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Eikozanoidler ve Diğer Otakoidler

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1 Eikozanoidler ve Diğer Otakoidler
Prof. Dr. Hakan KARADAĞ Eikozanoidler ve Diğer Otakoidler Prof. Dr. Hakan KARADAĞ Eikozanoidler ve Diğer Otakoidler

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3 Ders Planı Siklooksijenaz Ürünleri Lipoksijenaz Ürünleri
Prof. Dr. Hakan KARADAĞ Ders Planı Siklooksijenaz Ürünleri Prostaglandinler Prostasiklin (PG I2) Tromboksan A2 İlaç Olarak Kullanılan Prostaglandinler Dinoproston, Dinoprost, Karboprost, Gemeprost, Alprostadil, Mizoprostol, Rioprostil, Enprostil, Arboprostil, Latanoprost, Travoprost, Bimatoprost, İloprost Lipoksijenaz Ürünleri Sitokrom P450 Ürünleri Nitrik Oksid Trombosit Aktive-Edici Faktör (PAF) History and name The name prostaglandin derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler,[1] and independently by M.W. Goldblatt,[2] it was believed to be part of the prostatic secretions (in actuality prostaglandins are produced by the seminal vesicles); it was later shown that many other tissues secrete prostaglandins for various functions. In 1971, it was determined that aspirin-like drugs could inhibit the synthesis of prostaglandins. The biochemists Sune K. Bergström, Bengt I. Samuelsson and John R. Vane jointly received the 1982 Nobel Prize in Physiology or Medicine for their researches on prostaglandins. Eikozanoidler ve Diğer Otakoidler

4 Tarihçe İlk olarak semenden saflaştırılmıştır (1935). (Ulf von Euler)
Prof. Dr. Hakan KARADAĞ Tarihçe İlk olarak semenden saflaştırılmıştır (1935). (Ulf von Euler) Prostat kaynaklı olduğu düşünülerek PROSTAGLANDİN adı verilmiştir. Aspirin-benzeri ilaçların sentezlerini inhibe ettiğinin anlaşılması ile önemi anlaşılmıştır (1971) 1982 Nobel Ödülü: Sune K. Bergström, Bengt I Samuelsson, John R Vane Prostaglandins were discovered in the seminal plasma around 1930 by their physiological properties and were recognized as lipids by Ulf von Euler in 1935 who was awarded the Nobel Prize in 1970 for his investigations on neurotransmitters (Nobel prize with B Katz and J Axelrod "for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation". The chemical structure of prostaglandins was revealed by SK Bergstrom in Bergstrom laid the groundwork for the current development by isolating the first prostaglandins, showing too that originated from unsaturated fatty acids. His student, BI Samuelsson, isolated and determined the structure of several of most significant prostaglandins while JR Vane discovered prostacyclin.  All three were recipients of the Nobel Prize for physiology and medicine in A brief history of these discoveries may be found on the J Biol Chem internet site. In 1970, 14 natural prostaglandins were known, actually, with the help of efficient and sensitive analytical techniques, hundreds of these compounds have been described and their number is continually growing. Eikozanoidler ve Diğer Otakoidler

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7 Gamma-linolenic acid (GLA) via DGLA ω-6 series-1
Prof. Dr. Hakan KARADAĞ Name EFA Type Series Gamma-linolenic acid (GLA) via DGLA ω-6 series-1 Arachidonic acid (AA) series-2 Eicosapentaenoic acid (EPA) ω-3 series-3 Omega-3 fatty acids are a family of polyunsaturated fatty acids which have in common a carbon-carbon double bond in the ω-3 position. (See Nomenclature for terms and discussion of ω (omega) nomenclature.) Important nutritional essential omega-3 fatty acids are: α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). For a more complete list see List of omega-3 fatty acids. The human body cannot synthesize omega-3 fatty acids de novo, but it can form 20- and 22-carbon unsaturated omega-3 fatty acids from the eighteen-carbon omega-3 fatty acid, α-linolenic acid. These conversions occur competitively with omega-6 fatty acids, which are essential closely related chemical analogues that are derived from linoleic acid. Both the omega-3 α-linolenic acid and omega-6 linoleic acid are essential nutrients which must be obtained from food. Synthesis of the longer omega-3 fatty acids from linolenic acid within the body is competitively slowed by the omega-6 analogues. Thus accumulation of long-chain omega-3 fatty acids in tissues is more effective when they are obtained directly from food or when competing amounts of omega-6 analogs do not greatly exceed the amounts of omega-3. Eikozanoidler ve Diğer Otakoidler

8 Nomenclature and terminology
Prof. Dr. Hakan KARADAĞ Nomenclature and terminology Fatty acids are straight chain hydrocarbons possessing a carboxyl (COOH) group at one end. The carbon next to the carboxylate is known as α, the next carbon β, and so forth. Since biological fatty acids can be of different lengths, the last position is labelled ω, the last letter in the Greek alphabet. Since the physiological properties of unsaturated fatty acids largely depend on the position of the first unsaturation relative to the end position and not the carboxylate, the position is signified by (ω minus n). For example, the term ω-3 signifies that the first double bond exists as the third carbon-carbon bond from the terminal CH3 end (ω) of the carbon chain. The number of carbons and the number of double bonds is also listed. ω-3 18:4 (stearidonic acid) or 18:4 ω-3 or 18:4 n-3 indicates an 18-carbon chain with 4 double bonds, and with the first double bond in the third position from the CH3 end. Double bonds are cis and separated by a single methylene (CH2) group unless otherwise noted. So in free fatty acid form, the chemical structure of stearidonic acid is: Chemical structure of stearidonic acid showing physiological (red) and chemical (blue) numbering conventions. Nomenclature and terminology Fatty acids are straight chain hydrocarbons possessing a carboxyl (COOH) group at one end. The carbon next to the carboxylate is known as α, the next carbon β, and so forth. Since biological fatty acids can be of different lengths, the last position is labelled ω, the last letter in the Greek alphabet. Since the physiological properties of unsaturated fatty acids largely depend on the position of the first unsaturation relative to the end position and not the carboxylate, the position is signified by (ω minus n). For example, the term ω-3 signifies that the first double bond exists as the third carbon-carbon bond from the terminal CH3 end (ω) of the carbon chain. The number of carbons and the number of double bonds is also listed. ω-3 18:4 (stearidonic acid) or 18:4 ω-3 or 18:4 n-3 indicates an 18-carbon chain with 4 double bonds, and with the first double bond in the third position from the CH3 end. Double bonds are cis and separated by a single methylene (CH2) group unless otherwise noted. So in free fatty acid form, the chemical structure of stearidonic acid is: Chemical structure of stearidonic acid showing physiological (red) and chemical (blue) numbering conventions. Eikozanoidler ve Diğer Otakoidler

