Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1994-08-05
2003-05-06
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S252120, C514S252130, C514S252170, C514S252190, C514S253030, C514S253040, C514S253050, C514S254090, C514S310000, C514S354000, C514S410000, C514S462000, C514S562000, C514S643000, C514S651000, C514S654000, C514S655000
Reexamination Certificate
active
06559186
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to the diagnosis and treatment of sympathetically maintained pain using sympatholytic agents which are defined herein as compounds that interfere with sympathetic function in the peripheral tissue or interfere with the action of drugs associated with sympathetic function.
Several chronic, non-malignant pain syndromes such as causalgia and reflex sympathetic dystrophy have one feature in common: blockade of the sympathetic innervation of the affected body region can lead to pain relief. The pain may result from skeletal, soft tissue, or nerve injury. Terms such as reflex sympathetic dystrophy, Sudek's atrophy, and causalgia have all been used to refer to such patients. The term “sympathetically maintained pain” (“SMP”) encompasses all pain syndromes that can be relieved by sympathetic blockade.
Patients with SMP typically have both stimulus-independent (ongoing) pain and stimulus-dependent pain (hyperalgesia). Hyperalgesia is defined as a leftward shift of the stimulus-response function, such that a lowering of pain threshold and/or an increase in pain to suprathreshold stimuli is observed. The decrease in pain threshold to mechanical stimuli may be such that lightly stroking the skin evokes pain, a phenomenon sometimes referred to as allodynia.
Conventional treatments for SMP include repeated local anesthetic sympathetic blocks, intravenous regional guanethidine/reserpine blocks, surgical sympathectomy, or oral sympatholytic therapy. However, each of these treatments carries with it a degree of risk, side effects and discomfort.
One method of diagnosis of SMP is by assessment of the results of a local anesthetic blockade of the sympathetic ganglia (LABSG) that innervate the painful part. Because of the technical expertise required in the performance of the LABSG and the potential complications associated with the LASB, alternate tests for the diagnosis of SMP have been studied. For example, intravenous regional blockage (IVRB) of sympathetic function with guanethidine has been used as a means for the diagnosis and treatment of SMP.
There are several potential disadvantages to the use of LABSG and IVRB. LABSG is subject to false negative results if the local anesthetic fails to anesthetize adequately the sympathetic ganglia. The anesthetic may reach the somatic afferents in the nearby nerve roots and produce pain relief because of concurrent somatic blockade, and certain afferents may in addition course with sympathetic efferents. Certain patients tolerate poorly the application of the tourniquet required with IVRB. LABSG involves strategic localization of the needle prior to injection, and thus fluoroscopy is often needed. With IVRB, the guanethidine may escape into the systemic circulation with resultant systemic untoward effects. A series of complications have been reported with LABSG, including pneumothorax, injury to the kidney, inadvertent systemic application, spinal anesthesia, hemorrhage, etc. It is difficult to evaluate placebo responses with both LABSG and IVRB.
It would therefore be advantageous to have a method of diagnosis and treatment that does not exhibit these difficulties.
Several lines of evidence suggest that peripheral adrenergic receptors are involved in SMP. Stimulation of the peripheral but not central cut end of the sympathetic chain reproduces pain in causalgia patients after sympathectomy. Local anesthetic blockade of the appropriate sympathetic ganglion or adrenergic blockade via intravenous administration of phentolamine, rapidly abolishes sympathetically-maintained pain and hyperalgesia. Depletion of peripheral catecholamines by regional intravenous guanethidine relieves pain and hyperalgesia. Intradermal injection of norepinephrine rekindles the pain and hyperalgesia that had been relieved in patients by sympathectomy or sympathetic block but does not cause pain or hyperalgesia in normal subjects. The non-specific &agr;-adrenergic antagonist phenoxybenzamine and the specific &agr;
1
-adrenergic antagonist prazosin can be effective in relieving pain in patients with SMP. The beta-adrenergic antagonist propranolol has little effect on SMP.
It is therefore possible that administration of an &agr;-adrenergic blocking agent could be beneficial in the treatment of SMP patients. Therapeutic uses of the &agr;-adrenergic compounds, for example, phentolamine and clonidine, are known in the art. For example, U.S. Pat. No. 4,801,587 discloses the use of phentolamine as a vasodilator to treat impotence. U.S. Pat. No. 4,310,535 discloses the use of phentolamine in combination with other drugs for use in the control of immune reactions. The use of phentolamine and clonidine for controlling hypertension is disclosed in U.S. Pat. No. 4,250,191. &agr;-Adrenergic drugs have been found to be useful in the stabilization of intraocular lenses, as disclosed in U.S. Pat. No. 4,443,441. U.S. Pat. No. 4,201,211, discloses the use of a clonidine patch for therapeutic use as a stimulant for the central nervous system.
It is therefore an object of the present invention to provide a topical method of diagnosis for sympathetically maintained pain that has a low incidence of false positives and false negatives.
It is another object of the present invention to provide a topical method of diagnosis and treatment of sympathetically maintained pain that has a low incidence of adverse reactions with relatively minor complications.
SUMMARY OF THE INVENTION
Sympathetically maintained pain is treated topically by administering to the site where sympathetically maintained pain is present a sympatholytic agent, such as an &agr;-adrenergic antagonist, &agr;
1
-adrenergic antagonist, &agr;
2
adrenergic agonist, or other drug that depletes or blocks synthesis of norepinephrine from the sympathetic terminals. Specific chemical formulas of sympatholytic agents are disclosed
Examples demonstrate relief of pain by application of phentolamine or clonidine.
DETAILED DESCRIPTION OF THE INVENTION
Sympathetic efferent fibers release norepinephrine which in turn activates &agr;-adrenergic receptors. Activation of the &agr;-adrenergic receptors by norepinephrine, either directly or indirectly, excites nociceptors. Activity in the nociceptors then evokes pain and further activity in the sympathetic efferent fibers. This, in turn, results in further discharge of the nociceptors. The goal in therapy is to block the effects of norepinephrine on nociceptors. Topical application to the site where sympathetically maintained pain is present of an &agr;-adrenergic antagonist, &agr;
1
adrenergic antagonist, &agr;
2
adrenergic agonist, a combination thereof, or other drug that depletes or blocks synthesis of norepinephrine at the sympathetic terminals (collectively referred to herein as “sympatholytic agents”) relieves the pain.
Topical application of the sympatholytic agent is also used in the treatment of peripheral vascular diseases characterized by high alpha-adrenergic tone in cutaneous blood vessels, such as frostbite, Raynaud's disease, thrombophlebitis, and spastic peripheral vascular disorders.
The compounds used in the present method are known to those skilled in the art. For example, the various classes of compounds and examples thereof are described in
The Pharmacological Basis of Therapeutics
, 8th Edition, Gill, A. G., T. W. Rall, A. S. Nies, P. Taylor, editors (Pergamon Press, Co., Inc., NY 1990), the teachings of which are incorporated herein.
Several different structural classes of sympatholytic agents have been developed, from which a compound can be selected for use as a topical therapy for sympathetically maintained pain. For example, a class of cyclic amidine compounds from which a suitable sympatholytic agent with alpha-1 adrenoreceptor antagonist activity, alpha-2 adrenoreceptor agonist activity, or both activities combined may be selected can be represented by Formula I:
wherein A is selected from aryl, aryloxy, anilino, arylamino, diarylamino, heteroaryl, heteroaryloxy, or heteroarylamino, which may be substituted with one
Arc 1, Inc.
Holland & Knight LLP
Webman Edward J.
LandOfFree
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