Aspirin-like Drugs Research Articles

Fifty years with aspirin and platelets.

In 2021, we reached the 50th anniversary of the publication of Sir John Vane's seminal paper in Nature New Biology describing the experiments supporting his mechanistic hypothesis that inhibition of prostaglandin synthesis might explain the main pharmacological effects of aspirin and aspirin-like drugs, that is, reduction in pain, fever and inflammation. Bengt Samuelsson's subsequent discoveries elucidating the cyclooxygenase pathway of platelet arachidonic acid metabolism motivated my research interest towards measuring platelet thromboxane A2 biosynthesis as a tool to investigate the clinical pharmacology of cyclooxygenase inhibition by aspirin in health and disease. What followed was a long, winding road of clinical research leading to the characterization of low-dose aspirin as a life-saving antiplatelet drug that still represents the cornerstone of antithrombotic therapy. Having witnessed and participated in these 50 years of aspirin research, I thought of providing a personal testimony of how things developed and eventually led to a remarkable success story of independent research.

How Does Aspirin Work in Plants and Humans?

Millions of people rely on aspirin to treat their headaches, fevers, and other ailments. But most people do not know that the active ingredient in aspirin was first discovered in plants. In humans, the body converts aspirin into a substance called salicylic acid (SA). Plants make SA. They use it to help defend themselves against infection. To discover how SA works in plants, we used powerful methods to identify over two dozen proteins that bind to SA. SA binding changes the activities of these proteins. SA and related compounds also bind to multiple proteins in humans. We discovered several new human proteins that can bind SA. These proteins are associated with very common, devastating human diseases. In addition, we identified several new versions of SA that bind to these proteins more strongly than SA does. As a result, these versions of SA inhibit the disease-associated activities of these proteins better than SA. This gives hope that better aspirin-like drugs can be made.

In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.

The purpose of these studies was to test the hypothesis that a selected polypharmacological approach for treating the prostanoid-mediated component of inflammatory diseases would produce a therapeutic effect superior to global inhibition of prostaglandin (PG) biosynthesis by aspirin-like drugs. The compound studied was AGN 211377, which had been previously shown to produce a superior effect on cytokine release from human macrophages compared with cyclooxygenase (COX) inhibitors. AGN 211377 antagonizes prostanoid prostaglandin D2 (DP)1, DP2, prostaglandin E2 (EP)1, EP4, prostaglandin F2α, and thromboxane A2 receptors but not anti-inflammatory EP2, prostaglandin I2, or EP3 receptors. Established rodent models of ocular inflammatory diseases were used to determine therapeutic effects in living animals. The drugs were administered systemically after predetermination of their blood levels to ensure bioavailability at an appropriate dose level. Whereas compounds selective for a single prostanoid receptor typically exhibited modest but statistically significant inhibition, AGN 211377 profoundly inhibited S-antigen-induced uveitis and laser-induced retinal neovascularization. Consistent with previous polypharmacological studies on chemokine/cytokine release from human macrophages, the prostanoid EP1 receptor played a permissive role in suppressing neovascularization and inflammation in vivo Comparing AGN 211377 with a close structural congener lacking EP1 antagonism (AGN 197727), AGN 197727 was much less active than AGN 211377, but pronounced anti-inflammatory and angiostatic effects were achieved by adding the EP1 antagonist compound (SC-51322) to AGN 197727 in the systemic dosing regimen. Further, AGN 211377 produced superior anti-inflammatory activity compared with the nonsteroidal anti-inflammatory agent ketorolac. These results indicate the value of using a polypharmacological approach in the design of novel therapeutic agents in preference to compounds targeting a single receptor or enzyme. A compound such as AGN 211377 may represent more effective therapy than COX inhibitors in treating uveitis and ocular diseases where neovascularization is a significant part of the pathology.-Woodward, D. F., Wang, J. W., Ni, M., Bauer, A., Martos, J. L., Carling, R. W., Poloso, N. J. In vivo studies validating multitargeting of prostanoid receptors for achieving superior anti-inflammatory effects.

From plant extract to molecular panacea: a commentary on Stone (1763) 'An account of the success of the bark of the willow in the cure of the agues'.