9 α-Linolenic acid (18:3) - ω-3 Linoleic acid (18:2) - ω-6
Prof. Dr. Hakan KARADAĞ Examples For a complete tables of ω-3 and ω-6 essential fatty acids, see Polyunsaturated fatty acids. The essential fatty acids start with the short chain polyunsaturated fatty acids (SC-PUFA): α-Linolenic acid (18:3) - ω-3 Linoleic acid (18:2) - ω-6 These two fatty acids cannot be synthesised by humans, as humans lack the desaturase enzymes required for their production. They form the starting point for the creation of longer and more desaturated fatty acids, which are also referred to as long-chain polyunsaturated fatty acids (LC-PUFA): ω-3 fatty acids: eicosapentaenoic acid or EPA (20:5) docosahexaenoic acid or DHA (22:6) ω-6 fatty acids: gamma-linolenic acid or GLA (18:3) dihomo-gamma-linolenic acid or DGLA (20:3) arachidonic acid or AA (20:4) ω-9 fatty acids are not essential in humans, because humans possess all the enzymes required for their synthesis. The public is sometimes perceived as ignorant of this, as many supplement companies market Omega blends. What is "essential"? Between 1930 and 1950, arachidonic acid and linolenic acid were termed 'essential' because each was more or less able to meet the growth requirements of rats given fat-free diets. Further research has shown that human metabolism requires both ω-3 and ω-6 fatty acids. To some extent, any ω-3 and any ω-6 can relieve the worst symptoms of fatty acid deficiency. Particular fatty acids are still needed at critical life stages (e.g. lactation) and in some disease states. See (Cunnane 2003)[4] for a discussion of the current status of the term 'essential'. In scientific writing, common usage is that the term essential fatty acid comprises all the ω-3 or -6 fatty acids.[5] Authoritative sources include the whole families, without qualification.[6] [7] [8] The human body can make some long-chain PUFA (arachidonic acid, EPA and DHA) from lineolate or lineolinate. Some writers therefore hold that the LC-PUFA are not essential, but that is not how the field has generally used the term. Biologist Ray Peat, PhD, has pointed out flaws in the studies purportedly showing the need for n-3 and n-6 fats. He notes that so-called EFA deficiencies have been reversed by adding B vitamins or a fat-free liver extract to the diet. In his view, 'the optional dietary level of the "essential fatty acids" might be close to zero, if other dietary factors were also optimized.' [1] Essential fatty acids should not be confused with essential oils, which are "essential" in the sense of being a concentrated essence. Eikozanoidler ve Diğer Otakoidler

10 List of omega-6 fatty acids
Prof. Dr. Hakan KARADAĞ List of omega-6 fatty acids Common name Lipid name Chemical name Linoleic acid 18:2 (n-6) 9,12-octadecadienoic acid Gamma-linolenic acid 18:3 (n-6) 6,9,12-octadecatrienoic acid Eicosadienoic acid 20:2 (n-6) 11,14-eicosadienoic acid Dihomo-gamma-linolenic acid 20:3 (n-6) 8,11,14-eicosatrienoic acid Arachidonic acid 20:4 (n-6) 5,8,11,14-eicosatetraenoic acid Docosadienoic acid 22:2 (n-6) 13,16-docosadienoic acid Adrenic acid 22:4 (n-6) 7,10,13,16-docosatetraenoic acid Docosapentaenoic acid 22:5 (n-6) 4,7,10,13,16-docosapentaenoic acid Calendic acid 8E,10E,12Z-octadecatrienoic acid Omega-6 fatty acids are fatty acids where the term "omega-6" signifies that the first double bond in the carbon backbone of the fatty acid, occurs in the omega minus 6 position; that is, the sixth carbon from the end of the fatty acid. See essential fatty acids for more detail on the naming system. The biological effects of the ω-6 fatty acids are largely mediated by their interactions with the ω-3 fatty acids, see Essential fatty acid interactions for detail. Linoleic acid (18:2), the shortest chain omega-6 fatty acid is an essential fatty acid. Arachidonic acid (20:4) is a physiologically significant n-6 fatty acid and is the precursor for prostaglandins and other physiologically active molecules. Some medical research has suggested that excessive levels of omega-6 acids, relative to Omega-3 fatty acids, may increase the probability of a number of diseases and depression. Modern Western diets typically have ratios of omega-6 to omega-3 in excess of 10 to 1, some as high as 30 to 1. The optimal ratio is thought to be 4 to 1 or lower. [1] Dietary sources of omega-6 fatty acids include: nuts cereals whole-grain breads most vegetable oils eggs and poultry baked goods.[2] Eikozanoidler ve Diğer Otakoidler

11 Prof. Dr. Hakan KARADAĞ Phospholipid hydrolysis — In mammalian cells, the most common fatty acid substrate for both prostaglandins and leukotrienes is arachidonic acid (AA). Other polyunsaturated fatty acids may also serve as substrates, including eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA). Prostaglandin and thromboxane synthesis — The cyclooxygenase pathway represents the first divergent step in eicosanoid synthesis, leading to production of the prostaglandins (PGs) and thromboxanes (Tx). Metabolism of arachidonic acid by cyclooxygenase produces a number of compounds, including PGG2, H2, F2, I2, and D2, and TxA2 and B2 (show figure 1). These mediators, collectively known as the prostanoids, contain a five membered (prostaglandins) or six membered ring (thromboxanes). The numerical subscript "2" refers to two double bonds in the side chains. The "1" series mediators are produced when DGLA is used in place of arachidonic acid. The "3" series of PG and Tx are produced when EPA is used in place of arachidonic acid. The majority of prostaglandins that occur naturally arise from arachidonic acid; these have been studied most extensively. Thus, the "2" series will be discussed in greatest detail. Eikozanoidler ve Diğer Otakoidler

