Interventions for patent ductus arteriosus (PDA) in preterm infants: an overview of Cochrane Systematic Reviews.

BACKGROUND: Patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in preterm infants. Several non-pharmacological, pharmacological, and surgical approaches have been explored to prevent or treat a PDA. OBJECTIVES: To summarise Cochrane Neonatal evidence on interventions (pharmacological or surgical) for the prevention of PDA and related complications, and interventions for the management of asymptomatic and symptomatic PDA in preterm infants. METHODS: We searched the Cochrane Database of Systematic Reviews on 20 October 2022 for ongoing and published Cochrane Reviews on the prevention and treatment of PDA in preterm (< 37 weeks' gestation) or low birthweight (< 2500 g) infants. We included all published Cochrane Reviews assessing the following categories of interventions: pharmacological therapy using prostaglandin inhibitor drugs (indomethacin, ibuprofen, and acetaminophen), adjunctive pharmacological interventions, invasive PDA closure procedures, and non-pharmacological interventions. Two overview authors independently checked the eligibility of the reviews retrieved by the search, and extracted data from the included reviews using a predefined data extraction form. Any disagreements were resolved by discussion with a third overview author. Two overview authors independently assessed the methodological quality of the included reviews using the AMSTAR 2 (A MeaSurement Tool to Assess systematic Reviews) tool. We reported the GRADE certainty of evidence as assessed by the respective review authors using summary of findings tables. MAIN RESULTS: We included 16 Cochrane Reviews, corresponding to 138 randomised clinical trials (RCT) and 11,856 preterm infants, on the prevention and treatment of PDA in preterm infants. One of the 16 reviews had no included studies, and therefore, did not contribute to the results. Six reviews reported on prophylactic interventions for the prevention of PDA and included pharmacological prophylaxis with prostaglandin inhibitor drugs, prophylactic surgical PDA ligation, and non-pharmacologic interventions (chest shielding during phototherapy and restriction of fluid intake); one review reported on the use of indomethacin for the management of asymptomatic PDA; nine reviews reported on interventions for the management of symptomatic PDA, and included pharmacotherapy with prostaglandin inhibitor drugs in various routes and dosages, surgical PDA ligation, and adjunct therapies (use of furosemide and dopamine in conjunction with indomethacin). The quality of reviews varied. Two reviews were assessed to be high quality, seven reviews were of moderate quality, five of low quality, while two reviews were deemed to be of critically low quality. For prevention of PDA, prophylactic indomethacin reduces severe intraventricular haemorrhage (IVH; relative risk (RR) 0.66, 95% confidence interval (CI) 0.53 to 0.82; 14 RCTs, 2588 infants), and the need for invasive PDA closure (RR 0.51, 95% CI 0.37 to 0.71; 8 RCTs, 1791 infants), but it does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability (RR 1.02, 95% CI 0.90 to 1.15; 3 RCTs, 1491 infants). Prophylactic ibuprofen probably marginally reduces severe IVH (RR 0.67, 95% CI 0.45 to 1.00; 7 RCTs, 925 infants; moderate-certainty evidence), and the need for invasive PDA closure (RR 0.46, 95% CI 0.22 to 0.96; 7 RCTs, 925 infants; moderate-certainty evidence). The evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH (RR 1.09, 95% CI 0.07 to 16.39; 1 RCT, 48 infants). Necrotising enterocolitis (NEC) was lower with both prophylactic surgical ligation (RR 0.25, 95% CI 0.08 to 0.83; 1 RCT, 84 infants), and fluid restriction (RR 0.43, 95% CI 0.21 to 0.87; 4 RCTs, 526 infants). For treatment of asymptomatic PDA, indomethacin appears to reduce the development of symptomatic PDA post-treatment (RR 0.36, 95% CI 0.19 to 0.68; 3 RCTs, 97 infants; quality of source review: critically low). For treatment of symptomatic PDA, all available prostaglandin inhibitor drugs appear to be more effective in closing a PDA than placebo or no treatment (indomethacin: RR 0.30, 95% CI 0.23 to 0.38; 10 RCTs, 654 infants; high-certainty evidence; ibuprofen: RR 0.62, 95% CI 0.44 to 0.86; 2 RCTs, 206 infants; moderate-certainty evidence; early administration of acetaminophen: RR 0.35, 95% CI 0.23 to 0.53; 2 RCTs, 127 infants; low-certainty evidence). Oral ibuprofen appears to be more effective in PDA closure than intravenous (IV) ibuprofen (RR 0.38, 95% CI 0.26 to 0.56; 5 RCTs, 406 infants; moderate-certainty evidence). High-dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (RR 0.37, 95% CI 0.22 to 0.61; 3 RCTs, 190 infants; moderate-certainty evidence). With respect to adverse outcomes, compared to indomethacin administration, NEC appears to be lower with ibuprofen (any route; RR 0.68, 95% CI 0.49 to 0.94; 18 RCTs, 1292 infants; moderate-certainty evidence), oral ibuprofen (RR 0.41, 95% CI 0.23 to 0.73; 7 RCTs, 249 infants; low-certainty evidence), and with acetaminophen (RR 0.42, 95% CI 0.19 to 0.96; 4 RCTs, 384 infants; low-certainty evidence). However, NEC appears to be increased with a prolonged course of indomethacin versus a shorter course (RR 1.87, 95% CI 1.07 to 3.27; 4 RCTs, 310 infants). AUTHORS' CONCLUSIONS: This overview summarised the evidence from 16 Cochrane Reviews of RCTs regarding the effects of interventions for the prevention and treatment of PDA in preterm infants. Prophylactic indomethacin reduces severe IVH, but does not appear to affect the composite outcome of death or moderate/severe neurodevelopmental disability. Prophylactic ibuprofen probably marginally reduces severe IVH (moderate-certainty evidence), while the evidence is very uncertain on the effect of prophylactic acetaminophen on severe IVH. All available prostaglandin inhibitor drugs appear to be effective in symptomatic PDA closure compared to no treatment (high-certainty evidence for indomethacin; moderate-certainty evidence for ibuprofen; low-certainty evidence for early administration of acetaminophen). Oral ibuprofen appears to be more effective in PDA closure than IV ibuprofen (moderate-certainty evidence). High dose ibuprofen appears to be more effective in PDA closure than standard-dose ibuprofen (moderate-certainty evidence). There are currently two ongoing reviews, one on fluid restriction for symptomatic PDA, and the other on invasive management of PDA in preterm infants.

