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Respiratory Medicine Jan 2010Pulmonary arterial hypertension is a chronic, progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance that... (Review)
Review
Pulmonary arterial hypertension is a chronic, progressive disease characterized by elevation of pulmonary artery pressure and pulmonary vascular resistance that ultimately results in right ventricular failure and death. Multiple mechanisms are involved in the pathogenesis of pulmonary arterial hypertension, including prostacyclin, endothelin-1, and nitric oxide pathways amongst others. The first agent to be approved for the treatment of pulmonary arterial hypertension was synthetic prostacyclin (epoprostenol), followed by prostaglandin analogs (iloprost, treprostinil, and beraprost [Japan and Korea]), which act on prostaglandin receptors. This article reviews the physiology and pathophysiology of prostanoids, summarizes key clinical studies of prostaglandin analogs for the treatment of pulmonary arterial hypertension, and discusses important pharmacokinetic and pharmacodynamic distinctions between the various prostaglandin analogs. Different prostaglandin analogs have disparate binding affinities for the various prostaglandin receptors and different G-protein-coupled receptor interactions, which may result in varying clinical efficacy and safety depending on the target tissue. Differences in formulation, route of administration, effectiveness, and safety may all play a role in deciding which prostaglandin analog to prescribe for an individual patient. Head-to-head studies will be needed to confirm differences in efficacy and safety for the various prostaglandin analogs.
Topics: Dose-Response Relationship, Drug; Epoprostenol; Humans; Hypertension, Pulmonary; Prostaglandins, Synthetic; Treatment Outcome
PubMed: 19683911
DOI: 10.1016/j.rmed.2009.07.015 -
British Journal of Pharmacology Feb 2008The prostamides are part of a large and continually expanding series of pharmacologically unique neutral lipids. They are COX-2 derived oxidation products of the... (Review)
Review
The prostamides are part of a large and continually expanding series of pharmacologically unique neutral lipids. They are COX-2 derived oxidation products of the endocannabinoid/endovanniloid anandamide. Prostamide pharmacology is unique and, as in the case of the endocannabinoids anandamide and 2-arachidonylglycerol, bears little resemblance to that of the corresponding free acids. By virtue of its close relationship to the anti-glaucoma drug bimatoprost, prostamide F(2alpha) has received the greatest research attention. Prostamide F(2alpha) and bimatoprost effects appear independent of prostanoid FP receptor activation, according to a litany of agonist studies. Studies involving freshly isolated and separate feline iridial smooth muscle cells revealed that bimatoprost and FP receptor agonists stimulated different cells, without exception. This suggests the existence of receptors that preferentially recognize prostamide F(2alpha). The recent discovery of prostamide antagonists has provided further support for prostamide receptors as discrete entities. The prototypical prostamide antagonists, AGN 204396 and 7, blocked the effects of prostamide F(2alpha) and bimatoprost but not those of PGF(2alpha) and FP receptor agonists in the feline iris. Second generation more potent prostamide antagonists, such as AGN 211334, should allow the role of prostamides in health and disease to be elucidated. From the therapeutics standpoint, the prostamide F(2alpha) analogue bimatoprost is the most efficacious ocular hypotensive agent currently available for the treatment of glaucoma.
Topics: Amides; Animals; Bimatoprost; Cloning, Molecular; Cloprostenol; Cyclooxygenase 2; Dinoprostone; Ethanolamines; Humans; Prostaglandins; Receptors, Prostaglandin
PubMed: 17721551
DOI: 10.1038/sj.bjp.0707434 -
Experimental & Molecular Medicine Jan 2021Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small... (Review)
Review
Until recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.
Topics: Animals; Anti-Inflammatory Agents; Humans; Indoles; Nuclear Receptor Subfamily 4, Group A, Member 2; Prostaglandins; Protein Binding
PubMed: 33479411
DOI: 10.1038/s12276-021-00555-5 -
Canadian Medical Association Journal Jan 1980Prostaglandin I2 (PGI2), or prostacyclin, is a recently discovered prostaglandin that affects many organ systems. It is both a potent inhibitor of platelet aggregation... (Review)
Review
Prostaglandin I2 (PGI2), or prostacyclin, is a recently discovered prostaglandin that affects many organ systems. It is both a potent inhibitor of platelet aggregation and a powerful vasodilator. The recent demonstration that it is the main prostaglandin synthesized by the blood vessel wall suggests that it may play an important role in limiting platelet-mediated thrombosis. However, despite considerable investigation, the exact physiological role of PGI2 has yet to be elucidated.
