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WO1988006445A1 - Macromolecules de prostaglandine b1 servant d'agents anti-inflammatoires - Google Patents

Macromolecules de prostaglandine b1 servant d'agents anti-inflammatoires Download PDF

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Publication number
WO1988006445A1
WO1988006445A1 PCT/US1987/000408 US8700408W WO8806445A1 WO 1988006445 A1 WO1988006445 A1 WO 1988006445A1 US 8700408 W US8700408 W US 8700408W WO 8806445 A1 WO8806445 A1 WO 8806445A1
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agent
pathophysiological
treatment
pgbx
injury
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William Regelson
Richard Franson
Marc W. Fariss
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids

Definitions

  • PGBx polymeric derivati of prostaglandin B 1
  • the present invention describes the developme by the inventors, of something not taught in the Polis patent above, i.e., molecular mechanism of action of PGBx.
  • PGBx stabilizes membrane phospholipid composition and mainta cell function in situations of ischemia and injury because it possesses bo anti-phospholipase and anti-oxidant activities.
  • these dual properties we have invented unique, widespread and fundament uses for PGBx as an anti-inflammatory, anti-oxidant, and cytoprotective agen
  • PGBx enables cell membranes to resist injury and destructi by preserving membrane integrity and permits tissue repair mechanisms assist in stabilization and/or return to normal function of previously damag or inflamed tissues.
  • PGBx shall refer to the above polymeric derivatives of prostaglandin B. including macromolecules thereof, such as dimers, trimers, tetramers, and polymers, etc., known to the inventors.
  • macromolecule shall also mean dimers, trimers, tetramers and polymers of prostaglandin B...
  • PGBx shall further include that mixture made by Polis and taught in the above patents.
  • this PGBx contains macromolecules in the form of polymers and oligomers of prostaglandin B.
  • oligomers describes dimers, trimers, tetramers, etc., of prostaglandin B, .
  • the major presently used clinically effective prior art anti-inflammatory drugs are corticosteroids and non-steroidal anti-inflammatory agents (NSAIAs) . These drugs act to control inflammation and to minimize cell injury by regulating the formation of prostaglandins and leukotrienes (see figure 1) which are produced in increased quantities in inflammation and promote cell dysfunction and injury.
  • the mechanism of action of these drugs is to either suppress the release of free fatty acid (such as arachidonate) from the 2-position of membrane phospholipid by inhibiting cellular phospholipases (the mechanism of corticosteroid action), or for NSAIAs, to inhibit the further conversion of arachidonate, released by the action of cellular phospholipases, to prostaglandins.
  • free fatty acid such as arachidonate
  • NSAIAs the mechanism of corticosteroid action
  • cellular and extra cellular phospholipases may be activated by the generation of oxygen free radicals. This can establish a "vicious cycle" as phospholipase activation can release free radicals which, in turn, activate more phospholipases.
  • oxygen free radicals are produced from free fatty acids, released by the action of phospholipases, which are then converted to prostaglandins and leukotrienes.
  • Fig. 1 These oxygen free radicals generated from free fatty acids and tissue injury are inhibited by PGBx.
  • Fatty acids and free radicals are known to be prime mediators in the cascade of reactions that result in membrane injury and cell death.
  • One of the hallmarks of inflammation and cell injury is the breakdown o cellular membrane phospholipid.
  • Phospholipids are the major structural building blocks of the cell membrane; they give rise to the barrier structural and functional properties of membranes and their integrity is crucial to normal cell responsiveness and function. Phospholipid changes in cell membrane integrity alter the fluidity of cell membranes, their receptor availability and the leakiness or availability of cellular contents to the external environment.
  • phospholipases from whatever cause, that are normally under the control of natural suppressor systems are activated to degrade membrane phospholipid which, in turn, generates oxygen free radicals.
  • a key enzyme which is activated in inflammation is phospholipase A as which acts on phospholipids as enzyme targets to release free fatty acids. These fatty acids (i.e., arachidonate) released by phospholipase A_ degradation are converted to potent biologically active metabolites, prostaglandins and leukotrienes, with the concomitant generation of oxygen free radicals. These metabolites, fatty acids and free radicals are powerful mediators of pathophysiology which propagate injury and cell death.
  • phospholipases particularly phospholipase AZA, as mem- brane targeted enzymes, makes them veritable "death triggers" as the ex ⁇ pression of their degradative activity results in further production of inflammatory mediators leading to further membrane injury which propagates damage within the cell itself or into adjacent tissues.
  • the spread of injury from the initial site to contiguous or distant sites can be promoted by the activation and/or release of phospholipase A_.
  • phospholipases In addition to the intrinsic membrane-related tissue breakdown via the activation of phospholipase A political, phospholipases, and particularly phospholipase A concerns are part of the normal host defensive system of the body. Phospholipase A réelle is found in particularly high levels in human white blood cells (WBCs or PMNs) or phagocytic cells. WBCs play a role in resisting infection, but when these cells are mobilized to ward off injury and infection, phospholipases A_ are released from adherent and circulating WBCs and produce local tissue necrosis which increases the extent of initial injury. In addition, WBCs adhere to blood vessel walls where they release enzymes such as phospholipase A vide.