Approaches to Potentiated Neuroprotective Treatment in the Rodent Model of Ischemic Optic Neuropathy.

Nonarteritic anterior ischemic optic neuropathy (NAION) commonly causes sudden optic nerve (ON)-related vision loss. The rodent NAION model (rAION) closely resembles NAION in presentation and physiological responses. We identified early rAION-associated optic nerve head (ONH) inflammatory gene expression responses and the anti-inflammatory prostaglandin PGJ2's effects on those responses. We hypothesized that blocking pro-inflammatory prostaglandin (PGE2) production by inhibiting monoacylglycerol lipase or cyclooxygenase activity and co-administering PGJ2 would potentiate RGC survival following ischemic neuropathy. Deep sequencing was performed on vehicle- and PGJ2-treated ONHs 3d post-rAION induction. Results were compared against responses from a retinal ischemia model. Animals were treated with PGJ2 and MAGL inhibitor KML29, or PGJ2 + COX inhibitor meloxicam. RGC survival was quantified by stereology. Tissue PG levels were quantified by ELISA. Gene expression was confirmed by qPCR. PGJ2 treatment nonselectively reduced inflammatory gene expression post-rAION. KML29 did not reduce PGE2 1d post-induction and KML29 alone increased RGC loss after rAION. Combined treatments did not improve ONH edema and RGC survival better than reported with PGJ2 alone. KML29's failure to suppress PGE2 ocular synthesis, despite its purported effects in other CNS tissues may result from alternative PG synthesis pathways. Neither KML29 nor meloxicam treatment significantly improved RGC survival compared with vehicle. While exogenous PGJ2 has been shown to be neuroprotective, treatments combining PGJ2 with these PG synthesis inhibitors do not enhance PGJ2's neuroprotection.

