a major cyclooxygenase mediator that is synthesized by activated human mast cells and other immune cells. The biological effects of PGD2 are mediated by D-prostanoid (DP1), DP2 (CRTH2) and thromboxane prostanoid (TP) receptors that are expressed on several immune and non-immune cells involved in allergic inflammation. PGD2 exerts various proinflammatory effects relevant to the pathophysiology of allergic disorders. Several selective, orally active, DP2 receptor antagonists and a small number of DP1 receptor antagonists are being developed for the treatment of allergic disorders.Areas covered: The role of DP2 and DP1 receptor antagonists in the treatment of asthma and allergic rhinitis.Expert opinion: Head-to-head studies that compare DP1 antagonists with the standard treatment for allergic rhinitis are necessary to verify the role of these novel drugs as mono- or combination therapies. Further clinical trials are necessary to verify whether DP2 antagonists as monotherapies or, more likely, as add-on therapies, will be effective for the treatment of different phenotypes of adult and childhood asthma. Long-term studies are necessary to evaluate the safety of targeted anti-PGD2 treatments.

Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial

Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma. We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to-severe asthma and an elevated sputum eosinophil count (≥2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13. Between Feb 10, 2012, and Jan 30, 2013, 61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was included in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5·4% (95% CI 3·1-9·6) to 1·1% (0·7-1·9) in the fevipiprant group and from 4·6% (2·5-8·7) to 3·9% (CI 2·3-6·7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4·5 times in the fevipiprant group and by 1·3 times in the placebo group (difference between groups 3·5 times, 95% CI 1·7-7·0; p=0·0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug. Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment. Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research.

The Editor takes a closer look at some of this month's articles

The Editor takes a closer look at some of this month's articles

Short-Term Effects of Extended-Release Niacin With and Without the Addition of Laropiprant on Endothelial Function in Individuals With Low HDL-C: A Randomized, Controlled Crossover Trial

BackgroundReduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation. ObjectiveThis study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C. MethodsAsymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2. ResultsEighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD. ConclusionsIn these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291.

Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients

The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2. We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma. Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV(1), symptom scores, rescue short-acting β-agonist use, and exacerbations. Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, -0.492; range for AMG 853 groups [n = 317], -0.444 to -0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator. AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma.

Effects of coadministered extended-release niacin/laropiprant and simvastatin on lipoprotein subclasses in patients with dyslipidemia

The use of extended-release niacin and the prostaglandin D₂ receptor antagonist laropiprant (ERN/LRPT) reduces niacin-induced flushing in patients while preserving its lipid-modifying effects. This predefined exploratory analysis examined the individual and combined effects of ERN/LRPT and simvastatin (SIM) on lipoprotein subclasses. This double-blind study randomized 1398 dyslipidemic patients equally to ERN/LRPT 1 g/20 mg, SIM (10, 20, or 40 mg), or ERN/LRPT 1 g/20 mg + SIM (10, 20, or 40 mg) once daily for 4 weeks. At week 5, doses were doubled, except SIM 40 mg (unchanged) and ERN/LRPT 1 g/20 mg + SIM 40 mg (switched to ERN/LRPT 2 g/40 mg + SIM 40 mg). Cholesterol associated with lipoprotein subclasses was quantified by vertical auto profile II (VAP II). ERN/LRPT + SIM and SIM alone lowered LDL-C 1 and 3, whereas the effects were variable for ERN/LRPT; all three treatments increased LDL-C 4. ERN/LRPT + SIM and ERN/LRPT raised HDL-C 2 and 3, with greater relative percent changes in HDL 2 than HDL 3. ERN/LRPT + SIM for 12 weeks produced substantial reductions in IDL-C, which was additive compared with each monotherapy. Coadministered ERN/LRPT + SIM produced marked reductions in atherogenic lipoproteins, with the greatest effect on IDL-C, and increases in protective HDL subclasses.