  • WBCs or PMNs human white blood cells
  • phospholipases A_ are released from adherent and circulating WBCs and produce local tissue necrosis which increases the extent of initial injury.
  • WBCs adhere to blood vessel walls where they release enzymes such as phospholipas
  • WBC's also generate free radicals and thus promote damage to the vascular endothelium, lung alveoli or to tissue sites contiguous with WBC infiltration or concentration. This WBC adherence to vascular endothelium with release of phospholipase A_ activation results in damage to vascular integrity during shock and ischemia. Thus, in addition to being a prime defensive system of the body against infection, WBC's can also damage the body by propagating injury and inflammation beyond their normal defensive role.
  • PGBx by inhibiting WBC adherence and phospholipase activity, and by scavenging or neutralizing WBC free radical generating activity protectively modulate the toxic inflammatory activity of WBC's to permit the body to develop a reparative equilibrium which permits adequate host defense while minimizing or putting an end to WBC mediated tissue damage and inflammation.
  • PGBx prevents platelet induced vascular occlusion and tissue injury.
  • Platelets are circulating non-nucleated particulates that induce blood clotting, promote phagocytosis and plug holes in blood vessels and thus are necessary to the integrity of vessel function and host defense.
  • platelets stimulated by infection, ischemia or trauma can propagate injury by perverting their normal protective role.
  • PGBx by inhibiting platelet aggregation and platelet release of reactive products, can prevent propagation of platelet mediated occlusive injury or injury related to the release of platelet contained vasoactive toxins permitting the body to restore functional equilibrium to inflamed or damaged tissues.
  • PGBx can be of value in the control of atherosclerosis as smooth muscle hyperplasia is part of the pathology that narrows blood vessels arteriosclerosis ("hardening of the arteries”) .
  • PGBx has the dual action o inhibiting phospholipases, particularly phospholipase A_ as well as possessin antioxidant activity.
  • PGBx protects lysosomal membranes intracellular digestive vacuoles (called "suicide bags") whose rupture ca result in cell injury and death from autodigestion.
  • PGBx protects previousl oxidized phospholipid membranes from further phospholipase degradation
  • PGBx is of value as an anti-inflammatory agent and wil be useful wherever anti-inflammatory agents have been shown to be of value.
  • Inflammation has been defined as th reaction of irritated and damaged tissues which still retain vitalit
  • Inflammation is a process which, at one level, can go on t cell death, tissue necrosis and scarring and at another level, inflammatio can resolve with return to normalcy and no apparent injury or with minima changes, i.e., pigmentation, fibrosis or tissue thickening with collage formation related to healing and scarring.
  • the process is dynamic with cel death as one consequence and recovery, healing and scarring as another.
  • Fo inflammation to occur as a process cells must retain their vitality, dead o severely compromised cells do not respond with inflammatory reactions. Injur in inflammation can also relate to the late results of fibrosis and scarrin with the loss of blood vessels, tissue elasticity and cosmetic quality.
  • Inflammation while a normal process of the body's resistance to injur and infection can become aberrant leading to propagated injury with extensiv scarring, tissue death and/or the death of the organism. "Within certai limits, the inflammatory reaction is stereotyped and it cannot distinguis between those instances in which the process protects the host and those in which the host is harmed.” (Ebert, 1965) Microscopically inflammation is characterized by vasodilation, vascular leakage, enhanced lymphatic flow, platelet vascular adherence and clumping and white blood cell infiltration and vascular adherence and phagocytosis with slowing of blood flow, red cell aggregation on the formation of blood clots. Clinically, these local phenomenon can be associated with pain, fever and swelling which can lead to local tissue destruction (granulation, caseation and necrosis) healing or scarring or to systemic symptoms of fever, shock (prostration) hypotension, leading to death or recovery.
  • Inflammation can be mediated by humoral substances produced by tissue elements or infectious agents or by changes in H (acidity) or oxygen concentration. Clinically, pain, fever, malaise, muscle, arterial and visceral spasm as well as headache can accompany inflammation from whatever primary cause.
  • Free radicals produced by white blood cells or tissue injury, are high reactive chemical species which, in the case of tissue injury, are most oft derived from respiratory oxygen. Oxygen, while necessary for the energeti of life, is also a toxin which, as the highly chemically related superoxid or as peroxides, can damage tissue instead of supporting it. Free radica derived from oxygen are critical to damage produced by radiation, inflammati ischemia (loss of blood supply) or through excess oxygen inhalation and, stated previously, free radicals are used by white blood cells to destr infecting organisms, but can, under circumstances of shock, infection a ischemia, damage or destroy the tissue they were meant to protect.
  • white blood cell reaction can or may be tiss damaging or important to mutational changes associated with aging or t development of cancer and hyperimmune proliferative diseases such rheumatoid arthritis.
  • Immune responses can be both beneficia protective or tissue damaging as can be seen in their being responsible f resistance or cure of infection on the one hand, or capable of produci autoimmune phenomenon that result in allergy, i.e., asthma, urticaria, ho versus graft disease, glomerular nephritis, rheumatic fever, lupus a rheumatoid arthritis.
