Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-11-15
2001-09-11
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C514S279000, C514S280000, C514S281000, C514S908000
Reexamination Certificate
active
06288074
ABSTRACT:
SPECIFICATION
This invention relates to the treatment of lymphoproliferative syndrome and is concerned specifically with treatment of this syndrome, including by such diseases as malignant lymphoma, chronic lymphocytic leukemia, Hodgkin's lymphoma, and non-Hodgkin's lymphoma, by administration of an essentially pure opiate receptor antagonist such as Naltrexone and Naloxone at a low level dosage.
BACKGROUND
The use of an essentially pure opiate receptor antagonist in the treatment of several diseases has already been disclosed in patents in which I am named as an inventor. In U.S. Pat. No. 4,888,346, issued Dec. 19, 1989, the treatment was for the acquired immune deficiency syndrome (or AIDS) in any of its known states, including AIDS-related complex. In U.S. Pat. No. 5,013,739, issued May 7, 1991, the disease treated was chronic fatigue syndrome while in U.S. Pat. No. 5,346,900, issued Oct. 18, 1994, the disease was chronic herpes virus infections. In the latter patent, examples of treatment of multiple sclerosis was also disclosed.
For the treatment of all these diseases, the amount of the essentially pure opiate receptor antagonist was required to be at a quite low level corresponding in results to those obtained by the administration of Naltrexone at a dosage level of from 1.0 mg. to 10 mg., preferably at a dosage level of 1.0 mg. to about 5 mg., and most preferably up to about 3.0 mg. At dosage levels above about 10 mg., not only were the desired therapeutic results not obtained but the effect of the treatment appeared to be negative in acerbating the disease.
I have now discovered that administration of an essentially pure opiate receptor antagonist gives desirable and beneficial therapeutic results in the treatment of a group of closely related malignancies known as lymphoproliferative syndrome, which includes malignant lymphoma, chronic lymphocytic leukemia, Hodgkin's disease (or Hodgkin's lymphoma), and non-Hodgkin's lymphoma. As the generic name suggests, these diseases are characterized by the multiplication or proliferation of tissue of the lymphatic system, especially lymphocytes (cells) produced in the lymph nodes. Lymphocytes are important components of the human immune response system and upon exposure to a foreign antigen in the human body naturally proliferate or multiply to combat the antigen. In this group of malignancies, the proliferation goes out of control, resulting in an abnormal level of lymphocytes in the blood stream, enlargement of the lymph nodes due to accumulation of the lymphocytes there, and other symptomatic characteristics.
In the past, these diseases were generally treated by radiology and chemotherapy often employing a combination of antineoplastic agents. I have discovered that the lymphoproliferative syndrome can respond to an entirely different therapeutic approach involving the administration of essentially pure opiate receptor antagonists at the same relatively low quantitative level that was found useful for the treatment of the disorders disclosed in the above-specified patents despite the totally different nature of the earlier diseases which did not involve any malignant behavior.
It is not possible to provide any coherent rationale for the therapeutic effectiveness of an essentially pure opiate receptor antagonist against the diseases falling within the lympholiferative syndrome. Indeed, any therapeutic activity of these antagonists for the lymphoproliferative syndrome would appear from general principles of immune action to be highly unlikely if not entirely out of the question. It is generally believed that the immunocompetent action of lymphocytes arises out of some surface structural feature, usually called “receptor”, that is capable in some way of “recognizing”, perhaps by “capture”, some structural feature of an invading foreign antigen. This “recognition” mechanism, whatever its nature, initiates the production of antibodies effective against the particular antigen. Even assuming that lymphocytes have receptors for opiates, it is quite puzzling that blocking of these receptors by an opiate antagonist would in some way interfere with whatever is the causative factor or factors in lymphatic cancers.
If an occurrence of the lymphoproliferative syndrome could be traced strongly to viral or bacterial action and if such action is assumed to involve receptor sites on lymphocytes, one could possibly theorize that an opiate receptor antagonist might be preferentially blocking such sites and preventing any connection with viral or bacterial particles. However, viral and bacterial sources are usually accepted as having a limited association with any disease of the lymphoproliferative syndrome and this theory thus could hardly apply to all of the diseases of this syndrome.
In any case, while such an association might explain how administration of an opiate receptor antagonist could reduce the likelihood of the original initiation of the malignancy, it would not explain how such administration could provide a therapeutic action after the malignancy has progressed to the point of treatment. It is true for lymphatic cancers as for all cancers that at the time diagnosis is possible, the cancer is necessarily at a well-developed, if not “advanced”, stage of development. Receptor site preclusion cannot therefore explain an interference with a malignant proliferation of the lymphocytes. This is particularly true since the presence of the opiate receptor antagonist does not appear to block normal proliferation of the lymphocytes in the system and their differentiation into B- and T-type cells as is essential to a viable immune function.
McLaughlin et al have disclosed in U.S. Pat. No. 4,689,332; among others, that opiate receptor antagonists. exemplified by Naltrexone and Naloxone, when administered to a variety of living organisms, including tissue and cells, can exert either a growth accelerating or a growth inhibiting effect dependent upon the length of time the opiate receptor sites of the organism are “completely and continuously” blocked or occupied by the antagonist. Specifically, a growth accelerating or promoting action occurs with blockage for a period of at least 12 hours per day, as can be achieved with a dosage of at least about 10 mg. and preferably about 20 mg. per day, whereas a growth inhibiting action occurs with blockage for only a period of about 2 to 12 hours per day, as can be achieved with a dosage of less than 10 mg. down to about 0.1 mg. per day.
The growth accelerating embodiment is said to be effective “to proliferation, migration, and differentiation of certain specific cells or tissue, including organ tissues, neural tissue, bone marrow, red blood cells, lymphocytes, liver cells, etc.” (See patent, col. 9, lines 15-25.) This disclosure, however, is silent as to whether these any of these same “cells or tissues” can be subject to the growth inhibiting embodiment, the focus of the inhibiting embodiment disclosure paralleling the above excerpt being on weight loss of the organism as a whole. (See col. 9, lines 32-45 and col. 10, lines 45-59.)
In addition, the growth inhibiting aspect is described as “related to the prevention, treatment and control of cancer” (see col. 10, line 60—col. 11, line 47), the essential disclosure in this connection being as follows; “The action of the compounds of the invention can be employed to terminate the rapid growth patterns of cancer and related abnormalities. It should be understood, that a regime of the present compounds cannot dissipate or reduce a tumor mass or other metastasized growth. These compounds can only terminate the growth of the abnormal cells and inhibit the continued growth thereof. However, by preventing tumor growth to continue [sic], i. e. reducing the tumor burden, the body's own defense mechanism, i. e. the immune system, has the opportunity to rid the body of the cancerous growth whether benign or malignant. This aspect of the invention is particularly significant in light of early diagnostic techniques which do redu
Daniel William J.
Delacroix-Muirheid C.
Jones Dwayne C.
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