Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-04-12
2003-04-15
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S017900
Reexamination Certificate
active
06548484
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to dopaminergic compositions and methods of their preparation and use for treating neurological diseases including Parkinson's and related diseases.
BACKGROUND OF THE INVENTION
Parkinson's disease reportedly affects one person in fifty over fifty years of age and one is twenty over seventy. A degenerative disease of the nervous system described in 1817 and characterized by progressive loss of nigrostriatal neurons, a shaking palsy with tremor at rest, muscular rigidity and slowness of movement, the possible etiology, the cell biology, biochemistry and pathophysiology are still areas of intense speculation and ongoing research. Diseases related by clinical symptomology, and progressive clinical symptomology in Parkinson's patients, include post-encephalitic syndromes, Wilson's disease, Parkinsonism secondary to cerebrovascular trauma and stroke, dementia, Alzheimer's disease, Lou Gehrig's disease, psychomotor retardation, certain schizophreniform behavior, anxiety and depression. The primary biochemical defect in Parkinson's disease is loss of nigrostriatal dopamine synthesis.
Catecholamines including dopamine, norepinephrine and epinephrine are produced by chromaffin cells in the adrenal medulla responding as a specialized ganglion to sympathetic enervation from preganglionic fibers of the splanchic nerve. However, catecholamines do not cross the blood-brain barrier, hence, the need for synthesis within the CNS. L-Dopa, the precursor of dopamine, readily crosses the blood-brain barrier but is unstable and rapidly inactivated in blood. Levodopa (a precursor of dopamine) and its derivatives are used for treatments of Parkinson's disease. Dopamine administered intravenously, while not crossing the blood brain barrier, binds D1-like and D2-like dopamine receptors in the periphery and is reportedly useful in certain treatments for peripheral defects such as congestive heart failure and hypertension (e.g., Kuchel, 1999).
Pharmaceutical compositions for treatments of Parkinsonism include: Levodopa (e.g., U.S. Pat. Nos. 3,253,023, 3,405,159), Carbidopa (e.g., U.S. Pat. No. 3,462,536), aminoindans (e.g., U.S. Pat. No. 5,891,923), benzhydrylamines (e.g., Diphenhydramine, U.S. Pat. No. 2,427,878); benzenemethanamines (e.g., U.S. Pat. Nos. 2,599,000; 5,190,965), piperidines (e.g., Budipine, U.S. Pat. No. 4,016,280; Biperiden, U.S. Pat. No. 2,789,110; Trihexylphenidyl, U.S. Pat. No. 2,682,543), pyrrolidines (e.g., Procyclidine, U.S. Pat. No. 2,891,890), tropines (e.g., Benztropine, U.S. Pat. No. 2,595,405; Hyoscyamine, Fodor et al. 1961), criptines (e.g., Bromocriptine, U.S. Pat. No. 3,752,814) and ergolines (e.g. Pergolide, U.S. Pat. No. 4,166,182).
Metabolic replacement therapy compounds that are endogenously converted to dopamine, e.g., Levodopa, results in stimulation of both D1-like and D2-like dopaminergic families of receptors. While agonists are theoretically superior to Levodopa (i.e., because they should not be dependent on enzymatic conversion), in clinical use they have been shown to lack the therapeutic potency of Levodopa. Direct acting D2 agonists (e.g., bromocriptine, lisuride and pergolide) have shown limited efficacy in monotherapy and are primarily used as add-on therapy to L-Dopa. Recent identification of novel structural classes of D1-selective isochroman dopamine agonists has led to renewed interest in possible use of D1 selective agonists in treatments for Parkinson's and other neurological diseases.