  • corticosteroids ar effective anti-inflammatories, but must be used with caution clinicall because they are powerful immunosuppressants and inhibitors of fibroblas activity necessary for wound and bone repair.
  • corticosteroid are diabetogenic drugs and their toxic side effects involve interference with wound repair, bone matrix formation, sodium retention, potassium loss, resis ⁇ tance to infection, as well as effects on sex steroid formation, blood pres ⁇ sure and body habitus.
  • NSAIAs non-steroidal anti-inflammatory agents
  • the side effects of NSAIA's include gastric ulceration and metabolites of prostaglandin can be either damaging or protective to cells depending on the structure of the prostaglandin produced or utilized pharmacologically and the cell or tissue affected.
  • leukotrienes In conjunction with fatty acid release, as part of phospholipid cell membrane mediated injury produced by phospholipase activation, leukotrienes are generated (See Fig. 1). These leukotrienes produced from membrane phospholipid breakdown, damage tissue through direct toxic action, and associated free radical formation; or by indirect effects on vascular smooth muscle or vascular endothelial lining via platelet, WBC, endothelial (blood vessel lining) or smooth muscle constricting interactions.
  • Leukotrienes are responsible for smooth muscle constriction leading to bronchospasm and the asthmatic attacks seen in allergy or infectious asthma. There is an active search for leukotriene inhibitors for clinical application In the treatment of allergy, asthma and tissue injury and inflammation.
  • PGBx is both an inhibitor of leukotriene production and a leukotriene antagonist through its dual action as a phospholipase A perennial Inhibitor and anti-oxidant. PGBx inhibits both leukotriene generation and acts directly on its free radical tissue damaging activity. For this reason, PGBx has activity as an agent to relieve bronchospasm and smooth muscle constriction involving leukotriene action on blood vessel, bowel or ureteral smooth muscle.
  • PGBx inhibits bot phospholipases AZA and C in_ vitro which are the major cellular phospholipases that release arachidonate from membrane phospholipid.
  • PGBx inhibits the release of arachidonic acid from membrane phospholipid in intact human endothelial cells. This effect is selective in that PGBx inhibits preferentially when arachidonic acid production is stimulated, but levels are minimally effected in non-stimulated endothelial cells.
  • PGBx inhibits the auto-oxidation of membrane phospholipid and, therefore, is a powerful anti-oxidant.
  • PGBx has potent anti-inflammatory activity in _in vivo animal studies.
  • PGBx can inhibit the release of humoral and inflammatory agents (i.e., histamine, slow reactive substance) as well as free radical release involved in the process of injury and the body's reaction to injury or infection.
  • PGBx is unique in having dual action as a phospholipase inhibitor and an anti-oxidant thus simultaneously acting protectively at two sites whic simultaneously prevent the production of substances injurious and inflammatory to tissue.
  • PGBx also is unique in protecting previously damaged tissue; i.e., containing already oxidized lipld in the cell membrane from further injury by phospholipase action (see Fig. 6), as well as in distinguishing betwee stimulated and normal cells in effecting the release of arachidonic acid fro blood vessel endothelial cells.
  • PGBx will have value wherever steroidal and non-steroidal anti-inflammatory agents have been shown to be of benefit. PGBx will be equal or superior to known clinically useful anti-inflammatories because of its dual membrane protective action. In this regard, PGBx has been shown to block mast cell proliferation to IL-3 mast cells which are specialized cells in vessel walls and connective tissue that release histamine and phospholipases, increasing vascular permeability wherever injury or immune responses occur (see fig. 9).
  • PGBx membrane protective action
  • PGBx is a pivotally active modulator of the key pathways that lead to cell injury and death.
  • the pathophysiology of injury and death is a phospholipid mediated event.
  • the pathophysiology of tissue injury and the body's respons to injury is primarily mediated by phospholipase activation and free radica formation.
  • Cell membranes, which provide for functional and structural integrity necessary for life are made up of phospholipids and the destructio of phospholipid integrity leads to not only organizational and functiona change, but also the formation of free radical chemical destructive agents which propagate further phospholipase activity and membrane destruction.
  • Fre radicals are responsible for protein denaturation and nucleic acid stra breaks which propagate injury beyond the initial insult.
  • t pattern of injury functions in a manner analogous to a breeder reactor whi results in destructive energy formation beyond the initial input of energy the system.
  • PGBx can be likened to the graphite rods that absorb neutrons stop an atomic reactor, i.e., PGBx inhibits both phospholipases and the fr radicals generated from phospholipase or host reactivity (white blood cell that enhance or propagate the initial infectious, ischemic hypoxic, chemic or traumatic insult to the host.
  • Cell injury is membrane mediated and if y protect the cell membranes, you prevent or limit injury and permit recover PGBx stabilizes the lysosomal enzyme containing phospholipid envelope to blo the release of proteolytic hydrolases that destroy intracellular extracellular protein or connective tissue matrices necessary for cell a tissue integrity.
  • PGBx can distinguish between stimulated a unsti ulated cells to block the release of prostaglandin and leukotrie precursors that play a role in inflammation.