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13 ARAŞİDONİK ASİT Membran Fosfolipidleri Prostaglandinler
Prof. Dr. Hakan KARADAĞ Membran Fosfolipidleri Fosfolipaz A2 ARAŞİDONİK ASİT Siklooksijenaz Sitokrom P450 Phospholipid hydrolysis — In mammalian cells, the most common fatty acid substrate for both prostaglandins and leukotrienes is arachidonic acid (AA). Other polyunsaturated fatty acids may also serve as substrates, including eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) [6]. Phospholipid hydrolysis is catalyzed by phospholipase A2 (PLA2); this enzyme exists in at least 16 isoenzymes, each with different properties such as calcium dependence and subcellular localization. Five significant mammalian classes of PLA2s have been characterized: The "secretory" PLA2s, four structurally related enzymes, comprise groups I, II, V, and X. The multiple isoenzymes of these families are characterized by conservation of 12 to 16 cysteine residues and highly homologous catalytic and calcium binding domains. These molecules were originally described in the pancreas and in inflammatory exudates (such as inflammatory synovial fluid), respectively. They are also found in granules of mast cells and platelets, suggesting a role for providing eicosanoids in pathophysiologic processes [7]. Inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNFa) induce group II PLA2, an effect that is attenuated by corticosteroids [7]. The fifth major family, Group IV PLA2, referred to as cytoplasmic PLA(2) (cPLA2), is relatively specific for arachidonic acid hydrolysis from phospholipids and has no amino acid homology to the families of PLA2 enzymes. The cPLA2 is activated by micromolar increases of calcium, resulting in translocation to the perinuclear membrane and augmented function via MAP-kinase-dependent serine phosphorylation [7,8]. Gene deletion experiments in the mouse suggest that the cPLA2 isoform is the most important PLA2 involved in the formation of eicosanoids in neutrophils and monocytes. Similar to the secretory isoforms, inflammatory cytokines upregulate the production of cytosolic PLA2 and corticosteroids inhibit this process. Following release of arachidonic acid from the cell membrane, the remaining lysophospholipid (lyso-platelet activating factor) may be converted to platelet activating factor (PAF), another inflammatory mediator. PAF upregulates production of the inflammatory cytokines TNFa, IL-1, IL-2, and IL-6 in hematopoietic cells and macrophages via receptor-mediated action. It also increases leukotriene generation in granulocytes, and affects a variety of other cells including B-lymphocytes, NK cells, and vascular endothelial cells. 5 Lipoksijenaz Sitokrom P450 Ürünleri Prostaglandinler 12 Lipoksijenaz 15 Lipoksijenaz Lökotrienler ve Diğer Lipoksijenaz Ürünleri Eikozanoidler ve Diğer Otakoidler

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15 Araşidonik asit PGG2 PGH2 PGI2 TxA2 PGF2a PGE2 PGD2

16 Prostanoidler Prostaglandinler Prostasiklinler Tromboksanlar

17 FOSFOLİPİDLER Araşidonik Asit PGG2 PGH2 TxA2 PGI2 TxB2 6-keto PGF1a
Siklooksijenaz (COX) COX1 COX2 PGG2 Tromboksan sentaz Prostasiklin sentaz PGH2 TxA2 PGI2 non enzimatik non enzimatik Endoperoksit E izomeraz Endoperoksit D izomeraz Endoperoksit redüktaz TxB2 6-keto PGF1a 9-hidroksiprostaglandin dehidrojenaz PGE2 PGF2a PGD2 6-keto PGE1 9 hidroksiprostaglandin dehidrojenaz 9 ketoredüktaz PGF2a PGE2

18 (İndüklenebilir Form)
COX1 (Konstitütif Form) Damar endoteli Mide mukozası Böbrek Kalp Trombosit FOSFOLİPİDLER COX2>COX1 Nimesulid Etodolak Meloksikam Araşidonik Asit COX2>>COX1 Selekoksib Rofekoksib COX2 (İndüklenebilir Form) Makrofajlar Diğer inflamatuar hücreler Siklooksijenaz (COX) COX1 COX2 PGG2 Tromboksan sentaz Prostasiklin sentaz PGH2 TxA2 PGI2 non enzimatik non enzimatik Endoperoksit E izomeraz Endoperoksit D izomeraz Endoperoksit redüktaz TxB2 6-keto PGF1a 9-hidroksiprostaglandin dehidrojenaz PGE2 PGF2a PGD2 6-keto PGE1 9 hidroksiprostaglandin dehidrojenaz 9 ketoredüktaz PGF2a PGE2

19 Prof. Dr. Hakan KARADAĞ Eikozanoidler ve Diğer Otakoidler

20 Eikozanoidler ve Diğer Otakoidler
Prof. Dr. Hakan KARADAĞ The first committed step in the biosynthesis of these compounds is the sequential formation of PGG2 and PGH2 from arachidonic acid. This reaction is catalyzed by the prostaglandin H synthase isozymes, PGHS-1 and 2, also known as cyclooxygenase-1 and -2 (COX-1 and COX-2) (show table 1). These isozymes have been characterized as constitutive (PGHS-1) and inducible (PGHS-2) based upon their regulation and action of their products [9]. However, this generalization that the PGHS-1 is the "housekeeping" isoform and that the inducible PGHS-2 is solely responsible for inflammatory conditions is oversimplified: Although PGHS-1 is predominantly constitutive and regulates homeostatic processes (such as gastric cytoprotection, vascular homeostasis, platelet aggregation and kidney function), PGHS-1 levels change significantly during development and may be moderately inducible in certain circumstances. In pharmacologic and gene-disrupted animal models, for example, preferential PGHS-1 inhibition reduces chronic inflammatory changes, and paradoxically, disruption of the PGHS-1 gene leads to increased propensity to NSAID-induced gastric ulceration. By comparison, PGHS-2, which is implicated in predominantly inflammatory conditions and is upregulated by multiple inflammatory or noxious stimuli, was previously thought not to exist constitutively in most tissues. Recently, however, PGHS-2 has been observed in cells of several tissues, such as the kidney, brain, and reproductive system [10]. Furthermore, animal models of induced inflammation reveal that PGHS-2 appears to have anti-inflammatory properties [11], which presents obvious implications for the development of drugs with PGHS-2 selectivity. This oversimplified partitioning of homeostatic (PGHS-1) versus inflammatory (PGHS-2) functions has a similar (though less well defined) counterpart in the PLA2 isozymes (show figure 4). In addition to the functional partitioning of products of these isozymes, PGHS-1 and PGHS-2 demonstrate some separation into respective intracellular membrane compartments (show table 1) [9,10]. PGHS-1 and PGHS-2 have 61 percent overall amino acid identity, although crystallographic structure demonstrates that each have distinct substrate specificities and binding characteristics. These structural differences have allowed for the development of specific inhibitors of PGHS-2 [9]. (See "Overview of selective COX-2 inhibitors"). PGG2 is the common substrate for the remaining products of the cyclooxygenase pathway. Following production of PGG2, the PGHS isozymes catalyze a peroxidase reaction, converting it to PGH2. PGH2 may then be used as a substrate for the other terminal enzymes which are cell and tissue specific. These include prostacyclin (PGI2) synthase, thromboxane (TxA2) synthase, PGD2 synthase, or glutathione S-transferases for the conversion to PGE2. Eikozanoidler ve Diğer Otakoidler