A Novel Second-Generation EP2 Receptor Antagonist Reduces Neuroinflammation and Gliosis After Status Epilepticus in Rats.

Prostaglandin-E2 (PGE2), an important mediator of inflammation, achieves its functions via four different G protein-coupled receptors (EP1, EP2, EP3, and EP4). We previously demonstrated that the EP2 receptor plays a proinflammatory and neurodegenerative role after status epilepticus (SE). We recently developed TG8-260 as a second-generation highly potent and selective EP2 antagonist. Here, we investigate whether TG8-260 is anti-inflammatory and combats neuropathology caused by pilocarpine-induced SE in rats. Adult male Sprague-Dawley rats were injected subcutaneously with pilocarpine (380-400 mg/kg) to induce SE. Following 60 min of SE, the rats were administered three doses of TG8-260 or vehicle and were allowed to recover. Neurodegeneration, neuroinflammation, gliosis, and blood-brain barrier (BBB) integrity were examined 4 days after SE. The results confirmed that pilocarpine-induced SE results in hippocampal neurodegeneration and a robust inflammatory response that persists days after SE. Furthermore, inhibition of the EP2 receptor by TG8-260 administered beginning 2 h after SE significantly reduced hippocampal neuroinflammation and gliosis but, in distinction to the earlier generation EP2 antagonist, did not mitigate neuronal injury or BBB breakdown. Thus, attenuation of neuroinflammation and gliosis is a common feature of EP2 inhibition following SE.

Interplay Between Oxidative Stress, Cyclooxygenases, and Prostanoids in Cardiovascular Diseases.

Significance: Endothelial cells lining the lumen of blood vessels play an important role in the regulation of cardiovascular functions through releasing both vasoconstricting and vasodilating factors. The production and function of vasoconstricting factors are largely elevated in hypertension, diabetes, atherosclerosis, and ischemia/reperfusion injuries. Cyclooxygenases (COXs) are the major enzymes producing five different prostanoids that act as either contracting or relaxing substances. Under conditions of increased oxidative stress, the expressions and activities of COX isoforms are altered, resulting in changes in production of various prostanoids and thus affecting vascular tone. This review briefly summarizes the relationship between oxidative stress, COXs, and prostanoids, thereby providing new insights into the pathophysiological mechanisms of cardiovascular diseases (CVDs). Recent Advances: Many new drugs targeting oxidative stress, COX-2, and prostanoids against common CVDs have been evaluated in recent years and they are summarized in this review. Critical Issues: Comprehensive understanding of the complex interplay between oxidative stress, COXs, and prostanoids in CVDs helps develop more effective measures against cardiovascular pathogenesis. Future Directions: Apart from minimizing the undesired effects of harmful prostanoids, future studies shall investigate the restoration of vasoprotective prostanoids as a means to combat CVDs. Antioxid. Redox Signal. 34, 784-799.

EP4 receptor as a novel promising therapeutic target in colon cancer.

The most prevalent malignancy that can occur in the gastrointestinal tract is colon cancer. The current treatment options for colon cancer patients include chemotherapy, surgery, radiotherapy, immunotherapy, and targeted therapy. Although the chance of curing the disease in the early stages is high, there is no cure for almost all patients with advanced and metastatic disease. It has been found that over-activation of cyclooxygenase 2 (COX-2), followed by the production of prostaglandin E2 (PGE2) in patients with colon cancer are significantly increased. The tumorigenic function of COX-2 is mainly due to its role in the production of PGE2. PGE2, as a main generated prostanoid, has an essential role in growth and survival of colon cancer cell's. PGE2 exerts various effects in colon cancer cells including enhanced expansion, angiogenesis, survival, invasion, and migration. The signaling of PGE2 via the EP4 receptor has been shown to induce colon tumorigenesis. Moreover, the expression levels of the EP4 receptor significantly affect tumor growth and development. Overexpression of EP4 by various mechanisms increases survival and tumor vasculature in colon cancer cells. It seems that the pathway starting with COX2, continuing with PGE2, and ending with EP4 can promote the spread and growth of colon cancer. Therefore, targeting the COX-2/PGE2/EP4 axis can be considered as a worthy therapeutic approach to treat colon cancer. In this review, we have examined the role and different mechanisms that the EP4 receptor is involved in the development of colon cancer.

