WO1993008801A1

WO1993008801A1 - Prevention of drug-induced agranulocytosis with free radical scavengers

Info

Publication number: WO1993008801A1
Application number: PCT/US1992/009126
Authority: WO
Inventors: Ronald P. Mason
Original assignee: US Department of Health and Human Services; Government of the United States of America
Current assignee: US Department of Health and Human Services; Government of the United States of America
Priority date: 1991-10-31
Filing date: 1992-10-30
Publication date: 1993-05-13
Anticipated expiration: 1994-04-30
Also published as: AU2935292A

Abstract

A method is provided of preventing an occurence of granulocytopenia or agranulocytosis as a drug-induced side effect in a patient. The method entails co-administering to the patient (1) an active drug other than clozapine with which granulocytopenia or agranulocytosis is a possible side effect, and (2) an effective amount of a free radical scavenger for preventing the occurence of the side effect. Pharmaceutical preparations and kits containing the active drug and the free radical scavenger are also provided.

Description

PREVENTION OF DRUG-INDUCED AGRANULOCYTOSIS WITH FREE RADICAL SCAVENGERS

FIELD OF THE INVENTION

The present invention relates to novel pharma ceutical preparations and kits comprising (1) a effective amount of an active drug, except clozapine, having as a possible side effect thereof agranulocytosi or granulocytopenia when administered to a patient, an (2) a radical scavenger (preferably L-ascorbic acid o a derivative thereof) . Administration of the preparations to patients prevents the occurrence of the possibly fatal side-effects of agranulocytosis and granulocytopenia. The invention also relates to a method of preventing the drug-induced side effects of agranulocytosis and granulocytopenia.

BACKGROUND OF THE INVENTION

Agranulocytosis and granulocytopenia are acute conditions which are characterized by pronounced leukopenia with a great reduction in the number of poly- morphonuclear leukocytes. As a result of these conditions, infected ulcers are likely to develop in the throat, intestinal tract, and other mucous membranes, as well as in the skin. The conditions can result from, among other things, the administration of certain drugs, and in such instances, the conditions are referred to as being "drug-induced side effects". Such conditions can be fatal.

U.S. Patent application Serial Number 07/569,689, filed on August 20, 1990, discloses pharmaceutical preparations containing the antipsychotic active agent clozapine (i.e., 8-chlo-ro-ll-(4-methyl-l-piperizinyl)- 5H-dibenzo[b,e] [l,4]diazepine) and a free radical scavenger , preferably L-ascorbic acid. Clozapine is a drug which, upon administration to a patient, can cause the possible side effects of granulocytopenia and agranulocytosis.

SUMMARY OF THE INVENTION

In accordance with the present invention, it has now surprisingly been found that pharmaceutical preparations and kits that allow for the co-admini¬ stration of active drugs other than clozapine which have as a possible side effect thereof granulocytopenia or agranulocytosis when administered to a patient, and a free radical scavenger (e.g., L-ascorbic acid, or a derivative thereof) , exhibit particularly advantageous and unforeseen properties. Specifically, such pharma¬ ceutical preparations and kits allow those skilled in the art to administer such active drugs without en- countering the occurrence of granulocytopenia or agranulocytosis as a side effect. Co-administration may be achieved with a single pharmaceutical composition if so desired or with a pharmaceutical kit containing spacially separate components. Additionally, when desired, the pharmaceutical compositions and kits disclosed herein can be utilized in a method of preventing the occurrence of granulo¬ cytopenia or agranulocytosis in a patient on drug treatment with a drug other than clozapine having granulocytopenia or agranulocytosis as a possible drug- induced side effect thereof.

BRIEF DESCRIPTION OF THE DRAWING

The present invention will become more fully understood from the detailed description given here and below and the accompanying drawings which are given by way of illustration only, and thus, are not limitative of the present invention, and wherein:

Figure 1 - Oxygen consumption curves of 1.8 ml incubations containing 10 mM glutathione in 0.05 M phosphate buffer adjusted to pH 7.4; Five ug/ml of horseradish peroxidase (HRP, type VI) , 100 uM ranitidine and 0.7 mM sodium ascorbate were added at the points indicated;

Figure 2 - Oxygen consumption curves of 1.8 ml incubations containing 10 mM glutathione in 0.05 M phosphate buffer adjusted to pH 7.4; Five ug/ml of horseradish peroxidase (HRP, type VI) , 100 uM acetaminophen and 0.7 mM sodium ascorbate were added at the points indicated; and

Figure 3 - Oxygen consumption curves of 1.8 ml incubations containing 10 mM glutathione in 0.05 M phosphate buffer adjusted to pH 7.4; Five ug/ml of horseradish peroxidase (HRP, type VI) , 100 uM ritodrine and 0.7 mM sodium ascorbate were added at the points indicated.

