Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-07-25
2003-11-04
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...
C514S002600, C514S012200, C514S014800, C530S350000, C530S412000, C435S069100, C435S069700, C435S070100, C435S320100, C435S325000, C435S252300
Reexamination Certificate
active
06641820
ABSTRACT:
BACKGROUND
The present invention relates to methods for treating pain. In particular, the present invention relates to methods for treating pain associated with a bone tumor using a Clostridial toxin derivative.
Many, if not most ailments of the body cause pain. The causes of pain can include inflammation, muscle spasm, the onset of a neuropathic event or syndrome, and bone tumor.
Pain can be experienced when the free nerve endings which constitute the pain receptors in the skin as well as in certain internal tissues are subjected to mechanical, thermal or chemical stimuli. The pain receptors transmit signals along afferent neurons into the central nervous system and thence to the brain.
The transduction of sensory signals, such as pain signals, from the periphery to sensation itself is achieved by a multi-neuronal pathway and the information processing centers of the brain. The first nerve cells of the pathway involved in the transmission of sensory stimuli are called primary sensory afferents. The cell bodies for the primary sensory afferents from the head and some of the internal organs reside in various ganglia associated with the cranial nerves, particularly the trigeminal nuclei and the nucleus of the solitary tract. The cell bodies for the primary sensory afferents for the remainder of the body lie in the dorsal root ganglia of the spinal column. The primary sensory afferents and their processes have been classified histologically; the cell bodies fall into two classes: A-types are large (60-120 micrometer in diameter) while B-types are smaller (14-30 micrometer) and more numerous. Similarly the processes fall into two categories: C-fibers lack the myelin sheath that A-fibers possess. A-fibers can be further sub-divided into A beta-fibers, that are large diameters with well developed myelin, and A delta-fibers, that are thinner with less well developed myelin. It is generally believed that A beta-fibers arise from A-type cell bodies and that A delta—and C-fibers arise from B-type cell bodies.
After the activation of the primary sensory afferents the next step in the transduction of sensory signals is the activation of the projection neurons, which carry the signal, via the spinothalamic tract, to higher parts of the central nervous system such as the thalamic nuclei. The cell bodies of these neurons (other than those related to the cranial nerves) are located in the dorsal horn of the spinal cord. This is also where the synapses between the primary afferents and the projection neurons are located. The dorsal horn is organized into a series of laminae that are stacked, with lamina I being most dorsal followed by lamina II, etc. The different classes of primary afferents make synapses in different laminae. For cutaneous primary afferents, C-fibers make synapses in laminae I and II, A delta-fibers in laminae I, II, and V, and A beta-fibers in laminae III, IV, and V. Deeper laminae (V-VII, X) are thought to be involved in the sensory pathways arriving from deeper tissues such as muscles and the viscera.
The predominant neurotransmitters at the synapses between primary afferents and projection neurons are substance P, glutamate, calcitonin-gene related peptide (CGRP) and neuropeptide Y. The efficiency of transmission of these synapses can be altered via descending pathways and by local interneurons in the spinal cord. These modulatory neurons release a number of mediators that are either inhibitory (e.g. opioid peptides, glycine) or excitatory (e.g. nitric oxide, cholecystokinin), to provide a mechanism for enhancing or reducing awareness of sensations.
The bones of the mammalian skeleton are covered by a thick, fibrous membrane, the periosteum. Except for the richly innervated periosteum, bone is relatively insensitive to painful stimuli and surgical trauma can usually be inflicted upon bone with little or no patient discomfort. Even though bone is generally insensitive to pain, nerve fibers exist in bone, usually closely associated with blood vessels. Sherman, M. S. et al.
The Nerves of Bone
, J. Bone & Joint Surgery, 45-A(3);522-528:1963. The nerves in bone are apparently derived from the autonomic system and influence intraosseal blood flow as well as sensation of pressure and position. Halperin N., et al. Osteoid
Osteoma of the Proximal Femur Simulating Spinal Root Compression
, Clinical Orthopaedics & Related Research, 162;191-194;1982.
