Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Matrices
Reexamination Certificate
2000-02-14
2002-05-28
Patterson, Jr., Charles L. (Department: 1652)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Matrices
Reexamination Certificate
active
06395299
ABSTRACT:
2. INTRODUCTION
Many clinical conditions, deficiencies, and disease states may be remedied or alleviated by providing to a patient beneficial biologically active agents or removing from the patient deleterious biologically active agents. In many cases, provision of beneficial agents or removal of deleterious ones may restore or compensate for the impairment or loss of function or homeostasis. An example of a disease or deficiency state whose etiology includes loss of such an agent include Parkinson's disease, in which dopamine production is diminished. The impairment or loss of such agents may result in the loss of additional metabolic functions.
Parkinson's disease, one of many motor system disorders, results in symptoms such as tremor, bradykinesia, and impaired balance. Keller in
Handbook of Parkinson's Disease
(Marcel-Dekker Inc.: New York 1992). Parkinson's disease is both chronic and progressive, and nearly 50,000 Americans are diagnosed with Parkinson's disease each year. More than half a million Americans are currently being treated for Parkinson's disease. Bennett et al.
Dis. Mon
. 38:1 (1992).
A specific area of the brain known as the basal ganglia is affected in Parkinson's disease. The basal ganglia plays a vital role in voluntary movement control. A region of the basal ganglia termed the substantia nigra is important in the synthesis of the neurotransmitter dopamine. Deterioration of the dopamine producing cells in the substantia nigra results in the characteristic symptoms of Parkinson's disease. These symptoms are thought to be due to a deficiency of dopamine in both the substantia nigra and the striatum. Obeso et al.,
Advances in Neurology
74:143 (1997). The striatum requires a balance of the neurotransmitters dopamine and acetylcholine in order to control properly movement, balance, and walking. The cause of the impairment or death of the cells responsible for the production of dopamine in the substantia, although currently unknown, has been attributed to a number of factors, including oxidant stress, mitochondrial toxicity, and autoimmunity. Olanow et al., in
Neurodegenetaion and Neuroprotection
(Academic Press: San Diego 1996).
There are currently a number of methods being used for treating Parkinson's disease, which can be grouped into two categories, namely chemical and surgical methods. Yahr et al.
Advances in Neurology
60: 11-17 (1993). In chemical treatment methods, the goal is to achieve a stasis between the counterbalancing dopamine and acetylcholine neurotransmitters. Jankovic et al., in
Parkinson's Disease and Movement Disorders
115-568 (Williams and Wilkins: Baltimore). The correct balance of the neurotransmitters produces a therapeutic effect in the Parkinson's disease patient. At least three methods of accomplishing or restoring a therapeutic balance are presently possible. First, in the dopaminergic method, a balance may be achieved by increasing deficient dopamine levels by using dopamine precursors or by increasing levels of dopamine agonists in the brain. Controlled release systems have been used to increase dopamine levels. Becker et al.
Brain Res
. 508:60 (1990); Sabel
Advances in Neurology
, 53:513-18 (1990). Second, monoamine oxidase inhibitors (MAO) reduce the rate of dopamine breakdown catalyzed by monoamine oxidase enzymes and thereby increase the dopamine levels in the brain. Third, anticholinergics block the receptor sites for acetylcholine in an attempt to compensate for low dopamine levels.
Currently, there are at least two surgical methods being utilized in Parkinson's therapy. Jankovic et al., supra. In ablative surgeries, a small portion of the globus pallidus (pallidotomy) or the thalamus (thalamotomy) is destroyed, which has been shown to be effective in treating Parkinson's disease. In tissue transplants, dopaminergic cells, such as fetal nigral primordia and adrenal chromaffin cells, are grafted into the basal ganglia region or striatum. Fetal dopaminergic neurons have been observed to provide superior functional recovery in terms of both magnitude and duration of effects. Kordower et al., in
Therapeutic Approaches To Parkinson's Disease
443-72 (Roller et al. eds., Mercer Dekker Inc.: New York (1990)). This is true for both rodent and nonhuman primate models of Parkinson's disease as well as clinical trials in Parkinson's disease patients. Bakay et al.
Ann. NY Acad. Sci
. 495:623-40 (1987); Bankiewiez et al.
Progress in Brain Research
78:543-50 (1988); Freed et al.
New England Journal of Medicine
327:1549-55 (1992). In addition, such cells have been encapsulated, Emerich et al.
Neurosci. Behav. Rev
. 16:437-47 (1992), and found to alleviate symptoms of Parkinson's disease in rodents, Aebischer et al.
Brain Res
. 560:43 (1991); Lindner et al.
Exp. Neurol
. 132:62-76 (1995); Subramanian et al.
Cell Transplant
6:469-77 (1997).
Although both chemical and surgical methods help to decrease the symptoms of Parkinson's disease, there are a number of areas requiring improvement. With respect to chemical methods, delivery to the striatal region of any biologically active agent, such as dopamine, MAO inhibitors, or anticholinergics, is complicated, in part, because of the presence of the blood-brain barrier, which may result in low bioavailability of any such agents. As an alternative, direct administration of dopamine into the central nervous system may require the frequent and repeated use of invasive procedures which compromise the integrity of the blood-brain barrier. Those techniques require repeated infusions into the brain, either through injections via cannulae, or from pumps which must be replaced every time the reservoir is depleted. Even with the careful use of sterile procedures, there is risk of infection. It has been reported that even in intensive care units, intracerebroventricular catheters used to monitor intracranial pressure become infected with bacteria after about three days. Saffran,
Perspectives in Biology and Medicine
35:471-86 (1992). In addition to the risk of infection, there seems to be some risk associated with the infusion procedure. Infusions into the ventricles have been reported to produce hydrocephalus, Saffran et al.
Brain Research
492:245-54 (1989), and continuous infusions of solutions into the parenchyma is associated with necrosis.
Because of the fact that dopamine itself does not readily cross the blood-brain barrier, many of the drug therapies utilize the dopamine precursor L-dopa.
Modern Pharmacology
108 (2d ed, Craig et al. eds, 1986). Conversion of L-dopa to dopamine requires the enzyme amino acid decarboxylase, which is found in the substantia nigra of the brain. The progression of Parkinson's disease and the need for larger doses of
L
-dopa in order to produce therapeutic effects may be due to the loss of the enzyme required for this conversion. This loss of therapeutic efficacy is known as long-term
L
-dopa syndrome and occurs in 3 to 5 years in 50% of Parkinson's disease patients being treated with
L
-dopa. Brannan et al.
Neurology
45:596 (1991).
Surgical tissue transplantation suffers from a number of factors such as immunogenic complications, delayed improvement results, and low tissue survival rates of around 10%. The use of fetal tissue has formidable hurdles, including the failure to reestablish the normal neural circuitry, high mortality and morbidity associated with the transplant procedure, and the ethical issue of human fetal tissue research. Aebischer et al.
Transactions of the ASME
113:178 (1991). Adrenal cells are generally only implanted in patients less than 60 years of age, as the adrenal gland of older patients may not contain sufficient dopamine-secreting cells, which limits the usefulness of the procedure as a treatment method because the disease most often affects the elderly. With respect to encapsulation of dopamine producing cells, questions remain concerning cell viability upon encapsulation and their resulting durability and ou
Babich John W.
Bonavia Grant
Zubieta Jon
Biostream Inc.
Foley Hoag & Eliot LLP
Patterson Jr. Charles L.
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