  • Topical application to inflamed skin and mucous membrane i.e. poison ivy, allergy, thermal, actinic, chemical and radiation burns conjunctivitis and mucositis.
  • Rapid damage to phospholipid membranes involves free radical chai reactions which propagate on their own. These reactions oxidize th constituent fatty acids to alkyl radicals which, upon oxygenation form lipi hydroperoxides" (Petkau, 1980). Peroxidation products have direct mutageni effects on DNA and, in addition, lipid hydroperoxides which result fro membrane injury or radiation can activate carcinogens such as N-hydroxy-N Acetyl 2-aminofluorene which can lead to tumor formation or effects on hos resistance, i.e., host response to infection and tumor growth via immunity o macrophage response.
  • carcinogens such as N-hydroxy-N Acetyl 2-aminofluorene which can lead to tumor formation or effects on hos resistance, i.e., host response to infection and tumor growth via immunity o macrophage response.
  • autoimmune disease i.e., lupus
  • rheumatoi arthritis is associated with free radical related clastogenic product produced by lymphocyte reaction in serum which have chromosomal breaking o mutational effects.
  • PGBx can be expected to block this because of its fre radical inhibiting action.
  • acute cerebral or spinal cord injury from trauma or ischemia i also associated with lipid peroxidation.
  • PGBx has a place i stroke, spinal cord injury and infectious encephalitides.
  • Polymorphonuclear leukocytes and macrophages which are mobilized during tissue injury and infection release the superoxide anion radical into the tissue space. These give rise to activated oxygen species such as hydrogen peroxide, hydroxyl radicals and singlet oxygen all of which have tissu damaging properties and increase microvascular permeability destroying th integrity of the blood supply governing oxygen and carbon dioxide diffusio tissue nutrition and the fluid mechanics responsible for tissue turgor an homeostasis.
  • Shock is simply defined "as the loss of effective circulating bloo volume" and the causes of shock can be multiple: trauma, blood and fluid loss sepsis, endotoxemia, ischemia and hypoxia, but the final common pathway i associated with damage to the microcirculation which loses its integrity t allow blood cells and fluid to leave the vascular system with decline i oxygenation and a fall in pH (increased acidity) .
  • the latter activate phospholipase A Ag to destroy phospholipid membranes and vascular and cellula integrity.
  • phospholipases release fatty acid to propagate free radical formation resulting in further injury an phospholipase activation.
  • Shock states are reversible depending on the extent and type of injur or circulatory loss, but in time become irreversible, despite efforts t improve circulatory tone or replace fluid and blood loss.
  • the irreversible stage of shock has been called "stagnant anoxia" state associated with sludging of blood and intravascular coagulation.
  • PGBx as a phospholipase A réelle and C inhibitor and a free radica scavenger, permits recovery from shock by blocking the primary steps whic lead to the loss of microcirculatory integrity and tissue injury and, i addition, block the damaging action of platelets or WBC's which propagat injury during fluid or blood replacement on perfusion efforts to promot recovery.
  • inflammation, shock and ischemia have related final commo pathways of pathophysiology based on platelet, cellular or WBC phospholipas activation, vascular injury and free radical formation which propagate injury.
  • PGBx In the case of thrombosis or ischemia as seen in stroke, coronar insufficiency with myocardial infarction or peripheral vascular disease, th loss of blood perfusion decreases oxygen availability with increased fall i pH (acidity) and/or PMN adherence which results in tissue damage or death unless the process can be arrested.
  • PGBx arrests the physiologic instrument of injury and, in addition, even after membrane phospholipid oxidation afte injury, PGBx protects from further phospholipid destruction and permits tissu recovery. In this regard, PGBx stabilizes lysosomal membranes which protect cells from the action of endogenous proteolytic and lipolytic enzyme mediating autolysis and death.
  • PGBx stabilizes the sarcoplasmi reticulum, maintaining the integrity of the muscle's contractile protei through its inhibition of phospholipases A réelle and C and free radical action. I addltion, this action protects mitochondria, as described by Polis (1981) necessary for survival of the muscle and its tissue energy system.
  • PGBx As discussed previously, there is an added advantage to PGBx as, becaus of its phospholipase inhibition, it also interferes with platelet release o toxic factors and in addition, PGBx blocks the primary stages of intravascula coagulation to maintain the vascular patency which is lost in shock, ischemi and tissue injury.
  • PGBx is also of value in hyperimmune states such as is seen in allergy anaphylaxis, tissue transplant rejection and autoimmune disease.
  • Immun reactions are associated with the same tissue events found in inflammation an at extreme levels, i.e., anaphylaxis, Arthus's phenomenon, tissue or orga rejection and immune reactions, can result in shock or tissue death.
  • corticosteroids whic produce inhibitors of phospholipase A_ have clinical value and have been use with varied but significant success for the last 35 years. More recently, th NSAIA compounds have been shown effect experimental endotoxic or septic shock but in contrast to corticosteroids, have had little success in the clinica treatment of allergy or acute trauma.
  • PGBx inhibits mast cell proliferation and inhibitors of mast cel degranulation, I.e., chromolyn, have been of value in allergic asthma.
