Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-04-28
2003-05-20
Caputa, Anthony C. (Department: 1642)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06565870
ABSTRACT:
BACKGROUND
The present invention relates to methods for treating bone tumors. In particular, the present invention relates to methods for treating pain associated with a bone tumor by local administration of a neurotoxin.
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.
The non-myelinated axons found in bone are apparently postganglionic fibers derived from sympathetic ganglia and act upon vasoconstrictor or vasodilatory fibres in bone blood vessel walls. Bone nerves can also comprise post-ganglionic parasympathetic fibers, which are also usually non-myelinated, as well as being cholinergic. Significantly, sympathetic, cholinergic vasodilatory nerve fibers in association with blood vessels have been reported. Schulman L., et al.,
Nerve Fibers in Osteoid Osteoma,
J. Bone & Joint Surgery, 52-A(7);1351-1356:1970. See also page 1469 of Williams P. L., et al,
Gray's Anatomy,
38
th
Edition (1995), Churchill Livingstone, N.Y.
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 and 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 interfere 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 bone tumors, whether by drugs or surgery, have many drawbacks and deficiencies. Thus, the typical oral, parenteral or topical 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 risks attendant to surgical intervention. Additionally, surgery for a benign neoplasm can be refused by the patient or be contraindicated in a frail, elderly or osteoporeitic patient. Furthermore, the intramedullary nature of certain bone tumors can render them inoperable.
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 is the most lethal natural biological agent known to man. About 50 picograms of a commercially available botulinum toxin type A (available from Allergan, Inc., of Irvine, Calif. as a purified neurotoxin complex under the tradename BOTOX®) is a LD
50
in mice (i.e. 1 unit). Thus, one unit of BOTOX® contains about 50 picograms of botulinum toxin type A complex. Interestingly, on a molar basis, botulinum toxin type A is about 1.8 billion times more lethal than diphtheria, about 600 million times more lethal than sodium cyanide, about 30 million times more lethal than cobra toxin and about 12 million times more lethal than cholera. Singh,
Critical Aspects of Bacterial Protein Toxins,
pages 63-84 (chapter 4) of Natural Toxins II, edited by B. R. Singh et al., Plenum Press, New York (1996) (where the stated LD
50
of botulinum toxin type A of 0.3 ng equals 1 U is corrected for the fact that about 0.05 ng of BOTOX® equals 1 unit). One unit (U) of botulinum toxin is defined as the LD
50
upon intraperitoneal injection into female Swiss Webster mice weighing 18 to 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 type-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 botulinum toxin type A is 500 times more potent, as measured by the rate of paralysis produced in
Allergan Inc.
Baran Robert J.
Caputa Anthony C.
Fisher Carlos A.
Voet Martin A.
LandOfFree
Methods for treating bone tumors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for treating bone tumors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for treating bone tumors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3053906