Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-06-29
2004-04-27
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06727253
ABSTRACT:
The present invention relates to a method and medicament for pharmacological treatment of accidental extravasation of topoisomerase II poisons such as anthracyclines.
In particular, the invention relates to the systemic as well as the local administration of a topo II inhibitor such as the bisdioxopiperazine ICRF-187 in the treatment of accidental extravasation of a topoisomerase II poison such as the anthracyclines daunorubicin, doxorubicin, epirubicin, or idarubicin.
BACKGROUND OF THE INVENTION
Topoisomerase II, topoisomerase II poisons, and topoisomerase II catalytic Inhibitors
The topoisomerase II (topo II) enzymes belong to a system of nuclear enzymes involved in the processing of DNA during the cell cycles. In short, they are able to introduce transient cleavage of both strands of the DNA double helix, thereby allowing the passage of another intact DNA double strand through the cleavage. The cleavage time is very short. Drugs acting on topo II are divided into two main categories, topo II poisons and topo II catalytic inhibitors.
The topo II poisons shift the equilibrium of the catalytic cycle towards cleavage, thereby increasing the concentration of the transient protein-associated breaks in the genome (1) (see FIG.
1
). That is, they trap the cleavable complexes, which converts the essential topo II enzyme into a lethal one (2).
The topo II catalytic inhibitor is an entirely different group of drugs. They act by interfering with the overall catalytic function, which can be accomplished in at least two ways. One is the inhibition of the initial binding of topo II to DNA as in the case of chloroquine (3) and aclarubicin (4,5). The other is by locking topo II in its closed-clamp step after religation as appears to be the case for the ICRF-187 and its analogues (6-9).
Anthracyclines
The anthracyclines comprise a group of widely used cytotoxic compounds with activity in numerous malignant diseases.
Daunorubicin, the first anthracycline antibiotic to be discovered in the early 1960's, was isolated from streptomyces cultures. Soon hereafter, doxorubicin was extracted and investigated clinically. The two drugs have a wide range of activity against malignant diseases—daunorubicin primarily in the field of haematological malignancies and doxorubicin against solid tumors. Epirubicin is a stereoisomer of doxorubicin with the same indications as but slightly lesser potency and less cardiac toxicity than the parent drug. Idarubicin (4-demethoxydaunorubicin) resembles daunorubicin but lacks a methoxyl group at the C-4 position. It is more lipophilic than the other anthracycline compounds and penetrates the blood-brain barrier more readily.
The mechanism of action of these drugs is not well understood. The antitumor effect is explained by the ability to inhibit the nuclear enzyme DNA topo II. Thus, the anthracyclines are classified as topo II poisons. However, the drugs also interact with other enzymes, e.g. topo I, DNA- and RNA polymerases, and helicases. Furthermore, they are able to intercalate with DNA, a process that may initiate free radical damage. During the intracellular metabolism of the anthracycline, the anthraquinone nucleus is converted to a free radical semiquinone intermediate that might exert local DNA destruction. Moreover, the anthracyclines are capable of chelating iron and forming ternary complexes with DNA. However, the drug concentration required to induce free radical DNA damage is higher than the achievable clinical concentrations. Thus, this mechanism appears to be less important in regard to antitumor effect.
The most pronounced side effects of anthracycline therapy are cardiotoxicity (10,11), hematological toxicity, gastointestinal toxicity, and the extremely severe local toxicity following accidental extravasation (see below).
ICRF-187
The bisdioxopiperazine ICRF-187 (dexrazoxane) is the water-soluble (+) enantiomer of razoxane (ICRF-159). It is a highly specific topo II catalytic inhibitor. A hypothesis has been that ICRF-187, as an analogue of the cation binder EDTA, protects against free radical damage by binding and thus concealing iron from oxygen (12). However, we have recently demonstrated that cells with acquired resistance to ICRF-187 carry mutations in topo II (a subtype of topo II) which are in different sites than those induced by topo II poisons such as daunorubicin and etoposide. We confirmed that these mutations were functional using humanised topo II in yeast (13, 14). Accordingly, our assumptions were correct when we suggested that ICRF-187 was a specific topo II agent. We have demonstrated that it is possible to abolish the cell kill caused by etoposide, daunorubicin, and idarubicin at 2 different steps (See also
FIG. 2
) in the enzyme's catalytic cycle. Thus, intercalating drugs as chloroquine inhibit the enzyme from reaching its target (3,15,16) and the bisdioxopiperazine ICRF-187 locks the enzyme at a closed clamp step (4,17,18).
ICRF-187 is registrated as a cardioprotective agent (Zinecard®, Cardioxane®) against anthracycline induced cardiotoxicity.
Extravasation of Anthracyclines
Accidental extravasation has been estimated to occur in 0.6 to 6% of all patients receiving chemotherapy. Chemotherapeutic agents such as the anthracyclines which bind to DNA are especially prone to cause severe tissue damage on extravasation. The tissue injury may not appear for several days or even weeks and may continue to worsen for months, probably due to drug recycling into adjacent tissue. The local toxicity is characterized by acute pain, erythema, and swelling at the extravasation site and it often progresses to ulceration. Indeed, it has been demonstrated that the anthracyclines, e.g. doxorubicin, can persist in the tissue for at least a month (20). While small ulcerations may on occasion heal, large ulcerations require surgical excision for relief of pain and salvage of underlying tissue. An early surgical approach with extensive debridement of the involved area followed by skin grafting is therefore the treatment of choice (21).
During the last two decades a number of possible treatment modalities have been investigated.
Local cooling with ice lasting from 1 hour to 3 days or longer is a widely used treatment (22), that should be initiated immediately. The use of local injection or topical administration of corticosteroids as an anti-inflammatory treatment has produced contradictory results in animal and human studies (23). Inflammation does not seem to be a part of the pathophysiology and corticosteroids may even worsen the lesions. The effect of local sodium bicarbonate (24) has been investigated in experiments with varying results as have local sodium thiosulphate, hyaluronidase (25), and beta-adrenergics (agonists and antagonists) (26). Experimental treatment and clinical use of topical dimethyl sulfoxide (DMSO) for 2 to 7 days with or without &agr;-tocoferol (vitamin E) (27-29) has indicated beneficial effect in both animal and in uncontrolled clinical studies, at least of DMSO. The results are however not uniform. In one study intraperitoneal (IP) as well as topical treatment with &agr;-tocoferol,
Ginkgo biloba
extract, or pentoxifylline of intradermal (ID) doxorubicin in rats decreased the tissue level of malondialdehyde, thus suggestive of scavenge of free radicals (29). Bi(3,5-dimethyl-5-hydroxymethyl-2-oxomorpholin-3-yl) (DHM3) can react with doxorubicin in vitro to produce an inactive metabolite deoxy-doxorubicin aglycone, and intralesional treatment with DHM3 of ID doxorubicin extravasation in a swine has shown some benefit (30). No confirmative studies have though been published since 1988.
In the almost all animal studies anthracycline has been injected intradermally. It has been argued, that injections beneath the rodent skin muscle layer, panniculus carnosus, tend to cause irregular ulcerative lesions, whereas intradermal injection produces uniform skin necrosis and ulceration (32). However, ID injection of anthracyclines has also been the investigated methods in swine models.
Frozen-section fluorescence of dox
Jensen Peter B.
Langer Seppo W.
Sehested Maxwell
Antianthra APS
Cooper Iver P.
Spivack Phyllis G.
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