Inhibition Of Prostaglandin Synthesis Research Articles

Disruption of periovulatory FSH and LH surges during induced anovulation by an inhibitor of prostaglandin synthesis in mares

The role of passage of follicular fluid into the peritoneal cavity during ovulation in the transient disruption in the periovulatory FSH and LH surges was studied in ovulatory mares ( n = 7) and in mares with blockage of ovulation by treatment with an inhibitor of prostaglandin synthesis ( n = 8). Mares were pretreated with hCG when the largest follicle was ≥32 mm (Hour 0). Ultrasonic scanning was done at Hours 24 and 30 and every 2 h thereafter until ovulation or ultrasonic signs of anovulation. Blood samples were collected at Hours 24, 30, 32, 34, 36, 38, 48, and 60. Ovulation in the ovulatory group occurred at Hours 38 (five mares), 40, and 44. Until Hour 36, diameter of the follicle and concentrations of FSH, LH, and estradiol-17β (estradiol) were similar between groups. Between Hours 34 and 36, a novel transient increase in estradiol occurred in each group, and color-Doppler signals of blood flow in the follicular wall decreased in the ovulatory group and increased in the anovulatory group. In each group, FSH and LH periovulatory surges were disrupted by a decrease or plateau between Hours 38 and 48 and an increase between Hours 48 and 60. The discharge of hormone-laden follicular fluid into the peritoneal cavity at ovulation was not an adequate sole explanation for the temporally associated transient depression in FSH and LH. Other routes from follicle to circulation for gonadotropin inhibitors played a role, based on similar depression in the ovulatory and anovulatory groups.

Difference in incidence of cough induced by imidapril and ramipril: Role of prostaglandin synthesis inhibition

Aim of this study was to evaluate whether treatment with imidapril reduced cough induced by ramipril. The effect of adding indomethacin, a known inhibitor of prostaglandin (PG) synthesis, to the two ACE-inhibitors (ACE-I) on cough frequency and intensity was also assessed. After a 2-week placebo period, 97 hypertensive patients who developed cough during ramipril treatment were randomized to ramipril 10 mg or imidapril 20 mg for 8 weeks. Thereafter, patients still complaining cough continued the respective ACE-inhibitor treatment, but in each arm they were allocated to receive also indomethacin 50 mg or placebo for 4 weeks according to a double-blind, cross-over design. At the end of each phase of the study cough was assessed by means of a self-administered questionnaire with an ordinal 10-point visual analogue scale for rating daily cough intensity and frequency. At the end of the 8-week monotherapy phase, cough was complained by 48 of 49 (98%) patients randomized to ramipril and by 24 of the 48 (50%) patients randomized to imidapril, the difference between the two groups being significant ( P < 0.01). Indomethacin significantly reduced the mean score for cough intensity and frequency ( P < 0.01) in both ramipril and imidapril treated patients, with no difference between the two groups. These results indicate that the incidence of cough recurrence is lower with imidapril than with ramipril. The finding that the effect of indomethacin on cough frequency and intensity is the same in the two treatment groups suggests that the lower incidence of cough observed with imidapril might be mediated by some mechanism independent of PG synthesis.

Influence of Combined Nitric Oxide and Prostaglandin Inhibition on Contraction‐induced Rapid Vasodilation

A monophasic increase in skeletal muscle blood flow is observed following a brief single forearm contraction in young healthy adults. The factors facilitating this rapid vasodilatory response are unclear. We tested the hypothesis that nitric oxide (NO) and prostaglandins (PGs) contribute to contraction-induced rapid vasodilation in humans. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10s prior to, and for 30s after a single 1-s dynamic forearm contraction at mild and moderate exercise intensity. Trials were performed in eight young subjects before and after combined inhibition of NO and PG synthesis. For both workloads, the immediate and peak dilatory responses (cardiac cycles 1 – 4 P>0.05) were not influenced by combined inhibition, however the sustained dilation was blunted (cardiac cycles 5 – 23; P<0.05). The total hyperemic response to a single contraction was significantly attenuated at both mild and moderate contraction intensity (~70%). The present study indicates that NO and vasodilating PGs contribute to the latter sustained portion of the contraction-induced rapid vasodilatory response. Our collective findings suggest that multiple vasoactive signals are likely acting in concert, and have a specific role in coordinating the magnitude and temporal pattern of contraction-induced rapid vasodilation. Supported by HL-095573

Combined inhibition of nitric oxide and vasodilating prostaglandins abolishes forearm vasodilatation to systemic hypoxia in healthy humans

We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation ~85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.

