Continuous low-dose cytokine infusion therapy

Details Continuous low-dose cytokine infusion therapy Continuous low-dose cytokine infusion therapy

2002-03-22

2002-10-08

Kunz, Gary L. (Department: 1647)

Drug, bio-affecting and body treating compositions

Lymphokine

Interferon

C424S085100, C424S085400, C424S228100, C514S002600, C514S012200, C514S894000, C435S811000

Reexamination Certificate

active

06461605

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a method of treating medical conditions, in particular viral infections, that are susceptible to treatment with a cytokine comprising the continuous administration of a low dose of the cytokine. In a preferred embodiment of the invention, continuous low-dose infusion of interferon is used to treat chronic hepatitis C.
BACKGROUND OF THE INVENTION
Interferons are a family of naturally occurring small proteins and glycoproteins produced and secreted by most nucleated cells in response to viral infection as well as other antigenic stimuli. Interferons render cells resistant to viral infection and exhibit a wide variety of actions on cells. They exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events. In vitro studies demonstrated that these include the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.
Nonimmune interferons, which include both alpha and beta interferons, are known to suppress human immunodeficiency virus (HIV) in both acutely and chronically infected cells. Poli and Fauci, 1992
, AIDS Research and Human Retroviruses
8(2):191-197. Interferons, in particular, alpha interferons, have received considerable attention as therapeutic agents in the treatment of hepatitis C virus (HCV)-related disease due to their antiviral activity. Hoofnagle et al., in:
Viral Hepatitis
1981
International Symposium
, 1982, Philadelphia, Franklin Institute Press; Hoofnagle et al, 1986
, New Eng. J Med
. 315:1575-1578; Thomson, 1987
, Lancet
1:539-541 Kiyosawa et al., 1983, in: Zuckerman, ed.,
Viral Hepatitis and Liver Disease
, Allen K. Liss, New York pp. 895-897; Hoofnagle et al., 1985
, Sem. Liv. Dis.,
1985, 9:259-263.
Chronic hepatitis C is an insidious and slowly progressive disease having a significant impact on the quality of life. Despite improvement in the quality of the blood-donor pool and the recent implementation of testing of donated blood for HCV, the estimated incidence of acute infection among persons receiving transfusions is 5 to 10%. Alter et al., in: Zuckerman, ed.,
Viral Hepatitis and Liver Disease
, Allen K. Liss, New York, 1988, pp. 537-542. Thus, of the approximately 3 million persons who receive transfusions in the United States each year, acute hepatitis C will develop in about 150,000. While many patients who contract hepatitis C will have subclinical or mild disease, approximately 50% will progress to a chronic disease state characterized by fluctuating serum transaminase abnormalities and inflammatory lesions on liver biopsy. It is estimated that cirrhosis will develop in up to about 20% of this group. Koretz et al., 1985
, Gastroenterology
88:1251-1254.
Interferons are known to affect a variety of cellular functions, including DNA replication and RNA and protein synthesis, in both normal and abnormal cells. Thus, cytotoxic effects of interferon are not restricted to tumor or virus infected cells but are also manifested in normal, healthy cells as well. As a result, undesirable side effects arise during interferon therapy, particularly when high doses are required. Administration of interferon can lead to myelosuppression resulting in reduced red blood cell, white blood cell and platelet levels. Higher doses of interferon commonly give rise to flu-like symptoms (e.g., fever, fatigue, headaches and chills), gastrointestinal disorders (e.g., anorexia, nausea and diarrhea), dizziness and coughing.
Interferon alpha-2b has been shown to be safe and effective when administered subcutaneously at a dose of 3×1 Q6 international units (IU) three times a week for 24 weeks for the treatment of chronic hepatitis C. Causse et al., 1991
, Gastroenterology
101:497-502; Davis et al., 1989
, New Eng. J Med.
321:1501-1506; Marcellin et al., 1991
, Hepatology,
13(3):393-393. This amount and duration alleviates symptoms of hepatitis C and biochemical or histological evidence of ongoing inflammation of the liver in some patients but it also causes undesirable side effects, e.g., flu-like symptoms. While Carreno et al. (
Journal of Medical Virology
, 1992, 37:215-219) reported treatment of patients with chronic hepatitis C with a daily dose of 9×106 IU Roferon® A administered for 28 days by continuous subcutaneous infusion to patients with chronic hepatitis C, all twelve of the patients treated had flu-like symptoms and fever. During the first week of treatment 8 patients experienced headache and arthralgias. Eight patients had some hair loss, 9 patients suffered weight loss of between 2-5 kg, and 11 patients had decreases in platelet and leukocyte counts. While significant decreases in serum ALT levels were reported, HCV RNA remained positive during the treatment period.
Continuous infusion of interferon has also been used in the treatment of cancer patients. See Dorr et al., 1988
, Journal of Interferon Research
8:717-725, which reports continuous 28-day subcutaneous infusion of Roferon®A at doses of from 0.7×106 to 5.0×106 IU/in
2
body surface area and Ludwig et al., 1986
, Proc. Am. Soc. Clin. Oncol.
5:234, Abstr. 915, which reports continuous subcutaneous infusion of 3-18×106 IU/day of Roferon®A for periods of more than 3 months.
Undesirable side effects, such as those accompanying interferon therapy, also occur in treatment protocols employing other cytokines. Such side effects frequently limit the therapeutic usefulness of such agents. Thus, a need exists to reduce or eliminate the undesirable side effects of cytokine therapy without diminishing the therapeutic benefits of such therapy.
SUMMARY OF THE INVENTION
The present invention fulfills this need by providing a method of treating conditions that are susceptible of treatment with a cytokine, wherein undesirable side effects normally associated with such treatments are significantly diminished or eliminated entirely.
An object of the invention is to provide a method of treating a mammal afflicted with a condition that is susceptible to treatment with a cytokine comprising administering to a mammal in need of cytokine therapy a low-dosage amount of a cytokine by continuous infusion of the cytokine.
Another object of the invention is to treat viral infections comprising continuously administering a low dosage amount of a cytokine to a mammalian host infected with a virus susceptible to treatment by the cytokine.
Yet another object of the invention is directed to a method of treating chronic hepatitis C virus infection comprising continuously administering to a mammalian host infected with hepatitis C virus a low dosage amount of interferon, preferably alpha interferon, more preferably interferon alpha-2b.
DETAILED DESCRIPTION OF THE INVENTION
All references cited herein are incorporated in their entirety by reference. The invention is directed to a method of treating conditions that are susceptible of treatment with a cytokine. It has been unexpectedly discovered that continuous administration of low doses of cytokines over a prolonged period of time provides effective therapeutic benefits, while significantly diminishing the undesirable side effects normally associated with conventionally practiced cytokine treatment regimes.
Conditions that can be treated in accordance with the present invention are generally those that are susceptible to cytokine treatment. Cytokine-susceptible conditions include conditions which would respond positively or favorably as these terms are known in the medical arts to cytokine based therapy. For purposes of the invention, conditions that can be treated with cytokine therapy include those conditions in which treatment with a cytokine shows some efficacy, but which may not be treatable with the cytokine because the negative side e

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