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Leukotrienes: Biosynthesis and mechanisms of action
In summary, this study provides evidence for the occurrence of transcellular biosynthesis of cysLTs in vivo. Given the efficiency of transfer of the reactive intermediate LTA4 to generate cysLTs, it appears that transcellular synthesis could be a sizable component of cysLT production during inflammation and contribute to the overall inflammatory response. The separation of critical enzymes in different cells probably constitutes an additional regulatory mechanism controlling production of these important mediators, and as such it provides a potentially unique target for pharmacological intervention.
Leukotrienes (LTs) are biologically active lipid mediators that play important roles in inflammation and are involved in pathological states with an inflammatory component, such as asthma, cardiovascular disease, or cancer (–). They derive from arachidonic acid (AA) through the action of 5-lipoxygenase (5LO) (), an enzyme expressed in a limited number of cells, including neutrophils, eosinophils, monocytes, macrophages, mast cells, and basophils (, ). Considerable work has led to our current understanding of events regulating the formation of these mediators. AA is released from phospholipids by cytosolic phospholipase A2α (cPLA2α) after this enzyme translocates from cytosol to perinuclear membranes of cells, usually following an increase in calcium ion concentration (). 5LO, a soluble protein in the cytosol or nucleoplasm of resting cells, also translocates to perinuclear membranes when calcium levels increase (). 5LO oxidizes free AA to 5-hydroperoxyeicosatetraenoic acid. This intermediate can be reduced by peroxidases to 5-hydroxyeicosatetraenoic acid (5-HETE) or dehydrated, in a second 5LO-catalyzed reaction, to leukotriene A4 (LTA4). 5LO action is facilitated by 5LO-activating protein (FLAP), an integral nuclear membrane protein, and the assembly of a multienzymatic machine to make LTs (–). Thus, LTA4 is formed near the nuclear envelope, and this chemically reactive molecule must find its way either to leukotriene C4 synthase (LTC4S), another nuclear membrane protein that conjugates LTA4 with glutathione to form leukotriene C4 (LTC4), or to cytosolic LTA4 hydrolase (LTA4H), which stereospecifically opens the epoxide ring and controls the addition of water at carbon-12 to form leukotriene B4 (LTB4). LTC4 can be metabolized by sequential proteolytic hydrolysis to leukotriene D4 (LTD4) and leukotriene E4 (LTE4); these 3 compounds are collectively termed cysteinyl LTs (cysLTs). The final LT products derived from LTA4 play important roles in inflammation, such as inducing neutrophil chemotaxis (LTB4) or causing edema and smooth muscle contraction (LTC4, LTD4) (, ). The effects of these eicosanoids are mediated by G-protein coupled receptors. Two have been identified for LTB4 (BLT1 and BLT2) (, ), and 3 for cysLTs (cysLT1, cysLT2, and GPR17) (–). Although the protein has not been identified, a novel receptor showing specificity for LTE4 has been recently described (). CysLT1 receptor antagonists are currently used to help control asthma symptoms, and drugs that interfere with LT biosynthesis or action are candidates for preventing cardiovascular disease (, ).
Pathways in biosynthesis of eicosanoids from arachidonic acid: ..
LT production is regulated at different levels (), including methylation of the 5LO promoter () and posttranslational control of 5LO activity through phosphorylation, interaction with FLAP (, ), and translocation induced by calcium or free AA (). Additionally, experimental evidence suggests that cells cooperate in the synthesis of LTB4 and LTC4. For example, human platelets, which express no 5LO, can interact with activated neutrophils, which do not express LTC4S, to generate LTC4 (). Many other instances of transcellular LT biosynthesis have been described (). The chemical half-life of LTA4 in buffer is less than 5 s (), which implies some protective mechanism of the epoxide ring during transfer from the donor cell to the acceptor cell.
Pathophysiology of common diseases; Basic Principles of Cell Injury and Adaptations: Causes of Cellular injury, pathogenesis, morphology of cell injury, adaptations and cell death. Basic Mechanisms involved in the process of inflammation and repair: Vascular and cellular events of acute inflammation, chemical mediators of inflammation, pathogenesis of chronic inflammation, brief outline of the process of repair. Immunopathophysiology: T and B cells, MHC proteins, antigen presenting cells, immune tolerance, pathogenesis of hypersensitivity reactions, autoimmune diseases, AIDS, Amyloidosis. Pathophysiology of Common Diseases: Asthma, diabetes, rheumatoid arthritis, gout, ulcerative colitis, neoplasia, psychosis, depression, mania, epilepsy, acute and chronic renal failure, hypertension, angina, congestive heart failure, atherosclerosis, myocardial infarction, congestive heart failure, peptic ulcer, anemias, hepatic disorders, tuberculosis, urinary tract infections and sexually transmitted diseases. Wherever applicable the molecular basis should be discussed.
