Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-10-16
2004-11-30
Chang, Celia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S212010, C514S318000, C514S422000, C540S596000, C540S597000, C540S602000, C540S609000, C546S193000, C546S212000, C546S240000, C548S517000, C548S518000, C548S527000, C548S574000
Reexamination Certificate
active
06825217
ABSTRACT:
FIELD OF THE INVENTION
This invention describes the use of 4-aryl-4-piperidinecarbinols in the treatment of neuropathic dysfunction and neuropathic pain.
BACKGROUND OF THE INVENTION
Many people, including over three million in the United States alone, experience neuropathic dysfunction. Neuropathic pain associated with neuropathic dysfunction is defined as pain associated with damage or dysfunction of peripheral or central nervous system.
Neuropathic pain is considered a malfunction in the response to a pathologic process occurring along and within the nervous system nociceptive pathways and is a much more complex phenomenon than simple pain. Pain has been defined as “an unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage.”
The most common types of conventional pain are associated with a response to a pathophysiologic process occurring within the tissues, such as inflammation, due to an ongoing injury or damage. The pain signal generates from intact primary afferent nerves that signal noxious events, or nociceptors. Nociceptors can be sensitized by release of algogenic agents (eg, protons, prostaglandins, bradykinin, serotonin, adenosine, cytokines, etc).
In contrast, neuropathic pain is associated with signals generated ectopically and often in the absence of ongoing noxious events by pathologic processes in the peripheral or central nervous system. This dysfunction is associated with common symptoms such as allodynia (pain evoked by normally nonpainful touch), hyperalgesia (abnormally intensive and long-lasting pain from a painful stimuli), intermittent abnormal sensations, and spontaneous, burning, shooting, stabbing, paroxysmal or electrical-sensations.
Neuropathic pain has been associated with sensory changes such as paresthesias (abnormal, intermittent but nonpainful sensations, perceived spontaneously or evoked by a stimulus) or dysesthesias (abnormal painful sensations that are spontaneous or evoked). Allodynia, hyperalgesia and hyperpathia are positive sensory phenomena as opposed to the negative sensory phenomena defined by anesthesia and hypoesthesia. Allodynia, which may be mechanical or thermal, is the painful response to an ordinarily non-noxious stimulus, such as one's clothing, the mere movement of air, touch, or the nonpainful application of a cold or warm stimulus. Hyperalgesias are exaggerated pain responses to a mildly noxious mechanical or thermal stimulus. Hyperpathia may be characterized as a delayed and explosive pain response to a noxious, or at times, non-noxious stimulus.
Neuropathic pain may result from peripheral or central nervous system pathologic events (eg, trauma, ischemia, infections) or from ongoing metabolic or toxic diseases, infections or endocrinologic disorders (eg, diabetes mellitus, diabetic neurophathy, amyloidosis, amyloid polyneuropathy (primary and familial), neuropathies with monoclonal proteins, vasculitic neuropathy, HIV infection, herpes zoster—shingles and postherpetic neuralgia, etc), neuropathy associated with Guillain-Barré syndrome, neuropathy associated with Fabry's disease, entrapment due to anatomic abnormalities, trigeminal and other CNS neuralgias, malignancies, inflammatory conditions or autoimmune disorders (including demyelinating inflammatory disorders, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome), and cryptogenic causes (idiopathic distal small-fiber neuropathy). Other causes of neuropathic pain include exposure to toxins or drugs (such as aresnic, thallium, alcohol, vincristine, cisplatinum and dideoxynucleosides), dietary or absorption abnormalities, immuno-globulinemias, hereditary abnormalities and amputations (including mastectomy). Neuropathic pain may also result from compression of nerve fibers, such as radiculopathies and carpal tunnel syndrome.
