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Method of treating atherosclerosis or restenosis using microtube stabilizing agent

a technology of stabilizing agent and atherosclerosis, which is applied in the field of methods, can solve the problems of incalculable cost of human suffering and material resources, death and disability in the developed world, and afflicting the elderly, so as to and prevent or reduce the development of atherosclerosis or restenosis

Inactive Publication Date: 2006-05-11
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0018] In accordance with these and other objects of the present invention, method of preventing or reducing atherosclerosis or restenosis is provided, which comprises ta ent with a therapeutically effective amount of a microtubule stabilizing agent such as taxol or a water soluble taxol derivative. % A therapeutically effective amount of agent is an amount sufficient to prevent or reduce the development of atherosclerosis or restenosis.
[0019] This method provides an effective way of preventing or reducing the development of atherosclerosis or restenosis in those patients susceptible to such disease. Additionally, because of the low dose of chemotherapeutic agent used, the chance of a patient developing adverse reactions is potentially reduced.

Problems solved by technology

Vascular disease is the leading cause of death and disability in the developed world, particularly afflicting the elderly.
The cost of this disease in terms of human suffering and of material resources is almost incalculable.
Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to critical body organs, resulting in heart attack, stroke, and kidney failure.
Additionally, atherosclerosis causes major complications in those suffering from hypertension and diabetes, as well as tobacco smokers.
These VSMC become abnormally proliferative, secreting substances (growth factors, tissue-degradation enzymes and other proteins) which enable them to invade and spread into the inner vessel lining, blocking blood flow and making that vessel abnormally susceptible to being completely blocked by local blood clotting, resulting in the death of the tissue served by that artery.
The most effective way to prevent this disease is at the cellular level, as opposed to repeated revascularization surgery which can carry a significant risk of complications or death, consumes time and money, and is inconvenient to the patient.
Assembly under physiologic conditions requires guanosine triphosphate (GTP) and certain microtubule associated and organizing proteins as cofactors; on the other hand, high calcium and cold temperature cause depolymerization.
However, it is has been demonstrated that the incidence and severity of allergic reactions is affected by the dosage and rate of taxol infusion (Weiss, R. B., et al.
Additionally, it has been observed that the incidence of severe cardiac events is low in patients receiving taxol alone.
During angioplasty, intraarterial balloon catheter inflation results in deendothelialization, disruption of the internal elastic lamina, and injury to medial smooth muscle cells.
The art fails to suggest the use of a microtubule stabilizing agent such as taxol in preventing or reducing this disease.

Method used

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  • Method of treating atherosclerosis or restenosis using microtube stabilizing agent
  • Method of treating atherosclerosis or restenosis using microtube stabilizing agent
  • Method of treating atherosclerosis or restenosis using microtube stabilizing agent

Examples

Experimental program
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Effect test

example 1

[0034] The in vitro ability of cultured VSMCs, pretreated with different taxol concentrations, to invade filters coated with reconstituted basement membrane proteins was tested to evaluate how taxol-induced microtubule bundling would impair cell processes necessary for in vivo neointimal formation.

[0035] Vascular Smooth Muscle Cells (VSMCs) were isolated by collagenase / elastase enzymatic digestion of the medial layers of the rat aorta obtained from 6 month old Wistar rats. The cells were maintained in culture with 10% fetal calf serum, high glucose DMEM, and amino acid supplement. Cell cultures were maintained at 37° C. in 5% CO2.

[0036] After 18-hour taxol pre-treatment in culture, cells were fixed in 3.7% formalin, permeabilized with 1% Triton X-100, and polymered tubulin was labelled with mouse anti-6-tubulin antibody (SMI 62 monoclonal antibody to polymerized 6-tubulin, Paragon Biotec, Inc., Baltimore, Md.). Secondary labelling was achieved with silver-enhanced, 1 nm gold-conju...

example 2

[0041] To confirm the fact that microtubule stabilization and hyperpolymerization is the critical and sufficient factor involved in taxol-inhibition of VSMC invasiveness, the chemoinvasion (Boyden chamber) assay was run with deuterium oxide (2H2O, heavy water). Deuterium oxide enhances microtubule / tubulin polymerization via a mechanism distinct from that of taxol. A combination of the isotope and solvent effects of deuterium oxide reversibly increases microtubule polymerization both by reducing the critical concentration for polymerization for α6-tubulin heterodimers via enhanced tubulin hydrophobic interactions (Itoh, T. J., et al. (1984) Biochim. Biophys. Acta., 800:21-27), and by converting a population of unpolymerizable tubulin to the polymerizable form (Takahashi, T. C., et al. (1984) Cell Struct. Funct., 9:45-52).

[0042] VSMC's were isolated by collagense / elastase enzymatic digestion of the medial layers of the rat aorta obtained from 6 month old Wistar rats. The cells were m...

example 4

[0049] Incorporation of the thymidine analog, bromodeoxyuridine (BrDU) was measured to determine the effect of deuterium oxide on VSMC DNA synthesis. VSMCs were plated at 4.5×104 on 24-well plates. Following 20 hr incubation in 10% FCS+DMEM at various 2H2O concentrations, 10 μM BrDU was added and the incubation continued for an additional 4 hr. Cells were washed twice with phosphate-buffered saline (PBS) and fixed with 100% methanol (−20° C.) for 10 minutes. The cells were incubated for 2 hr with 1N HCl to denature the DNA, and subsequently washed 4 times in PBS. Mouse monoclonal BrDU antibody (Boehringer Mannheim) in 2% BSA-PBS was incubated with cells for 1 hr. After PBS wash, goat anti-mouse antibody conjugated with alkaline phosphatase was added. Cell nuclei containing BrDU substituted for thymidine stained red with alkaline phosphatase substrate, while all other nuclei stained blue. The fraction of BrDU-positive nuclei was compared between control (defined as 100%) and that of ...

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Abstract

The present invention is a method of preventing or reducing atherosclerosis or restenosis, and a pharmaceutical preparation used therefor. In particular, it is a method of preventing or reducing atherosclerosis or restenosis after arterial injury by treatment with a low dose of a microtubule stabilizing agent such as taxol or a water soluble taxol derivative. The low dose used in the present invention prevents artery blockage while minimizing any negative side effects associated with the drug.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a method of treating patients at risk of developing atherosclerosis or restenosis. [0002] More particularly, the invention relates to treatment of these patients with a low dose taxol solution to prevent or reduce the development of atherosclerosis or restenosis. BACKGROUND OF THE INVENTION [0003] Vascular disease is the leading cause of death and disability in the developed world, particularly afflicting the elderly. In the United States alone, despite recent encouraging declines, cardiovascular disease is still responsible for almost one million fatalities each year and more than one half of all deaths; almost 5 million persons afflicted with cardiovascular disease are hospitalized each year. The cost of this disease in terms of human suffering and of material resources is almost incalculable. [0004] Atherosclerosis is the most common form of vascular disease and leads to insufficient blood supply to critical body orga...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/337A61K9/00C07D305/14A61K31/335A61L31/16A61P9/00A61P9/10
CPCA61K9/0024A61K31/335A61K31/337A61L31/16A61L2300/416A61L2300/602Y10S514/824A61P9/00A61P9/10A61P9/12A61P3/10
Inventor KINSELLA, JAMES L.SOLLOTT, STEVEN J.
Owner UNITED STATES OF AMERICA
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