Thus, it is known that both bone and periosteum have both afferent sensory and efferent autonomic innervation. Hukkanen M., et al.,
Rapid Proliferation of Calcitonin Gene
-
Related Peptide
-
Immunoreactive Nerves During Healing of Rat Tibial Fracture Suggests Neural Involvement in Bone Growth and Remodelling
, Neuroscience 54(4);969-979:1993. See also O'Connell J. X. et al.,
Osteoid Osteoma: The Uniquely Innervated Bone Tumor
, Mod Pathol 11(2);175-180:1998.
Bone tumors can arise from bone tissues as well as from nerves located within bone. Lichtenstein, L.,
Classification of Primary Tumors of Bone
, Cancer 335-341;1951. Benign bone tumors of cartilaginous origin include enchondroma, osteochondroma, chondroblastoma and chondromyxoid. Benign bone tumors of bone tissue proper origin include osteoid osteoma and osteoblastoma.
Nerve fibers have been demonstrated within various bone tumors, including in the nidus of osteoid osteomas and in osteoblastomas. Schulman L. et al.,
Nerve Fibers in Osteoid Osteoma
, J. Bone & Joint Surgery, 52-A(7);1351-1356:1970. The nerve fibers within bone tumors are predominately non-myelinated, hence presumably arising from the sympathetic and/or parasympathetic nervous systems and are believed to have at least a vasomotor action upon tumor blood vessels. Additionally, myelinated nerve fibers located within bone tumors are postulated to function as afferent nociceptors. Greco F., et al.,
Nerve Fibres in Osteoid Osteoma
, Int. J. Orthop Trauma, 16; 89-94:1988.
Typically, an intramedullary neoplasm will remain asymptomatic, even if rather large, until it breaks through the bone and contacts the periosteum. Osteoid osteomas are small, benign and richly vascularized bone neoplasms. Osteoid osteomas are rarely greater than one or two centimeters in diameter. Though surrounded by bone tissue and not in contact with the periosteum, even a small osteoid osteoma can cause intense throbbing pain. The pain generated by the presence of an osteoid osteoma can generally be relieved, at least to some extent, by oral salicyliates, such as aspirin. The pain can be described as local and more severe at night. Jaffe, H. L. Osteoid-Osteoma, Arch Surg 31;709-728:1935. Pain generated by a bone tumor if ineffectively treated, can limit function, reduce mobility, complicate sleep, and dramatically interfering with the quality of life.
It has been hypothesized that the pain which accompanies osteoid osteoma is due to vascular pressure changes within the neoplasm, presumably by direct stimulation of local nerves around intraosseous vessels. Sherman, M. S. et al., Mechanism of Pain in Osteoid Osteomas, Southern Medical Journal 58;163-166:1965.
Present methods for treating pain associated with bone tumors, whether by drugs or surgery, have many drawbacks and deficiencies. Thus, the typical oral, parenteral ortopical administration of an analgesic drug (such as a NSAID) to treat the symptoms of pain or of, for example, a salicylate, can result in widespread systemic distribution of the drug and undesirable side effects. Additionally, current drug therapy for bone tumor pain suffers from short drug efficacy durations which necessitate frequent drug re-administration with possible resulting drug resistance, antibody development and/or drug dependence and addiction, all of which are unsatisfactory. Furthermore, frequent drug administration increases the expense of the regimen to the patient and can require the patient to remember to adhere to a dosing schedule.
Surgical excision is unnecessary in the case of a benign bone tumor and should be avoided to prevent the bone destruction inevitable upon surgical removal and to avoid the
Allergan Inc.
Kam Chih-Min
Low Christopher S. F.
Stout, Uxa Buyan & Mullins, LLP
Uxa Frank J.
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