Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-13
2001-05-15
Fonda, Kathleen K. (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S275000, C514S318000, C514S333000
Reexamination Certificate
active
06232326
ABSTRACT:
BACKGROUND OF THE INVENTION
Schizophrenia is a serious disease affecting one percent of the entire global population including about three million Americans. The annual cost of this disorder to the United Sates alone due to loss of employment, hospitalizations, medications, and the like exceeds 60 billion dollars annually and its toll in human suffering is shown by the ten to thirteen percent suicide rate for people who have the disease (American Psychiatric Association Public Information Online [1998] http://www.psych.org). A permanent or long-term cure for this tragic disease would be of tremendous value to the human race.
Schizophrenia appears to be genetically transmitted. Concordance rates of monozygous twins has been shown to be 48 percent while for dizygous twins concordance was only 17 percent. Concordance for offspring having two schizophrenic parents was 46 percent, while for those with only one schizophrenic parent, concordance was 17 percent. The “schizophrenic” environment and being raised by a schizophrenic parent or step-parent also increases the likelihood of this illness manifesting in exposed children. (Rosenhan, D., and Seligman, M. [1995
], Abnormal Psychology
, 3d. Ed., Norton & Co, NY, p. 443). Finding an effective treatment could also decrease the prognosis of schizophrenia in children being raised by someone who suffers from this illness.
The symptoms of schizophrenia can be grouped into three separate categories. These are (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy and loss of verbal fluency (O'Donnell, P. O. and Grace, A. A. [1998], “Dysfunctions in multiple interrelated systems as the neurobiological bases of schizophrenic symptom clusters,”
Schizophrenia Bull
., 24(2):267-283). A long history of research has demonstrated the efficacy of D2 receptor antagonism in the alleviation of positive and disorganized symptoms (Gray, J. A. [1998], “Integrating schizophrenia,”
Schizophrenia Bull
., 24(2): 249-266). Persistence of negative symptoms often continues, even following neuroleptic treatment (Arndt, S. et al. [1995], “A longitudinal study of symptom dimensions in schizophrenia,”
Arch. Gen. Psychiatry
, 52:352-359). The stability of negative symptoms has been, by some, attributed to the neuroleptic medications themselves (Carpenter, W. T. [1997], “The risk of medication-free research,”
Schizophrenia Bull
., 23(1): 11-18).
Dysfunction of the limbic-cortical system may be implicated in all three types of symptoms. Reduced excitory glutamatergic inputs from the hippocampus and other limbic structures to the ventral striatum may be implicated in positive symptoms of psychosis and thought disorganization, and negative symptoms are likely to result from abnormal functioning of frontal lobe structures, e.g. those that receive connections from limbic structures, and/or anatomical irregularities. (Csernansky, J. G. and Bardgett, M. E. [1998], “Limbic-Cortical Neuronal Damage and the Pathophysiology of Schizophrenia,”
Schizophrenia Bull
. 24(2):231-248.)
Excess dopamine production is implicated in schizophrenia. The dopamine hypothesis of schizophrenia associates the disease with increased activity in dopaminergic neurons. Schizophrenic symptoms may be caused by an abnormal dopaminergic state brought about by a primary limbic-cortical lesion and deficits in glutamatergic inputs to the ventral striatum. (Csernansky, J. G. and Bardgett, M. E. [1998], supra.) Radiotracer studies have shown elevated D2 dopamine receptor levels in schizophrenic patients with increases in striatal dopamine receptors sometimes many times increased over normal values. (Seeman, P. et al. [1993], “Dopamine D2 receptors elevated in schizophrenia,”
Nature
, 365:441-445; Tune, L. E. et al. [1993], “Dopamine D2 Receptor Density Estimates in Schizophrenia: A Positron Emission Tomography Study with
11
C-N-Methylspiperone,”
Psychiatry Research
49:219-237.) Pharmacologically-invoked dopamine release is estimated to be 300% higher than normal levels. (Breier, A. et al. [1997], “Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentration: evidence from a novel positron emission tomography method,”
Proc. Nat'l Acad. Sci
., 94(6):2569-2574.) Dopamine projections from the substantia nigra modulate striatal neuronal activity via dopamine D1 and D2 receptors. (Egan et al. [1997], “Treatment of Tardive Dyskinesia,”
Schizophrenia Bull
. 23(4):583-609).
One of the strongest pieces of evidence for a dopamine disturbance in schizophrenia arises from the ability of D2 receptor antagonists to alleviate schizophrenic symptoms.
Effective antipsychotics acting on D2 receptors, including “typical” antipsychotics such as haloperidol and “atypical” antipsychotics such as clozapine, result in disruptions of the dopamine system. Long-term haloperidol treatment reduces the activity of dopamine cells in the substantia nigra. Clozapine reduces the activity of dopamine cells in mesolimbic/mesocortical cells in the ventral tegmental area that projects to the limbic system. (O'Donnell, P. and Grace, A. A. [1998], “Dysfunctions in Multiple Interrelated Systems as the Neurobiological Bases of Schizophrenic Symptom Clusters,”
Schizophrenia Bull
. 24(2):267-284.)
Past research has demonstrated a prominent role for dopamine and D2 receptors in the manifestation of psychosis, progression and complications of this disorder. More recent research has uncovered a multitude of abnormalities of the dopamine system itself and in its relation to other neurotransmitter systems in schizophrenia. A review of these studies will convey a general understanding of other more subtle symptoms involved in schizophrenia which manifest from excessive stimulation of other than D2 dopamine receptors.
The five distinct dopamine receptors have been clustered into two families: the D1-like dopamine receptors consist of the D1 and D5 receptors; and the D2-like dopamine receptors consist of the D2, D3 and D4 receptors, the latter having high affinities for a number of antipsychotic drugs. (Damask, S. P. et al. [1996], “Differential effects of clozapine and haloperidol on dopamine receptor mRNA expression in rat striatum and cortex,”
Molecular Brain Res
. 41:241-249.) D4 receptors have been found to be elevated in schizophrenia. (Seeman, P. et al. [1993], “Dopamine D4 receptors elevated in schizophrenia,”
Nature
365:441-445.) The “typical” antipsychotics that are highly effective in reducing hallucinations and delusions are selective antagonists of D2 receptors. The “atypical” antipsychotics, to which negative symptoms such as affective flattening, and lack of motivation respond, show affinity for both D1 and D2 receptors. (Swerdlow, Neal R. and Geyer, Mark A., “Using an Animal Model of Deficient Sensorimotor Gating to Study the Pathophysiology and New Treatments of Schizophrenia,” Schizophrenia Bulletin 24(2):285-301; Benes, F. M., “Model Generation and Testing to Probe Neural Circuitry in the Cingulate Cortex of Postmortem Schizophrenic Brain,”
Schizophrenia Bull
. 24(2):219-230.) The D
1
receptor is broadly distributed, while the D
5
receptor is restricted to expression in the hippocampus, thalamus and hypothalamus in the rodent. D
2
, D
3
and D
4
have high affinities for dopaminergic antagonist drugs. The D
2
receptor appears to be expressed in most dopaminoceptive regions of the brain including motor and limbic structures. The D
3
and D
4
receptors are enriched in subcortical limbic system components. (Damask, S. P. et al., “Differential expression in rat striatum and cortex,” [1996
] Molecular Brain Res
. 41:241-249.)
More recent studies have demonstrated the involvement of D1, D3 and D4 receptors as contributing to other symptoms of schizophrenia. For example, D1 recep
Fonda Kathleen K.
Greenlee Winner and Sullivan P.C.
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