  • PGBx has been shown (Fig.7) to inhibit lymphocyte respons indicating that, in similar fashion to corticosteroids, it has a primary rol for its effects on inhibiting the effector lymphocytes from producing thei immune responses which provides a place for PGBx in blocking tissue rejectio as well as the symptoms of allergy, asthma and other hyperimmune states.
  • the anti-inflammatory and immune modulating action o PGBx provide a place for it in rheumatoid arthritis, rheumatic fever glomerular nephritis, lupus erythematosis, periarteritis and encephalitide and/or neuropathies (i.e., multiple sclerosis, amyotrophic lateral sclerosis which may have an immune basis, as well as to prevent rejection in tissu transplantation.
  • the effects of PGBx on these immune mediated syndromes ar provided through its anti-inflammatory action as well as its action i directly modulating lymphocyte response.
  • PGBx may have direct modulatin action of its own on host resistance as the anti-viral modulator interfero induces prostaglandin biosynthesis (Fitzpatrick and Stringfellow, 1980) i association with viral infection.
  • phospholipase A phospholipase A
  • Endotoxins are toxic bacterial products responsible fo platelet aggregation, neutrophil vascular adherence, fever and shock.
  • PGBx, as a phospholipase A réelle inhibitor will alter shock states secondary t infection.
  • Inflammation characterizes viral and rickettsial infection (i.e., hepatitis, encephalitis, enterovirus, colitis and respiratory infection), bacterial and fungal infection (i.e., pneumonia, abscess formation, granulomas) as well as parasitic disease of protozoal or helminthic origin.
  • PGBx can modulate and moderate the degree of toxic inflammatory reaction to infectious agents.
  • Snake venoms are lethal because as hemolytic or neurotoxic poisons the function as phospholipase activators to destroy cell membranes and this can b inhibited by PGBx action.
  • Insect venoms release tissue damaging substance which can behave like snake venoms for local toxic action or can produc inflammation or allergic responses, i.e., bee stings, tick and mosquit reactions.
  • Muscle fatigue from excess exercise is associated ' with a pH fall anoxemia, heat generation and muscle tissue destruction in similar fashion t what is seen in ischemia.
  • muscle fatigue can b reversible, but under some clinical circumstances in marathon runners and rac horses fatigue and heat buildup, can result in diffuse Irreversible damage This is similar to what can occur in coronary ischemia when cardiac output i increased.
  • PGBx can relieve symptoms and protect from damage related t muscle fatigue, spasm, ischemia, trauma and sprain because of it anti-inflammatory action and protective action in ischemic injury.
  • Prostaglandins have been shown to be cytoprotective in blocking pepti ulceration, as well as preventing GI tract and bladder injury to chemotherapy PGBx, because of its membrane stabilizing action, has value in the preventio of ulcerogenic and autolytic activity.
  • Burns Thermal and radiation: While anti-inflammatory actions of PGB may be a factor in burn injury, the activation of leukotrienes may also be factor in effecting the extent of tissue injury. PGBx may be useful i treatment of both first and secondary burns, i.e., sunburn, which have a inflammatory component. There is evidence that phospholipase A Benjamin activity is associated wit metastases and nidation of tumor cells (Liotta, 1986) .
  • PGBx a a phospholipase AZA inhibitor will be useful in preventing metastatic tumo spread or local tumor growth by direct extension. Tumor growth is modulate by effecting platelet, vascular or inflammatory events.
  • Prostaglandin D2 is inversely associated with lung metastases of B melanoma in a rodent model and indomethacin increases metastatic spread. possible mechanism for this is related to the action of prostaglandin D2 blocking platelet adherence and release of coagulation factors which similar to the action of PGBx.
  • PGBx phospholipase A_ activity
  • PGBx may also serve inhibit the expression of tumor virus related cancer development.
  • Another area of PGBx action involved in the prevention or modulation inflammation is its effects on blood coagulation.
  • Platelets respond physiologic stimuli, i.e., thrombin, collagen and ADP, by aggregating wi other platelets and blood cell elements and, in this process, degranulating releasing the contents of intracellular granules. The degranulation o release phase of the platelet reaction recruits more platelets and blood cell into the region to promote clot formation or thrombosis.
  • PGBx inhibits th platelet aggregation release reaction and evidence that PGBx also affect clotting time (See Fig. 9).
  • Pain hyperalgesic states elicited by inflammation or injury t peripheral nerves is mediated by prostaglandins, particularly, prostaglandi E_.
  • Prostaglandin effects on pain production occur via bradykinin o noradrenalin action, mediators which effect pain nerve afferents and ar released in inflammation or injury.
  • Corticosteroids can suppress bradykini or noradrenalin related pain and, in similar fashion to PGBx, suppres prostaglandin synthesis and work through effects on inhibition o phospholipase A relie.
  • PGBx wil inhibit not only the primary inflammatory response, but suppress the action o post ganglionic neurons, small diameter afferents responsible for pai perception and generation.
  • Tissue stabilization Use as food additives to prolong th shelf-life of foods or pharmaceutical preparations. Subject to oxidativ injury, i.e., rancidity, discoloration, loss of taste.