The application of aspirin-like drugs in modern medicine is very broad, encompassing the treatment of inflammation, pain and a variety of cardiovascular conditions. Although anecdotal accounts of willow bark extract as an anti-inflammatory drug have occurred since written records began (for example by Hippocrates), the first convincing demonstration of a potent anti-pyretic effect of willow bark containing salicylates was made by the English cleric Edward Stone in the late eighteenth century. Here, we discuss the route to optimizing and understanding the mechanism of action of anti-inflammatory drugs that have their origins in Stone's seminal study, ‘An account of the success of the bark of the willow in the cure of agues’. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Synergy between medicinal chemistry and biological research.

Salvador Moncada studied medicine at the University of El Salvador (El Salvador) before coming to the UK in 1971 to work on a PhD with Professor John Vane at the Institute of Basic Medical Sciences, Royal College of Surgeons (UK). After a short period of research at the University of Honduras (Honduras), he joined the Wellcome Research Laboratories (UK) where he became Head of the Department of Prostaglandin Research and later, Director of Research. He returned to academic life in 1996 as founder and director of the Wolfson Institute for Biomedical Research at University College London (UK). Moncada played a role in the discovery of the mechanism of action of aspirin-like drugs and later led the teams which discover prostacyclin and identified nitric oxide as a biological mediator. In his role as a Director of Research of the Wellcome Laboratories, he oversaw the discovery and development of medicines for epilepsy, migraine, malaria and cancer. Currently, he is working on the regulation of cell proliferation as Director of the Institute of Cancer Sciences at the University of Manchester (UK). Moncada has won numerous awards from the international scientific community and in 2010, he received a knighthood from Her Majesty Queen Elizabeth II for his services to science.

Appropriate Assessment of the Functional Consequences of Platelet Cyclooxygenase-1 Inhibition by Aspirin in vivo

Chronic use of low dose aspirin (acetylsalicylic acid) is generally an effective and relatively low cost strategy for preventing and treating cardiovascular disease [1]. John Vane reported the inhibition of prostaglandin synthesis as a mechanism of action of aspirin-like drugs in 1971 by demonstrating a dose-dependent inhibition of prostaglandin synthesis by aspirin, sodium salicylate and indomethacin [2]. Thromboxane A2 (TxA2) was subsequently identified by Samuelsson’s group as the potent vasoconstrictor and platelet agonist the synthesis of which was inhibited by aspirin [3].

Angiogenic and Anti-Angiogenic Therapy for Gastrointestinal Ulcers: New Challenges for Rational Therapeutic Predictions and Drug Design

Gastrointestinal (GI) ulcers are essentially internal wounds that resist normal healing processes. Since their pathogenesis is poorly understood, and the etiologic (e.g., gastric acid, aspirin-like drugs, stress) and aggravating factors (e.g., H. pylori) are not well characterized, the remaining therapeutic option is to accelerate healing. Superficial mucosal lesions, i.e., erosions usually heal by epithelial regeneration and restitution, but when ulcers involve the muscularis propria, smooth muscle cells do not divide/regenerate. These deep lesions are filled by granulation tissue, i.e., angiogenesis followed by proliferation of connective tissue fibroblasts that deposit collagen over which adjacent surviving and dividing epithelial cells migrate to complete the healing. Our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the GI tract. Indeed, daily treatment of rats with bFGF, PDGF or VEGF markedly improved the healing of cysteamine-induced chronic duodenal ulcers, without any reduction in gastric acid secretion. These results were reproduced by a single dose of gene therapy by adenoviral vectors encoding PDGF or VEGF genes. The molar potency of angiogenic growth factors was 2-7 million times better than the antiulcerogenic effect of antisecretory H2 antagonists. Since histologically & pathologically gastroduodenal ulcers look similar to ulcers in the lower GI tract, we also predicted that the healing of experimental ulcerative colitis might be also improved by these angiogenic growth factors. Rectal enemas containing bFGF or PDGF indeed accelerated the healing of chemically induced ulcerative colitis in rats. VEGF, also known as VPF (vascular permeability factor), however, had no effect or slightly aggravated the colonic lesions. Injection of anti-VEGF neutralizing antibodies, however, counteracted the increased vascular permeability in the early stages of experimental ulcerative colitis and subsequently decreased the number of inflammatory cells in colonic ulcers in rats, resulting in significantly improved healing in the lower GI tract lesions. Thus, the three angiogenic growth factors tested exerted beneficial effect on gastroduodenal ulcers, and rectal enemas with bFGF or PDGF also accelerated the healing of experimental ulcerative colitis. Surprisingly, we achieved the latter effect with anti-VEGF antibodies, most likely because of the pro-inflammatory actions of VEGF in the pathogenesis of ulcerative colitis.

