Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1992-04-03
1996-06-25
Jones, W. Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 241, 435 6, C07H 2104, A61K 4800, C12Q 168
Patent
active
055301142
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to therapies, diagnostics, and research reagents for disease states which respond to modulation of the synthesis or metabolism of arachidonic acid. In particular, this invention relates to antisense oligonucleotide interactions with certain messenger ribonucleic acids or DNA involved in the synthesis of proteins regulating arachidonic acid synthesis or metabolism. These oligonucleotides have been found to lead to the modulation of the activity of the RNA or DNA, and thus to the modulation of the synthesis and metabolism of arachidonic acid. Palliation and therapeutic effect result.
BACKGROUND OF THE INVENTION
The Eicosanoids
Metabolites of arachidonic acid and related fatty acids exhibit a wide range of biological activities affecting every organ system in the body. There are over thirty metabolites of arachidonic acid which exhibit biological activity. These metabolites are collectively termed eicosanoids.
Arachidonic acid is stored in the cell esterified to membrane lipids. Once released from membrane lipids, arachidonic acid may either be re-esterified back into membrane lipids or metabolized via a variety of oxidative enzymes. There are two oxidative pathways which are of importance for therapeutic intervention; the cyclo-oxygenase pathway which generates prostaglandins, thromboxanes and prostacyclin, and the lipoxygenase pathway which generates leukotrienes, lipoxins, hydroperoxyeicosatetraenoic acids and the mono- and di-hydroxyeicosatetraenoic acids (mono- and di-HETE's). (See FIG. 1). Although platelet activating factor (PAF) is not a direct metabolite of arachidonic acid, it is generated through one of the pathways which generate free arachidonic acid. Thus, in some cases, generation of free arachidonic acid also results in the generation of lyso-PAF, a direct precursor for PAF.
Prostaglandins of the E series (PGE.sub.1, PGE.sub.2) are potent vasodilators and smooth muscle relaxants. Thus, PGE.sub.2 promotes hypotension and relaxes bronchial, tracheal and uterine smooth muscle. Other effects of these prostaglandins include inhibition of platelet aggregation, inhibition of mediator release from mast cells, increased renal blood flow, diuresis, increased circulating concentrations of ACTH, and inhibition of gastric acid secretion. PGEs cause pain when injected intradermally and sensitize afferent nerve endings to the effects of chemicals or mechanical stimuli.
Prostaglandin D2, like PGE1, is an inhibitor of platelet aggregation. PGD2 enhances the release of histamine from basophils, promotes chemokinesis and enhances the chemotactic response of other mediators in polymorpholeukocytes. Prostacyclin (PGI.sub.2) is a potent vasodilatory substance and, general smooth muscle relaxant. PGI.sub.2 is 30 to 50 times more potent than PGE2 and PGD2 in inhibiting platelet aggregation. PGI2 inhibits gastric acid secretion, relaxes bronchial and uterine smooth muscle, and increases renal blood flow. Thus, PGE2, PGI2, and, to a lesser extent PGD2, are important in maintaining normal homeostasis and have beneficial effects in many clinical situations.
Prostaglandins of the F series, i.e., PGF2.alpha., in general exhibit biological activity opposite to PGE on smooth muscle tissue. PGF2.alpha. contracts bronchial and tracheal smooth muscle, contracts both pregnant and nonpregnant uterine smooth muscle, and contracts gastrointestinal smooth muscle. In subprimates PGF2.alpha. is the leutolytic hormone.
Thromboxane A.sub.2 (TXA.sub.2) is a potent smooth muscle contractile agent, contracting all smooth muscle strips tested including vasculature, bronchial, and tracheal. TXA.sub.2 promotes platelet aggregation and decreases renal blood flow.
In general, the peptidoleukotrienes (leukotrienes C.sub.4, D.sub.4, and E.sub.4) are potent smooth muscle contractile agents, while leukotriene B.sub.4 (LTB4) is a chemotactic factor for circulating neutrophils and monocytes. LTB.sub.4 also promotes lysosomal enzyme release and superoxide anion generation from neutrophils, both of w
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Bennett Clarence F.
Crooke Stanley T.
Ecker David J.
Mirabelli Christopher K.
Arthur Lisa
ISIS Pharmaceuticals Inc.
Jones W. Gary
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