  • Anti-autolysis (a) prolongation of half life of muscle at higher temperatures o in pigs with the autolytic muscle destroying syndrome.
  • PGBx preservation of pathologic or embryonic tissue specimens.
  • PGBx can prolong the shelf life of foods, or pharmaceutical preparation subject to oxidative injury, i.e., rancidity, discoloration, odor and loss o taste.
  • PGBx can provide a substitute to sodium bisulfite (NaBiSulfite) , vitami E, vitamin C, BHT and other antioxidants in use by the Food and Pharmaceutica Industry (common food preservative used to maintain the color and taste vegetables, fruit, meat and dairy products in restaurants and shops as well preserving potency of antibiotic, vaccines or chemical drug preparation).
  • NaBiSulfite sodium bisulfite
  • vitami E vitamin C
  • BHT antioxidants
  • PGBx can substitute for BHT, vit. E, vit. phenols and related anti-oxidant preservatives.
  • PGBx a naturally deriv product can extend the shelf life of milk, cream, butter, bacon and oth preserved meats by reducing the endogenous breakdown of phospholipid membran and the action of free radicals.
  • PGBX can be used in embalming for both immediate and long te preservation of tissue. Because of its phospholipase inhibiting and fr radical scavenging activity, PGBx can be useful in tissue culture and isolat organ maintenance (kidneys, heart, lung, liver) to prolong the half life cultures so important to monoclonal antibody, or leukokine production, i.e
  • PGBx interferons, or organ transplantation.
  • the anti-autolytic, cytoprotective action of PGBx will be of value i pig strains whose meat is unusable following slaughter because their muscl autolyze (dissolve) too rapidly.
  • PGBx stabilizes meat to provide for long half life at higher temperatures.
  • PGBx can be administered prior slaughter, injected post mortem via arteries under pressure, or appli directly to meat preparations.
  • PGBx is useful in preservi organs for transplantation, i.e., kidney, heart, lung, liver, skin, as well a preserving pathology specimens that autolyze rapidly, i.e., stomach and G tract, epithelium, brain following surgical biopsy or autopsy.
  • Fig 1 is a chart showing fatty acid release from membrane phospholipid and the action of anti-inflammatory agents.
  • Fig 2 is a chart showing inhibition of phospholipase A_ by PGBx and PGB.. on phospholipase A Benjamin activity.
  • Fig 3 is a chart showing the inhibitory effect of PGBx on lysosomal phospho ⁇ lipase A_ and phosphatidyl inositol-specific phospholipase C.
  • Fig 4 is a chart showing the specific interaction of PGBx with highly purified snake venom phospholipase A unpleasant.
  • Fig 5 is a chart showing inhibitory effect of PGBx on auto-oxidation of phosphatidylethanolamine.
  • Fig 6 is a chart showing inhibitory effect of PGBx on the preferential hydrol ⁇ ysis of peroxidized phosphatidylethanolamine by dog sarcoplasmic reticulum phospholipase C.
  • Fig 7 is a chart showing the inhibitory effect of PGBx on the generation of cytotoxic T lymphocytes.
  • Fig 8 is a chart showing the inhibitory effect of PGBx on IL-3 dependent proliferation of mast cells.
  • Fig 9 is a chart showing the inhibitory effect of PGBx on human platelet aggregation.
  • Cells contain lysosomal phospholipases that are most active at acid p (pH 4 to 5) . These enzymes contained within an organelle, the lysosome degrade ingested intracellular membrane phospholipids such as those fro phagocytized bacteria. These enzymes are also released externally o interstitially by phagocytic cells in response to inflammatory stimuli a contribute to adjacent, or contiguous membrane breakdown in inflammato fluids.
  • phosphatidylinositol (PI) specif phospholipase C plays an important role in membrane signal transduction specifically hydrolyzing PI, a membrane phospholipid present in sma quantities but highly enriched in arachidonic acid.
  • PI phosphatidylinositol
  • PGBx could inhibit the cellular turnover of arachidonic acid and this, i turn, would suppress the production of further pro-inflammatory metabolites prostaglandins, leukotrienes and free radicals. Therefore, human umbilica
  • 14 cord endothelial cells were cultured in the presence of C-arachidonic aci to allow for incorporation of the radiolabelled fatty acid into cell membran phospholipid. Washed cells were challenged with histamine and A23187 neurotransmitter or ionophore stimulants known to cause the mobilization o arachidonic acid from cell membrane phospholipid.
  • the carbon-carbon double bonds of unsaturated fatty acids fo predominately in the 2 position of mammalian phospholipids are particula susceptible to attack by oxygen free radicals. Radical-induced peroxidat of membrane phospholipid is a well-known mediator of cell injury from expos to toxic drugs and chemical agents as well as oxidative injury to foo pharmaceutical agents and biological specimens. Therefore, anti-oxidants h widespread industrial and pharmacologic uses as preservatives.
  • Peroxidati of membrane phospholipid initiates a self-propagating free-radical reacti that results in membrane dysfunction with concomitant alterations phospholipid composition mediated by activated phospholipases. The fact th PGBx interacted with membrane phospholipid to inhibit _in vitro and _in. si phospholipase activities and contains peroxidizable double bonds itsel indicated to us that PGBx might also influence the susceptibility phospholipid to auto-oxidation.