Prostanoids and inflammation: a new concept arising from receptor knockout mice

Prostanoids including various types of prostaglandins and thromboxanes are arachidonate metabolites produced and released in response to a variety of physiological and pathological stimuli and function to maintain the body homeostasis. Since cyclooxygenase, the enzyme initiating their biosynthesis, is inhibited by aspirin-like antipyretic, anti-inflammatory, and analgesic drugs, contribution of prostanoids to acute inflammation such as fever generation, pain sensitization, and inflammatory swelling has been recognized very early. On the other hand, since aspirin-like drugs generally show little effects on allergy and immunity, it has been believed that prostanoids play little roles in these processes. Prostanoids act on a family of G-protein-coupled receptors designated PGD receptor, PGE receptor subtypes EP1-EP4, PGF receptor, PGI receptor, and TX receptor to elicit their actions. Studies using mice deficient in each of these receptors have revealed that prostanoids indeed function in the above aspirin-sensitive processes. However, these studies have also revealed that prostanoids exert both pro-inflammatory and anti-inflammatory actions not only by acting as mediators of acute inflammation but also by regulating gene expression in mesenchymal and epithelial cells at inflammatory site. Such dual actions of prostanoids are frequently seen in immune and allergic reactions, where different type of prostanoids and their receptors often exert opposite actions in a single process. Thus, a new concept on the role of prostanoids in inflammation has arisen from studies using the receptor knockout mice.

The Interrelationship Between Gastric pH and Therapeutic Response to Esomeprazole in Patients with Uninvestigated Dyspepsia

Purpose: Management of dyspepsia remains a challenge both in research and clinical practice. Pharmacological therapy, targeting gastric acid suppression results in relief of symptoms in majority of patients complaining of epigastric pain/discomfort related to uninvestigated dyspepsia; however, the relationship between symptom relief and the degree of acid suppression has not been adequately explored. Therefore, the aims of the study were as follows: 1. To evaluate the impact of esomeprazole vs. placebo on gastric acid during 24 h pH monitoring. 2. To asses the relationship between relief of dyspepsia symptoms and changes in gastric pH. Methods: This randomized, double-blind trial was conducted on KUMC patients with uninvestigated dyspepsia, diagnosed acc. to Rome II criteria, with at least moderately severe symptoms of epigastric pain/discomfort. Patients with heartburn or regurgitation as their predominant symptoms, H. pylori (+) or aspirin-like drugs users were excluded. Patients (mean age of 44.2; 62.2% F) were randomized to placebo (N = 35) or esomeprazole (N = 38) 40 mg QD groups. Primary outcome measures were satisfactory relief of pain/discomfort symptoms, a 7-day daily diary preceding each visit, quality of life questionnaire, and global overall symptoms assessment. Gastric pH was monitored for 24 h at baseline and after 4 and 8 weeks of therapy, using dual probe catheter and pH Monitoring System (Sandhill Sci.). Results: Both responders (R) and non-responders (NR) exhibited similar baseline gastric acid secretion at distal (D) and proximal (P) probes: (pH > 4.0 in min) 201 min RD, 177 min NRD, 641 min RP, and 628 min NRP, respectively. Administration of esomeprazole for 4 weeks resulted in profound inhibition of gastric acid secretion reflected by significant (P < 0.01) increase in time pH > 4.0 both among R and NR at D and P pH probe locations. During 2nd therapy interval R exhibited, however, higher degree of gastric acid inhibition, 361% (P < 0.001) increase of time pH >4.0 over baseline value in D probe, whereas NR only 157% (P= 0.12) increase. Higher degree of gastric acid inhibition, 162% (P < 0.001) over baseline value, was also revealed in the P probe in R vs. only 97% increase in NR (P= 0.22). Conclusion: 1. Intragastric pH monitoring before and after therapy may help to address interrelationship between symptomatic relief of dyspepsia symptoms and gastric acid secretion inhibition and could potentially help to tailor individual therapy. 2. Esomeprazole, 40 QD, provides profound inhibition of gastric acid secretion as reflected in time pH > 4.0 in patient with dyspepsia accompanied by significant relief of symptoms.

