Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1999-11-26
2000-10-31
Celsa, Bennett
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
A61K 3123
Patent
active
061403644
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The inflammatory response is an important element of a host's natural defense mechanism against pathogens. It also is involved in wound healing. Despite the central beneficial role that the inflammatory response plays in host survival, excessive inflammation may have clinically adverse results in some medical conditions.
Leukocytes, which are the major cellular components of inflammatory and immune responses, encompass a broad class of cells including neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Neutrophils, which play a key role in the inflammatory response, are generally present within the body in a resting unstimulated state. Once stimulated, the neutrophils migrate to the site of injury and release toxic factors.
The migratory capability of a neutrophil is dependent on the ability of the neutrophil to alter its adhesive properties. In a resting unstimulated state a neutrophil is not adhesive and cannot migrate. Once the neutrophil has been stimulated, however, it becomes more adhesive and is capable of migrating. The increase in neutrophil adhesiveness causes the stimulated neutrophil to aggregate and to adhere to endothelium. Stimulation of the neutrophil also causes the neutrophil to undergo diapedesis, which involves the migration of the neutrophil between post-capillary endothelial cells into the tissues.
In the tissues, an activated neutrophil releases enzymes such as collagenase and elastase, among others. Neutrophil stimulation may also initiate a burst of oxygen consumption, with concomminant activation of the hexose-monophosphate shunt and activation of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. Activation of these systems results in the formation and release of factors such as hydrogen peroxide and hydroxyl radicals, which are toxic to microorganisms and tumor cells, and thereby facilitating the destruction of the injury causing agent.
Several studies have focused on analyzing the control and regulation of the adhesive properties of neutrophils. Much of this research has centered on adhesion receptors and also on metabolites of arachidonic acid, C20 carbon fatty acid found in every cell membrane. Arachidonic acid metabolism occurs by different mechanisms in stimulated versus unstimulated neutrophils and results in the production of a different spectrum of metabolites in stimulated versus unstimulated neutrophils.
In stimulated neutrophils, the cytochrome P450 mixed function oxidase system appears to be more active. Moreover, during neutrophil stimulation, 5-lipoxygenase is translocated to the membrane compartment fraction, where it produces 5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-HPETE is then either metabolized to 5-hydroxyeicosatetraenoic acid (5-HETE) by peroxidase or dehydrated to form leukotriene A.sub.4. Leukotriene A.sub.4 is converted into leukotriene B.sub.4 which is a potent chemotactic agent and promoter of neutrophil adhesion.
In unstimulated neutrophils, the metabolism of arachidonic acid is markedly different than that in stimulated neutrophils. The metabolism of arachidonic acid in unstimulated neutrophils is sensitive to cytochrome P450 inhibitors but not to cyclooxygenase or lipoxygenase inhibitors. Hatzelmann and Ullrich characterized the metabolites produced in unstimulated neutrophils, reporting the finding that arachidonic acid is metabolized to 20-HETE and 15-HETE. Hatzelmann, Eur. J Biochem. 173, 445-452 (1988). Another study, Kraemer et al., found that the arachidonic acid metabolic products formed in unstimulated neutrophils exhibited a potent anti-aggregatory activity toward human neutrophils, suggesting that the identified arachidonic acid metabolites may play some role in the regulation of neutrophil adhesion and aggregation properties. Kraemer et al., Am. J. Pathol. 128, 446-454 (1987).
SUMMARY OF THE INVENTION
Several diseases or conditions are characterized by excessive inflammation associated with neutrophil adhesion and neutrophil aggregation. The present invention provides methods a
REFERENCES:
patent: 5164381 (1992-11-01), Wachter et al.
patent: 5256538 (1993-10-01), Aiken et al.
patent: 5334736 (1994-08-01), Sun et al.
patent: 5434186 (1995-07-01), Cohen et al.
patent: 5466669 (1995-11-01), Konig et al.
patent: 5527890 (1996-06-01), Rao et al.
patent: 5552441 (1996-09-01), Dillard et al.
patent: 5612377 (1997-03-01), Crooks et al.
patent: 5753702 (1998-05-01), Bednar et al.
Database Chemcial Abstracts on STN, AN 1984:203312, Morita et al, "Mechanism of anti-thrombogenic effect of eicosapentaenoic acid", Int. Congr. Ser.--Excerpta Med. (1983), 623(Perspect. Prostaglandin Res.), 144-9, Jan. 1983.
Falck, J. R. et al., The Journal of Biological Chemistry, vol. 265 (18):10244-10249 (1990).
Heckmann, B. et al., Tetrahadron Letters, vol. 37(9):1425-1428 (1996).
Knickle, L. et al., Mol Pharmacol, 45:6:1273-80, Abstract.
Bednar, M. M. et al., Abstract from meeting held in Florence, Italy (Jun. 1994).
Ying Zhu et al., Hypertension, vol. 25 (4), Part 2:854-859 (Apr. 1995).
Setty, B., et al., Blood, 80:11:2765-73, (1992).
Lee, T. H. et al., The New England Journal of Medicine, vol. 312(19):1217-1224 (May. 9, 1985).
Gross, C. E. et al., Neurological Res., vol. 16:465-470 (Dec. 1994).
Lesch, M. E. et al., Agents and Actions, vol. 34:25-27 (1991).
Hill, E. et al., Biological Mass Spectrometry, vol. 21:249-253 (1992).
Watanabe, Masako et al., Br. J. Pharmacol. 102:239-245 (1991).
Laethem, R. M. et al., The Journal of Biological Chemistry, vol. 268(17):12912-12918 (1993).
Balazy, M., The Journal of Biological Chemistry, vol. 266(35):23561-23567 (1991).
Bednar, M. M. et al., Journal of Thrombosis and Thrombolysis:1:179-185 (1995).
Springer, T. A., Annu. Rev. Cell Biol., 6:359-402 (1990).
Kraemer, R. et al., American Journal of Pathology, vol. 128(3):446-454 (1987).
Hatzelmann A. et al., Euro. J. Biochem. 173:445-452 (1988).
Luo, G., et al., Archives of Biochemistry and biophysics, 357:1:45-57, (1998).
Takada et al., Chemical Abstracts, 1995:138771, (1994).
Falck, et al., Chemical Abstracts, 1990:493392, (1990).
Knickle, et al., Chemical Abstracts, 1994:474474, (1994).
Balazy Michael
Bednar Martin M.
Falck John R.
Gross Cordell E.
Board of Regents , The University of Texas System
Celsa Bennett
Hsu Grace C.
New York Medical College
The University of Vermont and State Agricultural College
LandOfFree
Arachidonic acid metabolite, 16-HETE does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Arachidonic acid metabolite, 16-HETE, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Arachidonic acid metabolite, 16-HETE will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2052294