Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1998-09-01
2002-08-27
Celsa, Bennett (Department: 1627)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S009100, C514S015800, C514S016700, C514S017400, C530S300000, C530S317000, C530S327000, C530S328000, C530S345000, C546S134000, C546S288000, C546S290000, C546S314000
Reexamination Certificate
active
06440933
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to peptide derivatives designed to deliver peptides having growth factor inhibitory activity into the retina by sequential metabolism. These peptide derivatives, which comprise a dihydropyridine
pyridinium salt-type redox targetor moiety, a bulky lipophilic function and an amino acid/dipeptide/tripeptide spacer, are of use in the prevention and treatment of diabetic retinopathy.
BACKGROUND OF THE INVENTION
The leading cause of blindness in adults between the ages of 20 and 74 years is diabetic retinopathy (DR). Seven million people in the United States have diabetes. Diabetic retinopathy will affect the vast majority during their lifetime, with 8,000 to 40,000 of these people becoming blind each year. While management of diabetic retinopathy has improved as a result of landmark clinical trials, risk of complications, such as loss of visual acuity, loss of night vision and loss of peripheral vision, remains significant and treatment sometimes fails. Currently, laser photocoagulation is the most effective form of therapy for advanced disease.
Diabetic retinopathy is characterized by aberrant neovascularization of the retinal vasculature with edema and breakdown in the blood-retinal barrier (BRB) that leads to hemorrhage, tissue damage and retinal scarring. Unfortunately, current treatment options are inadequate and the disease is often progressive even with successful glucose control. An increasing body of evidence indicates that growth factor inhibitors offer the potential to treat a probable cause of diabetic retinopathy by blocking key mediating steps in disease progression.
A. Diabetic Retinopathy and Growth Hormone Inhibitors
Diabetic retinopathy is recognized as a retinal vascular disorder that includes: (i) excess capillary permeability, (ii) vascular closure, and (iii) proliferation of new vessels. The disease is characterized by a loss of retinal capillary pericytes, thickening of the basement membrane, microaneurysms, dot-blot hemorrhages, and hard exudates. The more severe form of the disease is proliferative retinopathy with extensive neovascularization, vessel intrusion into the vitreous, bleeding and scarring around new vessels that leads to severe vision impairment. However, the mechanisms of disease progression remain incompletely understood.
A half century ago, Michaelson postulated that humoral factors stimulated neovascularization in response to anoxia in his studies of retinal disease and an increasing body of evidence indicates growth factors play a pivotal role in progression of diabetic retinopathy.
Evidence linking increased growth hormone (GH) and diabetic retinopathy is substantial. An important role for growth hormone in diabetic retinopathy was indicated 40 years ago when Poulsen described DR regression in a post-partum woman with spontaneous pituitary infarction and proposed hypophysectomy to treat the disease. Controlled clinical trials have shown pituitary ablation could improve diabetic retinopathy and therapeutic success was correlated with the magnitude of growth hormone decrease. Additional support for the growth hormone hypothesis includes: (i) the observation that retinopathy accelerates during puberty when tissue sensitivity to GH is increased; (ii) diabetic patients with hemochromatosis and infiltrative destruction of the pituitary have little eye disease; and (iii) GH-deficient dwarfs with diabetes have no evidence of either macro or microvascular disease. Even diabetics with adequate glucose control show excess GH profiles and diabetic retinopathy is correlated with the magnitude of growth hormone hypersecretion.
Recognition that insulin-like growth factor 1 (IGF-1) mediates most of the anabolic effects of growth hormone has implicated IGF-1 in diabetic vascular complications. Several clinical studies support a role for IGF-1 in development of retinal neovascularization. Merimee and colleagues found increased serum IGF-1 levels from patients with rapidly accelerating diabetic retinopathy. A subsequent prospective study showed that patients had elevated IGF-1 serum levels at the time new retinal vessels first appeared compared to their serum IGF-1 levels three months before the onset of retinal neovascularization. In a large population-based study of 928 diabetic patients, higher levels of IGF-1 were correlated with an increased frequency of proliferative retinopathy.
However, other studies have shown that circulating IGF-1 levels are inappropriately low in most insulin dependent diabetes mellitus (IDDM) patients given their higher-than-normal growth hormone levels. The major source of circulating IGF-1 is the liver, where GH in the presence of insulin triggers IGF-1 gene transcription. IDDM patients have a lower IGF-1 response to exogenous GH, indicating a form of growth hormone resistance. An explanation for clinical studies that showed low IGF-1 patterns in IDDM but high IGF-1 in severe diabetic retinopathy may involve portal insulin levels in IDDM patients. Sönksen et al. recently suggested that the lower portal insulin in IDDM subjects (compared to levels seen by the liver during pancreatic insulin secretion) is responsible for decreased circulating IGF-1 in response to GH stimulation. Thus, endocrine conditions in insulin dependent diabetes mellitus are ideal for excess IGF-1 formation in local tissues, since high circulating levels of GH and insulin (an obligatory consequence of insulin injections in IDDM patients and insulin resistance in NIDDM patients) are available to stimulate IGF-1 local production in peripheral tissues, including the retina. The dynamics between endocrine serum IGF-1 and paracrine tissue IGF-1 production in IDDM subjects is not understood.
Yet other recent studies by Grant support paracrine/autocrine regulation of IGF-1 in diabetic retinopathy. Vitreous levels of IGF-1 better reflect the local levels of growth factors seen in retinal tissue and were measured in 23 diabetic patients with proliferative diabetic retinopathy and compared with age-matched control values. A 3-fold increase was observed in the DR samples compared with controls. IGF-1 secretion was augmented by basic fibroblast growth factor (b-FGF) in cultured human retinal endothelial cells, supporting a paracrine role. Other investigators have shown that IGF- 1 receptors increase in retina from diabetic rats that are a model for IDDM.
IGF-1 appears to mediate retinal neovascularization. New vessel formation starts with basement membrane degradation followed by endothelial cell migration and proliferation. IGF-1 stimulates the release of tissue-type plasminogen activator (t-PA) from retinal endothelial cells derived from diabetic patients, but not from retinal endothelial cells derived from nondiabetic individuals. t-PA converts plasminogen to plasmin which can lyse thrombus as well as degrade most of the components of the extracellular matrix. Diabetic endothelial cells have a different response to growth factors. IGF-1 increases the expression of mRNA and protein for type IV collagenase in these same cells and acts synergistically with b-FGF on expression of both t-PA and type IV collagenase that are required for basement membrane degradation. IGF-1 receptors are present on retinal microvascular cells and these cells respond to IGF-1 with a five-fold increase in DNA synthesis. IGF-1 significantly promotes chemotaxis (migration) of human and bovine retinal endothelial cells and fetal bovine aorta endothelial cells in a dose-dependent manner. Thus, IGF-1 seems to act in concert with other growth factors in diabetic retinopathy.
Several studies indicate a role for b-FGF, endothelial growth factor (EGF) and transforming growth factor-&agr; (TGF-&agr;) in neovascularization. The precise functions of each of these factors in angiogenesis is yet to be elucidated. A common link may be response of the receptors upon binding these growth factors. IGF-1, insulin, b-FGF, platelet derived growth factor (PDGF), and EGF receptors belong to an expanded family of growth factor receptors, each sharing the common featur
Bodor Nicholas Stephen
Grant Maria Bartolomeo
Burns Doane Swecker & Mathis L.L.P.
Celsa Bennett
University of Florida
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