Prostaglandin E2 Attenuates Preoptic Expression of GABAA Receptors via EP3 Receptors

Prostaglandin E(2) (PGE(2)) has been shown to produce fever by acting on EP3 receptors within the preoptic area of the brain. However, there is little information about the molecular events downstream of EP3 activation in preoptic neurons. As a first step toward this issue, we examined PGE(2)-induced gene expression changes at single-cell resolution in preoptic neurons expressing EP3. Brain sections of the preoptic area from PGE(2)- or saline-injected rats were stained with an anti-EP3 antibody, and the cell bodies of EP3-positive neurons were dissected and subjected to RNA amplification procedures. Microarray analysis of the amplified products demonstrated the possibility that gene expression of gamma-aminobutyric acid type A (GABA(A)) receptor subunits is decreased upon PGE(2) injection. Indeed, we found that most EP3-positive neurons in the mouse preoptic area are positive for the alpha2 or gamma2 GABA(A) receptor subunit. Moreover, PGE(2) decreased the preoptic gene expression of these GABA(A) subunits via an EP3-dependent and pertussis toxin-sensitive pathway. PGE(2) also attenuated the preoptic protein expression of the alpha2 subunit in wild-type but not in EP3-deficient mice. These results indicate that PGE(2)-EP3 signaling elicits G(i/o) activation in preoptic thermocenter neurons, and we propose the possibility that a rapid decrease in preoptic GABA(A) expression may be involved in PGE(2)-induced fever.

The roles of prostanoids in inflammation, allergy, and immunity

Prostanoids, consisting of the prostaglandins (PGs) and the thromboxanes (TXs), are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. Given that aspirin-like nonsteroidal anti-inflammatory drugs exert their actions by suppressing prostanoid production, prostanoids have been implicated in processes inhibited by these drugs, including inflammation, fever, and pain. However, how prostanoids exert such a variety of actions had remained unclear. Prostanoids are released outside of the cells immediately after synthesis, and exert their actions by binding to receptors on the surface of target cells. We have identified a family of eight types or subtypes of G protein-coupled receptors that mediate prostanoid actions. They are the PGD receptor (DP), four subtypes of the PGE receptor (EP1, EP2, EP3, and EP4), the PGF receptor (FP), PGI receptor (IP), and TXA receptor (TP). Recently mice deficient in each of these prostanoid receptors were generated and subjected to various experimental models of disease. These studies have not only elucidated the molecular and cellular mechanisms of known prostanoid actions but also revealed previously unknown actions. In this article, we review several recent findings of the roles of prostanoid receptor signalling in inflammation, allergy, and immunity.

The roles of prostanoids in infection and sickness behaviors

A systemic infection in patients causes so-called sickness behaviors, such as fever generation, adrenocorticotropic hormone release, reduced locomotion, loss of social contact, anorexia, and increased sleep. As aspirin-like non-steroidal anti-inflammatory drugs alleviate most of these symptoms, the involvement of prostanoids in the generation of sickness behaviors has been strongly suggested. Prostanoids, consisting of prostaglandins (PGs) and thromboxanes (TXs), are a group of lipid mediators formed in response to various stimuli. They include PGD2, PGE2, PGF2alpha, PGI2, and TXA2. Immediately after synthesis, they are released outside the cells, and exert their actions by binding to a G-protein-coupled rhodopsin-type receptor on the surface of target cells. There are eight types of prostanoid receptors: the PGD receptor, four subtypes of PGE receptor, the PGF receptor, the PGI receptor, and the TXA receptor. Recently, mice deficient in each of these prostanoid receptors were generated and the examination of these mice in various experimental disease models revealed the important roles of prostaglandin receptor signaling in various pathological processes. In this review, we describe several recent findings that have addressed the mechanisms underlying sickness behaviors and that have identified the critical roles of the signaling of each prostanoid receptor in the elicitation of the stress responses associated with these sickness behaviors.

Stimulating the development of mechanism-based, individualized pain therapies

Biomedical science has greatly improved our understanding of pain in recent decades, but few novel molecular entities that address fundamentally new pain mechanisms have entered the clinic, despite dramatically increased pharmaceutical investment. Indeed, virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin-like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. Here, we discuss factors contributing to this lack of innovation in therapies for pain and advocate public-private partnerships (PPPs) to translate new knowledge into more efficacious and safer treatments.

