Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-19
2003-02-25
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S269000, C514S866000, C514S908000, C514S922000
Reexamination Certificate
active
06525089
ABSTRACT:
This application is a 35 USC §371 filing of PCT/KR99/00632, filed Oct. 21, 1999 and claims priority from KR 1998-44339 and KR 1998-44340, both filed Oct. 22, 1998. The entire disclosures of the earlier applications are incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to a pharmaceutical composition containing decursin and its pharmaceutically acceptable carrier.
BACKGROUND ART
As a great number of the pharmaceutical compositions used in the prevention or treatment of various diseases have a variety of toxicities including nephrotoxicity (i.e., toxicity on the kidney), due care should be exercised in their clinical use. In particular, when using antineoplastic or antibiotic composition, since its side effect such as nephrotoxicity is very serious, its clinical use has been extremely restricted. For example, cisplatin is an antineoplastic agent used in the treatment of various tumors of the testis, esophagus, stomach, bladder, prostate, lung, neck of uterus and osteosarcoma, notably of genital tumors. However, its serious toxicities on the kidney, ears, gastro-intestine and bone marrow have been reported including allergies. Among these, nephrotoxicity becomes so severe as to lead renal failure with high dose of cisplatin for a long-term period, and thus clinical use of cisplatin has been extensively restricted. Under this situation, it is clinically important to reduce the toxicity of cisplatin on the bone marrow, gastrointestinal tract, and particularly on the kidney in the treatment of various cancers using cisplatin.
Intensive researches have been focused on the alleviation of nephrotoxicity associated with the use of cisplatin. The conventional methods designed to reduce the nephrotoxicity are as follows: One is to synthesize platinum derivatives less toxic than cisplatin; one example being carboplatin. However, its toxicity on the bone marrow is very severe even though its nephrotoxicity is less than cisplatin. Another is to facilitate the excretion of drug for reducing the toxicity. To this end, mannitol or hypertonic saline solution is concurrently used. However, this method may shorten the half-life of cisplatin, resulting in decreasing the antineoplastic effect. A third is to administer an antineoplastic agent together with antidotes via a two-route chemotherapy (TRC) so as to reduce the toxicities of cisplatin. To this end, bismuthsubnitrate or selenium is concurrently used. Ho,A/ever, this method may cause some adverse effect such as accumulation of heavy metals in the body.
In the meantime, all of the normal cells in the human body are formed by proliferation to a certain extent and a subsequent differentiation as an indispensable process. It is believed that such proliferation and differentiation process are controlled at the genetic level. Unlike the normal cells, however, cancer cells consist of immature cells that freely proliferate without any differentiation, despite the fact that the cells are derived from normal tissue. As a result, cancer cells differ from normal cells in terms of metabolism, enzyme patterns and surface structure of cells (Raymond W. Ruddon, Cancer: A disease of abnormal differentiation, Cancer Biology, 2nd edition: 69, 1987).
The development mechanism of such undifferentiated cancer cells has yet to be reported. However, the main debate on the development of cancer cells has been centered on whether the differentiation-completed adult cells are dedifferentiated or the undifferentiated cells lose their differentiation capacity. According to the report up to the present, the transformation into cancel cells occurs only in the normal cells capable of proliferation; while the differentiation of cells in which its short-term fate to a certain path way is already programmed is irreversible, the terminal differentiation itself is reversible (D. Yaffe, Cellular aspects of muscle differentiation in vitro. Current Topics in Developmental Biology, 4:39, 1969).
Pierce et al. reported that normal tissue stem cells with renewal capacity are origins of malignant tumor (G. B. Pierce, Differentiation of normal and malignant cells, Fed. Proc.29: 1248, 1970). The stem cells coincide with the cancer cells in that they are products of undifferentiated cells with sustained proliferation capacity. However, recent studies revealed that the abnormality in cancer cell is not completely irreversible. The conventional method that is frequently applied to leukemia, hepatocyte and fibroblast cells, is to induce differentiation of cancer cells into the normal cells or their similar cells by way of differentiation induction agent (Alphonse Krystosek and Leo Sachs, Control of lysozyme induction in the differentiation of myeloid leukemia cells, Cell, 9:675:684, 1976; Shinichi Murao, M. Anne Gemmell, Michael F. Callaham, N. Leigh Anderson and Eliezer Huberman, Control of macrophage cell differentiation in human promyelocytic U-937 leukemia cells by 1,25-dihydroxy vitamin D3 and phorbol-12 myristate-13-acetate, Cancer Research, 43:4989-4996, 1983). Unlike the conventional antineoplastic agents based on the cytotoxic mechanism, this method is significant in that it is designed to treat the neoplastic tumors via new pathway. Moreover, some of the conventional antineoplastic agents are reported to have differentiation induction function at a concentration lower than cytotoxic concentration, which is very stimulating in that side effect of the antineoplastic agent can be alleviated by using at a very low concentration.
In fact, active vitamin A, which is known as a differentiation induction agent, is clinically employed to the treatment of acute promyelocytic leukemia (APL) where the combined therapy of multi-drug using daunomycin has been mainly conducted hitherto. According to the Journal of American Blood Association published on November 1988, it is reported that when a large dose of retinoic acid was administered to 22 APL patients, 96% of them were in complete remission. Thereafter, this method was adopted in many medical institutions in the United States, France, Japan, etc., and achieved an average remission rate of more than 80% with an average remission time of 29 days. In addition, there showed side effects including skin dryness and gastric disturbance, but their severity was milder than other antineoplastic agents. Thus, it can be said that the differentiation induction agent has been significantly recognized as a beneficial antineoplastic agent from the worldwide medical arena.
The therapeutic mode of action in conventional antineoplastic agents is related to the cytotoxicity to kill the rapid growing cancer cells via inhibition of DNA replication, reduction of intracellular metabolism and biosynthesis or generation of free radicals. Therefore, a very high dose of the agent has been required. In this case, adverse effects are expected in various organs where cell proliferation is fairly rapid such as bone marrow, as well as in the organs where the agent is metabolized and excreted such as gastrointestinal tract, liver, kidney and cardiovascular tissues. In fact, administration of such antineoplastic agent is much limited due to such severe side effects. Accordingly, there has been a strong need for the development of a novel antineoplastic agent with less toxicity, i.e., the agent with cancer-cell differentiation induction function.
Decursin is a natural product that was firstly isolated from
Angelica decursiva
(Fr. et Sav.) in Japan in 1966. It was reported in 1967 and 1969 that
Angelica gigas
Nakai contains a large amount of decursin (J. Pharm. Soc. Korea, 11: 22-26, 1967 and 13: 47-50, 1969). In addition, decursin was also isolated from the fruit of
Peucedanum terebinthaceum
(Fisher et Turcz) (Korea Pharmacology Journal 30(2): 73-78, 1986). As for the pharmacological effect of decursin, the present inventors discovered in 1993 that decursin has toxicity on various cell lines of uterine cancer, leukemia, hepatoma or large intestine cancer at concentration of more than 10 ppm (See Korean Patent Application No. 93-17935).
Discl
Ahn Kyung Seop
Chong Se Young
Kim Ik Hwan
Kim Sang Ki
Binex Co., Ltd.
Clement, Esq. Candice J.
Heslin Rothenberg Farley & & Mesiti P.C.
Krass Frederick
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