Topics: Animals; Arteriosclerosis; Aspirin; Blood Vessels; Cardiovascular Physiological Phenomena; Chemical Phenomena; Chemistry; Depression, Chemical; Epoprostenol; Female; Genitalia, Female; Genitalia, Male; Humans; Hydrocortisone; Kidney; Male; Platelet Aggregation; Prostaglandins; Thrombosis
PubMed: 6988063
DOI: No ID Found -
Pharmacological Reports : PR 2008Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA).... (Review)
Review
Prostanoids are cyclic lipid mediators which arise from enzymic cyclooxygenation of linear polyunsaturated fatty acids, e.g. arachidonic acid (20:4 n 6, AA). Biologically active prostanoids deriving from AA include stable prostaglandins (PGs), e.g. PGE(2), PGF(2alpha), PGD(2), PGJ(2) as well as labile prostanoids, i.e. PG endoperoxides (PGG(2), PGH(2)), thromboxane A(2) (TXA(2)) and prostacyclin (PGI(2)). A "Rabbit aorta Contracting Substance" (RCS) played important role in discovering of labile PGs. RCS was discovered in the Vane's Cascade as a labile product released along with PGs from the activated lung or spleen. RCS was identified as a mixture of PG endoperoxides and thromboxane A(2). Stable PGs regulate the cell cycle, smooth muscle tone and various secretory functions; they also modulate inflammatory and immune reactions. PG endoperoxides are intermediates in biosynthesis of all prostanoids. Thromboxane A(2) (TXA(2)) is the most labile prostanoid (with a half life of 30 s at 37 degrees C). It is generated mainly by blood platelets. TXA(2) is endowed with powerful vasoconstrictor, cytotoxic and thrombogenic properties. Again the Vane's Cascade was behind the discovery of prostacyclin (PGI(2)) with a half life of 4 min at 37 degrees C. It is produced by the vascular wall (predominantly by the endothelium) and it acts as a physiological antagonist of TXA(2). Moreover, prostacyclin per se is a powerful cytoprotective agent that exerts its action through activation of adenylate cyclase, followed by an intracellular accumulation of cyclic-AMP in various types of cells. In that respect PGI(2) collaborates with the system consisting of NO synthase (eNOS)/nitric oxide free radical (NO)/guanylate cyclase/cyclic-GMP. Both cyclic nucleotides (c-AMP and c-GMP) act in synergy as two energetic fists which defend the cellular machinery from being destroyed by endogenous or exogenous aggressors. Recently, a new partner has been recognized in this endogenous defensive squadron, i.e. a system consisting of heme oxygenase (HO-1)/carbon monoxide (CO)/biliverdin/biliverdin reductase/bilirubin. The expanding knowledge on the pharmacological steering of this enzymic triad (PGI(2)-S/eNOS/HO-1) is likely to contribute to the rational therapy of many systemic diseases such as atherosclerosis, diabetes mellitus, arterial hypertension or Alzheimer diseases. The discovery of prostacyclin broadened our pathophysiological horizon, and by itself opened new therapeutic possibilities. Prostacyclin sodium salt and its synthetic stable analogues (iloprost, beraprost, treprostinil, epoprostenol, cicaprost) are useful drugs for the treatment of the advanced critical limb ischemia, e.g. in the course of Buerger's disease, and also for the treatment of pulmonary artery hypertension (PAH). In this last case a synergism between prostacyclin analogues and sildenafil (a selective phosphodiesterase 5 inhibitor) or bosentan (an endothelin ET-1 receptor antagonist) points our to complex mechanisms controlling pulmonary circulation. At the Jagiellonian University we have demonstrated that several well recognised cardiovascular drugs, e.g. ACE inhibitors (ACE-I), statins, some of beta-adrenergic receptor antagonists, e.g. carvedilol or nebivolol, anti-platelet thienopyridines (ticlopidine, clopidogrel) and a metabolite of vitamin PP--N(1)-methyl-nicotinamide--all of them are endowed with the in vivo PGI(2)-releasing properties. In this way, the foundations for the Endothelial Pharmacology were laid.
Topics: Animals; Cardiovascular Agents; Endothelium, Vascular; History, 20th Century; Humans; Prostaglandin H2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Prostaglandins G; Prostaglandins I; Signal Transduction; Thromboxane A2
PubMed: 18276980
DOI: No ID Found -
Respiratory Medicine Jun 2011Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmonary arterial pressure ≥25 mm Hg and normal pulmonary capillary wedge... (Review)
Review
Pulmonary arterial hypertension is a progressive, fatal disease characterized by elevated pulmonary arterial pressure ≥25 mm Hg and normal pulmonary capillary wedge pressure ≤ 5 mm Hg. Physiological features of pulmonary arterial hypertension are characterized clinically by the presence of pre-capillary pulmonary hypertension not caused by other conditions such as lung diseases or chronic thromboembolic pulmonary hypertension. There are several therapies currently available that have been shown to improve hemodynamics and improve outcomes in patients with pulmonary arterial hypertension. These therapies include synthetic prostacyclin and prostaglandin analogs, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors. Multiple prostacyclin and prostaglandin analog formulations are currently in use (both branded and generic), available for parenteral, inhaled, or oral administration. This review discusses the pharmacology, clinical effects, and routes of administration of prostacyclin and prostaglandin analogs, emphasizing the advantages and disadvantages of each from the clinical perspective.