DETAILED DESCRIPTION OF THE INVENTION

The following description is provided in order to aid those desiring to practice the present inventions. However, the same is not limiting to the inventions herein encompassed since, for example, those of ordinary skill in the art will readily recognize that other active drugs and/or free radical scavengers than those specifically mentioned herein, or excluded herein, may be utilized in the present inventive preparations, kits and methods, without departing from the spirit or scope of the inventors¹ discovery. Granulocytopenia is defined herein as a drop in the granulocyte count to less than 1500/mιrr in the blood; the term agranulocytosis is used when the granulocyte count drops below 500/mm . Granulocytopenia and agranulocytosis are described herein as drug-induced side effects since they are an established risk of treatment with many different types of drugs (for example, see Table I) . These side effects may result from immunogenic or cytotoxic factors, and many active drugs which are associated with such hemato- logical toxic side effects are oxidized to free radicals by myeloperoxidase released by activated neutrophils. Also, some immature cells in the bone marrow contain myeloperoxidase, and in some cases the hematological toxicity appears to involve destruction of the bone marrow, while in other cases the hematological toxicity appears to involve peripheral destruction of cells by antibodies.

The inventor hereof postulates that the drug- induced side effects of agranulocytosis and granulo¬ cytopenia are due to the formation of free radicals and/or free radical-derived reactive metabolites of active drugs, which are generated by activated neutrophils or other cells that contain myeloperoxidase. For example, such side effects could result from the active drug acting as a hapten which induces the synthesis of anti-neutrophil antibodies. Moreover, such antibodies may not only recognize neutrophils which have been modified by the active drug, but may also cross- react with normal neutrophils. In other cases, a free radical metabolite could cause direct toxicity to bone marrow, even though bone marrow destruction could also involve an immune mechanism.

While the inventor hereof has postulated that drug- induced side effects of agranulocytosis and granulocy¬ topenia are due to the formation of free radicals and/or free radical-derived active metabolites, this postulation is not to be construed as limiting to the present inventive discovery. In this respect, it is fully envisioned that so long as a pharmaceutical composition or kit contains an effective amount of an active drug which possesses the possibility of pro¬ ducing a side effect of agranulocytosis or granulo¬ cytopenia, and further contains an effective amount of a free radical scavenger for preventing the occurrence of such a side effect, then the a composition or kit is encompassed by the present invention. However, if the active drug in the composition or kit is clozapine, the same composition or kit is excluded from the present invention. Furthermore, when one uses a pharmaceutical composition or kit of the present invention, or an equivalent thereof, in a method of preventing the occurrence of agranulocytosis or granulocytopenia as a drug-induced side effect in a patient, the same method is encompassed by the present invention.

In order to evidence the efficacy of the present inventive methods, compositions and kits, the free radical nature of reactive intermediates which can lead to agranulocytosis was investigated by monitoring oxygen consumption using a Clarke oxygen electrode in incu¬ bations of drug (lOOμM) , horseradish peroxidase or myeloperoxidase (5 μg/ml) and glutathione (10 mM) in phosphate buffer (0.05 M, pH 7.4). Oxygen consumption in these incubations indicates formation of a reactive free radical metabolite of the drug tested (Table I) . These free radical metabolites are capable of oxidizing glutathione to a thiyl radical (known as "thiyl pumping") , which ultimately leads to the observed oxygen consumption forming superoxide, which can be observed by monitoring oxygen consumption. Oxygen consumption, i.e., free radical formation, was prevented in the presence of L-ascorbic acid at the physiological concentrations tested (0.7 mM) . The specific test method utilized to collect the data of Table I (and Figures 1-3) is similar to one dis¬ closed by Harman et al., J. Biol. Chem. , 261:1642-1648 (1986) ; and one disclosed by Subrahmanyam et al. , Chem.- Biol.Interactions. , 56:185-199 (1985). Both publi¬ cations are incorporated herein by reference in their entirety.