  • PGBx or bisulfite 51.5% of the phospholipid was peroxidized by this treatment. Both PGBx and bisulfite inhibited the peroxidation of phospholipid, but PGBx was 100-times more effective as an anti-oxidant than bisulfite; 10 uM PGBx provided 23.9% protection while 1000 uM bisulfite afforded 19.8% protection.
  • PGBx has potent anti-oxidant activity and, therefore, can be used as a commercial preservative to enhance the shelf-life of drugs, vaccines, and other chemicals susceptible to oxidative damage.
  • PGBx also inhibits phospholipas activities which contribute to autolysis of foods and biological tissu samples
  • PGBx can be used as a preservative for foods and meats as well as for blood and blood products, organs for transplantation and pathologic an embryonic tissue samples. PGBx survives autoclaving (Table I) and filtratio and, thus, can be a useful preservative or stabilizer in situations wher sterility is required.
  • PGBx can not only inhib peroxidation itself, but can also intervene in the injury process aft initiation of the oxidative insult.
  • Naturally occurring anti-oxidants such vitamins A, E, and C, B-carotene, superoxide dismutase (SOD) and catala function as cellular radical scavengers and SOD have known protective effec against cell injury or inflammation.
  • Table V compares the effectiveness of PGBx with a wide variety o anti-rheumatic nonsteroidal and steroidal anti-inflammatory agents.
  • PGBx is potent anti-inflammatory agent and is clearly more effective than all th NSAIA's currently in use and better than hydrocortisone and cortisone, th over-the-counter steroids, although not equal to paramethasone.
  • PGBx was tested at concentra ⁇ tions ranging from 1 to 50 uM by adding it to the culture medium (RPMI 1640 supplemented with 5% fetal calf serum, 2 mM L-glutamine, 50 uM 2-mercapto- ethanol, and antibiotics).
  • the culture medium RPMI 1640 supplemented with 5% fetal calf serum, 2 mM L-glutamine, 50 uM 2-mercapto- ethanol, and antibiotics.
  • CTL in MLC requires complex interactions between CTL precursors, helper T cells, and macrophages.
  • the macrophages and helper T cells produce the immune system hormones (leukokines) interleukin 1, interleukin 2, and gamma-interferon.
  • the suppressive effect of PGBx on CTL development could be exerted at one or more levels by inhibiting the production and/or activity of interleukin 1, interleukin 2 or gamma-inter- feron.
  • These immunologic hormones also contribute to the pathogenesis of chronic inflammatory disease (i.e., rheumatoid arthritis).
  • PGBx can effectively rival or replace both currently availabl steroids and NSAIAs in the treatment of inflammation and injury making it candidate for clinical application and usefulness in localized and systemic injury and disease.
  • the action of PGBx in inhibiting mast cell and lymphocyte response indicates that PGBx is useful in effecting the primary effector systems that are associated with inflammation and tissue injury in hypersensitivity states.
  • PGBx may be useful in preventing or modulating immunologic reactions involving mast cells (e.g., allergic reactions) by inhibition of mast cell development.
  • PGBx inhibits human platelet aggregation release reaction by approximately 50% compared to control. These data are consistent with previously described studies using prelabelled human neutrophils endothelial cells. PGBx inhibits stimulus response release of arachid acid from platelets to minimize the production of powerful mediators inflammation and injury.
  • Polis BD, Kwong S, Polis E, Nelson G and Shmukler HW Studies of PGBx. polymeric derivative of prostaglandin B. : I Synthesis and purification PGBx. Physiological Chemistry and Physics 11, 109-123, 1979.
  • Polis DB, Kwong S, Polic E and Nelson GL PGBx, an oligomeric derivati of prostaglandin B 1 : Physical and chemical and spectral propertie Physiological Chemistry and Physics 12, 167-177, 1980.
  • Shmukler HW Cation complex formation with PGBx, A prostagland oligomer, as measured by fluroescence quenching. Physiological Chemist and Physics 12, 558-563, 1980.
  • Polis BD, Polis E and Kwong S C Nuclear magnetic resonance studies prostaglandin B monomers as an approach to elucidation of the structu of PGBx, a prostaglandin B polymer. Physiological Chemistry and Physi 13, 111-119, 1981.
  • Polis DB, Polis E and Kwong S Structutal features of PGBx prostaglandin polymer) deduced by analogies with dimers derived fr 15-keto-prostaglandin B... Physiological Chemistry and Physics 1 531-548, 1981.
  • Polis BD, Grandizio AM and Polis E Some in vitro effects of a n prostaglandin derivative. Advances in Experimental Medicine and Biolo 33, 213-220, 1973.
  • Polis BD, Polis E and Kwong S Protection and reactivation of oxidati phosphorylation in mitochondria by a stable free-radical prostagland polymer (PGBx). Proc. Natl. Acad. Sci. U.S.A., 76, 1598-1602, 1979.
  • Ohnishi ST and Devlin TM Calcium ionophore activity of a prostagland B 1 derivative (PGBx). Biochemical and Biophysical Research Communic tions 89, 240-245, 1979.