L-dopa, Levodopa, Cardiodopa (an inhibitor of dopa decarboxylase), Deprenyl (inhibiting dopamine degrading monoamine oxidase), Sinemet (a controlled release form of Levodopa) and their combinations and derivatives suffer from many major disadvantages. Commonly these agents have poor aqueous solubility and relatively short half-lives. Observed side effects accompanying chronic use include motor fluctuation, dysfunctions, peak-dose dyskinesia, requirements for frequent dosing, involuntary movements, psychosis, confusion, visual hallucinations, bradykinesia, rigidity, tremors, gastrointestinal and gentiourinary dyantonomia, hypotension and cognitive decline (Hurtig, 1997). Often after 3-5 years of treatment patients develop complex dose-related unpredictable response fluctuations usually leading to a progressive decrease in therapeutic efficacy and also possible onset of serious side effects such as abnormal involuntary movements, end-of-dose deterioration and abrupt near instantaneous on-off changes in patient disability. “Adaptation” by neural tissues to chronic administration is complex, and may include down-regulation of dopamine receptor expression as well as metabolic changes in post-striatal neurons. In certain patients dyskinesia and response fluctuations would desirably be controlled by continuous intravenous infusion of drug at a constant level, however, because of the low aqueous solubility of Levodopa this is not a feasible solution. In addition to these neurologic disadvantages, metabolism of oral dopa compounds to dopamine in the stomach and gastrointestinal tract (even in the presence of decarboxylase inhibitors) can often lead to unwanted side effects including severe nausea and hypotension. Levodopa methyl and ethyl esters given orally suffer many of these same problems. Thus, all current therapies suffer from serious side effects, bioavailability problems, or both, and there has been a long-felt need for improved pharmaceutically active agents for metabolic replacement therapy in Parkinson's and related diseases (Hurtig, 1997). There has also been a long-standing need for improved dopaminergic catechol agonists with improved bloavailability and penetrability of myelinated nerves, i.e., for peripheral use in treatments of e.g. hypertension and congenital heart diseases.
Molecular cloning studies have identified several genes encoding dopamine receptors. D1-like receptors, (recognized pharmacologically by the SCH23390 agonist), activate adenylate cyclase resulting in increased intracellular cAMP. Two gene products have been identified, i.e., D1A and D1B. D1B may have been previously identified pharmacologically as D5 and may be responsible for SCH23390 specific agonist activity. D2-like dopamine receptors, (recognized pharmacologically by spiperone and sulpride agonists), appear to be encoded by three genes with multiple possible splice variants expressed in different brain regions, i.e., D2S, D2L, D3 and D4. D2-like receptors do not appear adenylate cyclase-linked and may decrease intercellular cAMP levels, perhaps a result of kinase-mediated phosphorylation. D2-like receptors have been identified as a potential target for development of anti-psychotic agents and treatments for schizoprenia, i.e., based on antipsychotic effects of chlorpromazine occurring with resultant drug-induced Parkinson's symptoms and increased risk of tardive dyskinesia. Schizoprenia is (at present) believed to result from hyperactive dopaminergic transmission in the mesolimbic region of the brain. While antipsychotic drugs with fewer side-effects have been developed (e.g., haloperidol, fluphenazine, clozapine, olanzapine, risperidone), to date, no consensus antipsychotic dopaminergic antagonist pharmacologic or receptor profile has emerged and approaches under active consideration include: (i) combination approaches for blockade of D2-like and D1-like receptors as well as 5-HT
2
and &agr;
1
adrenergic receptors; (ii) selective approaches for blocking D2 subtypes, e.g., D3 and/or D4 or D2L/S and D4; and (iii) attempts to develop partial agonists to compete with dopamine binding.
In pharmacologic studies conducted over the past 20 years, the results seem to suggest relatively stringent structural requirements for activation of the D1 receptors, particularly in regard to any nitrogen atoms present in the compound (e.g., see Seiler et al., 1991 ;Berger et al., 1989; Brewster et al., 1990; Kaiser et al., 1982; Dandridge et al., 1984; Brewster et al. 1990; Weinstock et al., 198
Biomed Patent
Fonda Kathleen K.
International Medical Innovations, Inc.
Sundsmo John S.
LandOfFree
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