Table I. Drugs Known, or Suspected to Cause

Agranulocytosis and Peroxidase- Dependent Oxygen Uptake by Thiyl Radicals, which is Inhibited by L- Ascorbic Acid.

Druq-Tvpe & Drug

Tricyclic Antipsychotic Acetopromazine

Chlorpromazine

Fluphenazine

Prochlorperazine

Thioridazine Trifluoperazine

Triflupromazine Tricyclic Tranquilizer

Acepromazine

Promazine Tricyclic Antipruritic

Trimeprazine Antithyroid

Propylthiouracil

Methimazole Rheumatoid Arthritis

Penicillamine Antihypertensive

Captopril

Hydralazine Anticonvulsant

Phenytoin

Mephenytoin

Tri ethadione

Ethosuximide Antituberculous

Isoniazid Anti-Inflammatory

Phenylbutazone Antipyretic, analgesic Acetaminophen

Aminopyrine

Antipyrine Anti-Ulcer

Ranitidine Relaxant

Ritodrine 6-Blockers

Propanolol Calcium antagonists, ni and other vasodilators

Nifedipine

Dipyridamole

Cinepazide

Antiarrhythmic drugs

Procainamide + +

Apridine + +

Antimalarial Amodiaquin + +

Antineoplastic

Hydroxyurea + +

~ plus sign (+) indicates oxygen uptake by the drug occurred. ^ plus sign (+) indicates L-Ascrobic acid inhibited oxygen uptake by the drug.

In addition to the test results provided in Table I, it is noted that test results for the active drugs acetaminophen, ranitidine and ritodrine are also provided in Figures 1-3, respectively. In each of Figures 1-3, oxygen consumption was measured for 1.8 ml incubations containing 10 mM glutathione in .0.05 M phosphate buffer adjusted to pH 7.4, with an addition of 5 ug/ml of horseradish peroxidase (HRP; type VI) at the indicated time. In each Figure, it can be seen that oxygen consumption occurred with the introduction of the test drug and that thereafter, when ascorbate was added, oxygen consumption was inhibited.

Based upon the results obtained above, the present inventor provides a method for preventing the occurrence of drug-induced agranulocytosis or granulocytopenia. In the method provided, an effective amount of an active drug other than clozapine which can produce a drug- induced side effect of agranulocytosis or granulo- cytopenia is administered in conjunction with an effective amount of a free radical scavenger for preventing the occurrence of the stated side effects. Preferably, L-ascorbic acid, or a derivative thereof, is utilized in the method. Advantageously, the phar a- ceutical compositions disclosed herein may be utilized in the method. Similarly, the pharmaceutical kits dis¬ closed herein may be utilized in practicing the in¬ ventive method. Generally, in the method employed the free radical scavenger is administered in an amount from about 0.5g to about 20g, preferably about lg to 20g, and most preferably about lg to 3g. However, the exact amount of the free radical scavenger employed will be dependent upon the free radical scavenger chosen as well as the active drug co-administered therewith.

When utilizing the methods of the present invention, the active drug and free radical scavenger utilized may be co-administered to a patient in need thereof from about 1 to 4 times daily, and when co-ad- ministered will be effective in preventing the occurrence of the drug-induced side effects of agranulo¬ cytosis and granulocytopenia in a patient.

As noted previously, the present invention is also concerned with providing pharmaceutical compositions which are useful in the present inventive methods, as well as pharmaceutical kits which advantageously allow those skilled in the art to practice the present in¬ ventive methods. The following detailed description relates to these pharmaceutical compositions and pharmaceutical kits.

The exact daily dosage of the active drug and the free radical scavenger used in the methods, preparations and kits of the invention will depend upon, inter alia , the active drug and free radical scavenger employed, the mode of administration utilized and the condition to be treated.

Suitable indicated daily dosages of the free radical scavengers are in the range of from about 0.5 g to about 20 g, preferably 1 to 10 g, most preferably about 1 to 3 g. Such daily dose can be administered in a single dose or may be administered in multiple daily doses (e.g., two to four doses daily). The term "derivatives of L-ascorbic acid" as used herein means L-ascorbic acid salts, iso-ascorbic acid and iso-ascorbic acid derivatives (e.g., L-ascorbic acid

6-palmitate or the like) which are useful as free radical scavengers.