Aspirin

> Among the many useful discoveries which this age has made, there are very few which better deserve the attention of the public that what I am going to lay before your Lordship. > > —Reverend Edward Stone –Chipping-Norton, Oxfordshire –April 25, 1763 These prophetic words, written by Reverend Edward Stone in a 1763 letter to George Parker, the second Earl of Macclesfield, describe the results of the first clinical trial recorded in medical history.1 Stone's report on the rediscovery of the medicinal value of willow bark among subjects suffering from malarial symptoms is considered a significant milestone in the development of aspirin. Although society now takes many of its beneficial effects for granted, aspirin did not suddenly appear for medicinal use after Reverend Stone's discovery. Instead, its tumultuous journey was fueled by individual scientific curiosity, accidental discoveries, and intense business rivalry.1 No other drug is used by a greater number of people worldwide than aspirin, the benefits of which span centuries, beginning with the very first uses of willow bark by Egyptian physicians (Figure 1). Aspirin single-handedly transformed a coal-dye company into a pharmaceutical giant and has emerged as a cornerstone in the present-day therapies available for treating cardiovascular disease (CVD), pain, and inflammation. This article discusses the sentinel historical aspects of the discovery and clinical cardiovascular developments of aspirin, as well as its contemporary use in today's medical arena. Figure 1. Timeline of historical events in the development of aspirin. ### Historical Developments of Salicylates On January 20, 1862, Edwin Smith made one of the most historically important purchases of his life. Well-regarded among his peers for his keen scholarship and intricate knowledge of Egyptology, Smith purchased, for £12, 2 worn papyrus scrolls in a local Luxor street market1 that later turned out to be a formative medical textbook unlocking ancient Egyptian's practice of medicine. Although authorless, the Ebers Papyrus is 110 pages …

The effect of fenugreek on the gene expression of arachidonic acid metabolizing enzymes

The main bioactive compounds of Trigonella foenum graecum L. (fenugreek) seeds are protodioscin, trigoneoside, diosgenin and yamogenin, which have anticarcinogenic potency through inhibition of cell proliferation and inhibition of prostaglandin synthesis. The effect of fenugreek on ALOX and COX genes was examined in AKR/J H-2(k) mice exposed to dimethylbenz[α]anthracene (DMBA), a potent carcinogen. The expression pattern of these genes was determined by detecting the mRNA expression in various tissues (the lungs, liver, spleen and the kidneys) in four groups of mice. Two groups were fed with normal and two of them with fenugreek containing nutriment. Each group divided into DMBA treated and control groups. Mice were autopsied on day 7 after DMBA treatment for mRNA isolation. Fenugreek consumption itself did not change gene expression compared with the control group. DMBA could increase the expression of ALOX12, ALOX15, ALOX5 genes mainly in all organs. Fenugreek consumption was generally protective in each organ in a different manner. DMBA treatment increased COX2 gene expression, but fenugreek was protective in all tissues examined. In COX1 gene, the fenugreek diet could suppress the expression, except for spleen, independently from carcinogen exposure. Therefore by inhibiting the arachidonic acid metabolism fenugreek may prevent tumorigenesis.

