Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2001-09-17
2003-09-23
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S247100, C435S071300, C514S002600, C514S012200, C530S350000, C530S344000
Reexamination Certificate
active
06623742
ABSTRACT:
BACKGROUND
Fibromyalgia is a persistent muscle pain that can be accompanied by severe fatigue, insomnia, diarrhea, abdominal bloating, bladder irritation and headache. The criteria for a diagnosis of fibromyalgia may include widespread pain throughout the body accompanied by tenderness in 11 of 18 specific tender points (FIG.
1
). Tenderness is determined by applying firm pressure over each designated area.
The underlying pathophysiology and pathology of fibromyalgia is not well understood. Radiographic and histological examinations of regions associated with tenderness reveal no abnormalities. Blood chemistries, CBC, erythrocyte sedimentation rate (ESR), as well as other immunologic manifestations commonly known for other diseases (i.e. autoantibodies in Lupus), are normally negative unless there is another underlying disorder.
The source of the pain appears to be somewhat unclear. Nociceptors are present in the interstitial space between muscle fibers, in particular, on blood vessels. Studies have reported intramuscular microcirculation abnormalities as well as a decrease in energy-rich phosphates in fibromyalgia musculature, Raj et al, Pain Digest, 8(6), 357-363 (1998)). These abnormalities may be important for producing muscle associated pain since 1) impaired microcirculation results in insufficient delivery of oxygen to localized muscle regions which results in sub-optimal working capacity of the musculature which may lead to exhaustion of some motor units; and 2) reduced energy-rich phosphates (ATP and phosphorylcreatine) means that demands of working muscles are not met by the energy supply, which may cause localized muscular strain, weakness, fatigue and pain.
Fibromyalgia tender points are characterized by allodynia (a•state where a normally non-painful stimulus elicits a painful perception). Muscular dysfunction, either mechanical or metabolic, can lead to a state of sensitization of the nociceptive sensory inputs into the spinal cord altering the neurochemical balance important for nociceptive control. The process of nociception may be accomplished by a controlled release of various pro-nociceptive and anti-nociceptive agents in the nervous system. These agents include excitatory amino acids, neuropeptides, biogenic amines, nitric oxide, and prostaglandins. One important pro-nociceptive mediator is the neuropeptide substance P, which is found to be consistently elevated in the cerebrospinal fluid of fibromyalgia patients. Substance P may be released by sensory afferents arising from the muscle into the dorsal horn of the spinal cord to interact with neurokinin-1 receptors. Activation of spinal neurons by substance P prepares the neurons for an inceptive pain signal, thereby facilitating nociceptive perception. Injection of substance P into animals causes allodynia by increasing the number of afferent neurons that are activated (e.g. discharge one or more action potentials) in response to a certain nociceptive stimulus and reducing the voltage threshold needed for their activation.
A recent finding of elevated nerve growth factor levels in cerebral spinal fluid of patients may exacerbate the condition by increasing the development of substance P-containing sensory neurons, which either contribute to or accentuate the painful symptoms brought about by an elevated level of substance P. Further, levels of anti-nociceptive substances such as the neuropeptide met-enkephalin and biogenic amine serotonin are found to be significantly reduced in fibromyalgia patients' cerebral spinal fluid.
Fibromyalgia tends to be chronic and often occurs after a stressful event suffered by the patient, either physical or psychological. Current treatments involve massages, exercise, changes in diet and anti-depressant medication. All of these forms of treatment are inadequate only providing some benefit to a small subset of patients.
What is needed are new effective methods to treat fibromyalgia, including pain associated with fibromyalgia. The present invention provides methods to treat the symptoms (including pain) of fibromyalgia by the injection of a Clostridial toxin, for example, a
botulinum
toxin, into a patient at a location that is not at or near a site where the patient perceives the pain to originate. It is hypothesized that
botulinum
toxin may interfere with the central pain pathway through routes not traditionally associated with the action of this neurotoxin.
Botulinum
Toxin
The anaerobic, gram positive bacterium
Clostridium botulinum
produces a potent polypeptide neurotoxin,
botulinum
toxin, which causes a neuroparalytic illness in humans and animals referred to as botulism. The spores of
Clostridium botulinum
are found in soil and can grow in improperly sterilized and sealed food containers of home based canneries, which are the cause of many of the cases of botulism. The effects of botulism typically appear 18 to 36 hours after eating the foodstuffs infected with a
Clostridium botulinum
culture or spores. The
botulinum
toxin can apparently pass unattenuated through the lining of the gut and attack peripheral motor neurons. Symptoms of
botulinum
toxin intoxication can progress from difficulty walking, swallowing, and speaking to paralysis of the respiratory muscles and death.
Botulinum
toxin type A (“BoNT/A”) is the most lethal natural biological agent known to man. About 50 picograms of
botulinum
toxin (purified neurotoxin complex) serotype A is a LD
50
in mice. One unit (U) of
botulinum
toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18-20 grams each. Seven immunologically distinct
botulinum
neurotoxins have been characterized, these being respectively
botulinum
neurotoxin serotypes A, B, C
1
, D, E, F and G each of which is distinguished by neutralization with serotype-specific antibodies. The different serotypes of
botulinum
toxin vary in the animal species that they affect and in the severity and duration of the paralysis they evoke. For example, it has been determined that BoNt/A is 500 times more potent, as measured by the rate of paralysis produced in the rat, than is
botulinum
toxin serotype B (BoNT/B). Additionally,
botulinum
toxin type B (“BoNt/B”) has been determined to be non-toxic in primates at a dose of 480 U/kg which is about 12 times the primate LD
50
for BoNt/A.
Botulinum
toxin apparently binds with high affinity to cholinergic motor neurons, is translocated into the neuron and blocks the release of acetylcholine.
Botulinum
toxins have been used in clinical settings for the treatment of neuromuscular disorders characterized by hyperactive skeletal muscles. BoNt/A has been approved by the U.S. Food and Drug Administration for the treatment of blepharospasm, strabismus, hemifacial spasm and cervical dystonia. Additionally a
botulinum
toxin type B has been approved by the FDA for the treatment of cervical dystonia.
Non-serotype A
botulinum
toxin serotypes apparently have a lower potency and/or a shorter duration of activity as compared to BoNt/A. Clinical effects of peripheral intramuscular BoNt/A are usually seen within one week of injection. The typical duration of symptomatic relief from a single intramuscular injection of BoNt/A averages about three months.
Although all the
botulinum
toxins serotypes apparently inhibit release of the neurotransmitter acetylcholine at the neuromuscular junction, they do so by affecting different neurosecretory proteins and/or cleaving these proteins at different sites. For example,
botulinum
serotypes A and E both cleave the 25 kiloDalton (kD) synaptosomal associated protein (SNAP-25), but they target different amino acid sequences within this protein. BoNT/B, D, F and G act on vesicle-associated protein (VAMP, also called synaptobrevin), with each serotype cleaving the protein at a different site. Finally,
botulinum
toxin serotype C
1
(BoNT/C
1
) has been shown to cleave both syntaxin and SNAP-25. These differences in mechanism of action may affect the relative potency and/or duration of action of the various
Allergan Inc.
Baran Robert J.
Donovan Stephen
Fisher Carlos A.
Kam Chih Min
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