Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-10-09
2002-03-05
Moezie, Minna (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S317000, C514S318000, C514S326000, C514S406000
Reexamination Certificate
active
06353004
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to peripherally acting anti-pruritic opiates having substantially no effects on the central nervous system and method of topically treating pruritic conditions therewith.
2. Reported Developments
The prior art has investigated the physiology and treatment of pruritus as illustrated hereunder.
Itch is a well known sensory state associated with the desire to scratch. As with pain, itch can be produced by a variety of chemical, mechanical, thermal or electrical stimuli. In addition to the difference in the sensory quality of itch and pain, they also differ in that (1) itch, unlike pain, can only be evoked from the superficial layers of skin, mucosa, and conjunctiva, and (2) itch and pain usually do not occur simultaneously from the same skin region; in fact, mildly painful stimuli, such as scratching, are effective in eliminating itch. In addition, the application of histamine to skin produces itch but not pain. Itch and pain are further dissociated pharmacologically: itch appears to be insensitive to opiate and non-steroidal anti-inflammatory drug (NSAID) treatment, both of which are effective in treating pain.
Although itch and pain are of a class in that both are modalities of nociception transmitted by small unmyelinated C fibers, evidence that itch is not just a variety of low threshold pain is overwhelming. Itch leads to the reflex or urge to scratch; pain leads to withdrawal. Removal of the epidermis elimnates itch but causes pain. Analgesics, particularly opiods, relieve pain but often cause itch (see, for example
J. Am. Acad. Derm
. 24: 309-310, 1991). There can be no doubt that itching is of eminent clinical importance; many systemic and skin diseases are accompanied by persistent or recurrent itch attacks. Current knowledge suggests that itch has several features in common with pain but exhibits intriguing differences as well (see, for example, W. Magerl,
IASP Newsletter
, pp. 4-7, September/October 1996).
McMahon et al (
TINS
, Vol. 15, No. 12, pp. 497-501, 1992) provides a description of stimuli (Table a) and a comparison of the established features of itch and pain (Table b):
Table a
Stimuli that can elicit or augment itch
Physical
Mechanical. Light touch, pressure, suction.
Thermal. Warming.
Electrical. Focal transcutaneous repetitive stimulation, transcutaneous constant current stimulation, intraneural microstimulation.
Chemical
Non-specific irritants. Acids, alkalis.
Inflammatory mediators. Histamine, kallikrein, bradykinin, prostaglandins.
Histamine-releasing substances. Compound 48/80, protamine, C3a.
Peptidases. Mucunain, papain, trypsin, mast cell chymase.
Neuropeptides. Substance P, vasoactive intestinal polypeptide, neurotensin, secretin.
Opioids. Morphine, &bgr;-endorphin, enkephalin analogues.
TABLE b
Comparison of the established features of itch and pain
ITCH
PAIN
Psychophysiology
Tissue
Skin. Mucous membranes
Most tissues
Stimulus
See Table a
Many stimuli
Intraneural microstimulation
Occasionally
Yes
Secondary sensations
Allokinesis (itchy skin)
Hyperalgesia
Psychogenic modification
Pronounced
Present
Counterstimuli
Scratching, pain, cooling
Tactile
stimuli,
cooling
Neurophysiology
Primary afferent neurons
C- and A&dgr;-fibres
C- and
A&dgr;-fibres
Flare size
Large
Small
Spinal pathway
Anterolateral funiculus
Anterolateral
funiculus
Protective reflexes
Scratching, sneezing
Flexion,
guarding
Autonomic reflexes
Yes
Yes
Pharmacology
Capsaicin sensitivity
Yes
Chemogenic
pain; yes
NSAID sensitivity
Probably not
Yes
Morphine sensitivity
No
Yes
Abbreviation: NSAID, non-steroidal anti-inflammatory drugs.
