Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-08-24
2001-08-21
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S234500, C514S237500, C514S357000, C514S449000, C514S461000, C514S468000, C514S470000, C514S886000, C514S887000
Reexamination Certificate
active
06277846
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and means for treating pruritus. More particularly, this invention concerns the use of platelet activating factor (PAF) antagonists or anti-pruritic agents.
BACKGROUND OF THE INVENTION
Itch, or pruritus, is a common and distressing symptom in a variety of diseases. Pruritus typically occurs in peripheral diseases such as allergic conjunctivitis, allergic rhinitis, hemorrhoids, and dermatoses of fungal, allergic and non-allergic origin. Itching can also be a major symptom of certain systemic diseases such as, Hodgkin's disease, chronic renal failure, polycythema vera, hyperthyroidism and cholestasis (see, for example, Herndon, J. H. Jr., Int. J. Derm. 14, 465-484 (1975); Winkelmann, R. K., Med. Clins. N. Am. 66, 1119-1133 (1982)]. The clinical importance of pruritus is undeniable but research efforts in this area have been modest, to great extent due to the absence of established, specific experimental models, especially in preclinical research.
The intracutaneous injection of histamine or proteases elicits itch, and may be used as an experimental model for itch studies (Cormia, F. E., J. Invest. Derm. 19, 21 (1952); Shelley, W. B. and Arthur, R. P., Arch. Derm. (Chicago) 26, 296, 323 (1957)]. It was, therefore, postulated that these agents are involved as mediators in various itching conditions. Since histamine was believed to be the primary mediator of the itch sensation, conventional itch therapy involves H
1
-antihistamines as a first-line medication. However, antihistamines have no general anti-pruritic effect, in many instances they are either ineffective or only partially effective. The physician is often obliged to resort to glucocorticoids to relieve pruritus but the potential undesirable side effects from glucocorticoid therapy are of great concern. Glucocorticoids cause skin atrophy and are absorbed systemically to cause Cushings disease-like effects. It has been concluded that although histamine is undoubtedly a potent pruritogen, at least one other itch-producing substance is involved in the clinically encountered spectrum of diseases where itch is a major symptom.
Although it is known that experimental pruritus may be evoked in human skin by the local administration of diverse pharmacologically active substances, the majority of which cause inflammation, demonstration that a chemical substance causes an itch sensation when locally administered does not necessarily mean that it is involved (as a mediator) in diseases in which itching is a symptom. Substances which have been reported to evoke or facilitate the itch sensation in human skin have not led to accepted anti-itch medications in those instances where compositions of matter are available to block the synthesis or activity of such substances. For example, according to Hagermark et al.,
J. Invest. Dermatol
. 69, 527-539 (1977), prostaglandins E
2
and H
2
produce itch in human skin and potentiate the itch evoked by histamine. However, according to an earlier article by Hagermark [
Acta Dermatovener
53, 363-368 (1973)) a known inhibitor of PGE
2
synthesis, aspirin, did not act as an anti-pruritic agent, rather it actually prolonged experimental itch produced by trypsin or histamine. These experimental findings are amply supported by clinical experience where drugs like aspirin and indomethacin are not generally regarded as useful in treating itch.
The pruritogenic activity of other substances has been attributed to an indirect mechanism involving histamine release, these postulates being based on the activity systemically administered or locally injected H
1
-antihistamines. Thus, synthetic platelet activating factor (PAF) has been reported to cause pruritus in human skin [Fjellner and Hagermark,
Acta Derm. Venereol
. 65, 409-412 1985)] “via indirect and mainly histamine-dependent mechanism”. Based upon their experimental findings, the authors concluded that PAF probably produced itch in human skin by release of mast cell bound histamine.
Given the complicating factors which may confound interpretation of itching studies, proof of involvement of a substance in mediating itch is provided only by studies which demonstrate that a composition of matter which interferes with the synthesis of pharmacological action of the substance in question attenuates pruritus in either an experimental model of itching disease or in a study involving clinically encountered itch. Further, the beneficial effect of such a composition of matter in relieving itch should be demonstrated as independent of the actions of histamine.
SUMMARY OF THE INVENTION
The present invention is based on the unexpected finding that platelet activating factor (PAF) is a very potent pruritogen and platelet activating factor antagonists (PAF antagonists) of highly diverse structures prevent itching episodes of allergic origin and the further unexpected finding that PAF antagonists are more potent in relieving itch than in relieving inflammation. The previously unrecognized antipruritic activity of such PAF antagonists is demonstrated as being independent of histaminergic mechanisms.
In one aspect, the present invention relates to a method for treating pruritus by administering a therapeutically effective amount of a PAF antagonist to a mammal afflicted with pruritus. The PAF antagonists may, for example, be selected from synthetic PAF analogues, natural products isolated from plants having PAF antagonist activity, and triazolobenzodiazepines. The PAF antagonists are preferably applied topically to the afflicted site but systemic such as oral, parenteral, nasal and intrarectal administration, is also possible.
In another aspect, the invention relates to the use of PAF antagonists in the preparation of pharmaceutical compositions intended for the treatment of pruritus.
In yet another aspect, the invention relates to the use of PAF antagonists in treatment of idiopathic itching, that is, itch which occurs spontaneously, without an underlying or identifiable physiological cause.
DETAILED DESCRIPTION OF THE INVENTION
Platelet activating factor (PAF) is a term coined by Benveniste et al. [J. Exp. Med. 136, 1356-137 (1972)] to describe a fluid phase mediator of unknown chemical structure. This mediator has later been identified as a phospholipid autocoid, which structurally is 1-0-alkyl-2-acetyl-sn-glycero-3-phosphocholine of the formula (I)
wherein R is 15 or 17, i.e. the alkyl moiety is hexadecyl or octadecyl. The isolation, chemical synthesis and biological and biochemical characteristics of PAF are, for example, disclosed by Hanahan and Kumar in
Prog. Lipid Res
. 26, 1-28(1987).
PAF is not stored in cells but is synthesized in response to appropriate stimuli by a two-step process. The precursor 1-o-alkyl-(R)acyl-glycero-3-phosphatidylcholine is converted to lyso-PAF by phospholipase A
2
and subsequent acetylation results in PAF formation. In fact lyso-PAF is both a precursor and a metabolite of PAF. PAF is known to be an important factor of physiological reactions including platelet aggregation, inflammation, contraction of smooth muscle, alterations in the respiratory and circulatory systems, etc. PAF antagonists have been discovered comparatively recently, and comprise a series of compounds of diverse structures effective in the treatment of conditions traditionally associated with PAF. The PAF antagonists reported so far in the art may be broadly classified according to their origin and structures as follows: (a) synthetic analogues of the PAF structure; (b) natural products isolated from plants; (c) triazolobenzo-diazepines. By virtue of these antagonists, it has become apparent that PAF exerts its known biological effects by stimulating specific PAF-sensitive receptors.
A PAF antagonist, which is a synthetic analogue of the PAF structure is the compound of formula (II),
which was disclosed by Terashita et al, in
J. Pharm. Exp. Ther
. 242, 263-268 (1987). Other synthetic lipid PAF inhibitors are described In the Published European Patent Appl
Williams Linda Sue
Woodward David F.
Allergan Sales Inc.
Baran Robert J.
Delacroix-Muirheid C.
Jones Dwayne C.
O'Donohue Cynthia H.
LandOfFree
Use of platelet activating factor antagonists as... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Use of platelet activating factor antagonists as..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Use of platelet activating factor antagonists as... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2497709