Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 

 

 

Link:  Pharm/Biotech Resources


Title:  Method of treating leukopenia with adenosine

United States Patent:  6,911,435

Issued:  June 28, 2005

Inventors:  Cohn; Ilan (Herzlia, IL); Fishman; Pnina (Herzlia, IL)

Assignee:  Can-Fite Biopharma Ltd. (Petach Tikva, IL)

Appl. No.:  462202

Filed:  July 10, 1998

PCT Filed:  July 10, 1998

PCT NO:  PCT/IL98/00324

371 Date:  January 4, 2000

102(e) Date:  January 4, 2000

PCT PUB.NO.:  WO99/02143

PCT PUB. Date:  January 21, 1999

Abstract

Adenosine and active agent which interact with the adenosine system are used to treat conditions of weakened, immune system, as an anti-cancer therapy and for improving the therapeutic index of a variety of therapeutic drugs.

GENERAL DESCRIPTION OF THE INVENTION

The present invention concerns a novel use of adenosine and various agents, including other nucleosides, nucleoside derivatives, and agents that interact with the adenosine system, that include: agonists and antagonists of adenosine receptors, inhibitors or blockers of adenosine transporters, as well as inhibitors of enzymes involved in adenosine metabolism, e.g. adenosine kinase inhibitor and adenosine diaminase inhibitor.

In accordance with the present invention it was found that adenosine has an effect in inducing proliferation of bone marrow cells, resulting in increase in the number of leukocytes and particularly of neutrophils in the peripheral blood. It was furthermore found in accordance with the invention that adenosine has a protective effect against some toxic effect of chemotherapeutic drugs, particularly protection against reduction in count of leukocytes, particularly neutrophils, which is otherwise caused by the chemotherapeutic drug. In addition, it was found in accordance with the invention that adenosine potentiates the specific anti-tumor activity of chemotherapeutic drugs. Still further, it was found in accordance with the invention, that certain of the adenosine activities noted above can be modulated by various agents that interact with the adenosine system.

In in vivo studies in experimental animal it was shown that the overall effect of adenosine when administered together with a chemotherapeutic drug is to increase the therapeutic index, namely, reducing toxic side effects and improving specific activity. In the following, the term "increase in therapeutic index" will be used to denote either improvement in the therapeutic effect of a drug, namely increasing its efficacy on a specific target cell, or reducing non desired toxic side effects manifested on cells other than the target cells, or both.

In the following, the term "target cells" will be used to denote the target of said drug; the term "non-target cells" will be used to denote cells other than target cells on which the drug reserves a cytotoxic side effect.

The term "anti-cancer chemotherapeutic drug" will be used to denote a cytotoxic drug or a cocktail comprising a combination of two or more cytotoxic drugs given to an individual for the purpose of reducing the patient's tumor mass.

The term "agents that interact with the adenosine system" used above and which may be used further below, means to denote a variety of agents which interact with receptors, transporters or enzymes which regulate or mediate the adenosine interaction with cells. As known, extracellular adenosine can bind to a number of receptors on the cell membrane including, among others, the A1 and the A2 receptors. Furthermore, cell membranes typically contain nucleoside transporters which can transport adenosine (as well as other nucleosides) into and out of the cell. Furthermore, in the extracellular medium surrounding the cells, as well as within the cells, there are various enzymes which can metabolize adenosine. The effect of extracellularly applied adenosine on cells is a combination of these three different mechanisms, (namely binding to receptors, transport through nucleoside transporters and breakdown by enzymes). It was found in accordance with the invention that adenosine exerts its differential effect on bone marrow cells on the one hand and cancer cells on the other hand, through interaction via these mechanisms (different ones in each case) and use of agents which interact through these mechanisms may thus have similar effects to that of adenosine or an effect in modulating the adenosine activity. Agents that interact with the adenosine system include receptor agonists and antagonists, adenosine diaminase or adenosine kinase inhibitors, transport inhibitors, etc. In addition, as will no doubt be appreciated by the artisan, although the use of adenosine is preferred in accordance with the invention, other nucleosides, as well as nucleoside derivatives, may potentially be used to obtain qualitatively similar effects to that of adenosine. In the following, the invention will be described at times with particular reference to adenosine, it being understood that the invention is not limited thereto but rather applies also to all the other active ingredients mentioned above.