21 From Wikipedia, the free encyclopedia
Lipoxin From Wikipedia, the free encyclopedia • Interested in contributing to Wikipedia? • Jump to: navigation, search Lipoxins are a series of anti-inflamatory mediators. Lipoxins are short lived endogenously produced eicosanoids whose appearance in inflammation signals the resolution of inflammation. During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins (LXs) and IL-4, which promote the resolution phase of inflammation.[1] They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. Lipoxins are derived from arachidonic acid, an ω-6 fatty acid An analogous class, the resolvins, is derived from EPA and DHA, ω-3 fatty acids.[2] At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4). Lipoxins, as well as certain peptides, are high affinity (sub nanomolar) ligands for the lipoxin A4 receptor (ALXR), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the ALXR inhibits chemotaxis, transmigration, superoxide generation and NF-kB activation.[3] Conversely, peptide signalling through the same receptor, in vitro, has been shown to stimulate chemotaxis of PMN and calcium mobilization.[3] The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase proteins, bacterial peptides, HIV envelope proteins and neurotoxic peptides. Lipoxins are also high affinity antagonists to the cystienyl leukotriene receptor 1 (CysLT1) to which several leukotrienes (LTC4, LTD4 and LTE4) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug, Montelukast(Singulair)[4] Prof. Dr. Hakan KARADAĞ Lipoxin From Wikipedia, the free encyclopedia • Interested in contributing to Wikipedia? • Jump to: navigation, search Lipoxins are a series of anti-inflamatory mediators. Lipoxins are short lived endogenously produced eicosanoids whose appearance in inflammation signals the resolution of inflammation. During the acute inflammatory process, the proinflammatory cytokines such as IFN-γ and IL-1β can induce the expression of anti-inflammatory mediators such as lipoxins (LXs) and IL-4, which promote the resolution phase of inflammation.[1] They are abbreviated as LX, an acronym for lipoxygenase (LO) interaction products. Lipoxins are derived from arachidonic acid, an ω-6 fatty acid An analogous class, the resolvins, is derived from EPA and DHA, ω-3 fatty acids.[2] At present two lipoxins have been identified; lipoxin A4 (LXA4) and lipoxin B4 (LXB4). Lipoxins, as well as certain peptides, are high affinity (sub nanomolar) ligands for the lipoxin A4 receptor (ALXR), which was first identified based on sequence homology as the formyl peptide receptor like receptor (FPRL1). Lipoxin signaling through the ALXR inhibits chemotaxis, transmigration, superoxide generation and NF-kB activation.[3] Conversely, peptide signalling through the same receptor, in vitro, has been shown to stimulate chemotaxis of PMN and calcium mobilization.[3] The peptides that have ALXR affinity tend to be signals for leukocyte migration and subsequent phagocytosis such as acute phase proteins, bacterial peptides, HIV envelope proteins and neurotoxic peptides. Lipoxins are also high affinity antagonists to the cystienyl leukotriene receptor 1 (CysLT1) to which several leukotrienes (LTC4, LTD4 and LTE4) mediate their smooth muscle contraction and eosinophil chemotactic effects. The CysLT1 receptor is also the site of action for the asthma drug, Montelukast(Singulair)[4] [edit] References ^ McMahon, Blaithin and Godson, Catherine. Lipoxins: endogenous regulators of inflammation. Retrieved on February 7, Invited review article. ^ Charles N. Serhan, Mats Hamberg, and Bengt Samuelsson (September 1, 1984). Lipoxins: Novel Series of Biologically Active Compounds Formed from Arachidonic Acid in Human Leukocytes. Retrieved on February 2, Original description of lipoxins. ^ a b Chiang N., Arita M., and Serhan CN. (2005). Anti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX. Retrieved on April 28, 2006. ^ Drazen J., Israel E., and O'Byrne P. (1999). "Treatment of Asthma with Drugs Modifying the Leukotriene Pathway". PMID Retrieved on   Eikozanoidler ve Diğer Otakoidler

22 From Wikipedia, the free encyclopedia
Resolvins From Wikipedia, the free encyclopedia • Learn more about using Wikipedia for research • Jump to: navigation, search Resolvins are compounds that are made by the human body from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). They are produced by the COX-2 pathway especially in the presence of aspirin. Experimental evidence indicates that resolvins reduce cellular inflammation by inhibiting the production and transportation of inflammatory cells and chemicals to the sites of inflammation. They are released and used immunologically by the kidneys as a tool against acute renal failure, when it occurs. Resolvins are sometimes classed with the eicosanoids. Prof. Dr. Hakan KARADAĞ Eikozanoidler ve Diğer Otakoidler

23 Prof. Dr. Hakan KARADAĞ Fig. 2: hypothesis of the events occurring in the microvasculature after ingestion of aspirin. A: once in the systemic circulation aspirin acetylates constitutively-expressed COX 2 in the microvascular endothelium and/or the circulating leukocytes to generate 15-epi-lipoxin A4. This 15 epi-lipoxin A4 then triggers endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) synthesis in an unknown manner. This eNOS-derived NO plays two roles _ the control of early phase leukocyte/endothelial cell interaction (up to 2-3 h); B: the subsequent induction of inducible nitric oxide sysnthase (iNOS) in the endothelium, the leukocytes or both. NO from iNOS is then responsible for the later phase of control of leukocyte trafficking Eikozanoidler ve Diğer Otakoidler

24 FOSFOLİPİDLER Araşidonik Asit PGG2 PGH2 TxA2 PGI2 TxB2 6-keto PGF1a
Prof. Dr. Hakan KARADAĞ FOSFOLİPİDLER NSAİİ Glukokortikoidler Araşidonik Asit Siklooksijenaz (COX) COX1 COX2 PGG2 Tromboksan sentaz Prostasiklin sentaz ifetroban, ramatroban, daltroban, sulotroban: TxA2 reseptör antagonist PGH2 TxA2 PGI2 non enzimatik non enzimatik Endoperoksit E izomeraz Endoperoksit D izomeraz Endoperoksit redüktaz TxB2 6-keto PGF1a 9-hidroksiprostaglandin dehidrojenaz PGE2 PGF2a PGD2 6-keto PGE1 Dazoksiben Dazmegral 9 hidroksiprostaglandin dehidrojenaz 9 ketoredüktaz Eikozanoidler ve Diğer Otakoidler PGF2a PGE2

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27 Salıverilme Prostanoidler depolanmazlar.
Sentezlendikleri yerden salıverilirler. Sentezlerinin artırılması ya da azaltılması, salıverilen prostanoid miktarını artırır ya da azaltır.

28 Metabolizma PGE ve PGF’ler
Sentezlendikleri dokularda ya da kan dolaşımı sırasında akciğerler tarafından metabolize edilir. PGI2 Akciğerde metabolize edilmez. Karaciğer ve böbrek tarafından metabolize edilir. Ayrıca, plazmada enzimatik olmayan bir yıkıma da uğrar. TxA2 Metabolizması karmaşıktır. Enzimatik olmayan hidrolizle TxB2’ye dönüşebilir.