Cyclooxygenases. Methods and Protocols. Springer Protocols. Methods in Molecular Biology 644

This excellent work is part of a long-established series of protocols on ‘methods in molecular biology’. It is much broader in scope than this series title might suggest, and includes many pharmacologists (clinical as well as basic) among the distinguished list of authors. The series is edited by Dr John M. Walker and employs consistent templates for each protocol, as follows: an introductory overview, a list of reagents and materials, step-by-step descriptions of the procedures with notes on troubleshooting and practical tips. The strength of the present volume is the outstanding authorship, including John Oates, Brendan Whittle and Paula Patrignani among many others, renowned not only for the depth and consistency of their own published work on eicosanoids – unsurprisingly the introductory overviews are distinctive as well as authoritative – but also for having remained close to the coalface of hands-on experiment. Practical aspects are very well covered in consequence. The scope is such that the work will be of considerable interest to basic and clinical pharmacologists engaged in experimental work not only on nonsteroidal anti-inflammatory drugs (NSAIDs, the main focus) but also on pretty much any aspect of eicosanoid pharmacology. The protocols are detailed and lucid and will provide a running start for any PhD student, postdoctoral worker or established scientist getting into this field for the first time or expanding their experimental repertoire. The authors include several of the scientists who pioneered this therapeutically important area, notably several collaborators of the late Sir John Vane, whose pioneering work first explained the mechanism of NSAIDs as inhibitors of cyclooxygenase (COX) enzyme activity and prostaglandin synthesis. The authorship includes an impressive international spread as well as a good mix of industry- with academic-based scientists. The first part of the book is devoted to in vitro protocols for studying expression and activity of COX enzymes and characterization of their inhibition. The second part describes methods for extracting and measuring eicosanoids; clinical pharmacologists will be particularly interested, especially in the chapter on measurement of 8-iso-prostaglandin F2α in view of the use of this biomarker of oxidative stress in vivo. They will also be interested in the final section, which addresses in vivo models for studying COX products in health and disease. These include a chapter by Brendan Whittle on assessing gastrointestinal adverse effects of NSAIDs, and a chapter by Moore, Ayoub and Seed on COX enzymes and their products in carageenan-induced pleurisy. Inevitably, in a work of this length (215 pages; it fits conveniently on a laboratory shelf) coverage is not comprehensive and some topics that are included, while very interesting (e.g. iloprost nociception), are perhaps somewhat arbitrary. One omission that might be considered in a future edition is ex vivo stimulation of prostaglandin E2 synthesis by lipopolysacharide in whole blood, a method developed by Patrignani that provides a robust approach to investigating COX2 inhibition in early-phase human drug development. In summary, this is an invaluable laboratory manual with thoughtful, succinct and authoritative introductory comments that will be of great interest to investigators working on eicosanoid pharmacology.

Dysmorphic child born after maternal diclofenac therapy

Sir, A five-month-old baby was brought with complaints of abnormal facial features. A detailed birth and past history revealed that the baby was the third child, born of a non-consanguineous marriage. The mother was prescribed tablet diclofenac sodium (100 mg thrice daily) by a general practitioner for joint pain during the first trimester of pregnancy. The joint pain disappeared after four days. However, she continued taking tablet diclofenac on her own. There was no significant antenatal history suggestive of systemic disease. She delivered a full-term baby boy, with a birth weight of 2.25 kg, and was discharged on breast feeds on the second postnatal day. After three months an echocardiography was done in view of recurrent lower respiratory tract infections. It showed a 4.5 mm non-restrictive patent ductus arteriosus (left to right), 4 mm atrial septal defect (left to right), and severe pulmonary artery hypertension. On examination, the head circumference was 41 cm., weight was 3.1 kg, and length was 58 cm (below the fifth percentile for age and gender), suggestive of failure to thrive. Dysmorphic facies were present in the form of low set and deformed external ears. Oral cavity examination revealed a high arched palate. He also had hypertelorism and wide spaced nipples [Figure 1]. Serologic tests for toxoplasma, rubella, cytomegalovirus, and herpes simplex were negative. The complete blood count, ultrasound of the skull, and chromosomal analysis was normal. Ultrasound of the abdomen showed absent left kidney. Family history revealed that the other siblings were normal, without any dysmorphic facies or systemic abnormality.With a history of maternal intake of diclofenac during early pregnancy and normal family history, it can be postulated that a high dose diclofenac could have been responsible for the multiple anomalies seen in this patient. This can be considered as a possible adverse drug reaction as per causality assessment, on Naranjo's scale. Figure 1 Clinical Photograph of the child showing dysmorphic facies in the form of low set and deformed external ears. Also seen is the presence of hypertelorism and wide spaced nipples Diclofenac is a non-steroidal, anti-inflammatory drug, widely prescribed in India to women of child bearing age for the treatment of various conditions, including arthritis, musculo-skeletal pain, dysmenorrhea, and menorrhagia. The primary mechanism responsible for its action is inhibition of prostaglandin synthesis via the cyclo-oxygenase enzyme.[1] It is placed under ‘category C’ in the ′United States Food and Drug Administration′ classification of the pregnancy categories for pharmaceuticals.[2] Even though conclusive evidence about the teratogenecity of diclofenac in human embryos is lacking, animal studies have shown that administration of the drug at a high concentration, in early gestation, inhibits implantation and embryonic development.[1] It crosses the human placenta readily during the first trimester and should be considered as potentially teratogenic.[3] Ventricular septal defect and aplasia cutis congenita have been reported in babies born to mothers on diclofenac therapy.[4,5] The drug is known to accumulate in the fetal tissue with time. It is usually prescribed in multiple doses, thereby resulting in a high probability of fetal tissue concentration reaching the teratogenic level.[1] The exact mechanism of diclofenac-induced teratogenecity is uncertain. It may result from free oxygen radical damage to the developing embryo. Also, it has been postulated that by inhibiting the synthesis of vasodilatory prostaglandins, diclofenac can cause transient vasoconstriction and decreased blood supply, resulting in malformation and cellular death.