Tamoxifen and Its Metabolites Cause Acute Vasorelaxation of Aortic Rings by Inducing Vasodilator Prostanoid Synthesis

The vascular effects of tamoxifen (Tam) and its metabolites are poorly known. We compared the vasorelaxation induced by Tam and its metabolites (N-desmethyl-Tam, 4-hydroxy-Tam, and endoxifen) in aortic rings from rats using standardized organ bath procedures, and we investigated the mechanisms involved in this effect. Tam and its metabolite-induced vasorelaxation in a concentration-dependent manner. Although 4-hydroxy-Tam and Tam had similar potency (pD2 = 8.5 ± 0.1 vs. 8.8 ± 0.1, respectively) and maximum effect (Emax = 88.5% ± 1.3% vs. 92.6% ± 1.3%, respectively), N-desmethyl-Tam and endoxifen were more potent and showed higher Emax than Tam did (pD2 = 9.0 ± 0.1 and 8.9 ± 0.1; Emax = 101.1% ± 1.8% and 101.0% ± 1.8% for N-desmethyl-Tam and endoxifen, respectively). Although preincubation of aortic rings with the estrogen receptor antagonist ICI 182780 or with the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester hydrochloride induced no changes in the vasorelaxation induced by Tam or 4-hydroxy-Tam, both drugs significantly reduced Emax in response to N-desmethyl-Tam or to endoxifen. Inhibition of cyclooxygenase with indomethacin or the incubation with the prostaglandin D2 and E2 receptor antagonist AH6809 reduced the vasorelaxation-induced Tam and its metabolites by approximately 50%. Preincubation with Nω-nitro-L-arginine methyl ester hydrochloride combined with indomethacin abolished the vasorelaxation-induced Tam and its metabolites. These results show that Tam and its metabolites cause acute vasorelaxation by inducing vasodilator prostanoids synthesis.

Discovery of new orally active prostaglandin D2 receptor antagonists

To identify an orally available drug candidate, a series of 3-benzoylaminophenylacetic acids were synthesized and evaluated as prostaglandin D2 (PGD2) receptor antagonists. Some of the compounds tested were found to exhibit excellent inhibitory activity against cAMP accumulation in human platelet rich plasma (hPRP), which is one of the indexes of DP antagonism. The optimization process including improvement of the physicochemical properties such as solubility, which may result in an improved pharmacokinetic (PK) profile, is presented. Optimized compounds were studied for their pharmacokinetics and in vivo potential. A structure–activity relationship study is also presented. Some of the test compounds were found to have in vivo efficacy towards the inhibition of PGD2-induced and OVA-induced vascular permeability in guinea pig conjunctiva.

Design and synthesis of new prostaglandin D2 receptor antagonists

To identify new cost-effective prostaglandin D2 (DP) receptor antagonists, a series of novel 3-benzoylaminophenylacetic acids were synthesized and biologically evaluated. Among those tested, some representative compounds were found to be orally available. Receptor selectivity and rat PK profiles were also evaluated. The structure–activity relationship (SAR) study is presented.

Pleiotropic Effects of Nicotinic Acid: Beyond High Density Lipoprotein Cholesterol Elevation

Treatment with statins has significantly reduced cardiovascular morbidity and mortality, an effect attributed to both the low-density lipoprotein cholesterol (LDL-C) lowering capacity and the pleiotropic actions of these drugs. However, residual risk remains even after intense LDL-C lowering. Therefore, additional treatment with lipid-lowering drugs which improve other lipid parameters and have favourable non-lipid effects may be of clinical value. The aim of the present article is to review the actions of nicotinic acid and comment on the limitations and possible benefits of this drug in clinical practice. Relevant articles were identified through a Pubmed search up to July 2010. Nicotinic acid (niacin) improves the lipid profile and has been associated with reduction in morbidity and mortality from cardiovascular disease. This favourable outcome may be due to several beneficial actions of this drug, such as antithrombotic, anti-inflammatory and antioxidant. However, its use has been limited due to side effects, especially flushing. A novel formulation with a prostaglandin D2 receptor antagonist (laropiprant) appears to substantially decrease the frequency and intensity of flushing, without affecting the other properties of niacin. Some concerns regarding treatment with nicotinic acid include impaired glucose metabolism and elevations in uric acid and homocysteine levels. Nicotinic acid is a safe supplementary (to statins) lipid lowering agent which may also improve cardiovascular outcomes. Whether its combination with laropiprant will be proved equally effective and more favourable in terms of adverse effects remains to be established by large clinical trials.