Experimental focal itch stimuli are surrounded by a halo of seemingly unaffected tissue where light tactile stimuli are capable of eliciting itch-like sensations. The term itchy skin or allokinesis has been coined for these secondary sensations that are reminiscent of the features of secondary hyperalgesia evolving around a painful focus. A crucial observation is that itch and pain usually do not coexist in the same skin region and a mild noxious stimulus such as scratching is in fact the singly most effective way to abolish itch. This abolition of itch can be prolonged producing an ‘antipruritic state’. Although mild scratch is often not painful, microneurographic recordings from humans have directly determined that such stimuli are among the most effective ways to excite cutaneous unmyelinated nociceptive afferents. (See, for example:
Shelly, W. B. and Arthur, R. P. (1957)
Arch. Dermatol
. 76, 296-323;
Simone, D. A. et al. (1987)
Somatosens. Res
. 5, 81-92;
Graham, D. T., Goodell, H. and Wolff, H. G. (1951)
J. Clin. Invest
. 30, 37-49;
Simone, D. A., Alreja, M. and LaMotte, R. H. (1991)
Somatosens, Mot
. Res. 8, 271-279;
Torebjörk, E (1985)
Philos. Trans. R. Soc. London Ser
. B 308, 227-234; and
Valbo, A. B., Hagbarth, K. E., Torebjörk, H. E. and Wallin, B. G. (1979)
Physiol. Rev
. 59, 919-957).
Physiologically, there is evidence that substance P released from nociceptor terminals can cause the release of histamine from mast cells. Activation of mast cells, with release of the pruritogen histamine, occurs in immediate type hypersensitivity diseases, such as anaphylactic reactions and urticaria. Urticarial eruptions are distinctly pruritic and can involve any portion of the body, and have a variety of causes beyond hypersensitivity, including physical stimuli such as cold, solar radiation, exercise and mechanical irritation. Other causes of prutitus include: chiggers, the larval form of which secretes substance that creates a red papule that itches intensely; secondary hyperparathyroidism associated with chronic renal failure; cutaneous larva migrans, caused by burrowing larvae of animal hookworms; dermal myiasis, caused by maggots of the horse botfly, which can afflict horseback riders; onchocerciasis (“river blindness”) caused by filarial nematodes; pediculosis, caused by lice infestations; enterobiasis (pinworm) infestations, which afflict about 40 million Americans, particularly school children; schistosome dermatitis (swimmer's itch); psoriasis; poison ivy and asteatotic eczema (“winter itch”). The role of histamine or other endogenous pruritogens in mediating itch associated with these and other pruritic conditions, such as atopic dermatitis, its not yet well established. For atopic dermatitis, in particular, it appears that itch is not inhibited by antihistamines, but by cyclosporin A, a drug which inhibits the production of cytokines which have been proposed as potential pruritogens.
Current therapies for the treatment of itch include a variety of topical and systemic agents, such as steroids, antihistamines, and some psychotherapeutic tricyclic compounds, such as doxepin hydrochloride. Many such agents are listed in
PDR Generics
(see Second Edition, 1996, p. cv for a listing of said agents). The limitations of these agents are well known to medical practitioners, and are summarized in the “Warnings” and “Precautions” sections for the individual agents listed in
PDR Generics
. In particular, the lack of complete efficacy of antihistamines is well known, but antihistamines are frequently used in dermatology to treat prutitus due to urticaria, atopic dermatitis, contact dermatitis, psoriasis, and a variety of other conditions. Although sedation has been a frequent side effect of conventional systemically administered antihistamines, a new generation of antihistamines has been developed that are nonsedating, apparently due to their inability to cross the blood-brain barrier.
Intravenous administration of opiate analgesics, such as morphine and hydromorphone has been associated with prutitus, urticaria, other skin rashes, and wheal and flare over the vein being injected. These itch and itch-related reactions are believed to be due to a histamine-releasing property of these opiates, via mast cell degranulation. These opiates are thought to act upon the mu subtype of opiate receptor, but the possibility of interactions at the other principal opiate receptor subtype
Cowan Alan
Farrar John J.
Adolor Coporation
Jiang Shaojia A.
Moezie Minna
Woodcock & Washburn LLP
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