Fundamentals of general pharmacology: Dosage forms and routes of administration, mechanism of action, combined effect of drugs, factors modifying drug action, tolerance and dependence; Pharmacogenetics; Principles of Basic and Clinical pharmacokinetics, absorption, Distribution, Metabolism and Excretion of drugs, Adverse Drug Reactions; Bioassay of Drugs and Biological Standardization; Discovery and development of new drugs, Bioavailability and bioequivalence studies; Pharmacology of Peripheral Nervous System: Neurohumoral transmission (autonomic and somatic), Parasympathomimetics, Parasympatholytics, Sympathomimetics, Adrenergic receptor and neuron blocking agents, Ganglion stimulants and blocking agents, Neuromuscular blocking Agents, Local anesthetic Agents.
Pharmacology of Central Nervous System: Neurohumoral transmission in the C.N.S., General Anesthetics, Alcohols and disulfiram, Sedatives, Hypnotics, Anti-anxiety agents and Centrally acting muscle relaxants, Psychopharmacological agents (anti-psychotics), anti-maniacs and hallucinogens, Antidepressants, Anti-epileptics drugs, Anti-Parkinsonian drugs, Analgesics, Antipyretics, Narcotic analgesics and antagonists, C.N.S. stimulants, Drug Addiction and Drug Abuse.
Pharmacology of Cardiovascular System: Drugs used in the management of congestive cardiac failure, Antihypertensive drugs, Anti-anginal and Vasodilator drugs, including calcium channel blockers and beta adrenergic antagonists, Anti-arrhythmic drugs, Anti-hyperlipedemic drugs, Drugs used in the therapy of shock.
Drugs Acting on the Hemopoietic System: Hematinics, Anticoagulants, Vitamin K and hemostatic agents, Fibrinolytic and anti-platelet drugs, Blood and plasma volume expanders.
Drugs acting on urinary system: Fluid and electrolyte balance, Diuretics. Autacoids: Histamine, Antihistaminic drugs, 5-HT- its agonists and antagonists, Prostaglandins, thromboxanes and leukotrienes, Angiotensin, Bradykinin and Substance P and other vasoactive peptides, non-steroidal anti-inflammatory and anti-gout agents.
Drugs Acting on the Respiratory System: Anti-asthmatic drugs including bronchodilators, Anti-tussives and expectorants, Respiratory stimulants.
Drugs acting on the Gastrointestinal Tract: Antacids, Anti-secretory and Anti-ulcer drugs, Laxatives and anti-diarrhoeal drugs, Appetite Stimulants and Suppressants, Emetics and anti-emetics, Miscellaneous: Carminatives, demulcents, protectives, adsorbents, astringents, digestants, enzymes and mucolytics.
Pharmacology of Endocrine System: Hypothalamic and pituitary hormones, Thyroid hormones and anti thyroid drugs, parathormone, calcitonin and Vitamin D, Insulin, glucagons, incretins, oral hypoglycemic agents and insulin analogs, ACTH and corticosteroids, Androgens and anabolic steroids, Estrogens, progesterone and oral contraceptives,
Drugs acting on the uterus & Chemotherapy: General Principles of Chemotherapy, Bacterial resistance; Sulfonamides and cotrimoxazole, Antibiotics- Penicillins, Cephalosporins, Aminoglycosides, Chloramphenicol, Macrolides, Tetracyclines, Quinolones, fluoroquinolones and Miscellaneous antibiotics; Chemotherapy of tuberculosis, leprosy, fungal diseases, viral diseases, HIV and AIDS, urinary tract infections and sexually transmitted diseases, malaria, amoebiasis and other protozoal infections and Anthelmentics. Chemotherapy of malignancy and immunosuppressive agents. Principles of Toxicology: Definition of poison, general principles of treatment of poisoning with particular reference to barbiturates, opioids, organophosphorous and atropine poisoning, Heavy metals and heavy metal antagonists.
Basic Concepts of Pharmacotherapy: Clinical Pharmacokinetics and individualization of Drug therapy, Drug delivery systems and their Biopharmaceutic & Therapeutic considerations, Drugs used during infancy and in the elderly persons (Pediatrics & Geriatrics), Drugs used during pregnancy, Drug induced diseases, The basics of drug interactions, General principles of clinical toxicology, Common clinical laboratory tests and their interpretation; Important Disorders of Organs, Systems and their Management: Cardio-vascular disorders- Hypertension, Congestive heart failure, Angina, Acute myocardial infarction, Cardiac arrhythmias. CNS Disorders: Epilepsy, Parkinsonism, Schizophrenia, Depression Respiratory disease-Asthma. Gastrointestinal Disorders- Peptic ulcer, Ulcerative colitis, Hepatitis, Cirrhosis. Endocrine Disorders- Diabetes mellitus and Thyroid disorders. Infectious Diseases- Tuberculosis, Urinary tract infections, Enteric infections, Upper respiratory infections. Hematopoietic Disorders- Anemias, Joint and Connective tissue disorders- Rheumatic diseases, Gout and Hyperuricemia. Neoplastic Diseases- Acute Leukaemias, Hodgkin’s disease. Therapeutic Drug Monitoring, Concept of Essential Drugs and Rational Drug use.
leukotrienes, prostanoids, and ..
They are generated by cyclooxygenase isozymes and 5-lipoxygenase, respectively, and their biosynthesis and actions are blocked by clinically relevant nonsteroidal anti-inßammatory drugs, the newer generation coxibs (se-lective inhibitors of cyclooxygenase-2), and leukotriene modiÞers.
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