Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-02-14
2003-07-15
Wortman, Donna (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C514S236200, C514S652000
Reexamination Certificate
active
06593094
ABSTRACT:
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not Applicable
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates generally to drug compositions that optimize or maximize the therapeutic effects of particular receptor-specific agonists, while concurrently preventing or, in the least, significantly ameliorating receptor desensitization, and which derive from the methodology of the inventor's U.S. Pat. No. 5,597,699. More particularly, the instant invention sets forth the methodological improvements, and compositions, that are derived from application of that patent's teachings. These improvements usher in classes of compositions that are pharmaceutically compensated (or fitted) to harmonize with physiologies of diverse therapy recipients.
2. Discussion of Relevant Art
An agonist is a substance/drug that has affinity for and stimulates physiologic activity at cell receptors that are normally stimulated by naturally occurring substances. As used throughout, an agonist is such a substance/drug that produces a maximal or a nearly maximal response, whereas an antagonist or inhibitor is a substance or molecule that produces no response, but can block the action of the drug-agonist. A partial agonist produces a moderate response and can also block the response of the receptor to the agonist-compound. A competitive antagonist is a substance that competes with the agonist for the receptor, but produces no response. [Note: Hereinafter, the combination of a specific agonist with a suitable antagonist or inhibitor will have one of the identifying forms of notation: agonist-antagonist or agonist/antagonist or antagonist: agonist; in such instances, the dash (-), slash (/) and semicolon (:) connoting the same.]
More than twenty years ago, the idea that beta-adrenergic antagonists could be used to treat heart failure was considered heretical although clinical data were emerging to support this viewpoint (White, D. C., Hata, J. A., Shah, A. S., Glower, D. D., Lefkowitz, R. J., and Koch, W. J., “Preservation of myocardial &bgr;-adrenergic receptor signaling delays the development of heart failure after myocardial infarction.”
PNAS,
97: 5428-5433 (2000) and references therein). Previously it was thought that failing hearts required positive inotropic support and that the use of beta-antagonists would depress heart function. After more than two decades, the conventional wisdom on this point has been overturned.
In heart failure, there is a biochemical alteration of the &bgr;-adrenergic receptor signaling system leading to the loss of cardiac inotropic reserve through &bgr;-adrenergic receptor desensitzation. It was demonstrated in a recent study (White, D. C., et al.) that observed desensitization and down-regulation of &bgr;-adrenergic receptors, seen in the failing heart, is deleterious for normal heart function (see 2 and references therein). In this study, paraphrasing what the authors wrote:
(1) In a rabbit model of heart failure induced by myocardial infarction, which recapitulates the biochemical &bgr;-adrenergic receptor abnormalities seen in human heart failure, delivery of the &bgr;-adrenergic receptor kinase ct transgene at the time of myocardial infarction prevents the rise in &bgr;-adrenergic receptor kinase 1 activity and expression and thereby maintains &bgr;-adrenergic receptor density and signaling at normal levels. Rather than leading to deleterious effects, cardiac function is improved, and the development of heart failure is delayed. These results appear to challenge the notion that dampening of &bgr;-adrenergic receptor signaling in the failing heart is protective, and they may lead to novel therapeutic strategies to treat heart disease via inhibition of &bgr;-adrenergic receptor kinase 1 and preservation of myocardial &bgr;-adrenergic receptor function.
(2) The most promising current therapies in heart failure is the use of &bgr;-adrenergic receptor antagonists, which presumably block the chronic activation of the &bgr;-adrenergic receptor system by norepinephrine. &bgr;-adrenergic receptor kinase 1 up-regulation could be the “first-response” feedback mechanism responding to the enhanced sympathetic nervous system activity because the expression of &bgr;-adrenergic receptor kinase 1 in the heart can be stimulated by catecholamine exposure. An opposing hypothesis, however, is that the increase in myocardial G protein-coupled receptor kinase (GRK) activity often observed in the failing heart can mediate changes within the &bgr;-adrenergic receptor system that are not protective but that rather take part in the pathogenesis of heart failure. If such is the case, then the inhibition of &bgr;-adrenergic receptor kinase 1 might represent a novel therapeutic target in the treatment of the failing heart.
(3) To address specifically the issue of whether &bgr;-adrenergic receptor desensitization might have maladaptive rather than adaptive consequences in the setting of heart failure, we have delivered a peptide inhibitor of &bgr;-adrenergic receptor kinase 1 activity via in vivo intracoronary adenoviral-mediated gene delivery to the hearts of rabbits that have a surgically induced myocardial infarction (MI). We have shown previously that this model of MI in rabbits results in overt heart failure within 3 weeks, including pleural effusions, ascites, and significant hemodynamic dysfunction.
(4) The conventional view of the role of sympathetic activation in heart failure is that the resultant elevated myocardial &bgr;-adrenergic receptor kinase 1 levels and &bgr;-adrenergic receptor desensitization in the dysfunctional heart are actually protective mechanisms. Abrogation of such compensatory mechanisms, it has been reasoned, would only worsen the physiologic deterioration caused by excess catecholamine stimulation. Indeed, the chronic use of &bgr;-agonists in heart failure is harmful.
(5) First, administration of an oral &bgr;-agonist leads to further &bgr;-adrenergic receptor down-regulation in the lymphocytes of patients with heart failure. Additionally, the &bgr;-adrenergic receptor kinase 1 expression is increased after &bgr;-adrenergic receptor stimulation. Therefore, the use of &bgr;-agonists in heart failure patients exacerbates disturbances in the myocardial &bgr;-adrenergic receptor system, leading to further receptor down-regulation and increases in &bgr;-adrenergic receptor kinase 1. In contrast, restoration of &bgr;-adrenergic receptor signaling through gene delivery of the &bgr;-adrenergic receptor kinase ct has a fundamentally opposite effect at a molecular level, i.e., it preserves the number of &bgr;-adrenergic receptors and inhibits &bgr;-adrenergic receptor kinase 1. [end paraphrasing]
It is interesting that &bgr;-adrenergic receptor kinase 1 inhibition shares with &bgr;-blockade the potential to normalize or remodel signaling through the cardiac &bgr;-adrenergic receptor system in heart failure. Moreover, both treatments lower cardiac GRK activity, enhance catecholamine sensitivity, and raise or preserve myocardial levels of &bgr;-adrenergic receptors (White, et al. and included references). Thus, it is possible that part of the salutary effects of &bgr;-blockers on the failing heart is because of their demonstrated ability to reduce expression of &bgr;-adrenergic receptor kinase 1 in the heart. With the overwhelming positive data showing the beneficial effects of &bgr;-blockers in the treatment of heart failure, it is reasonable to question whether the strategy of adding a &bgr;-adrenergic receptor kinase 1 inhibitor adds anything novel to the therapeutic armamentarium. However, given the results of this study, it is apparent that &bgr;-antagonist therapy and &bgr;-adrenergic receptor kinase 1 inhibition may in fact be complementary therapeutic modalities. [See SUMMARY OF THE INVENTION]
Present theories of receptor activation calculate the response of a receptor as some function of an agonist-receptor complex. There have been several modifications and criticisms of receptor theory (se
Morelle Fredric
Wortman Donna
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