INFLUENCE OF HYPERGLYCEMIA ON OXIDATIVE STRESS AND DNAase-MEDIATED GENOMIC FRAGMENTATION COUPLED WITH APOPTOTIC AND NECROTIC CELL DEATHS IN KIDNEY

Diclofenac (DCLF) is a potent inhibitor of prostaglandin synthesis and an established antipyretic and analgesic agent. It also has a nephrotoxic profile caused by generation of reactive oxygen species and enhanced apoptotic DNA fragmentation. The specific goals of this investigation were to determine

Insulin/FOXO Signaling Regulates Ovarian Prostaglandins Critical for Reproduction

Abnormalities in insulin/IGF-1 signaling are associated with infertility, but the molecular mechanisms are not well understood. Here we use liquid chromatography with electrospray ionization tandem mass spectrometry to show that the C. elegans insulin/FOXO pathway regulates the metabolism of locally acting lipid hormones called prostaglandins. C. elegans prostaglandins are synthesized without prostaglandin G/H synthase homologs, the targets of nonsteroidal anti-inflammatory drugs. Our results support the model that insulin signaling promotes the conversion of oocyte polyunsaturated fatty acids (PUFAs) into F-series prostaglandins that guide sperm to the fertilization site. Reduction in insulin signaling activates DAF-16/FOXO, which represses the transcription of germline and intestinal genes required to deliver PUFAs to oocytes in lipoprotein complexes. Nutritional and neuroendocrine cues target this mechanism to control prostaglandin metabolism and reproductive output. Prostaglandins may be conserved sperm guidance factors and widespread downstream effectors of insulin actions that influence both reproductive and nonreproductive processes.

Many Putative Endocrine Disruptors Inhibit Prostaglandin Synthesis

BackgroundProstaglandins (PGs) play key roles in development and maintenance of homeostasis of the adult body. Despite these important roles, it remains unclear whether the PG pathway is a target for endocrine disruption. However, several known endocrine-disrupting compounds (EDCs) share a high degree of structural similarity with mild analgesics.Objectives and MethodsUsing cell-based transfection and transduction experiments, mass spectrometry, and organotypic assays together with molecular modeling, we investigated whether inhibition of the PG pathway by known EDCs could be a novel point of endocrine disruption.ResultsWe found that many known EDCs inhibit the PG pathway in a mouse Sertoli cell line and in human primary mast cells. The EDCs also reduced PG synthesis in ex vivo rat testis, and this reduction was correlated with a reduced testosterone production. The inhibition of PG synthesis occurred without involvement of canonical PG receptors or the peroxisome proliferator–activated receptors (PPARs), which have previously been described as targets of EDCs. Instead, our results suggest that the compounds may bind directly into the active site of the cyclooxygenase (COX) enzymes, thereby obstructing the conversion of arachidonic acid to PG precursors without interfering with the expression of the COX enzymes. A common feature of the PG inhibitory EDCs is the presence of aromatic groups that may stabilize binding in the hydrophobic active site of the COX enzymes.ConclusionOur findings suggest a hitherto unknown mode of action by EDCs through inhibition of the PG pathway and suggest new avenues to investigate effects of EDCs on reproductive and immunological disorders that have become increasingly common in recent decades.