Nitroparacetamol (NCX‐701) and Pain: First in a Series of Novel Analgesics

The combination of numerous classic drugs with nitric oxide donors has led to the development of new compounds with promising therapeutic activities in a great variety of situations, including cardiovascular and respiratory systems, ocular pressure, inflammation, and pain. One of the first compounds developed was NCX-701 or nitroparacetamol, resulting from the combination of paracetamol, a classic and popular analgesic used in a great number of over-the-counter medications because of its antipyretic and analgesic properties, and a nitrooxybutyroyl moiety, which releases nitric oxide at a low but steady level. Although paracetamol is devoid of most of the gastrointestinal toxicity associated with aspirin-like drugs, this type of compounds was first designed to take advantage of the cytoprotective properties of nitric oxide when released at low concentrations. However, the combination of these molecules also resulted in an unexpected enhancement of the analgesic activity of paracetamol. In fact, NCX-701 has been shown to be effective in acute nociception as well as in neuropathic pain, situations in which paracetamol and other COX inhibitors are devoid of any effect. In addition, NCX-701 is more potent and, in some circumstances, more effective than its parent compound in different models of inflammatory pain. Furthermore, whereas paracetamol lacks any effective antiinflammatory action, NCX-701 might reduce inflammation. All these results taken together imply that the mechanism of action of NCX-701 is different from that of paracetamol, although it is not yet established for either molecule. NCX-701 appears to be a promising compound in the treatment of different types of pain, with a likely better profile of side effects than its parent molecule, paracetamol. Although recent clinical trials provided data consistent with the preclinical profile of NCX-701, further studies are needed to support its clinical use.

Inhibition of Cyclooxygenases by Dipyrone

Dipyrone is a potent analgesic drug that has been demonstrated to inhibit cyclooxygenase (COX). In contrast to classical COX-inhibitors, such as aspirin-like drugs, dipyrone has no anti-inflammatory effect and a low gastrointestinal toxicity, indicating a different mode of action. Here, we aimed to investigate the effects of dipyrone on COX. The four major metabolites of dipyrone, including the two pharmacologically active metabolites, 4-methyl-amino-antipyrine (MAA) and amino-antipyrine (AA), were used to characterise their binding to COX and haem as well as their effects on the biochemical properties of COX. Mass spectrometry, UV and visible photometry were used to study binding and prostaglandin production. Levels of anti-oxidant enzymes were assessed by Western blotting. The pharmacologically active metabolites of dipyrone, MAA and AA, did not inhibit COX activity in vitro like classical COX inhibitors, but instead redirected the prostaglandin synthesis, ruling out inhibition of COX through binding to its active site. We found that MAA and AA formed stable complexes with haem and reacted with hydrogen peroxide in presence of haem, ferrous ions (Fe(2+)) or COX. Moreover, MAA reduced Fe(3+) to Fe(2+) and accordingly increased lipid peroxidation and the expression of anti-oxidant enzymes in cultured cells and in vivo. Our data suggest that the pharmacologically active metabolites of dipyrone inhibit COX activity by sequestering radicals which initiate the catalytic activity of this enzyme or through the reduction of the oxidative states of the COX protein.

Evidence for in situ ethanolamine phospholipid adducts with hydroxy-alkenals

Hydroxy-alkenals, such as 4-hydroxy-2(E)-nonenal (4-HNE; from n-6 fatty acids), are degradation products of fatty acid hydroperoxides, including those generated by free radical attack of membrane polyunsaturated fatty acyl moieties. The cytotoxic effects of hydroxy-alkenals are well known and are mainly attributable to their interaction with different molecules to form covalent adducts. Indeed, ethanolamine phospholipids (PEs) can be covalently modified in a cellular system by hydroxy-alkenals, such as 4-HNE, 4-hydroxy-2(E)-hexenal (4-HHE; from n-3 fatty acids), and 4-hydroxy-dodecadienal (4-HDDE; from the 12-lipoxygenase product of arachidonic acid), to form mainly Michael adducts. In this study, we describe the formation of PE Michael adducts in human blood platelets in response to oxidative stress and in retinas of streptozotocin-induced diabetic rats. We have successfully characterized and evaluated, for the first time, PEs coupled with 4-HHE, 4-HNE, and 4-HDDE by gas chromatography-mass spectrometry measurement of their ethanolamine moieties. We also report that aggregation of isolated human blood platelets enriched with PE-4-hydroxy-alkenal Michael adducts was altered. These data suggest that these adducts could be used as specific markers of membrane disorders occurring in pathophysiological states with associated oxidative stress and might affect cell function.