In addition, as will be explained further below, the invention has several different aspects. One aspect is concerned with the induction of proliferation of bone marrow cells. Another aspect is concerned with inhibition of proliferation of tumor cells. A third aspect is concerned with the increased efficacy of some drugs, notably chemotherapeutic drugs, on target cells, particularly cancer cells. A fourth aspect is concerned with increasing therapeutic index of certain drugs, notably chemotherapeutic and neuroleptic drugs, by either increasing their specific effect on the target cell, by reducing their toxic side effects in reducing blood leukocyte count, or both. While adenosine is useful, and indeed the preferred active agent in all such aspects of the invention, other active ingredients which may be contemplated in accordance with the invention may not be readily utilized in all aspects of the invention and may thus be chosen for use in connection with one or more specific aspects only. For example, an adenosine receptor antagonist may be used in the bone marrow proliferation inducing aspect of the invention, as it was found to have such an activity. Against this, the adenosine receptor antagonist was found to have an effect in neutralizing adenosine's inhibitory effect on proliferation of tumor cells, and accordingly may not be used in the tumor proliferation inhibition aspect of the invention.

Active ingredients other than adenosine for use in each of the invention's therapeutic aspects, may be chosen based on simple screening using in vitro proliferation assays.

Many drugs have cytotoxic side effects on a variety of cells, particularly metabolically active and dividing cells. These include hematopoietic cells such as bone marrow cells, leukocytes, particularly neutrophils, as well as fibroblasts, cells of the digestive tract, and others. In the following, a reduction in leukocyte count or neutrophil count by cytotoxic drugs, will be referred to herein, at times, as "drug-induced leukopenia" or "drug-induced neutropenia", respectively.

In the following, whenever mention is made to "leukopenia", it should be understood as referring particularly to "neutropenia" (drug-induced leukopenia is primarily manifested in reduction in the level of neutrophils).

Adenosine and some other of said active ingredients may be used in accordance with one aspect of the invention for inducing proliferation of bone marrow cells. This aspect of the invention is applicable in a variety of clinical situations, For example, adenosine and the other of said active ingredients may be used for treatment of patients having a disease or disorder caused by or associated with weakening of the immune system, e.g. in the case of inherited or acquired immune deficiency. Also certain autoimmune diseases are associated with an overall weakening of the immune system and said active ingredients may be used then as well. Another situation of a weakened immune system which may be treated in accordance with this aspect of the invention, is such which often occurs in advanced stages of cancer. This aspect of the invention is also useful in therapy in the case of leukopenia and particularly neutropenia occurring as a result of chemotherapeutic drug or neuroleptic drug administration. The effect of adenosine or the other of said active ingredients in countering drug-induced leukopenia, can be manifested by more limited reduction in the amount (or count) of the leukocytes, as compared to the count without adenosine, or at times even an increase in the amount of the cells, even to levels above control.

In accordance with an additional aspect of the invention, adenosine, and some of said active ingredients, are used to inhibit proliferation of tumor cells, within the framework of anti-cancer therapy.

Furthermore, in accordance with another aspect of the invention, adenosine and some of said active ingredients may also be used to increase efficacy of cytotoxic drugs towards certain target cells, particularly of anti-cancer chemotherapeutic drugs towards cancer cells. This increase in efficacy can be manifested by a more pronounced destruction of tumor cells at a given dose of the drug, or reduction in the required dose of the drug needed to achieve a certain therapeutic effect

By a further of its aspects, adenosine as well as some of said active ingredients other than adenosine, are used for improving the therapeutic index of certain therapeutic drugs, particularly improving the ratio between a specific therapeutic effect of the chemotherapeutic drug or neuroleptic drug on its respective target cell versus toxic side effects of these drugs manifested by leukopenia. In other words, the adenosine or some of the active ingredients other than the adenosine may give rise either to an increase in efficacy of a drug which may mean the ability to use a lower dose, to shorten the treatment period, etc., may give rise to reduction of the aforementioned toxic side effect, or both. The active ingredient in accordance with this aspect may be administered in combination with the therapeutic drug, e.g. may be included together in one pharmaceutical composition with said therapeutic drug.