  • Aronson CE Relationships between PGBx and isoproterenol in the isolat perfused rat heart. Gen. Pharmac. 10, 103-107, 1980.
  • Aronson CE Interactions between PGBx and disophenol in the isolat perfused rat heart. Gen. Pharmac. 12, 249-252, 1980.
  • Kruger M and Booyens J The effect of the prostaglandin derivative PG on calcium uptake and release by skeletal muscle sarcoplasmic reticulu Sa Mediese Tydskrif Deel 62, 855-858, 1982.
  • Aronson CE Effects of PGBx on glucose utilization and glycogen conte of the isolated rat diaphragm. Gen. Pharmac. 14, 519-523, 1983.
  • Polis BD and Polis E Normalization of the diabetic syndrome hereditary diabetic mice by PGBx, a polymeric derivative of prostaglan B. Physiological Chemistry and Physics 8, 429-436, 1976.
  • Polis BD and Polis E Dose dependence of PGBx. A polymeric derivative prostaglandin B, for normalization of hereditary diabetics of the mous Physiological Chemistry and Physics 11, 3-8, 1979.
  • Kolata RJ and Polis BD Facilitation of recovery from ischemic bra damage in rabbits by polymeric prostaglandin PGBx, a mitochondri protective agent. Physiological Chemistry and Physics 12, 545-550, 1980
  • Polis E and Cope FW Dose-dependent reduction of hereditary obesity the non-diabetic mouse by polymeric prostaglandin PGBx. Physiologic Chemistry and Physics 12, 564-568, 1980.
  • Walls AP, Himori N and Burkman AM Comparison of the effects prostaglandin Bx and verapamil on changes in myocardial function th occur during ischemia (abstract). Federation Proceedings 40, 692, 1981.
  • Polis E, and Cope FW Chronic effects of PGBx, A polymeric prostaglandi on blood leukocyte counts. Physiological Chemistry and Physics 1 431-437, 1982.
  • Polis E and Cope FW Polymeric prostaglandin PGBx and other prostagland polymers prolong survival of the heart of the hypoxic mouse. Avia Space Environ. Med. 54, 420-424, 1983.

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Abstract

Cette invention décrit de nouvelles utilisations pour des dérivés macromoléculaires d'un acide gras tel que la prostaglandine B1, qui comporte des polymères, et leurs composés oligomères tels que des dimères, des trimères et des tétramères du même type. Lorsqu'utilisées in vivo et in vitro à des fins thérapeutiques, ces macromolécules se sont révélées effectivement anti-inflammatoires et anti-oxydantes. Les classes de macromolécules, décrites ci-dessus, sont génériquement appelées PGBx. On a découvert qu'elles sont d'excellents stabilisateurs de membrane et des agents cytoprotecteurs. Elles protègent les cellules en augmentant la résistance de chaque cellule contre les lésions provenant de phospholipases et d'oxydations provoquées par des radicaux libres, notamment la médiation d'enzymes phospholipase A2. PGBx se distingue de l'art antérieur de par au moins cette caractéristique qui en fait un agent double effectif agissant tant comme inhibiteur d'enzyme anti-phospholipase que comme anti-oxydant.
PCT/US1987/000408 1987-02-24 1987-02-24 Macromolecules de prostaglandine b1 servant d'agents anti-inflammatoires Ceased WO1988006445A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991003512A1 (fr) * 1989-08-29 1991-03-21 Virginia Commonwealth University Composes cytoprotecteurs a base de constituents graisseux
US6020510A (en) * 1996-04-15 2000-02-01 Virginia Commonwealth University Cytoprotective compounds
US6020489A (en) * 1988-02-18 2000-02-01 Virginia Commonwealth University Cytoprotective fatty moiety compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4153808A (en) * 1973-12-28 1979-05-08 Polis B David Novel prostaglandin derivatives, certain in vivo and in vitro effects thereof and processes for the preparation of same
US4245111A (en) * 1979-04-02 1981-01-13 The United States Of America As Represented By The Secretary Of The Navy Method of preparing prostaglandin B1 derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4153808A (en) * 1973-12-28 1979-05-08 Polis B David Novel prostaglandin derivatives, certain in vivo and in vitro effects thereof and processes for the preparation of same
US4245111A (en) * 1979-04-02 1981-01-13 The United States Of America As Represented By The Secretary Of The Navy Method of preparing prostaglandin B1 derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6020489A (en) * 1988-02-18 2000-02-01 Virginia Commonwealth University Cytoprotective fatty moiety compounds
WO1991003512A1 (fr) * 1989-08-29 1991-03-21 Virginia Commonwealth University Composes cytoprotecteurs a base de constituents graisseux
AU653709B2 (en) * 1989-08-29 1994-10-13 Virginia Commonwealth University Cytoprotective fatty moiety compounds
US6020510A (en) * 1996-04-15 2000-02-01 Virginia Commonwealth University Cytoprotective compounds
US6423855B2 (en) 1996-04-15 2002-07-23 Virginia Commonwealth University Cytoprotective compounds

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