Druggable Prostanoid Pathway.

Prostanoids (prostaglandins, prostacyclin and thromboxane) belong to the oxylipin family of biologically active lipids generated from arachidonic acid (AA). Protanoids control numerous physiological and pathological processes. Cyclooxygenase (COX) is a rate-limiting enzyme involved in the conversion of AA into prostanoids. There are two COX isozymes: the constitutive COX-1 and the inducible COX-2. COX-1 and COX-2 have similar structures, catalytic activities, and subcellular localizations but differ in patterns of expression and biological functions. Non-selective COX-1/2 or traditional, non-steroidal anti-inflammatory drugs (tNSAIDs) target both COX isoforms and are widely used to relieve pain, fever and inflammation. However, the use of NSAIDs is associated with various side effects, particularly in the gastrointestinal tract. NSAIDs selective for COX-2 inhibition (coxibs) were purposefully designed to spare gastrointestinal toxicity, but predisposed patients to increased cardiovascular risks. These health complications from NSAIDs prompted interest in the downstream effectors of the COX enzymes as novel drug targets. This chapter describes various safety issues with tNSAIDs and coxibs, and discusses the current development of novel classes of drugs targeting the prostanoid pathway, including nitrogen oxide- and hydrogen sulfide-releasing NSAIDs, inhibitors of prostanoid synthases, dual inhibitors, and prostanoid receptor agonists and antagonists.

Antagonism of the Thromboxane-Prostanoid Receptor as a Potential Therapy for Cardiomyopathy of Muscular Dystrophy.

Background Muscular dystrophy (MD) causes a progressive cardiomyopathy characterized by diffuse fibrosis, arrhythmia, heart failure, and early death. Activation of the thromboxane-prostanoid receptor (TPr) increases calcium transients in cardiomyocytes and is proarrhythmic and profibrotic. We hypothesized that TPr activation contributes to the cardiac phenotype of MD, and that TPr antagonism would improve cardiac fibrosis and function in preclinical models of MD. Methods and Results Three different mouse models of MD (mdx/utrn double knockout, second generation mdx/mTR double knockout, and delta-sarcoglycan knockout) were given normal drinking water or water containing 25 mg/kg per day of the TPr antagonist ifetroban, beginning at weaning. After 6 months (10 weeks for mdx/utrn double knockout), mice were evaluated for cardiac and skeletal muscle function before euthanization. There was a 100% survival rate of ifetroban-treated mice to the predetermined end point, compared with 60%, 43%, and 90% for mdx/utrn double knockout, mdx/mTR double knockout, and delta-sarcoglycan knockout mice, respectively. TPr antagonism improved cardiac output in mdx/utrn double knockout and mdx/mTR mice, and normalized fractional shortening, ejection fraction, and other parameters in delta-sarcoglycan knockout mice. Cardiac fibrosis in delta-sarcoglycan knockout was reduced with TPr antagonism, which also normalized cardiac expression of claudin-5 and neuronal nitric oxide synthase proteins and multiple signature genes of Duchenne MD. Conclusions TPr antagonism reduced cardiomyopathy and spontaneous death in mouse models of Duchenne and limb-girdle MD. Based on these studies, ifetroban and other TPr antagonists could be novel therapeutics for treatment of the cardiac phenotype in patients with MD.

Baicalein ameliorates pristane-induced lupus nephritis via activating Nrf2/HO-1 in myeloid-derived suppressor cells.