Non-Steroidal Anti Inflammatory Drugs Usage In Orthopaedics And Trauma Practice ---- A Guide And Review

Non steroidal anti-inflammatory drugs (NSAIDs) are a group of heterogeneous compounds with anti inflammatory, analgesic and often times anti pyretic properties. They are weak organic acids and are the most commonly used drugs in Orthopaedic/Trauma practice. They provide mild to moderate pain relief. NSAID share common therapeutic and side effects irrespective of the class or group to which an individual drug may belong. These side effects are many and varied and constitute a major concern in their usage since most of them are life threatening. The NSAIDs are also one of the most commonly abused drugs. The abuses stem mostly from poor prescription habit by the health professionals. The poor prescription habit by the professionals and laissez-a-faire attitude to NSAID Usage informed the need for this review which addresses the issues, controversies and preventive strategies to reduce the complications in Orthopedics/Trauma practice. Literature on the subject was reviewed extensively using manual library internet search. Publications from local and international Journals spanning a period of over thirty years were reviewed. The internet search was done using pubmed and ortholink search engines. NSAIDs act locally at the site of origin of pain by inhibiting the cyclooxygenase enzymes and induce no change in mood and dependency The inhibition of the Cox enzymes can be reversible or irreversible and leads to inhibition of prostaglandin synthesis. All the therapeutic and most of the side effects of NSAIDs result from the inhibition of the cyclooxygenase pathway. Thus the Cox-2 selective inhibitors have lesser side effects than the non selective Cox inhibitors; though there is recent evidence linking them with adverse cardiovascular events. There is paucity of information in literature on the guidelines of the prescription/usage of NSAIDs, and the preventive strategies in orthopedics and traumatology. NSAIDs are the most commonly prescribed group of drugs in orthopedics and trauma practice. They constitute a great asset to any Doctor who deals with pains associated with inflammation which they relief quite effectively. NSAID Usage is froth with significant life threatening complications. A high index of suspicion of the possibility of occurrence of these complications, adherence to proper prescription guidelines and preventive strategies, change of the laissez-a-faire attitude of the professionals to NSAID prescription and appropriate monitoring of the patients on the drugs are paramount in improving their safety profiles. Orthopedic and Trauma surgeons need to be aware of the serious side effects and the role of preventive strategies in the use of NSAIDs.

Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat

More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. In a prospective birth cohort study, 2297 Danish and Finnish pregnant women completed a questionnaire and 491 of the Danish mothers participated in a telephone interview, reporting on their use of mild analgesics during pregnancy. The testicular position of newborns was assessed by trained paediatricians. In rats, the impact of mild analgesics on anogenital distance (AGD) after intrauterine exposure was examined together with the effect on ex vivo gestational day 14.5 testes. In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort. Intrauterine exposure of rats to paracetamol led to a reduction in the AGD and mild analgesics accordingly reduced testosterone production in ex vivo fetal rat testes. There was an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings were supported by anti-androgenic effects in rat models leading to impaired masculinization. Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders.