Topics: Dose-Response Relationship, Drug; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Prostaglandins, Synthetic; Treatment Outcome
PubMed: 21273054
DOI: 10.1016/j.rmed.2010.12.018 -
Veterinary Immunology and... Jun 2021Prostaglandins (PGs) are lipid mediators derived from arachidonic acid by several enzymes including cyclooxygenase (COX)-1 and COX-2. We have previously shown that PGE...
Prostaglandins (PGs) are lipid mediators derived from arachidonic acid by several enzymes including cyclooxygenase (COX)-1 and COX-2. We have previously shown that PGE regulates immune responses, such as Th1 cytokine production and T-cell proliferation, in cattle. However, it is still unclear whether other PGs are involved in the regulation of immune responses in cattle. Here, immunosuppressive profiles of PGs (PGA, PGB, PGD, PGE, PGF and PGF) were firstly examined using bovine peripheral blood mononuclear cells (PBMCs). In addition to PGE, PGA significantly inhibited Th1 cytokine production from PBMCs in cattle. Further analyses focusing on PGA revealed that treatment with PGA in the presence of concanavalin A (con A) downregulated CD69, an activation marker, and IFN-γ expression in both CD4 and CD8 T cells. Sorted CD3 T cells stimulated with con A were cultivated with PGA, and IFN-γ and TNF-α concentrations decreased upon PGA treatment. Taken together, these results suggest that the treatment with PGAin vitro inhibits T-cell activation, especially Th1 cytokine production, in cattle.
Topics: Animals; Cattle; Cell Proliferation; Immunosuppression Therapy; Immunosuppressive Agents; Leukocytes, Mononuclear; Lymphocyte Activation; Prostaglandins; Th1 Cells
PubMed: 33857743
DOI: 10.1016/j.vetimm.2021.110238 -
British Medical Journal Mar 1972
Topics: Abortion, Induced; Adult; Drug Synergism; Female; Humans; Muscle Contraction; Oxytocin; Pregnancy; Prostaglandins; Uterus
PubMed: 5015335
DOI: 10.1136/bmj.1.5802.747-a -
Pharmacology 2021Postpartum hemorrhage (PPH) remains a common cause of maternal mortality worldwide. Medical intervention plays an important role in the prevention and treatment of PPH.... (Review)
Review
BACKGROUND
Postpartum hemorrhage (PPH) remains a common cause of maternal mortality worldwide. Medical intervention plays an important role in the prevention and treatment of PPH. Prostaglandins (PGs) are currently recommended as second-line uterotonics, which are applied in cases of persistent bleeding despite oxytocin treatment.
SUMMARY
PG agents that are constantly used in clinical practice include carboprost, sulprostone, and misoprostol, representing the analogs of PGF2α, PGE2, and PGE1, respectively. Injectable PGs, when used to treat PPH, are effective in reducing blood loss but probably induce cardiovascular or respiratory side effects. Misoprostol is characterized by oral administration, low cost, stability in storage, broad availability, and minimal side effects. It remains a treatment option for uterine atony in low-resource settings, but its effectiveness as a uterotonic for independent application may be limited. Key Messages: The present review article discusses the physiological roles of various natural PGs, evaluates the existing evidence of PG analogs in the prevention and treatment of PPH, and finally provides a reference to assist obstetricians in selecting appropriate uterotonics.
Topics: Carboprost; Dinoprostone; Drug Administration Routes; Drug Stability; Female; Humans; Misoprostol; Postpartum Hemorrhage; Prostaglandins; Receptors, Prostaglandin; Uterus
PubMed: 34237742
DOI: 10.1159/000516631 -
Reproduction (Cambridge, England) Nov 2003Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis,... (Review)
Review
Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine-paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E(2) and F(2alpha) in disorders of endometrial proliferation and menstruation in non-pregnant women.
Topics: Endometrial Neoplasms; Endometriosis; Enzyme Activation; Female; Humans; Menstruation Disturbances; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Receptors, Prostaglandin; Signal Transduction; Uterine Diseases
PubMed: 14611628
DOI: 10.1530/rep.0.1260559