Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
2000-04-06
2004-06-08
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S464000, C424S451000, C514S565000, C514S561000, C514S567000
Reexamination Certificate
active
06746678
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the clinical treatment of neurodegenerative diseases. For purposes of this invention, the category of neurodegenerative diseases includes hereditary motor and sensory neuropathies (HMSN, also known as peroneal muscular atrophy or Charcot-Marie-Tooth disease), diabetic polyneuropathy, Alzheimer's pre-senile and senile dementia, Down's syndrome, Parkinson's disease, olivopontocerebellar atrophy, Huntington's disease, amyotrophic lateral sclerosis, age-onset neurological deterioration, alcoholic polyneuropathy, tinnitus, multiple sclerosis, and pathophysiologically symptomology.
The clinical neurology literature includes many descriptions of patients having an incipient form of a disease, patients showing the recognized symptoms of a disease and additional symptomology, and patients demonstrating concurrent clinical symptomology of two or more of the disease entities included in the category of neurodegenerative diseases defined above. Such clinical disorders are frequently excluded from biochemical studies due to inherent problems of classification and their happenstance occurrence. Hence comparatively little research information is available on such clinical phenomena. Yet it is the understanding of this inventor that information available on the etiologies of well recognized neurological disorders, as summarized herein, can also be extrapolated to infer that the drug therapies described in this invention may also be applied with success to the incipient and more complex forms of the diseases mentioned above. Furthermore, many genetic sub-categories of these neurodegenerative diseases are now recognized in the prior art. For purposes of this invention, the term “pathophysiologically symptomology” shall include those various clinical and genetic sub-categories of the class of neurodegenerative diseases noted above as commonly recognized in the prior art.
2. Description of Prior Art
The logic and potential value, even synergistic value, of using two or more therapeutic agents in combination has been recognized previously [Ghose et al. Int.
J. Radiat. Biol.
44:175-181 (1983); Goldstein et al.
Adv. Neurol.
53:101-106 (1990); Rinne
Acta. Neurol Scand.
84[Suppl. 136]:95-98 (1991)]. For example, in a study on two-drug combinations of memory enhancing agents Flood and coworkers [
Life Sci.
42:2145-2154 (1988)] noted that:
The potential for clinically desirable drug interactions has been emphasized for drugs in general (1) and for memory enhancing drugs in particular (2,3). For example, individual cholinergic drugs which improve memory retention test scores (4,5,6) do so in two-drug combinations at substantially lower doses than would be predicted if the two drugs acted additively (7,8,9) . . .
In prior studies of the effect of two-drug combinations on memory processing (8,9), we determined the effect of varying the dose of two drugs while holding the ratio constant. The ratio was based on the optimal memory enhancing doses of each drug administered singly. These studies showed that drugs administered in certain combinations require 67 to 96% less drug to improve retention, than when the same drugs were administered alone. This type of drug interaction was said to yield supra-additivity.
The present disclosure describes the inventive concept of using the therapeutic technology of U.S. patent application Ser. No. 08/026,617 in combination with pharmaceutical agents recognized as having, or possibly having some medicinal value for treatment of the disease entities noted above. No pharmacological treatment of comprehensive effectiveness is currently available for any of the neurological disorders discussed herein. However, a variety of pharmaceutical agents have been described which may offer at least some degree of symptomatic relief from the clinical effects of these diseases.
The use of L-dopa as the primary therapeutic agent for treatment of Parkinson's disease may serve as an example of the limitations of present technology. Citing earlier work, Robin [
Am. J. Med. Sci.
301:277-280 (1991)] has noted that “ . . . chronic exposure to high dose L-dopa may accelerate the progression of Parkinson's disease.” Indeed, clinical benefits to be obtained from L-dopa therapy are predictably limited to perhaps three to five years. After that period, continued use of L-dopa will not provide clinical benefit. This situation exists because L-dopa therapy depends on conversion of this physiological precursor into dopamine within a population of substantia nigra neurons which is selectively deteriorating in this disease. Once the last of these nerve cells is gone, the therapeutic strategy has lost its physiological basis.
As noted by Ceballos and coworkers [in
Antioxidants in Therapy and Preventive Medicine
, Emerit, I, sr. ed. (New York, Plenum Press, 1990) pp. 493-498]:
. . . The development of clinical features in AD [Alzheimer's disease] is linked to the amount of deposition of amyloid in the limbic areas and cerebral cortex. Moreover, amyloid formation may arise as a consequence of membrane damage . . . due to lipid peroxidation . . . About 6% of PHF [paired helical filaments] is composed of the amino-acid, hydroxyproline. This amino-acid is not a constituent of cytoplasmic protein in normal brain and the abundance of hydroxyproline in cytoplasmic PHF involves non-enzymatic hydroxylation of proline residues probably by hydroxyl free radicals. This free radical hypothesis of PHF formation suggests that AD is an acceleration of the normal aging process in affected brain regions.
Some published work has reported that L-deprenyl (selegiline) may work in part by slowing the aging process [Sanchez-Ramos
Clin. Neuropharmocol.
14:391-402 (1991)]. Monoamine oxidase B (MAO-B) activity, which is thought to increase with aging in some areas of the brain, generates H
2
O
2
, which in turn may generate neurocytotoxic hydroxyl free radicals (HO
−
) and leads to subsequent lipid peroxidation. Hence, use of MAO-B inhibitors such as L-deprenyl may have an anti-aging clinical effect [Youdim
Adv. Neurol.
53:483-488 (1990)]. The use of L-deprenyl as a clinical agent for treatment of canine age-related dementia is an example of the potential veterinary applications of the prior art drugs included in this invention [Milgram U.S. Pat. No. 5,151,449 (Sep. 29, 1992)].
As discussed in U.S. patent application Ser. No. 08/026,617, a considerable body of prior art publications has provided evidence suggesting that the etiologies of certain neurodegenerative diseases include evidence of chemical crosslinking of neurofilaments. Such studies include work on hereditary motor and sensory neuropathies [Hughes and Brownell
J. Neurol. Neurosurg. Psych.
35:648-657 (1972); Brimijoin et al.
Science
180:1295-1297 (1973); van Weerden et al.
Muscle
&
Nerve
5:185-196 (1982); Goebel et al.
Ital. J. Neurol. Sci.
7:325-332 (1986)], giant axon neuropathy [Prineas et al.
J. Neuropathol. Exp. Neurol.
35:458-470 (1976)], diabetic polyneuropathy [Yamamura et al. in
Diabetic Neuropathy
, Goto, Y, sr. ed. (Princeton, Excerpta Medica, 1982) pp. 80-85; Sidenius and Jakobsen
Diabetes
31:689-693 (1982); Tomlinson and Mayer
J. Auton. Pharmac.
4:59-72 (1984)], Alzheimer's disease [Wisniewski et al.
J. Neuropath. Exp. Neurol.
29:163-176 (1970); Iqbal et al.
Brain Res.
142:321-332 (1978); Wisniewski et al. in
Aging and Cell Structure
, volume 1, Johnson, Jr., J E, ed. (New York, Plenum Press, 1982) pp. 110-112], Down's syndrome [Goodison et al.
Soc. Neurosci. Abstr.
15(pt. 2): 329 (abstract 135.6) (1989)], Pick's disease [Yoshimura
Clin. Neuropath.
8:1-6 (1989)], Parkinson's disease [Oppenheimer in
Greenfield's Neuropathology
, Blackwood, W and Corsellis, JAN, eds. (Chicago, Year Book Medical Publishers, 1976) pp.
Fubara Blessing
Page Thurman K.
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