Increased renal sodium absorption by inhibition of prostaglandin synthesis during fasting in healthy man. A possible role of the epithelial sodium channels

BackgroundTreatment with prostaglandin inhibitors can reduce renal function and impair renal water and sodium excretion. We tested the hypotheses that a reduction in prostaglandin synthesis by ibuprofen treatment during fasting decreased renal water and sodium excretion by increased absorption of water and sodium via the aquaporin2 water channels and the epithelial sodium channels.MethodsThe effect of ibuprofen, 600 mg thrice daily, was measured during fasting in a randomized, placebo-controlled, double-blinded crossover study of 17 healthy humans. The subjects received a standardized diet on day 1, fasted at day 2, and received an IV infusion of 3% NaCl on day 3. The effect variables were urinary excretions of aquaporin2 (u-AQP2), the beta-fraction of the epithelial sodium channel (u-ENaCbeta), cyclic-AMP (u-cAMP), prostaglandin E2 (u-PGE2). Free water clearance (CH2O), fractional excretion of sodium (FENa), and plasma concentrations of vasopressin, angiotensin II, aldosterone, atrial-, and brain natriuretic peptide.ResultsIbuprofen decreased u-AQP2, u-PGE2, and FENa at all parts of the study. During the same time, ibuprofen significantly increased u-ENaCbeta. Ibuprofen did not change the response in p-AVP, u-c-AMP, urinary output, and free water clearance during any of these periods. Atrial-and brain natriuretic peptide were higher.ConclusionDuring inhibition of prostaglandin synthesis, urinary sodium excretion decreased in parallel with an increase in sodium absorption and increase in u-ENaCbeta. U-AQP2 decreased indicating that water transport via AQP2 fell. The vasopressin-c-AMP-axis did not mediate this effect, but it may be a consequence of the changes in the natriuretic peptide system and/or the angiotensin-aldosterone systemTrial RegistrationClinical Trials Identifier: NCT00281762

ORIGINAL ARTICLE: Comparison of Two Neonatal Indomethacin Protocols: Efficacy and Outcome for Patent Ductus Arteriosus Closure

Indomethacin, a non-selective inhibitor of prostaglandin synthesis, is the gold standard treatment for patent ductus arteriosus (PDA). Indomethacin has been shown to permanently close the ductus and when given prophylactically, it reduces the incidence of PDA (1, 2). This study compares PDA closure and surgical ligation rates between patients using two different indomethacin administration protocols. This is a retrospective comparison analysis of 72 neonates, who received one of two indomethacin administration protocols. Our previous protocol suggested an initial dose of 0·2 mg/kg followed by two 0·1 mg/kg, with doses infused over 4 h and a 24-h dosing interval. A new potentially more useful protocol using the same mg/kg dose regimen but with doses infused over 30 min and a 12-h dosing interval, was evaluated. Each neonate was allowed three courses of treatment before surgical ligation was performed for persistent PDA. There were no statistically significant differences between the two protocol groups when comparing percentages of neonates with gestational age≤28 weeks, birth weight≤1000 g, male gender or receiving indomethacin for the indication of PDA prophylaxis vs. treatment. There was a trend towards a higher PDA closure rate and subsequently a lower PDA ligation rate in the new protocol when compared with the previous protocol. In this small population of premature neonates, there was a trend, but no significant difference, towards increasing PDA closure and lower surgical ligation rates in neonates given indomethacin with more frequent dosing and shorter infusion time. A well-powered randomized controlled trial is now needed.

TNF-α stimulates alkaline phosphatase and mineralization through PPARγ inhibition in human osteoblasts