As a free radical scavenger, preferably L-ascorbic acid is used, and if desired, a pharmaceutically acceptable salt thereof may be used (e.g., a sodium salt) . Examples of preferred amounts of L-ascorbic acid in a single unit dosage form are from about 100 to 3,000 mg, preferably about 250 to 1,000 mg and most preferably about 300 mg to 600 mg.

Conveniently, the chosen active drug and-the chosen free radical scavenger are administered from 1 to 4 times a day.

The preparations of the invention include any appropriate form suitable for enteral administration, preferably oral administration. Preferred preparations in accordance with the invention are forms suitable for oral administration such as tablets, especially effervescent tablets, sachets or capsules.

Preferably the preparations of the invention constitute a unit dosage form, whereby each unit dosage will comprise a predetermined amount of an active drug and a free radical scavenger (preferably L-ascorbic acid or a derivative thereof) . The preparations of the invention may contain the active drug and the free radical scavenger in admixture with- suitable pharmaceutical diluents, carriers or other excipients suitably selected with respect to conventional pharmaceutical practice. For example, tablets, may contain, besides the.active agents, fillers, granulating agents, disintegrating agents, binding agents, lubricating agents, stabilizing agents, dyestuffs, sweetening and flavoring agents. The present invention also provides for pharma¬ ceutical kits comprising as spacially separate components the following:

Component (A) - which comprises an effective amount of a drug other than clozapine having the occurrence of granulocytopenia or agranulocytosis as a possible side effect thereof in a patient on drug treatment therewith, and a pharmaceutically acceptable carrier therefor; and

Component (B) - which comprises an effective amount of a free radical scavenger for preventing the occurrence of granulocytopenia or agranulocytosis as a drug-induced side effect in a patient having ad¬ ministered thereto component (A) , and a pharmaceutically acceptable carrier therefor. The free radical scavenger in component (B) of the kits provided herein is preferably L-ascorbic acid, or a derivative thereof, and the free radical scavenger is preferably present in an amount of from about 100 to 300 mg, more preferably about 250 to 1,000 mg, and most preferably about 300 to 600 mg.

The component (A) drugs which have granulocytopenia or agranulocytosis as side effects thereof when ad¬ ministered to a patient are exemplified by those set forth in Table I (above) . However, the use of other drugs having such side effects are also envisioned herein (except for the use of the active drug clozapine) .

Further to the above, exemplary of the pharma¬ ceutical kits encompassed hereby are a pack and a dispenser device adapted for the concomitant presentation and/or administration of the component (A) drug and the component (B) free radical scavenger, as separately arranged. Conveniently, the drug component (A) and the free radical scavenger component (B) are contained in the pack or dispenser device in separated unit dosage forms (e.g., oral dosage forms such as tablets, liquids or capsules) . Preferably, the pack or dispenser device bears directions for the concomitant administration of a pre-determined amount of the component (A) drug and the component (B) free radical scavenger. The directions may, for example, be printed directly on the pack or device.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims.

Claims

What is claimed is:

Claim 1. A pharmaceutical preparation comprising: an effective amount of an active drug other than clozapine having an occurrence of granulocytopenia or agranulocytosis as a possible drug-induced side effect thereof when administered to a patient, an effective amount of a free radical scavenger for preventing the occurrence of the drug-induced side effect, and a pharmaceutically acceptable carrier therefor.

Claim 2. A preparation according to claim 1, wherein the free radical scavenger is L-ascorbic acid, or a derivative thereof.

Claim 3. A preparation according to claim 2, wherein the L-ascorbic acid, or the derivative thereof, is present in an amount of from about 100 to 3,000 mg.

Claim 4. A preparation as recited in claim 2, wherein the active drug having granulocytopenia or agranulocytosis as a possible side effect thereof is selected from the group consisting of: acetopromazine, chlorpro azine, fluphenazine, prochlorperazine, thioridazine, trifluoperazine, triflupromazine, acepromazine, promazine, trimeprazine, propylthiouracil, methimazole, penicillamine, captopril, hydralazine, phenytoin, mephenytoin, trimethadione, ethosuximide, isoniazid, phenylbutazone, acetaminophen, aminopyrine, antipyrine, ranitidine, ritodrine, propanolol, nifedipine, dipyridamole, cinepazide, procainamide, apridine, amodiaquin, and hydroxyurea.