INTRODUCTION: Lupus nephritis (LN) is a representative manifestation in systemic lupus erythematosus (SLE). Some studies have shown that myeloid-derived suppressor cells (MDSCs) play a vital role in the regulation of the SLE process. MDSC infiltration in the kidney as well as inflammation and oxidative stress provokes the acceleration and deterioration of LN. Nuclear factor E2-related factor 2 (Nrf2) is thought to be a major regulator of the antioxidant response. Baicalein is a flavonoid with known anti-inflammatory effects and antioxidant response. However, the effects of baicalein on MDSCs, inflammation, and oxidative stress are not evaluated in the development of pristane-induced LN in mice. METHODS: The renoprotective effect of baicalein was detected in a pristane-induced lupus mice model. NLRP3 inflammasome activation and NF-κB phosphorylation as well as reactive oxygen species (ROS) production and Nrf2 activation were examined. The percentages and function changes of MDSCs were measured. The possible mechanisms of the underlying effects of baicalein on ROS production and signaling pathways of Nrf2/heme-oxygenase (HO)-1, NLRP3 inflammasome, and NF-κB phosphorylation in lipopolysaccharide (LPS)-primed MDSCs were analyzed. RESULTS: Baicalein reduced proteinuria and attenuated renal function impairment and renal histopathology including intrinsic cell proliferation, cellular crescents, and podocyte injury as well as glomerulonephritis activity in lupus mice. Moreover, baicalein downregulated the activation of NLRP3 inflammasome and levels of ROS or NF-κB phosphorylation, and it enhanced Nrf2 activation. Of note, baicalein inhibited the expansion of MDSCs and improved the function of MDSCs in lupus mice. Through analyzing LPS-primed MDSCs in vitro, baicalein was found to exhibit cytoprotective effects coincident with the induction of Nrf2/HO-1 signaling and the suppression of the NLRP3 inflammasome. CONCLUSION: The data show that baicalein alleviates the symptoms of pristane-induced LN and suggest that the alleviation may be attributed to inhibition of MDSC expansion and regulation of the balance of the Nrf2/HO-1 signal and NLRP3 expression in MDSCs.

[Aspirin and preeclampsia]. / Aspirine et prééclampsie.

Indications for aspirin during pregnancy are a matter of debate and there is a recent trend to an extended prescription and an overuse of aspirin in pregnancy. Aspirin is efficient in secondary prevention of preeclampsia essentially in patients with a personal history of preeclampsia. The effect of aspirin on platelet aggregation and on the TXA2/PGI2 balance is dose-dependent. The optimum dosage, from 75mg/day to 150mg/day, needs to be determined. Fetal safety data at 150mg/day are still limited. The efficacy of aspirin seems to be subject to a chronobiological effect. It is recommended to prescribe an evening or bedtime intake. Aspirin, in primary prevention of preeclampsia, given to high-risk patients identified in the first trimester by screening tests, seems to reduce the occurrence of early-onset preeclampsia. Nevertheless, there are insufficient data for the implementation of such screening procedures in practice.

Nephrogenic Diabetes Insipidus.

Nephrogenic diabetes insipidus (NDI) results from the inability of the late distal tubules and collecting ducts to respond to vasopressin. The lack of ability to concentrate urine results in polyuria and polydipsia. Primary and acquired forms of NDI exist in children. Congenital NDI is a result of mutation in AVPR2 or AQP2 genes. Secondary NDI is associated with electrolyte abnormalities, obstructive uropathy, or certain medications. Management of NDI can be difficult with only symptomatic treatment available, using low-solute diet, diuretics, and prostaglandin inhibitors.

Targeting lipid mediators in asthma: time for reappraisal.

