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.

[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.

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.

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.

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.

Mast cell mediators cause early allergic bronchoconstriction in guinea-pigs in vivo: a model of relevance to asthma.

One feature of allergic asthma, the EAR (early allergic reaction), is not present in the commonly used mouse models. We therefore investigated the mediators involved in EAR in a guinea-pig in vivo model of allergic airway inflammation. Animals were sensitized using a single OVA (ovalbumin)/alum injection and challenged with aerosolized OVA on day 14. On day 15, airway resistance was assessed after challenge with OVA or MCh (methacholine) using the forced oscillation technique, and lung tissue was prepared for histology. The contribution of mast cell mediators was investigated using inhibitors of the main mast cell mediators [histamine (pyrilamine) and CysLTs (cysteinyl-leukotrienes) (montelukast) and prostanoids (indomethacin)]. OVA-sensitized and challenged animals demonstrated AHR (airway hyper-responsiveness) to MCh, and lung tissue eosinophilic inflammation. Antigen challenge induced a strong EAR in the sensitized animals. Treatment with a single compound, or indomethacin together with pyrilamine or montelukast, did not reduce the antigen-induced airway resistance. In contrast, dual treatment with pyrilamine together with montelukast, or triple inhibitor treatment, attenuated approximately 70% of the EAR. We conclude that, as in humans, the guinea-pig allergic inflammation model exhibits both EAR and AHR, supporting its suitability for in vivo identification of mast cell mediators that contribute to the development of asthma. Moreover, the known mast cell mediators histamine and leukotrienes were major contributors of the EAR. The data also lend further support to the concept that combination therapy with selective inhibitors of key mediators could improve asthma management.

A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins.

Surgery is a crucial intervention in most cancer patients, but the perioperative period is characterized by increased risks for future outbreak of preexisting micrometastases and the initiation of new metastases-the major cause of cancer-related death. Here we argue that the short perioperative period is disproportionately critical in determining long-term recurrence rates, discuss the various underlying risk factors that act synergistically during this period, and assert that this time frame presents an unexplored opportunity to reduce long-term cancer recurrence. We then address physiologic mechanisms that underlie these risk factors, focusing on excess perioperative release of catecholamines and prostaglandins, which were recently shown to be prominent in facilitating cancer recurrence through their direct impact on the malignant tissue and its microenvironment, and through suppressing antimetastatic immunity. The involvement of the immune system is further discussed in light of accumulating evidence in cancer patients, and given the recent identification of endogenously activated unique leukocyte populations which, if not suppressed, can destroy autologous "immune-resistant" tumor cells. We then review animal studies and human correlative findings, suggesting the efficacy of blocking catecholamines and/or prostaglandins perioperatively, limiting metastasis and increasing survival rates. Finally, we propose a specific perioperative pharmacologic intervention in cancer patients, based on simultaneous ß-adrenergic blockade and COX-2 inhibition, and discuss specific considerations for its application in clinical trials, including our approved protocol. In sum, we herein present the rationale for a new approach to reduce long-term cancer recurrence by using a relatively safe, brief, and inexpensive intervention during the perioperative period.

Macular edema--rationale for therapy.

Blood-retinal barrier breakdown with macular edema is caused by many diseases, which modulate--via different growth factors--the integrity of the tight junctions. Starling's law predicts furthermore that macular edema will develop if the hydrostatic pressure gradient between capillary and retinal tissue is increased, for example in the presence of elevated blood pressure, or if the osmotic pressure gradient is decreased, for example when protein accumulates excessively in the extracellular space within the retina. The rationale for clinical treatment of macular edema is based on the understanding and the inhibition of these pathophysiological mechanisms. On the medical side, nonsteroidal anti-inflammatory drugs inhibit the production of prostaglandins and leukotrienes, and modulate fluid movement coupled to chloride movement. Corticosteroids block cyclooxygenase and interleukin, downregulate vascular endothelial growth factor (VEGF) and decrease the phosphorylation of occludin, thereby increasing the tightness of the blood-retinal barrier. Carbonic anhydrase inhibitors are thought to modulate the polarized distribution of carbonic anhydrase at the level of the retinal pigment epithelium via extracellular pH gradients and thus the fluid resorption from the retina into the choroid. Anti-VEGF agents restore occludin proteins in the blood-retinal barrier and reduce protein kinase C activation. On the surgical side, the beneficial effect of vitrectomy with release of traction on the macula is explained by an increase in tissue pressure and a lowering of the hydrostatic pressure gradient, reducing the water flux from blood vessels into retinal tissue. The therapeutic action of vitrectomy in nontractional edema is thought to be based on two mechanisms: increased oxygen transport between the anterior and posterior segments of the eye and the removal of growth factors which are secreted in large amounts into the vitreous during proliferative vasculopathies.