The aims of the present study were to determine whether prostaglandins (PGs) and PPARγ are involved in the stimulation of tissue-non-specific alkaline phosphatase (TNAP) activity and mineralization by TNF-α in human osteoblasts. We used osteoblasts differentiated from MSCs from three different donors and MG-63 osteoblast-like cells. Inhibition of prostaglandin synthesis with the cyclooxygenase (COX) inhibitor indomethacin or the specific COX-2 blocker NS-398 abolished mineralization in the absence and presence of 1 ng/ml of TNF-α, suggesting that PGs were involved. The TNAP inhibitor levamisole abolished TNF-α effects on mineralization, suggesting that PGs were involved in TNAP expression and mineralization. TNF-α stimulated expression of COX-2 and PG E synthase before that of TNAP, but expression of PG D synthase later suggesting that PGE 2 and PGF 2α but not 15d-PGJ 2 were involved in TNF-α effects. However, both PGE 2 and PGF 2α dose-dependently inhibited mineralization indicating that endogenous PG are required for mineralization but that TNF-α does not increase mineralization by increasing PG synthesis. Interestingly, TNF-α inhibited PPARγ expression and binding activity to PPRE consensus sequences independently of 15d-PGJ 2. Inhibition of PPARγ activity with GW-9662 mimicked TNF-α effects in MG-63 cells, indicating that TNF-α stimulates mineralization by inhibiting PPARγ in osteoblasts. In MSC-derived osteoblast cultures, inhibition of PPARγ dropped TNAP expression and mineralization. Treatment of MG-63 cells with conditioned media from MSC-derived osteoblasts or MSC-derived adipocytes treated or not with GW-9662 revealed that TNF-α inhibition of PPARγ in undifferentiated MSCs and/or adipocytes was responsible for the decreased expression of TNAP in osteoblasts. In conclusion, TNF-α increases TNAP expression and stimulates mineralization by inhibiting PPARγ in osteoblasts, but PPARγ in adipocytes or undifferentiated MSCs controls the secretion of a factor leading to TNAP stimulation in osteoblasts.

Nitric oxide synthase inhibition attenuates cutaneous vasodilation during postmenopausal hot flash episodes

The purpose of this study was to test the hypothesis that local inhibition of nitric oxide and prostaglandin synthesis attenuates cutaneous vasodilator responses during postmenopausal hot flash episodes. Four microdialysis membranes were inserted into the forearm skin (dorsal surface) of eight postmenopausal women (mean +/- SD age, 51 +/- 7 y). Ringer solution (control), 10 mM ketorolac (Keto) to inhibit prostaglandin synthesis, 10 mM N-l-arginine methyl ester (l-NAME) to inhibit nitric oxide synthase, and a combination of 10 mM Keto + 10 mM l-NAME were each infused at the separate sites. Skin blood flow at each site was indexed using laser-Doppler flowmetry. Cutaneous vascular conductance (CVC) was calculated as laser-Doppler flux/mean arterial blood pressure and was expressed as a percentage of the maximal calculated CVC (CVCmax) obtained after infusion of 50 mM sodium nitroprusside at all sites at the end of the study. Data from 13 hot flash episodes were analyzed. At the control site, the mean +/- SD peak increase in CVC was 15.5% +/- 6% CVCmax units. This value was not different relative to the peak increase in CVC at the Keto site (13.0% +/- 5% CVCmax units; P = 0.09). However, the peak increase in CVC during hot flash episodes were attenuated at the l-NAME and l-NAME + Keto sites (7.4% +/- 4% and 8.7% +/- 7% CVCmax units, respectively) relative to both the control and the Keto sites (P < 0.05 for both comparisons). There were no significant differences in the peak increases in sweat rate between any of the sites (P = 0.24). These data demonstrate that the mechanism for cutaneous vasodilation during hot flash episodes has a nitric oxide component. Increases in CVC despite the inhibition of prostaglandin synthesis suggest that prostaglandins do not contribute to cutaneous vasodilation during hot flash episodes.

COX-2 inhibition improves immunotherapy and is associated with decreased numbers of myeloid-derived suppressor cells in mesothelioma. Celecoxib influences MDSC function

BackgroundMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature cells that accumulates in tumour-bearing hosts. These cells are induced by tumour-derived factors (e.g. prostaglandins) and have a critical role in immune suppression. MDSC suppress T and NK cell function via increased expression of arginase I and production of reactive oxygen species (ROS) and nitric oxide (NO). Immune suppression by MDSC was found to be one of the main factors for immunotherapy insufficiency. Here we investigate if the in vivo immunoregulatory function of MDSC can be reversed by inhibiting prostaglandin synthesis by specific COX-2 inhibition focussing on ROS production by MDSC subtypes. In addition, we determined if dietary celecoxib treatment leads to refinement of immunotherapeutic strategies.MethodsMDSC numbers and function were analysed during tumour progression in a murine model for mesothelioma. Mice were inoculated with mesothelioma tumour cells and treated with cyclooxygenase-2 (COX-2) inhibitor celecoxib, either as single agent or in combination with dendritic cell-based immunotherapy.ResultsWe found that large numbers of infiltrating MDSC co-localise with COX-2 expression in those areas where tumour growth takes place. Celecoxib reduced prostaglandin E2 levels in vitro and in vivo. Treatment of tumour-bearing mice with dietary celecoxib prevented the local and systemic expansion of all MDSC subtypes. The function of MDSC was impaired as was noticed by reduced levels of ROS and NO and reversal of T cell tolerance; resulting in refinement of immunotherapy.ConclusionsWe conclude that celecoxib is a powerful tool to improve dendritic cell-based immunotherapy and is associated with a reduction in the numbers and suppressive function of MDSC. These data suggest that immunotherapy approaches benefit from simultaneously blocking cyclooxygenase-2 activity.