Salicylates Trigger Protein Synthesis Inhibition in a Protein Kinase R-like Endoplasmic Reticulum Kinase-dependent Manner

The non-steroidal anti-inflammatory drug aspirin and its metabolite, sodium salicylate, have profound effects on cellular protein synthesis and cell physiology. However, the underlying mechanism by which they cause these responses remains unclear. We show here that salicylates induce phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha), resulting in the inhibition of mRNA translation in cells. Exposure of cells to acetyl salicylic acid resulted in strong activation of eIF2alpha stress-activated protein kinase R-like endoplasmic reticulum kinase (PERK). Analysis of fibroblasts with a targeted deletion of the perk gene revealed that PERK is indispensable for triggering the phosphorylation of eIF2alpha as well as the inhibition of protein synthesis induced by salicylates. Although salicylate treatment did not trigger activation of inositol-requiring enzyme 1, there was an increased expression of the pro-apoptotic transcription factor CHOP-(gadd153), a downstream event to eIF2alpha phosphorylation known to mediate endoplasmic reticulum stress-mediated responses. Thus, salicylates selectively trigger an endoplasmic reticulum stress-responsive signaling pathway initiated through activation of PERK to induce their cellular effects.

Ethanol-mediated Oxidative Changes in Blood Lipids and Proteins Are Reversed by Aspirin-like Drugs

Previous work from our laboratory revealed that administration of selected nonsteroidal anti-inflammatory drugs (NSAIDs)-aspirin, naproxen, nimesulide, and piroxicam-prevented some signs of oxidative stress produced in rat livers acutely intoxicated with ethanol. Our final aim was to pursue these advantageous effects of NSAIDs in humans in relation to opposing the oxidative action of ethanol. In preparation for these studies, we conducted a search for tissues that were more accessible than liver, such as plasma and blood cells. Either ethanol (5 g/kg body weight) or an isocaloric amount of glucose from a 30% solution alone or combined with one of the NSAIDs was administered orogastrically to rats; animals were sacrificed 5 h later. Ethanol increased both protein carbonylation (PCO) and thiobarbituric acid reactive substances (TBARS) in isolated lymphocytes, increased proteolysis in isolated red blood cells (RBC), and decreased the pool of plasma amino acids. The NSAIDs employed reversed the ethanol-mediated rise in PCO in plasma, but with the exception of aspirin failed to prevent the ethanol-produced decrease in the amino-acid serum pool. Additionally, the increase in TBARS and PCO promoted by ethanol in lymphocytes was reverted with aspirin. In contrast, ethanol-activated proteolysis was not modified by aspirin. The pro-oxidant effects of ethanol and certain beneficial actions of NSAIDs, especially those of aspirin, preventing these pro-oxidant effects can be followed in blood constituents of rats. Hence, these oxidative markers could be regarded as potential clinical monitors for ethanol-mediated oxidative stress.

Physiology and pathophysiology of prostanoid receptors

Prostanoids, consisting of prostaglandins (PGs) and thromboxanes (TXs), are oxygenated products of C20 unsaturated fatty acids. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. Given that aspirin-like nonsteroidal anti-inflammatory drugs exert their actions by suppressing prostanoid production, prostanoids have been implicated in processes inhibited by these drugs, including inflammation, fever, and pain. Prostanoids also contribute to vascular homeostasis, reproduction, and regulation of kidney and gastrointestinal functions. How prostanoids exert such a variety of actions had remained unclear, however. Prostanoids are released outside of cells immediately after their synthesis and exert their actions by binding to receptors on target cells. We have identified a family of eight types or subtypes of G protein–coupled receptors that mediate prostanoid actions. Another G protein–coupled receptor was also identified as an additional receptor for PGD2. Genes for these receptors have been individually disrupted in mice, and analyses of these knockout mice have not only elucidated the molecular and cellular mechanisms of known prostanoid actions but also revealed previously unknown actions. In this article, I review the physiological and pathophysiological roles of prostanoids and their receptors revealed by these studies.(Communicated by Tasuku HONJO, M.J.A.)

Du saule à l'aspirine

At the beginning was the willow bark, which was considered as a medicine by Hippocrates, Dioscorides and Plinus. During the XVIIIth century, the Reverend Edward Stone re-discovered the willow for the cure of agues. In 1829, the french pharmacist Pierre Joseph Leroux isolated salicin. Raffaelle Piria was the first to synthesize salicylic acid from salicin (salicoside). Hermann Kolbe prepared salicylic acid from sodium phenate and carbon dioxide. And then acetylsalicylic acid was first prepared by Charles Gerhardt in 1853, but he did not succeed in identifying its structure. Felix Hoffmann, Arthur Eichengrun and Heinrich Dresen from Bayer Laboratories were at the origin of the use of Aspirin as a medicine. In 1971, John Vane showed that aspirin-like drugs inhibited prostaglandine synthesis.