Claim 5. A preparation as recited in claim 4, wherein the free radical scavenger is L-ascorbic acid or a pharmaceutically acceptable salt thereof.

Claim 6. A preparation according to claim 1 in a form suitable for oral administration.

Claim 7. A preparation according to claim 6 in a tablet, capsule or liquid form.

Claim 8. A pharmaceutical kit containing the following spacially separate components which are de¬ signed to be conco itantly administered to a patient in need thereof:

Component (A) , which comprises an effective amount of an active drug other than clozapine having an occurrence of granulocytopenia or agranulocytosis as a possible drug-induced side effect thereof when ad¬ ministered to the patient, and a pharmaceutically acceptable carrier therefor; and

Component (B) , which comprises an effective amount of a free radical scavenger for preventing the occurrence of the drug-induced side effect of the active drug in component (A) , and a pharmaceutically acceptable carrier therefor.

Claim 9. A pharmaceutical kit as recited in claim

8, wherein the component (B) free radical scavenger is L-ascorbic acid, or a derivative thereof.

Claim 10. A pharmaceutical kit as recited in claim

9, wherein the L-ascorbic acid, or the derivative thereof, is present in an amount of from about 100 to 3,000 mg.

Claim 11. A pharmaceutical kit as recited in claim 8, wherein the component (A) active drug having the occurrence of granulocytopenia or agranulocytosis as a possible side effect thereof is selected from the group consisting of: acetopromazine, chlorpromazine, fluphenazine, prochlorperazine, thioridazine, trifluoperazine, triflupromazine, acepromazine, promazine, trimeprazine, propylthiouracil, methimazole, penicillamine, captopril, hydralazine, phenytoin, mephenytoin, trimethadione, ethosuximide, isoniazid, phenylbutazone, acetaminophen, aminopyrine, antipyrine, ranitidine, ritodrine, propanolol, nifedipine, dipyridamole, cinepazide, procainamide, apridine, amodiaquin, and hydroxyurea.

Claim 12. A pharmaceutical kit as recited in claim 11, wherein the free radical scavenger is L-ascorbic acid or a pharmaceutically acceptable salt thereof.

Claim 13. A pharmaceutical kit as recited in claim 8, wherein component (A) and component (B) are each in a form suitable for oral administration.

Claim 14. A pharmaceutical kit as recited in claim 13, wherein component (A) and component (B) are each in a tablet, capsule or liquid form.

Claim 15. A method of inhibiting an occurrence of granulocytopenia or agranulocytosis in a patient on drug treatment with an active drug other than clozapine having an occurrence of granulocytopenia or agranulo¬ cytosis as a possible drug-induced side effect thereof when administered to the patient, which method comprises co-administering to said patient (1) an effective amount of the active drug having granulocytopenia or agranulo¬ cytosis as a possible drug-induced side effect thereof and (2) an effective amount of a free radical scavenger for preventing the occurrence of the drug-induced side effect.

Claim 16. The method of claim 15, wherein the free radical scavenger is L-ascorbic acid, or a derivative thereof.

Claim 17. The method of claim 16, wherein the effective amount of the L-ascorbic acid, or a derivative thereof, is from about 100 to 1,000 mg.

Claim 18. The method of claim 14, wherein the active drug having granulocytopenia or agranulocytosis as a possible drug-induced side effect thereof is selected from the group consisting of: acetopromazine, chlorpromazine, fluphenazine, prochlorperazine, thioridazine, trifluoperazine, triflupromazine, acepromazine, promazine, trimeprazine, propylthiouracil, methimazole, penicillamine, captopril, hydralazine, phenytoin, mephenytoin, trimethadione, ethosuximide, isoniazid, phenylbutazone, acetaminophen, aminopyrine, antipyrine, ranitidine, ritodrine, propanolol, nifedipine, dipyridamole, cinepazide, procainamide, apridine, amodiaquin, and hydroxyurea.

Claim 19. The method of claim 18, wherein the free radical scavenger is L-ascorbic acid or pharmaceutically acceptable salt thereof.

Claim 20. The method of claim 19, wherein the free radical scavenger is administered to the patient in an amount of from about lOOmg to 3,000 mg, one to four times daily.