Indométacine : le retour d’un tocolytique controversé ? Point de vue de l’obstétricien

The main aim of tocolysis is to improve the health of newborns. Given the modest impact in terms of perinatal health of tocolysis we must emphasize the use of tocolytics which, equally effective, have fewer maternal side effects than beta-agonists and are devoid of potential complications for mother and the newborn. Inhibitors of prostaglandin synthesis and calcium antagonists of oxytocin seem to meet these criteria. The recent papers for the use of NSAIDs provide no fundamentally new scientific data. This therapy is potentially associated with severe neonatal complications and superiority to calcium channel blockers or antagonists of oxytocin in terms of prolongation of pregnancy is not established. It seems reasonable to reserve them for special situations by their severity, precocity of the age of gestation or by the ineffectiveness of other treatments. In practice, it is recommended not to use NSAIDs first line, beyond 32 weeks and treatment should be of short duration (less than 48 to 72 hours). Ideally, delivery should not occur within 48 hours after stopping treatment.

Modulation of the immune system by Boswellia serrata extracts and boswellic acids

Extracts from the gum resin of Boswellia serrata and some of is constituents including boswellic acids affect the immune system in different ways. Among the various boswellic acids 11-keto-beta-boswellic acid (KBA) and acetyl-11-keto-beta-boswellic acid have been observed to be active. However, also other boswellic acids may exhibit actions in the immune system. In the humoral defence system a mixture of boswellic acis at higher doses reduced primary antibody titres; on the other hand lower doses enhanced secondary antibody titres following treatment with sheep erythrocytes. In the cellular defence boswellic acides appear to increase lymphocyte proliferation whereas higher concentrations are even inhibitory. Moreover, BAs increase phagocytosis of macrophages. BAs affect the cellular defence system by interaction with production/release of cytokines. Thus, BAs inhibit activation of NFkappaB which is a product of neutrophile granulocytes. Consequently a down regulation of TNF-alpha and decrease of IL-1, IL-2, IL-4, IL-6 and IFN-gamma, which are proinflammatory cytokines by BEs and BAs has been reported. Suppressions of the classic way of the complement system was found to be due to inhibition of the conversion of C3 into C3a and C3b. However, which of these pharmacological actions contribute to the therapeutic effects and which is finally the best dosage of a standardized extract needs further examination. And it is also a question whether or not a single BA will have the same therapeutic effect as a standardized extract. Among the mediators of inflammatory reaction, mast cell stabilisation has been described by a BE. Inhibition of prostaglandin synthesis appears to play only a minor role as far as the anti-inflammatory effect is concerned. On the other hand the inhibitory action of BAs on 5-LO leading to a decreased production of leukotrienes has received high attention by the scientific community since a variety of chronic inflammatory diseases is associatied with increased leukotriene activity. At the end of the cascade of events in the cellular immune system as far as it directs to various tissues of the body - i.e. autoimmune diseases - formation of oxygen radicals and proteases (for example elastase) play an important destructive role. Here, BEs as well as BAs have been found to be inhibitory. From the pharmacological properties of BEs and BAs it is not surprising that positive effects of BEs in some chronic inflammatory diseases including rheumatoid arthritis, bronchial asthma, osteoarthritis, ulcerative colitis and Crohn's disease have been reported.