PURPOSE OF REVIEW: In the past decades, cysteinyl leukotrienes (CysLTs) and prostaglandin D2 have been recognized as key mediators of asthma and comorbid conditions for their potent broncho-active and proinflammatory properties. However, both the development and initial positioning of small molecules targeting these lipid mediators [i.e., leukotriene-synthesis inhibitors, CysLT-antagonists, and chemoattractant receptor homologous molecule on T-helper2-cells (CRTH2) antagonists] experienced drawbacks by lacking adequate biomarkers to define potential responders. RECENT FINDINGS: New insights into the mechanisms of airway inflammation in asthma including the interaction of leukotrienes and prostanoids has uncovered potential therapeutic targets. Emerging application of biomarkers in more recent clinical studies helped identify responders to therapies targeting lipid mediators and demonstrated their clinical efficacy in distinct asthma phenotypes and endotypes. SUMMARY: Interest in small molecules targeting lipid mediators in asthma and related conditions is emerging. Several clinical trials evaluating the efficacy and safety of CRTH2 (Prostaglandin D2 receptor 2) antagonists are ongoing. There is an urgent need for sensitive biomarkers to identify responders to such therapies and for monitoring of (long-term) effects. Furthermore, evaluation of effectiveness of combining different agents targeting lipid mediators or combining them with available or emerging biologics may uncover other potential benefits in certain asthma populations warranting future research.

Nonclonal Mast Cell Activation Syndrome: A Growing Body of Evidence.

Patients who present with typical features of mast cell activation with laboratory confirmation and without evidence of a clonal mast cell disorder or other medical condition should be initiated on medical treatment to block mast cells and their mediators. If a major response is achieved, a diagnosis of nonclonal mast cell activation syndrome (NC-MCAS) is likely and treatment should be optimized, including management of any associated conditions. In this review, the latest evidence with regard to the diagnosis and treatment of NC-MCAS is presented.

Furosemide-induced tubular dysfunction responding to prostaglandin synthesis inhibitor therapy in a child with nephrotic syndrome.

Furosemide is one of the most common drug used to treat anasarca in childhood nephrotic syndrome. It has minimal side effects on short-term usage, but prolonged use can result in polyuria, hypokalemia and metabolic alkalosis. This pseudo-bartter complication can be treated by discontinuation of the drug with adequate potassium replacement. We report a child who was given furosemide for 20 days elsewhere to treat the edema due to nephrotic syndrome and then presented to us with bartter-like syndrome. Furosemide was discontinued and potassium replacement was initiated. However, the child continued to have polyuria leading to repeated episodes of hypotensive shock. In view of severe symptoms, she was given a short course of oral indomethacin for 6 days, to which she responded. This case highlights the fact that indomethacin can provide symptomatic improvement in furosemide induced pseudo-bartter.

Therapeutic Applications of Prostaglandins and Thromboxane A2 Inhibitors in Abdominal Aortic Aneurysms.

BACKGROUND: Abdominal aortic aneurysm (AAA) is one of the leading causes of death in western countries. Surgery is still, at the present time, the sole treatment that has however a significant mortality and cost rate. Many pharmacological agents are under investigation aiming to reduce growth and prevent AAA rupture. These drugs target different pathological pathways and, notably, the excessive production of prostanoids by cyclooxygenases (COX). Intra-aneurysmal thrombus plays an adverse key role in the progression of AAA, platelets being a primary source of prostanoids as thromboxane A2. OBJECTIVE: In this review, we summarize studies targeting prostanoids production and down-stream pathways in cardiovascular diseases, and more specifically in AAA. RESULTS AND CONCLUSION: Various inhibitors of COX or antagonists of prostanoids receptors have been investigated in AAA animal models with conflicting results. In human AAA, only a few number of studies focused on anti-platelet therapy mostly using acetylsalicylic acid (aspirin, ASA), a COX1 inhibitor. Finally, we report preliminary promising results of a model of AAA in rats receiving a thromboxane A2 inhibitor, BM-573 that induced a reduction of aneurysmal growth.

Emerging therapies for atopic dermatitis: The prostaglandin/leukotriene pathway.

The role of leukotrienes and prostaglandins in development of atopy has been prototypically established in studies of asthma pathogenesis. Likewise, both in vitro and in vivo studies of atopic dermatitis have demonstrated that these molecules maintain important pathophysiologic roles. Thus, it follows that targeted therapies against these molecules may be promising in management of atopic dermatitis. Montelukast has had questionable efficacy in patients with atopic dermatitis, whereas small pilots using zileuton did have some clinically significant improvement. There are several agents in development that target leukotrienes and/or prostaglandins as well, including OC000459, Q301, and ZPL-521. In atopic dermatitis, OC000459 did not demonstrate efficacy in clinical trials, and the efficacy of the other 2 agents remains to be seen. Should these medications prove promising, these topical agents may play a future role in chronic maintenance therapy and flare prophylaxis in atopic dermatitis, as antileukotriene therapy does in asthma.

