Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-20
2002-03-26
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S211110, C514S252020, C514S252140
Reexamination Certificate
active
06362176
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to treatment of rheumatoid arthritis through coadministration of pentostatin and methotrexate and analogs and derivatives thereof.
2. Description of Related Art
Rheumatoid arthritis (RA) is a systematic inflammatory condition that results in swelling, pain, loss of motion, and tenderness of target joints throughout the body. RA is characterized by chronically inflamed synovium that is densely crowded with lymphocytes. The synovial membrane, which is typically one cell layer thick, becomes intensely cellular and assumes a form similar to lymphoid tissue, thus including vessels, dendritic cells, T, B, and NK cells, macrophages, and clusters of plasma cells. Additionally, there is often a plethora of immunopathological mechanisms at work, including antigen-antibody complexes, polymorphonuclear neutrophils, inflammatory T cells, and activated macrophages. Eventually, these processes result in destruction of the integrity of the joint, resulting in deformity and permanent loss of function. A more detailed description of the etiology and physiology of RA can be found in Zvaifler, N., “Etiology and Pathogenesis of Rheumatoid Arthritis in Arthritis and Allied Conditions” 659-73 (ed. D. M. McCarty). This document, and all other documents or references, cited to herein are incorporated by reference as if reproduced completely herein.
Rheumatoid arthritis is a common disease affecting 1 to 2% of the world's population with a female to male predominance of 3-4:1. The peak incidence is in the third to fourth decade. Once acquired the disorder is chronic; therefore the prevalence of the disease increases as one examines increasing age groups. The disease is of unknown cause, although genetics may impact the risk of developing rheumatoid arthritis. Although it is not certain, some common infection or infections might trigger the autoimmune process in susceptible individuals. Environmental influences are not thought to play a major role in the development of the disease. Interestingly, exogenous estrogens in the form of BCPS appear to reduce the risk.
This disease is relentless and progressively destructive unless medical therapy is effective in reducing the degree of inflammation. While some individuals do well, most are significantly disabled by their disease and some are crippled. Surprisingly, the disease is responsible for a two-fold increased mortality and a 5-year reduction in the life expectancy of both males and females.
RA is classified as an autoimmune inflammatory disease. Autoimmune inflammatory diseases are conditions in which a body mounts an immune response to itself. Initiation of such diseases is not well understood, but involves both genetic predisposition and environmental factors. Such diseases are usually classified clinically in a variety of ways. For example, autoantibodies or self-reactive lymphocytes can be transferred to an otherwise healthy individual to see if the disease can be reproduced. Other ways to characterize autoimmune inflammatory diseases include establishment of animal models, family history, involvement of immune cells and antibodies, and responsiveness of the disease to immunosuppressive pharmaceuticals.
Autoimmune inflammatory diseases such as rheumatoid arthritis are difficult to treat primarily because their causative mechanisms are so difficult to understand. Autoimmune inflammatory diseases are multifactorial—a variety of events must occur before the disease symptoms become apparent. The interplay of these events is highly complex.
Accordingly, treatments for rheumatoid arthritis have been difficult to develop. Conventional therapeutic strategies have focused on monotherapies, i.e. administration of a single active compound to treat the disease. The most common monotherapies are based on a class of pharmaceuticals known as DMARDS—disease modifying anti-rheumatic drugs. These pharmaceuticals are generally administered over a period of time, and can, in some cases, provide temporary relief for patients suffering from RA.
Methotrexate is a common DMARD for rheumatoid arthritis. Approximately 70% of individuals with RA get some sort of favorable response, and over 50% are still on the drug five years after starting. Severity of disease does not determine the responsiveness of the patient although more severely affected individuals may have less complete responses. There is some controversy about how effective methotrexate is for the prevention of erosive and destructive changes as measured by radiographs, but it may ameliorate this aspect of the disease in addition to its effect on pain and improved function.
Once administered, the effects of methotrexate on articular swelling and tenderness may be seen as early as three to six weeks after administration. Methotrexate monotherapy has been shown, in limited circumstances, to maintain an initial clinical improvement for at least two years with continued therapy. Methotrexate is often administered parenterally with generally complete absorption. It is also known to be administered intramuscularly, with peak serum concentrations occurring in thirty to sixty minutes, or orally, in the form of tablets. When methotrexate monotherapy is discontinued, the RA usually worsens within three to six weeks.
However, a significant patient population is refractory to conventional DMARD monotherapy; they get only partial or no relief from administration of conventional DMARDS such as methotrexate. Additionally, many patients build up a tolerance to DMARDS, requiring increasingly stronger doses. This can create problems for such patients, because stronger doses can lead to increased incidences of undesirable side effects due to the DMARDS.
Recent studies of RA monotherapy illustrate these difficulties. For example, while about 70% of patients receiving methotrexate might be expected to obtain at least partial relief, less than 30% of the patients enter remission as defined by American College of Rheumatology (ACR) criteria. Up to 70% of the patients remain on methotrexate for two or more years.
The relative scarcity of effective therapies has motivated researchers to develop improved therapies. In one instance, researchers turned to 2′-deoxycoformycin, also referred to as pentostatin. A study done in England under Dr. Gabriel Panayi investigated pentostatin monotherapy. Dr. Panayi's group administered pentostatin to RA patients on a bi-weekly basis. Unfortunately, a significant flare (recurrence or exacerbation of disease symptoms) occurred in 9 of 11 patients at months 1 and 3 in terms of duration of morning stiffness and tender and swollen joints. The treatment was subsequently discontinued.
The inventor has noted similar but less dramatic results using pentostatin monotherapy on a monthly schedule. When the treatment was continued past the flare, approximately a third of the patients entered a pharmaceutical free remission for a period of weeks or months. However, this still does not represent a significant overall improvement from conventional DMARD therapy, and adds the concern of the flare to other treatment concerns. Consequently, the current pentostatin monotherapy regimen, while it does provide the clinician with another RA treatment option, does not represent a significant advance beyond current RA therapy.
There is therefore the need for improved compositions, methods and kits for treating rheumatoid arthritis beyond those currently available.
SUMMARY OF THE INVENTION
In one aspect, the invention relates to a method of treating rheumatoid arthritis comprising coadministering pentostatin and methotrexate to a host in need thereof. In another aspect, the invention relates to a composition comprising pentostatin and methotrexate. In yet another aspect, the invention relates to a kit comprising pentostatin and methotrexate.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the invention relates to a method of treating rheumatoid arthritis comprising coadministering pentostatin and methotrexate to a host in need there
Criares Theodore J.
Super Gen, Inc.
Weitz David J.
Wilson Sonsini Goodrich & Rosati
LandOfFree
Compositions, methods and kits for treating rheumatoid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compositions, methods and kits for treating rheumatoid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compositions, methods and kits for treating rheumatoid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2858525