Sodium [2′-[(cyclopropanecarbonyl-ethyl-amino)-methyl]-4′-(6-ethoxy-pyridin-3-yl)-6-methoxy-biphenyl-3-yl]-acetate (AM432): A potent, selective prostaglandin D2 receptor antagonist

Compound 21 (AM432) was identified as a potent and selective antagonist of the DP(2) receptor (CRTH2). Modification of a bi-aryl core identified a series of tri-aryl antagonists of which compound 21 proved a viable clinical candidate. AM432 shows excellent potency in a human whole blood eosinophil shape change assay with prolonged incubation, a comparatively long off-rate from the DP(2) receptor, excellent pharmacokinetics in dog and in vivo activity in two mouse models of inflammatory disease after oral dosing.

Extended-release niacin and laropiprant in the management of dyslipidemias

Despite the use of statins for prevention of cardiovascular events, a residual risk remains in part due to persisting abnormalities on lipids. For decades, niacin has been used for the management of dyslipidemia, it improves multiple lipid parameters and is the most potent drug available to increase HDL-C. Niacin, either in monotherapy or in combination with other lipid-lowering agents, decreases the risk of cardiovascular events. However, its use is limited by the high incidence of flushing, even with the extensed-release formulation. Laropiprant, a selective antagonist of prostaglandin D2 receptor 1, is effective in reducing niacin-induced flushing, without affecting thelipid effects of niacin. The available data on a single-tablet combination of niacin and laropiprant are promising to allow more patients to achieve the therapeutic niacin dose of 2 g per day in clinical practice. However, the niacin/ laropiprant combination does not completely eliminate niacin-flushing side effects and this treatment requires careful instructions to the patient. The ongoing clinical trial, HPS2-THRIVE, will provide important information on the efficacy of extended-release niacin/laropiprant for reducing cardiovascular events, as well as on the long-term safety of this drug.

CRTH2 antagonist ameliorates airway inflammation in rats with asthma

To investigate the effect of prostaglandin D2 receptor antagonists on the airway inflammation in rats with asthma. Forty male SD rats were randomly divided into four groups: Group A (normal control), Group B (asthma group), Group C (CRTH2 antagonist BAYu3405 treatment group), Group D (DP1 antagonist BWA868C treatment group). Asthma was induced by ovalbumin (OVA) challenge. The rats in each group were sacrificed 24 h after the last challenge of OVA.DP1/CRTH2 receptors on eosinophils (EOS) were measured by radiological binding assay (RBA). The left lungs were used for histological examinations and bronchoalveolar lavage fluid (BALF) was collected from the right lungs. The total cell numbers, EOS absolute count and differential cell counts in BALF were performed. Serum concentrations of IL-4, 5 and IFN-gamma were measured by ELISA. Rats in BAYu3405 treatment group showed profoundly decreased infiltrates of EOS and lymphocytes in the wall of bronchus when compared with those of asthma group and BWA868C treatment group. Serum concentrations of IFN-gamma in rats of BAYu3405 treatment group increased, but IL-4 and IL-5 decreased significantly when compared with those in rats of asthma group and BWA868C treatment group (P<0.01), and BALF EOS count was decreased significantly (P<0.01). Peripheral blood EOS count was higher than that in rats of normal control group, but was not significantly different from that in rats of asthma group and BWA868C treatment group. The combining capacity of CRTH2 and DP total combining capacity on EOS in asthma group, BAYu3405 treatment group and BWA868C treatment group were significantly higher than those in Group A (P<0.01). There was no significant difference in DP1 among all the groups (P>0.05). CRTH2, but not DP1 antagonist can effectively ameliorate airway inflammation in rats with asthma.