The present invention provides, for each of the abovementioned aspects, a method of therapeutic treatment comprising administering an effective amount of the respective active ingredient to an individual in need. Still further provided for each of the aspects of the invention, is the use of the active ingredient for the purpose of preparing a pharmaceutical composition for the therapeutic treatments of diseases or conditions which are within the scope of the invention's various aspects, noted above. Furthermore, for each of these aspects, the present invention provides a pharmaceutical composition for use in the treatment of a variety of conditions, diseases or disorders, which are within the scope of the above aspects, the composition comprising an effective amount of said active ingredient.

The term "effective amount" used above and below should be understood as meaning an amount of adenosine or another of said active ingredients other than adenosine which is capable of achieving a desired therapeutic effect. The desired therapeutic effect depends on the type and mode of treatment When, for example, said active ingredient is administered to counter drug-induced leukopenia, an effective amount of the active ingredient may be an amount which protects the individual against the drug-induced reduction in the count of leukocytes, particularly neutrophils; an amount of the active ingredient which can give rise to an increase in an already decreased level of such cells, e.g. restore the level to a normal level or sometimes even above; etc. Where the active ingredient is administered in order to potentiate the effect of an anti-cancer chemotherapeutic drug, an effective amount may be an amount which either increases the cancer specific toxicity of the chemotherapeutic treatment; an amount which is effective in reducing the amount of the chemotherapeutic drug or drug combination required to achieve a desired effect of the chemotherapeutic drug or drug combination, i.e. reduction of the tumor load; etc. An example of an effective amount is a daily administration of adenosine of above about 10 μg./kg body weight, preferably at least about 25 μg/Kg body weight; and below about 50 mg/Kg body weight, preferably below about 10 mg/Kg body weight and most preferably below about 1 mg/Kg body weight. Typically, the amount of adenosine administered will be within the range of 30-100 μg/kg body weight. Such an amount of adenosine is typically administered in a single daily dose although at times a daily dose may be divided into several doses administered throughout the day or at times several daily doses may be combined into a single dose to be given to the patient once every several days, particularly if administered in a sustained release formulation.

By one embodiment of the invention, the composition, particularly where the active ingredient is adenosine, is an oral composition. Such a composition may be provided as a liquid, e.g. a syrup; it may be provided as powder or lyophilisate for mixing with a palatable liquid prior to administration; it may be provided in a dosage form, e.g. in the form of a capsule or a pill, etc.

By another embodiment, the composition is formulated for parenteral administration (intravenous, intramuscular, subcutaneous or intraperitoneal administration). A composition in accordance with this embodiment, may be provided as a liquid mixture ready for use, or may also be provided as a powder or lyophilisate for mixing with saline or any other physiological liquid prior to use.

In accordance with a further embodiment, the adenosine composition is provided as an inhalable composition in the form of a spray or aerosol.

In accordance with a still further embodiment, the composition is provided in the form of a patch for transdermal administration.

In the case of the aspects of the invention concerned with reducing toxic side effects or increasing therapeutic index of therapeutic drugs, the administration of said active ingredient may begin a period of time, several days, prior to treatment with the therapeutic drug, e.g. the chemotherapeutic drug or a neuroleptic drug, and may then be continued also throughout the period of administration of the drug. Such prior administration may provide an extra protective effect, for example against the drug-induced leukopenia

At times a pre-treatment with said active ingredient may be sufficient, and at other times said active ingredient may be administered once or several times during the period of administration of the therapeutic drug. During a period of combined administration of the active ingredient and the therapeutic drug, there may be a variety of possible combined administration regimes, for example, daily administration of both; daily administration of the therapeutic drug and several times daily administration of the active ingredient; a repeated cycle of administration comprising administering the therapeutic drug on one day and then the active ingredient on another day; etc.

According to an embodiment of the invention, the said active ingredient may be combined into a single composition with the other drug, and such a combined composition also forms an aspect of the invention.

Claim 1 of 15 Claims


1. A method of treating or preventing drug-induced leukopenia in an individual, comprising administering to the individual an effective amount of adenosine, wherein said effective amount is no more than 10 mg/kg body weight.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]