29 Prostaglandinlerin Etkileri
Prof. Dr. Hakan KARADAĞ Prostaglandinlerin Etkileri TxA2 PGF2a PGI2 PGE2 PGE1 PGD2 Damar düz kası +++ ‑ ‑ ‑ Trombosit adezyon‑ agregasyon ‑ ‑ ‑ ‑ ++ Uterus Mide asit salgısı  Sitoprotektif etki Bağırsak tonus ve motilitesi  sulu diyare  sulu diyare Bronşlar konstriksiyon gevşeme Adverse effects – The most frequent side effects of the E type prostanoids are dose-dependent crampy abdominal pain and diarrhea [45,46]. These side effects interfere with compliance in a many patients. The problem of misoprostol-induced diarrhea has been addressed in several ways: • The drug should be started after the patient has been informed of the potential problem. • The patient should be instructed not to use concomitant cathartic agents, to stop stool softeners unless absolutely necessary, and then to reevaluate the need for these agents after several weeks of therapy. 45. TI - Side effects of anti-ulcer prostaglandins: an overview of the worldwide clinical experience. AU - Bianchi Porro G; Parente F SO - Scand J Gastroenterol Suppl 1989;164:224-9; discussion Anti-ulcer prostaglandins (PG)--misoprostol, enprostil and rioprostil--have been given to more than 5000 patients in short-term studies on gastric and duodenal ulcer. Analysis of these studies shows the drugs to be safe. Their side effects appear to be dose-dependent and mainly restricted to the gastrointestinal system, the major syndromes being diarrhoea and abdominal pain. The clinical relevance of PG-related unwanted effects, though in average exceeding that of H2-blockers, seems to be sufficiently low. In terms of safety efficacy, however, they appear inferior to H2-antagonists, so their routine use in preference to the latter compounds is still premature. AD - Gastrointestinal Unit, L Sacco Hospital, Milan, Italy. PMID ================================================ 46. TI - Prevention of NSAID-induced gastric ulcer with misoprostol: multicentre, double-blind, placebo-controlled trial. AU - Graham DY; Agrawal NM; Roth SH SO - Lancet 1988 Dec 3;2(8623): A double-blind, placebo-controlled study was carried out to see whether the synthetic E prostaglandin, misoprostol, would prevent gastric ulcer induced by non-steroidal anti-inflammatory drugs (NSAIDs). 420 patients with osteoarthritis and NSAID-associated abdominal pain were studied; they were receiving ibuprofen, piroxicam, or naproxen. Endoscopy was done at entry and after 1, 2, and 3 months of continuous treatment with 100 micrograms or 200 micrograms misoprostol or placebo, given four times daily with meals and at bedtime, concurrently with the NSAID. Abdominal pain was rated independently by patients and physicians. A treatment failure was defined as development of a gastric ulcer. Gastric ulcers (0.3 cm in diameter or greater) occurred less frequently (p less than 0.001) in both misoprostol treatment groups (5.6% 100 micrograms and 1.4% 200 micrograms) than in the placebo group (21.7%). The significant difference in ulcer formation between the placebo and the misoprostol treatment groups remained when comparisons were restricted to ulcers greater than 0.5 cm in diameter (12.3% placebo, 4.2% 100 micrograms misoprostol, and 0.7% 200 micrograms misoprostol). Mild to moderate, self-limiting diarrhoea was the most frequently reported adverse effect attributed to misoprostol. These results provide the first clear indication that NSAID-induced ulcers are preventable. AD - Veterans Administration Medical Center, Houston, Texas. • The dose of misoprostol should begin at 100 microg three to four times daily, then increased as tolerated. Lower doses of misoprostol have been used with some success for ulcer prevention with a lower incidence of side effects [47]. (See "NSAIDs: Primary prevention of gastroduodenal toxicity"). Prostaglandins of the E group are uterotropic. Misoprostol has been given with mifepristone to induce abortion [45,48]. As a result, it is contraindicated in women of childbearing potential who are not on contraception. All patients should be informed of this risk to minimize the drug being inadvertently given by the patient to a pregnant woman. Eikozanoidler ve Diğer Otakoidler

30 Prostaglandinlerin Etkileri (devam)
Prof. Dr. Hakan KARADAĞ Prostaglandinlerin Etkileri (devam) TxA2 PGF2a PGI2 PGE2 PGE1 PGD2 Diğer Etkiler göz içi sıvısı basıncında azalma böbrek kan akımında artma hipertermi, hiperaljezi, diürezis, hipertermi Preparat Dinoprost Epoprostenol sodyum Dinoproston Alprostadil Analogları Karboprost Latanoprost Travaprost Bimatoprost Unoproston İloprost Sikaprost Arboprostil Enprostil Gemeprost Rioprostil Mizoprostol UpToDate 13, Prostaglandin analogs (eg, bimatoprost, latanoprost, travoprost, unoprostone) improve aqueous outflow. Side effects include iris and eyelid pigmentation, eyelash growth, and cystoid macular edema. Eikozanoidler ve Diğer Otakoidler

31 Alprostadil (PGE1) Ductus arteriosus açıklığının sürdürülmesinde Epoprostenol sodyum (PGI2) Ekstrakorporeal dolaşım (hemodiyaliz ya da kalp cerrahisi) sırasında pıhtı oluşmasını ve trombosit kaybını önlemek için İloprost Sikaprost Periferik vasküler hastalık Latanoprost Travaprost Bimatoprost Unoproston Açık açılı glokom Mizoprostol Rioprostil Enprostil Arboprostil Peptik ülserli, NSAİİ kullananlarda antiülser ajan olarak (H2-antihistaminiklere üstün bulunmamışlardır) Dinoproston (PGE2) Dinoprost (PGF2a) Karboprost Gemeprost Aborsiyon, uterus kasıcı

32 XALACOM 50 mg latanoprost+5 mg timolol, 2,5 ml göz damlası 36,64 YTL
Prof. Dr. Hakan KARADAĞ Mizoprostol CYTOTEC mg, 28 tablet 11,11 YTL Yan Etkiler Diyare, karın ağrısı, dispepsi, flatulans, bulantı, kusma, vajinal kanama Latanoprost XALACOM mg latanoprost+5 mg timolol, 2,5 ml göz damlası 36,64 YTL XALATAN %0,005’lik 2,5 ml göz damlası 28,77 YTL UpToDate 13, Prostaglandin analogs (eg, bimatoprost, latanoprost, travoprost, unoprostone) improve aqueous outflow. Side effects include iris and eyelid pigmentation, eyelash growth, and cystoid macular edema. Travoprost TRAVATAN mg, 2,5 ml göz damlası 25,82 YTL Bimatoprost LUMİGAN ,3 mg/mL, göz damlası 30,97 YTL Dinoproston PROPESS mg, 1 ovül 81,57 YTL İloprost İLOMEDİN ,20 mg/ml, 1 ampul 349,30 YTL Eikozanoidler ve Diğer Otakoidler

33 Prostaglandin Reseptörleri
Agonistler Antagonistler DP PGD2 EP PGE2 EP1 EP2 EP3 EP4 FP PGF2a İP PGI2 TP TxA2 PGG2 PGH2 İfetroban Ramatroban Daltroban, Sultroban Tümü 7 transmembranal segmentli, G proteini ile kenetli reseptördür.