Minimally Invasive Patent Ductus Arteriosus Ligation.

A patent ductus arteriosus is a common condition, particularly in premature infants. Many spontaneously resolve but those that lead to clinical instability require closure. Conservative measures can be highly successful in selected groups. Surgical repair is effective and both open and minimally invasive approaches can be used. The minimally invasive approach may result in less long-term morbidity from a thoracotomy and may prove advantageous for these fragile infants, including less pain, shorter time on the ventilator, and shorter hospital stays.

Prostaglandin-targeting agents and spectral heart rate variability in experimental partial bladder outlet obstruction in rats.

The purpose of this study was to determine the activity of the autonomic nervous system (ANS), using spectral analysis of the heart rate variability (HRV) in the model of partial bladder outlet obstruction (PBOO) in rats treated with selected non-steroidal anti-inflammatory drugs (NSAID): piroxicam (PRX) or meloxicam (MLX), and following administration of PGF2a prostaglandin analogue (Enzaprost F5). Neither the use of PGF2a analogue nor of MLX, caused significant changes in the HRV spectrum (except for HRV spectrum total power reduction with MLX). The use of PRX caused reduction of the total power and powers of all components of the HRV spectrum (except for VLF). Moreover, increased nLF and reduced nHF were observed. The obtained results suggest that the total prostaglandin synthesis block with a non-selective cyclooxygenase inhibitor (PRX) results in reduced ANS total activity, with decreased parasympathetic activity and a relative sympathetic predominance. The preferential cyclooxygenase-2 block (MLX) caused reduction of the total ANS activity as well, however with no clear disproportion of any part of the ANS. Therefore, prostaglandin synthesis inhibition and associated decrease of parasympathetic activity may constitute an additional and favourable feature of NSAID pharmacodynamics in the treatment of BPH.

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice.

Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

[Paracetamol (acetaminophen) use in neonatology: a (re)appreciation of an old drug]. / Utilisation du paracétamol (acétaminophène) en néonatologie : (re)découverte d'un ancien principe actif.

In neonates, paracetamol is mainly used for its analgesic action. This drug is actually preferred by neonatologists because of its broad therapeutic index. Recently, it has been demonstrated that paracetamol is also an anti-cyclooxygenase (COX) medication through its inhibitory action on the peroxidase arm of central and peripheral COX (Boutaud et al., 2002; Toussaint et al., 2010; Graham et al., 2013; Hinz et al., 2008; Hinz and Brune, 2011). As such, this drug interferes with the synthesis of prostaglandins. This inhibition of peroxidase is, however, limited to a low concentration of arachidonic acid (AA) (around 2µM, in vitro) when the plasmatic concentration of paracetamol is experimentally 10µM, actually within the same range as compared to the therapeutic concentrations in vivo. This may partly explain its low anti-inflammatory effect as compared to ibuprofen and indomethacin, which exert their inhibition on COX whatever the AA concentrations are. This new well-demonstrated action of paracetamol on peripheral COX-2 of intact cells could explain recent observations making this drug a potential alternative in treating patent ductus arteriosus. However, the higher dosages that have been claimed by some authors in this indication still remain to be validated. This inhibition that paracetamol shows on the physiological synthesis of prostaglandins E2 (PGE2) could also explain some long-term immune deviations because the physiological concentration of PGE2 is a well-known actor in the genesis of immune homeostasis in the submucosal area. Indeed, recent epidemiology studies have pointed out immune deviations in children repeatedly exposed to paracetamol earlier in life. Consequently, this is actually the new discovery of an old drug. From these new data on paracetamol, a more focused pharmacovigilance on the long-term effects of paracetamol repeatedly given in the early stage should be urgently initiated.