Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-07-13
2002-07-09
Kunz, Gary L. (Department: 1646)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C514S007600, C514S105000
Reexamination Certificate
active
06417177
ABSTRACT:
BACKGROUND
Idiopathic Parkinson's Disease (IPD) is a progressive neurodegenerative disorder. The onset of IPD symptoms begin to manifest when a threshold reduction of 60%-70% nigral neurons accompanied by an 80%-90% attenuation in striatal dopamine efflux, has been reached (Koller, W. C., “When does Parkinson's disease begin?”, (1992)
Neurology
42(S4):27-31). Symptoms include tremor, postural imbalance, rigidity, bradykinesia and akinesia (
Diagnostic Clinical Neuropsychology
, Bigler, E. and Clement, P., Eds., 3
rd
Ed. 1997). These symptoms intensify as the disease progresses. In severe stages of IPD, following the onset of akinesia, even the simplest movements require a monumental degree of concentration and mental effort, often to the point of anguish (
Textbook of Medical Physiology
, Guyton, A. C. and Hall, J. E., Eds., 9
th
Ed., W. B. Saunders Company, Philadelphia, Pa., 1996). IPD is also characterized by a number of autonomic (Vainshtok, A. B., “Treatment of Parkinsonism with delagil,” (1972)
Klin. Med
(
Mosk
) 50(9):51-56) and non-motor symptoms including depression (Cummings, J. L., “Depression and Parkinson's Disease: A Review,” (1992)
Am. J. Psychiatry
149(4):443-454) and frontal lobe dysfunction (Gotham, A. M. et al., “Levodopa treatment may benefit or impair ‘frontal’ function in Parkinson's disease,” (1986)
Lancet
25;2(8513):970-971).
In the United States, it is estimated that 5-24 in every 100,000 people suffer from IPD, with the majority of low income cases going undiagnosed (Chrischilles, E. A. et al., “The health burdens of Parkinson's disease,” (1998)
Movement Disorders
13(3):406-413 ). In 1995, the World Health Organization conducted a global epidemiological evaluation of the incidence of IPD, showing a worldwide incidence of 5.32 per 100,000 people with an astounding incidence rate of 49.33 per 100,000 people over the age of 65 (M. Privett, WHO). Although more recent epidemiological figures are unavailable, in 1996 with the world population being approximately 5.7 billion, an estimated 2.8 million people had a confirmed diagnosis of IPD.
Current pharmacological treatments for IPD and other Parkinsonian-like motor disorders include anticholinergic agents, catechol-o-methyltransferase inhibitors and dopaminergic agents (Physicians' Desk Reference, 2000, 54
th
Ed., Medical Economics Company, Inc., Montvale, N.J.). Since the late sixties, dopamine precursor L-DOPA, has been employed for the symptomatic relief of IPD motor dysfunction (Mena, M. A. et al., “Pharmacokinetics of L-DOPA in patients with Parkinson's disease,” (1986)
Advances in Neurology
45:481-486). However, following long term use of L-DOPA (generally 5-8 years), diminished therapeutic efficacy is observed in approximately 50% of IPD patients (Roos, R. A. et al., “Response fluctuations in Parkinson's disease,” (1990)
Neurology
40(9): 1344-1346). A wearing off of L-DOPA efficacy precedes the development of serious motor side effects such as on/off motor oscillations and dyskinesias (Carlsson, Arvid, “Development of new pharmacological approaches in Parkinson's disease,” (1986)
Advances in Neurology
45:513-518). Further, when medications are increased to compensate for the development of these new motor dysfunctions, more serious side effects are generally observed, including psychiatric complications, while producing only minimal therapeutic benefit (Stoof, J. C. et al., “Leads for the development of neuroprotective treatment in Parkinson's disease and imaging methods for estimating treatment efficacy,” (1999)
Eur. J. Pharmacol
. 375(1-3):75-86).