34 Prostaglandin Reseptörleri (IUPHAR Sınıflaması)
Prof. Dr. Hakan KARADAĞ Prostaglandin Reseptörleri (IUPHAR Sınıflaması) Agonistler Antagonistler DP1 PGD2 DP2 EP PGE2 EP1 EP2 EP3 EP4 FP PGF2a İP1 PGI2 TP TxA2 PGG2 PGH2 İfetroban Ramatroban Daltroban, Sultroban GENERAL Fatty acid cyclo-oxygenase (COX) converts arachidonic acid to prostaglandin H2 (PGH2), from which further prostanoids, PGD2, PGE2, PGF2α, PGI2 (prostacyclin) and thromboxane A2 (TXA2), may be derived. Based on the agonist potencies of the latter prostanoids, five prostanoid receptors were recognized and correspondingly named DP, EP, FP, IP and TP receptors [1]. Additionally, EP receptors have been subdivided into four groups, termed EP1, EP2, EP3 and EP4; the DP receptor also has two subtypes. cDNA cloning identified a family of eight G-protein coupled receptors (GPCRs) that correspond to these pharmacologically-defined receptors. cDNA cloning also revealed the presence of an additional GPCR called CRTH2 that mediates some PGD2 actions. Therefore, the DP receptor now has two subtypes, DP1 and DP2 (CRTH2). DP RECEPTORS DP1 receptors are coupled to adenylate cyclase via a Gs protein [10-12]. Activation of DP1 receptors leads to inhibition of platelet activation and vasodilatation [2]. DP1 receptors are expressed in the brain, where they may be involved in the regulation of sleep [13]. BW-245C is a selective DP1 agonist and its analogue BW A868C is a potent DP1 antagonist [8]. In addition to AH-6809 (see EP1 receptors), BW A868C suppressed itching in allergic conjunctivitis in the guinea-pig [460]. The DP2 receptor is structurally distinct from all of the other known prostanoid receptors, being more closely related to chemoattractant receptors such as fMLP and BLT receptors. Indeed this receptor was originally termed CRTH2 to indicate both its activity and the cell type in which it was initially identified [ ]. Unlike the DP1 receptor, it is activated by prostanoids with an unnatural configuration at C-15 and also by 15-oxo analogues (potential products of 15-hydroxy prostaglandin dehydrogenase). Furthermore, the COX inhibitor indomethacin is an agonist at the DP2 receptor [370]. Activation of DP2 receptors leads to eosinophil, basophil and Th2 cell activation, while DP1 receptor activation may oppose these events [461]. Ramatroban, originally developed as a TP antagonist, also blocks DP2 receptors [457]. EP RECEPTORS As a broad generalization, EP1 and EP3 receptors mediate excitatory effects, while EP2 and EP4 receptors mediate inhibitory effects. EP1 receptors are believed to be coupled via regulatory G proteins to (PLC-independent) influx of extracellular Ca2+; phosphatidylinostol hydrolysis ensues as a consequence of this influx [18]. EP3 receptors are subject to splice variance at the C-terminus [20,21] and, to date, ten isoforms have been identified across species, six of these being expressed in man [22]. These isoforms differ in their G-protein coupling thereby contributing to the wide spectrum of EP3 actions: contraction of smooth muscle, enhancement of platelet aggregation, inhibition of autonomic neurotransmitter release, inhibition of gastric acid secretion, and inhibition of fat cell lipolysis [2,19]. There is no published evidence that splice variance influences ligand affinity. EP2 and EP4 receptors are believed to be coupled through a Gs protein to stimulation of adenylate cyclase [2]. Both EP subtypes may be present on smooth muscle cells with the latter usually showing considerably higher sensitivity to PGE2. Selective agonists exist for all four EP subtypes [449]. Selective antagonists for EP1 receptors have been known for some time [445] and several have progressed into clinical trials as analgesic/anti-inflammatory agents. Blockers of EP3 and EP4 receptors have recently emerged mainly from screening of compound libraries. There is a need for a good EP2 antagonist; AH-6809 has found some utility [78], but it has low selectivity, also antagonizing EP1 and DP1 receptors. FP RECEPTORS FP receptors are believed to be coupled via a regulatory G protein to stimulation of PI hydrolysis [2,24,25]. They are found in smooth muscle, being particularly widely distributed in cats and dogs, where they mediate contraction. Fluprostenol is a highly selective FP agonist. FP receptors present in the corpus luteum of many species mediate luteolysis, and PGF2α analogues (fluprostenol, cloprostenol) have been used in animal husbandry to synchronize oestrus and induce parturition [450]. FP receptor-stimulation also profoundly lowers intraocular pressure in laboratory animal species and man [26,27] and FP agonists applied topically as C1-ester pro-drugs (latanoprost, travoprost) are increasingly used as anti-glaucoma drugs [448]. The evidence for subtypes of FP receptor is at best inconclusive, but it is now known that there is splice variance of the human FP receptor [334]. FP receptor antagonists have been slow to emerge; the PGF2α analogue AL-8810 appears to be a partial agonist at the FP receptor [392,459]. IP RECEPTORS IP receptors are coupled via a Gs protein to stimulation of adenylate cyclase [10]. IP receptors relax vascular smooth muscle and inhibit platelet aggregation. They appear to contribute to cardiovascular health by counteracting vasoconstriction and platelet activation mediated via TP receptors. Prostacyclin and a few of its stable analogues are used to treat pulmonary hypertension, with careful attention to dosage to avoid excessive lowering of arterial blood pressure [442]. Cicaprost is the most selective IP agonist [394]; other commonly used agonists (carbacyclin, iloprost) have sufficient EP1 and/or EP3 agonism to oppose their IP-receptor-mediated actions. A large range of non-prostanoid prostacyclin mimetics exists [453]; while some of these agents appear to be IP partial agonists, analysis is hampered by the their ability to inhibit PLC-driven events via a non-prostanoid mechanism [441]. Selective IP receptor antagonists that competitively block the vasodilator platelet-inhibitory actions of IP agonists have recently been described [395,396]. These agents suppress hyperalgesia and oedema in animal models of inflammation, indicating that PGI2 may not always have beneficial actions in the body. There is autoradiographic and functional evidence for a second type of IP receptor (IP2) in the central nervous system [33]. However data from the IP receptor knock-out mouse do not support this notion [34]. TP RECEPTORS TP receptors are present in nearly all mammalian blood vessels, airways and blood platelets, where they mediate smooth muscle contraction and platelet aggregation. Signal transduction occurs via regulatory G proteins linking to stimulation of PI hydrolysis [35]. Both PGH2 and TXA2 are potent agonists for the TP receptor, but are rarely used in characterization studies owing to the instability of their bicyclic ring systems. They are usually replaced by either 11,9-epoxymethano PGH2 (U-46619) or STA2, which are full agonists; other analogues often exhibit partial agonism (9,11-epoxymethano PGH2, CTA2, PTA2). A number of highly potent TP agonists have been synthesized (EP 171, I-BOP), but their utility is compromised by their slow onset / slow offset on isolated tissue preparations. There are many TP receptor antagonists, some of which are obviously analogues of PGH2 / TXA2, while others bear little structural resemblance to prostanoids. GR [451] and SQ [455] are in common use. Heterogeneity in the affinities of TP antagonists [63,37,38] has stimulated much debate about the existence of subtypes of TP receptor; however, species differences may account for much of the variation. On the other hand, there is now evidence for splice variance within TP receptors [39,40], and a resulting C-terminus extended form of the TP receptor has been shown to be particularly highly expressed in vascular endothelial cells [39]. Simple TP receptor antagonists have found little use in cardiovascular disease; preventative treatment with low-dosage aspirin is sufficient to tip the balance away from thromboxane [456]. Agents combining TP antagonism and TX synthase inhibition (ridogrel) have shown more promise [458]. ISOPROSTANES There is interest in the isoprostanes [41,42], a class of prostanoids that are not products of the enzyme cyclo-oxygenase, but are rather formed by direct oxidation of membrane phospholipids. The isoprostanes exhibit a wide range of biological actions, and most evidence suggests that they act at the same receptors as the 'classical' prostanoids [43]. There is evidence, however, that 8-epi PGF2α may act at a receptor that, although similar to a TP receptor, is not identical [44]. PROSTAMIDE RECEPTORS It has been proposed that C1-ethanolamides of PGE2 and PGF2&alpha and their analogues (e.g. bimatoprost) can activate prostamide receptors, which are distinct from the known prostanoid receptors [452]. The recent report that AGN blocks the 'prostamide receptor', but not the FP-receptor, present in cat iris sphincter supports this contention [459]. Tümü 7 transmembranal segmentli, G proteini ile kenetli reseptördür. Eikozanoidler ve Diğer Otakoidler