Role of endotoxin and cytokines in the systemic inflammatory response to heat injury.

Environmental heat exposure represents one of the most deadly natural hazards in the United States. Heat stroke is a life-threatening illness that affects all segments of society with few effective treatment strategies to mitigate the long-term debilitating consequences of this syndrome. Although the etiologies of heat stroke are not fully understood, the long-term sequelae are thought to be due to a systemic inflammatory response syndrome (SIRS) that ensues following heat-induced tissue injury. Endotoxin and cytokines have been implicated as key mediators of the heat-induced SIRS, based almost exclusively on correlative data that show high circulating concentrations of these substances in heat stroke patients and animal models. However, endotoxin and cytokine neutralization studies have not consistently supported this hypothesis indicating that the mechanisms of heat stroke morbidity / mortality remain poorly understood. This review discusses the current understanding of the role of endotoxin and cytokines in heat-induced SIRS. Insight is provided into genetic conditions that may predispose to heat stroke and potential therapeutic strategies that may be efficacious against the adverse consequences of this debilitating illness.

[Theophylline, a new look to an old drug]. / Teofilina, una nueva mirada a un medicamento antiguo.

OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC-2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma.

A small molecule CRTH2 antagonist inhibits FITC-induced allergic cutaneous inflammation.

A FITC-induced allergic contact hypersensitivity model was used to investigate the role that the prostaglandin D(2) receptor-chemoattractant receptor-homologous molecule expressed on T(h)2 cells (CRTH2) plays in modulating cutaneous inflammation. Our results show that inhibition of CRTH2, achieved via administration of a potent, small molecule antagonist, Compound A (Cmpd A), effectively blocked edema formation and greatly reduced the inflammatory infiltrate and skin pathology observed in drug vehicle-treated animals. Gene expression analysis revealed that Cmpd A administration down-regulated the transcription of a wide range of pro-inflammatory mediators. This correlated with decreases in cytokine and chemokine protein levels, notably IL-4, IL-1beta, tumor necrosis factor-alpha, transforming growth factor-beta, GRO-alpha, MIP-2 and thymic stromal lymphopoietin (TSLP) in FITC-challenged ears. The administration of an anti-TSLP-neutralizing antibody was only partially effective in lowering the FITC-induced inflammatory infiltrate and cytokine production compared with the CRTH2 antagonist. Taken together, these data suggest that blockade of CRTH2 inhibits multiple pathways leading to cutaneous inflammation in this model. This suggests that CRTH2 antagonism may be a viable route for therapeutic intervention in allergic skin diseases, such as atopic dermatitis.

Inibidores das prostaglandinas para profilaxia da patência do canal arterial em recém-nascidos prematuros: revisão sistemática / Prostaglandin inhibitors for prevention of patent ductus arteriosus in preterm infants: a systematic review

A avaliação das tecnologias neonatais assume grande importância em face dapredominância atual do componente neonatal na mortalidade infantil e da necessidade de melhor avaliação dos recursos tecnológicos utilizados na assistência a essa faixa etária. Oestudo teve por objetivo examinar as evidências acerca do uso profilático dosantiinflamatórios não-esteróides – indometacina e ibuprofeno - no fechamento do canal arterial em recém-nascidos prematuros, por intermédio de uma revisão sistemática. Foi executada busca nas bases de referências bibliográficas MEDLINE, Web of Science, Scopus e LILACS, além dos registros da Colaboração Cochrane e da International Network of Agencies for Health Technology Assessment (INAHTA). Foram encontradas 226 citações, dos quais 93 foram para avaliação de resumos. Destes, foram excluídos 68 trabalhos por não preencherem os critérios estabelecidos de inclusão e qualidade, restando 25 artigos para a revisão sistemática, sendo seis envolvendo o uso de ibuprofeno e 19, o de indometacina. O fechamento farmacológico do canal arterial, eleito como desfecho primário,esteve presente em todos os trabalhos incluídos. Outros desfechos estudados foram: fechamento cirúrgico do canal arterial, mortalidade neonatal, doença da membrana hialina, hemorragia intracraniana, sepse neonatal, enterocolite necrosante, tempo de ventilação mecânica invasiva, tempo de oxigenioterapia, tempo de internação hospitalar, pneumotórax, hemorragia pulmonar, hemorragia gastrointestinal, distúrbio de coagulação, creatinina,oligúria, retinopatia da prematuridade, broncodisplasia pulmonar e alterações neurológicas aos 36 meses...

Prostaglandin inhibitors in the treatment of single-system Langerhans cell histiocytosis: pharmacologic rationale and report of two cases.