Deprenyl, a monoamine oxidase (MAO) B inhibitor, was the first drug suggested to provide causal treatment of Parkinson's Disease by alleviating symptoms and attenuating the progression of the illness (Mytilineou, C. et al., “L-(−)-desmethylselegiline, a metabolite of selegiline [L-(−)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro,” (1997)
J. Neurochemistry
68(1):434-436). However, there remains much controversy regarding the therapeutic efficacy of Deprenyl. While some physicians prefer to prescribe Deprenyl when patients first present with symptoms of Parkinson's Disease (Goldstein, M. and Lieberman, A., “The role of the regulatory enzymes of catecholamine synthesis in Parkinson's disease,” (1992)
Neurology
42(S4):8-12), other physicians dispute claims of neural protection (Olanow, C. W. and Calne, D., “Does selegiline monotherapy in Parkinson's disease act by symptomatic or protective mechanisms?” (1992)
Neurology
42(S4):13-26).
Poewe and Wenning (Poewe, W. H. and Wenning, G. K., “The natural history of Parkinson's disease,” (1998)
Annals of Neurology
44(S1):S1-S9) reviewed several longitudinal studies which evaluated Parkinson's Disease medications. The Parkinson's Research Group of the United Kingdom found that when Deprenyl was co-administered with L-DOPA, a 60% increase in patient mortality was observed, compared to the group being treated with L-DOPA only. Deprenyl is now rarely prescribed by European physicians for the treatment of IPD. In contrast, American researchers determined that Deprenyl is capable of delaying the need to commence L-DOPA treatment for a period of up to nine months. However, no neural protection was found in two-year patient follow-up examinations (Poewe and Wenning, 1998, supra). In Parkinson's Disease the average lifespan is 9.4 years following an initial diagnosis. Further, the onset of gait disorders is closely associated with mortality rate. To be superior to current causal treatments (i.e—Deprenyl), a pharmacological treatment must: a) prolong the need to commence L-DOPA for more than nine months; b) retain efficacy beyond a two-year period; and, c) prevent, delay, or otherwise alleviate gait disorders.
Up to 20% of the people initially diagnosed with IPD, actually suffer from atypical IPD (APD), striatonigral degeneration (SND), or multiple symptom atrophy (MSA) (Antonini, A. et al., “Differential diagnosis of Parkinsonism with [
18
F]Fluorodeoxyglucose and PET,” (1998)
Movement Disorders
13(2):268-274). Little or no response to conventional Parkinson's Disease drug therapy is usually the differentiating factor between a diagnosis of APD, SND and MSA as opposed to IPD (Dethy, S. et al., “Asymmetry of basal ganglia glucose metabolism and dopa responsiveness in Parkinsonism,” (1998)
Movement Disorders
13(2):275-280). Often, little can be done for people suffering these atypical afflictions. Therefore, it would be of great benefit if a pharmacological means were identified that could alleviate symptoms of atypical Parkinson's Disease, as well as IPD.
The exact cause or causes of IPD are still unknown. Nonetheless, scientists have discovered a multitude of pathological abnormalities in the Parkinsonian brain. These findings include but are not limited to: a) toxic metabolite formation during neuromelanin (NM) synthesis (Graham, D. G., “Autoxidation versus covalent binding of quinones as the mechanism of toxicity of dopamine, 6-hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in vitro” (1978)
Molecular Pharmacology
14:644-653); b) heightened affinity of endogenous and exogenous toxins for NM (Tipton, K. F. and Singer, T. P., “Advances in our understanding of the mechanisms of the neurotoxicity of MPTP and related compounds,” (1993)
J. Neurochem
. 61(4):1191-1206); c) mitochondrial impairment (Mizuno, Y. et al., “Mitochondrial dysfunction in Parkinson's disease,” (1998)
Annals of Neurology
44(S1):S99-S109); d) increased oxidative stress potentiated by reduced levels of antioxidants (Merad-Boudia, M. et al., “Mitochondrial impairment as an early event in the process of apoptosis induced by glutathione depletion in neuronal cells: relevance to Parkinson's disease,” (1998)
Biochem. Pharmacology
56:645-655); e) protein oxidation and lipid peroxidation (Jenner, P. et al., “Understan
Alpha Research Group, LLC
Greenlee Winner and Sullivan P.C.
Kunz Gary L.
Parasad Sarada C
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