35 ARAŞİDONİK ASİT Membran Fosfolipidleri Prostaglandinler
Prof. Dr. Hakan KARADAĞ Membran Fosfolipidleri Fosfolipaz A2 ARAŞİDONİK ASİT Siklooksijenaz Sitokrom P450 Phospholipid hydrolysis — In mammalian cells, the most common fatty acid substrate for both prostaglandins and leukotrienes is arachidonic acid (AA). Other polyunsaturated fatty acids may also serve as substrates, including eicosapentaenoic acid (EPA) and dihomogammalinolenic acid (DGLA) [6]. Phospholipid hydrolysis is catalyzed by phospholipase A2 (PLA2); this enzyme exists in at least 16 isoenzymes, each with different properties such as calcium dependence and subcellular localization. Five significant mammalian classes of PLA2s have been characterized: The "secretory" PLA2s, four structurally related enzymes, comprise groups I, II, V, and X. The multiple isoenzymes of these families are characterized by conservation of 12 to 16 cysteine residues and highly homologous catalytic and calcium binding domains. These molecules were originally described in the pancreas and in inflammatory exudates (such as inflammatory synovial fluid), respectively. They are also found in granules of mast cells and platelets, suggesting a role for providing eicosanoids in pathophysiologic processes [7]. Inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNFa) induce group II PLA2, an effect that is attenuated by corticosteroids [7]. The fifth major family, Group IV PLA2, referred to as cytoplasmic PLA(2) (cPLA2), is relatively specific for arachidonic acid hydrolysis from phospholipids and has no amino acid homology to the families of PLA2 enzymes. The cPLA2 is activated by micromolar increases of calcium, resulting in translocation to the perinuclear membrane and augmented function via MAP-kinase-dependent serine phosphorylation [7,8]. Gene deletion experiments in the mouse suggest that the cPLA2 isoform is the most important PLA2 involved in the formation of eicosanoids in neutrophils and monocytes. Similar to the secretory isoforms, inflammatory cytokines upregulate the production of cytosolic PLA2 and corticosteroids inhibit this process. Following release of arachidonic acid from the cell membrane, the remaining lysophospholipid (lyso-platelet activating factor) may be converted to platelet activating factor (PAF), another inflammatory mediator. PAF upregulates production of the inflammatory cytokines TNFa, IL-1, IL-2, and IL-6 in hematopoietic cells and macrophages via receptor-mediated action. It also increases leukotriene generation in granulocytes, and affects a variety of other cells including B-lymphocytes, NK cells, and vascular endothelial cells. 5 Lipoksijenaz Sitokrom P450 Ürünleri Prostaglandinler 12 Lipoksijenaz 15 Lipoksijenaz Lökotrienler ve Diğer Lipoksijenaz Ürünleri Eikozanoidler ve Diğer Otakoidler

36 15-HPETE 12-HPETE 5-HETE LTA4 LTC4 LTB4 LTD4 LTE4 LTF4
FOSFOLİPİDLER 15-lipoksijenaz 12-lipoksijenaz Araşidonik Asit 15-HPETE 12-HPETE Zilöton 5-lipoksijenaz 5-HPETE 12-HETE SRS-A LTC4 LTD4 LTE4 LTA sentaz non-enzimatik LTC sentaz 5-HETE LTA4 LTC4 g-glutamil transpeptidaz LTA hidrolaz LTB4 Güçlü kemotaktik LTB4 LTD4 dipeptidaz LTC4, LTD4, LTE4 Bronkokonstriksiyon Pulmoner kan basıncı artışı Vazokonstriksiyon (arteriyel) Kapiler permeabilite artışı LTE4 g-glutamil transpeptidaz LTF4

37 Lipoksijenazlar 5 12 15 Lökosit + Trombosit Mast hücresi Endotel hücresi

38 Lökotrien Reseptörleri
Agonistler Antagonistler BLT LTB4 CysLT1 LTC4= LTD4 = LTE4 Zafirlukast Montelukast Pobilukast Pranlukast İbudilast CysLT2 LTC4 ≥ LTD4>> LTE4 Tümü 7 transmembranal segmentli, G proteini ile kenetli reseptördür.