Therapeutic trials have confirmed the efficacy of a number of approaches to the treatment of single-system Langerhans cell histiocytosis (LCH). Not so well studied, but with some pharmacologic rationale and anecdotal reports of clinical success, are prostaglandin inhibitors. We present here a review of the possible mechanism of action of prostaglandin inhibitors in LCH and 2 cases of single-organ, single-site LCH treated with only prostaglandin inhibitors, both with sustained favorable clinical outcomes.

Factors affecting successful closure of hemodynamically significant patent ductus arteriosus with indomethacin in extremely low birth weight infants.

BACKGROUND: The incidence of patent ductus arteriosus (PDA) is high in extremely low birth weight (ELBW) infants. Indomethacin has been widely used in the prophylaxis and treatment of hemodynamically significant PDA. This retrospective study was undertaken to identify factors such as birth weight, gestational age, gender, fetal growth retardation, ductal size, timing of the first dose of indomethacin and side effects of indomethacin, which may affect the successful closure of the PDA with indomethacin in ELBW infants. METHODS: A cohort of 139 ELBW infants who had received indomethacin treatment for PDA during a consecutive period of more than three years (September 2000 to December 2003) was retrospectively analyzed. Administration RESULTS: of indomethacin was associated with closure of PDA in 108 (77.7%) of 139 ELBW infants, and only 19.4% of infants required surgical ligation of the ductus eventually. There was no significant relationship between closure of PDA with gestational age, gender, fetal growth retardation, and ductal size. A higher birth weight and early use of indomethacin after birth could significantly increase the closure rate of PDA (P<0.05). Side effects of indomethacin such as transient oliguria and hyponatremia during indomethacin therapy did not affect PDA closure. CONCLUSIONS: Indomethacin is effective for the treatment of PDA in ELBW infants. A higher rate of ductal closure is related to the increase of birth weight. PDA closure with indomethacin is age-related, and early administration of indomethacin could increase PDA closure and reduce the incidence of hyponatremia. There is no significant difference in major morbidities such as bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), and retinopathy of prematurity (ROP) after early treatment. Early screening for hemodynamically significant PDA in ELBW infants and early treatment with indomethacin are recommended.

Orthostatic hypotension in the elderly: diagnosis and treatment.

Orthostatic hypotension is a common problem among elderly patients, associated with significant morbidity and mortality. While acute orthostatic hypotension is usually secondary to medication, fluid or blood loss, or adrenal insufficiency, chronic orthostatic hypotension is frequently due to altered blood pressure regulatory mechanisms and autonomic dysfunction. The diagnostic evaluation requires a comprehensive history including symptoms of autonomic nervous system dysfunction, careful blood pressure measurement at various times of the day and after meals or medications, and laboratory studies. Laboratory investigation and imaging studies should be based upon the initial findings with emphasis on excluding diagnoses of neurodegenerative diseases, amyloidosis, diabetes, anemia, and vitamin deficiency as the cause. Whereas asymptomatic patients usually need no treatment, those with symptoms often benefit from a stepped approach with initial nonpharmacological interventions, including avoidance of potentially hypotensive medications and use of physical counter maneuvers. If these measures prove inadequate and the patient remains persistently symptomatic, various pharmacotherapeutic agents can be added, including fludrocortisone, midodrine, and nonsteroidal anti-inflammatory drugs. The goals of treatment are to improve symptoms and to make the patient as ambulatory as possible rather then trying to achieve arbitrary blood pressure goals. With proper evaluation and management, the occurrence of adverse events, including falls, fracture, functional decline, and myocardial ischemia, can be significantly reduced.

Suspected panosteitis in a camel.

CASE DESCRIPTION: A 6-month-old male Bactrian camel was examined because of a 3-week history of lameness of the left hind limb. CLINICAL FINDINGS: Lameness was initially detected in the left hind limb but resolved and was detected in the right hind limb during treatment. Lameness increased during periods of rapid growth. Radiography revealed multiple small opacities of the medullary cavity of several long bones throughout treatment. Core bone biopsies of lesions in the tibiae revealed lamellar bone with areas of loose connective tissue, osteoblasts in the medullary cavity, and periosteal new bone formation, all which were consistent with panosteitis. TREATMENT AND OUTCOME: Palliative treatment was attempted with epidural and transdermal administration of analgesics. Flunixin meglumine was administered PO, which coincided with an abrupt increase in serum creatinine concentration. Performance of multiple diagnostic bone biopsies led to remission of clinical signs of pain. CLINICAL RELEVANCE: Panosteitis should be a differential diagnosis for shifting limb lameness in young camels. Bone biopsies can be useful for diagnosis of panosteitis and possible relief of pain associated with the disease. Bactrian camels may be susceptible to the renal toxicity of flunixin meglumine, especially when dehydrated.