During neuropathic pain, ectopic activity causes a spontaneous discharge in the peripheral nervous system (PNS) pathways, or depending on the location and type of nerve injury, ectopic discharge also may originate in the dorsal-root-ganglion (DRG) cells of damaged afferent axons. Within the same DRG, cell bodies of uninjured axons may exhibit ectopic activity too. Within the central nervous system (CNS), hyperexcitability of the signaling neurons may arise, and other mechanisms that facilitate or distort afferent input are likely. Central mechanisms underlying chronic neuropathic pain are poorly understood. Neuroanatomic, neurophysiologic, and neurochemical changes all occur as a response to PNS or CNS injury. Central sensitization at a dorsal horn level, which is mediated in part via the N-methyl-D-aspartate (NMDA) receptor, is the best characterized change involved in the generation of this dysfunction.
Table 4 below sets out common causes of neuropathic dysfunction. Se generally: www.uspharmacist.com/NewLook/DisplayArticle.cfm?item_num=536).
Common Etiologies of Neurophatic pain
Alcohol
Diabetes mellitus type 1 and 2
Eosinophilia-myalgia syndrome
Guillain-Barre syndrome
Heavy metals
Arsenic
Lead
Mercury
Thallium
HIV/AIDS
Malignant tumor-related
Medications
amiodarone
aurothioglucose
cisplatinum
dapsone
d4T (stavudine)
ddC (zalcitabine)
ddI (didanosine)
disulfiram
FK 506
hydralazine
isoniazid
metronidazole
nitrofurantoin
paclitaxel
phenytoin
vincristine
Monoclonal gammopathies
Multiple sclerosis
Post-stroke central pain
Postherpetic neuralgia
Traumatic/Compression
Carpal tunnel syndrome
Radiculopathy (sciatica, etc)
Cervical or lumbar radiculopathy
Complex regional pain syndrome
Spinal cord injury
Stump pain
Trigeminal neuralgia
Vasculitis
Vitamin B
6
megadosing
Vitamin deficiencies (B
12
, B
1
, B
6
and E)
The treatment of neuropathic pain continues to be a difficult and often unsuccessful medical challenge. For years neuropathic pain has confounded scientists. Drugs for the treatment of standard pain are typically ineffective against neuropathic pain, the drugs for the treatment of neuropathic pain often have no effect on normal pain sensation. Traditional pain treatments, including powerful medications of last resort such as morphine and other opioid analgesics, useful in the treatment of severe pain, rarely alleviate neuropathic pain. The development of tolerance, psychic and physical dependence and potentially serious opioid side effects also limit the usefulness of opioids in treating dysfunction. Anti-inflammatory analgesics, including the Cox-2 inhibitors, lack the efficacy of opioid analgesics and produce other serious side effects including gastrointestinal bleeding and gastric erosion that limits their usefulness in treating neuropathic pain.
Starting in 1988, researchers began to identify animal models that mimic the clinical signs of neuropathic pain. For example, a rat with nerve injuries has been found to exhibit a super-sensitive reaction to a hair tapped on its hindpaw. The rat will quickly jerk away. Some humans with neuropathic pain experience a similarly severe reaction. For them, the tickle of a hair can translate into a long lasting, burning sensation. The animal models of the ailment are helping scientists understand the underlying mechanism of neuropathic pain.
Drugs that have been investigated for the use to treat neuropathic pain include sodium channel antagonists, calcium channel supressors, N-methyl-D-aspartate (NMDA) receptor blockers, anticonvulsant medications, and oral tricyclic antidepressants.
Neurons have many calcium channels, including the high-conductance channel found in the NMDA receptor. Some participate in triggering the release of neurotransmitter from presynaptic vesicles. In chronic constriction injury (CCI) rats, calcium channels are known to affect the spontaneous discharge of injured nociceptive afferents (FIG.
2
). However, the drug also exerts its well-known effects on calcium channels in cardiovascular muscle, and the dosages that relieve pain are at or above those causing unacceptable heart-rate and blood-pressure changes.
However, among the many varieties of calcium channels, at least one, th
Carliss Richard
Lee David A. H.
Chang Celia
Endo Pharmaceuticals Inc.
Piper Rudnick LLP
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