39 Lökotrien Reseptörleri (IUPHAR Sınıflaması)
Prof. Dr. Hakan KARADAĞ Lökotrien Reseptörleri (IUPHAR Sınıflaması) Agonistler Antagonistler BLT1 LTB4 BLT2 CysLT1 LTC4= LTD4 = LTE4 Zafirlukast Montelukast Pobilukast Pranlukast İbudilast CysLT2 LTC4 ≥ LTD4>> LTE4 OXE ALX Lipoksin A4 LIPOXIN RECEPTORS At the molecular level the ALX receptor was the first recognized non-prostanoid eicosanoid G-protein coupled receptor [8,96]. Furthermore, ALX was initially identified as the only inhibitory or anti-inflammatory receptor which acted as a "stop signal" during inflammatory reactions [76,97]. This receptor was activated by lipoxin A4 and not by LXB4. ALX cDNA was cloned by several investigators who were exploring the FPR receptor [98-100] which was activated by formyl-methionyl-leucyl-phenylalanine (fmlp). ALX has high sequence homology (70%) to FPR and was initially designated as formyl peptide like receptor-1 (FPRL-1). However, ALX binds [3H]-fmlp with low affinity [101]. Although fmlp and a number of synthetic peptides, derived from peptide libraries, activate the ALX receptor, LXA4 was the most potent native endogenous ligand and has been the basis for the present nomenclature. This receptor is composed of 351 amino acids and a gene located to the X chromosome (19q13.3). This receptor is abundantly expressed in lung, peripheral blood leukocytes and spleen to lesser amounts in the heart, placenta and liver. Although functional data [102] have suggested the existence of a receptor activated by LXB4, this receptor has not been cloned and is presently referred to a putative receptor. This suggestion is also supported by the observations that lipoxin B4 analogs are potent anti-inflammatory compounds in vivo [103]. In addition, LXA4 shares some structural features with LTC4 and LTD4 and the ligand competed for CysLT1 receptors in endothelial cells [104] and mesangial cells [105]. LXA4 antagonized LTC4- and LTD4-induced bronchoconstriction in humans [106] and animals [7,107]. The data suggest that a "shared ALX/CysLT receptor" may also exist. However, the exact mechanisms by which this interaction occurs have not been elucidated. OXE RECEPTOR Oxoeicosanoids are a family of biologically active arachidonic acid derivatives that have been intimately associated with cellular migration [79, ]. These mediators are potent chemotaxins for eosinophils, monocytes and polymorphonuclear neutrophil [79,110]. However, these metabolites may also induce degranulation particularly in cells which have been primed with cytokines [108,111]. The receptor which is activated by the oxoeicosanoids has recently been cloned [ ]. This recombinant receptor has an amino acid composition of 423 and a gene localized to chromosome 2p21. This receptor is expressed principally in kidney, liver as well as in eosinophils, neutrophils, and lung macrophages. The native and most potent ligand is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE). The OXE receptor shares 23.2% and 25.3% identity with CysLT1 and CysLT1 respectively. In CHO cells transfected with the human recombinant OXE receptor, activation lead to calcium mobilization and the receptor was shown to be coupled to Gαi. Further investigations are necessary to establish what compounds may antagonize the chemotactic activities which have been reported. Tümü 7 transmembranal segmentli, G proteini ile kenetli reseptördür. Eikozanoidler ve Diğer Otakoidler

40 Montelukast LUXAT 10 mg, 28 tablet 53,46 YTL NOTTA 4 mg, 28 tablet 55,28 YTL 5 mg, 28 tablet 55,28 YTL 10 mg, 28 tablet 53,48 YTL ONCEAIR 4 mg, 28 tablet 55,28 YTL 5 mg, 28 tablet 55,28 YTL 10 mg, 28 tablet 53,46 YTL SINGULAIR 4 mg, 28 tablet 66,78 YTL 5 mg, 28 tablet 66,78 YTL 10 mg, 28 tablet 66,78 YTL 4 mg, ped 28 saşe 66,78 YTL ZESPIRA 4 mg, 28 tablet 53,59 YTL 5 mg, 28 tablet 53,59 YTL 10 mg, 28 tablet 53,48 YTL Yan Etkiler Gastrointestinal bozukluklar, ağız kuruluğu, aşırı duyarlılık reaksiyonları, ateş, artralji, baş ağrısı, uyku bozuklukları Zafirlukast ACCOLATE mg, 56 tablet 59,03 YTL CARROX mg, 56 tablet 25,84 YTL 20 mg, 56 tablet 51,41 YTL Yan Etkiler Gastrointestinal bozukluklar, baş ağrısı, aşırı duyarlılık reaksiyonları, artralji, karaciğer enzimlerinde yükselme, hepatit, trombositopeni

41 Nitrik Oksid (NO, EDRF) eNOS (endotel) Kalsiyum ve kalmoduline bağımlı
Keşif Furchgott ve Zawadzki 1979 L - Arjinin Nitrik Oksit Sentaz (NOS) NOS İnhibitörleri L - NAME (N G - nitroarjinin - L - metil ester) L - NMMA (N - monometil - L - arjinin) Nitrik Oksit (NO) eNOS (endotel) Kalsiyum ve kalmoduline bağımlı (NOS-3) bNOS (beyin) İnhibitörler (nNOS), (NOS-1) Glukokortikoidler TGF b , IL - 4, IL - 10 iNOS (indüklenebilir) Kalsiyum ve kalmoduline bağımlı değil İndükleyiciler (NOS-2) Sitokinler Makrofaj (TNF a , IL - 1 b , interferon - g) Hepatosit Endotoksin (Lipopolisakkarid)

42 Etki Mekanizması Etkileri
Solubl guanilat siklaz aktivasyonu intraselüler sGMP  NO Salıveren Maddeler Asetilkolin Histamin Serotonin Vazopresin Bradikinin PG I2 VIP P maddesi CGRP İnsulin Klonidin (a2-uyarı) Katekolaminler (a2-uyarı) Etkileri Düz kas gevşemesi Trombosit adezyonu ve agregasyonunun inhibisyonu Antiproliferatif etki

43

44 Trombosit Aktive Edici Faktör (TAF, PAF)
Membran fosfolipidlerinden üretilir. Kimyasal yapı: 1-alkil-2-asetilgliseril-3-fosfokolin

45 Güçlü vazodilatör (hipotansif etki)
Etkileri Güçlü vazodilatör (hipotansif etki) Pulmoner damar yatağında vazokonstriksiyon Kapiler ve venüllerin permeabilitesinde artma (Lewis’in üçlü yanıtı) Trombosit agregasyonu TxA2 üretiminde artma Trombosit yıkımının artması sonucu trombositopeni Düz kas kasıcı etki gastrointestinal bronş uterus Ülserojen Üretim Trombositler Nötrofil ve eozinofil lökositler Monositler Damar endotel hücreleri Mast hücreleri Böbrekte mezangial ve interstisyel hücreler

46 Basic Structure of Plasmalogens
Prof. Dr. Hakan KARADAĞ Basic Structure of Plasmalogens Plasmalogens are complex membrane lipids that resemble phospholipids, principally phosphatidylcholine. The major difference is that the fatty acid at C-1 (sn1) of glycerol contains either an O-alkyl or O-alkenyl ether species. A basic O-alkenyl ether species is shown in the Figure below. One of the most potent biological molecules is platelet activating factor (PAF) which is a choline plasmalogen in which the C-2 (sn2) position of glycerol is esterified with an acetyl group insted of a long chain fatty acid. Eikozanoidler ve Diğer Otakoidler

47 En güçlü Ülserojen PAF Antiagregan PGI2 Bronkokonstriktör ve kapiler permeabilite artışı yapan LTD4 Kemotaktik LTB4 Proinflamatuar ve hiperaljezik PGE2

48 2007 Eylül TUS

49 2007 Nisan TUS


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