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WO1993008801A1 - Prevention de l'agranulocytose induite par des medicaments avec piegeurs de radicaux libres - Google Patents

Prevention de l'agranulocytose induite par des medicaments avec piegeurs de radicaux libres Download PDF

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Publication number
WO1993008801A1
WO1993008801A1 PCT/US1992/009126 US9209126W WO9308801A1 WO 1993008801 A1 WO1993008801 A1 WO 1993008801A1 US 9209126 W US9209126 W US 9209126W WO 9308801 A1 WO9308801 A1 WO 9308801A1
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WO
WIPO (PCT)
Prior art keywords
drug
free radical
radical scavenger
side effect
granulocytopenia
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1992/009126
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English (en)
Inventor
Ronald P. Mason
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Health and Human Services
Government of the United States of America
Original Assignee
US Department of Health and Human Services
Government of the United States of America
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by US Department of Health and Human Services, Government of the United States of America filed Critical US Department of Health and Human Services
Publication of WO1993008801A1 publication Critical patent/WO1993008801A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof

Definitions

  • 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.
  • Agranulocytosis and granulocytopenia are acute conditions which are characterized by pronounced leukopenia with a great reduction in the number of poly- morphonuclear leukocytes.
  • leukopenia 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.
  • Co-administration may be achieved with a single pharmaceutical composition if so desired or with a pharmaceutical kit containing spacially separate components.
  • 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.
  • FIG. 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;
  • HRP horseradish peroxidase
  • FIG. 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
  • HRP horseradish peroxidase
  • FIG. 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.
  • HRP horseradish peroxidase
  • Granulocytopenia is defined herein as a drop in the granulocyte count to less than 1500/m ⁇ rr 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.
  • 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.
  • active drugs which are generated by activated neutrophils or other cells that contain myeloperoxidase.
  • side effects could result from the active drug acting as a hapten which induces the synthesis of anti-neutrophil antibodies.
  • such antibodies may not only recognize neutrophils which have been modified by the active drug, but may also cross- react with normal neutrophils.
  • a free radical metabolite could cause direct toxicity to bone marrow, even though bone marrow destruction could also involve an immune mechanism.
  • 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.
  • 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 (lOO ⁇ M) , horseradish peroxidase or myeloperoxidase (5 ⁇ g/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) .
  • ⁇ plus sign (+) indicates oxygen uptake by the drug occurred.
  • ⁇ plus sign (+) indicates L-Ascrobic acid inhibited oxygen uptake by the drug.
  • test results for the active drugs acetaminophen, ranitidine and ritodrine are also provided in Figures 1-3, respectively.
  • 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.
  • HRP horseradish peroxidase
  • the present inventor provides a method for preventing the occurrence of drug-induced agranulocytosis or granulocytopenia.
  • 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.
  • a free radical scavenger for preventing the occurrence of the stated side effects.
  • L-ascorbic acid, or a derivative thereof is utilized in the method.
  • the phar a- ceutical compositions disclosed herein may be utilized in the method.
  • the pharmaceutical kits dis ⁇ closed herein may be utilized in practicing the in ⁇ ventive method.
  • 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.
  • 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.
  • 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.
  • 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
  • L-ascorbic acid 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) .
  • a pharmaceutically acceptable salt thereof e.g., a sodium salt
  • 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.
  • the chosen active drug and-the chosen free radical scavenger are administered from 1 to 4 times a day.
  • 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.
  • 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.
  • 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) .
  • the use of other drugs having such side effects are also envisioned herein (except for the use of the active drug clozapine) .
  • 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.
  • 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) .
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On décrit un procédé conçu pour prévenir l'apparition de la granulocytopénie ou de l'agranulocytose se manifestant comme un effet secondaire induit par un médicament chez un patient. Le procédé consiste à co-administrer au patient (1) un médicament autre que la clozapine avec lequel la granulocytopénie ou l'agranulocytose présente un effet secondaire possible, et (2) une quantité efficace d'un piégeur de radicaux libres afin de prévenir l'apparition de l'effet secondaire. On décrit également des préparations pharmaceutiques et des kits contenant le médicament actif et le piégeur de radicaux libres.
PCT/US1992/009126 1991-10-31 1992-10-30 Prevention de l'agranulocytose induite par des medicaments avec piegeurs de radicaux libres Ceased WO1993008801A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US78600491A 1991-10-31 1991-10-31
US786,004 1991-10-31

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WO1993008801A1 true WO1993008801A1 (fr) 1993-05-13

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150010651A1 (en) * 2009-03-25 2015-01-08 Keshav Malshe Compositions and methods for the treatment of wounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025686A2 (fr) * 1979-09-14 1981-03-25 Beecham Group Plc Composition pharmaceutique contenant du paracétamol, emballage comprenant la composition et procédé pour la réduction de l'effet toxique sur le foie des compositions de paracétamol
EP0164036A1 (fr) * 1984-05-26 1985-12-11 Nissan Chemical Industries Ltd. Composition pour accélérer la récupération de la fonction des organes hématopoiétiques et son application
WO1992003138A1 (fr) * 1990-08-20 1992-03-05 Sandoz Ltd Composes organiques ameliores

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0025686A2 (fr) * 1979-09-14 1981-03-25 Beecham Group Plc Composition pharmaceutique contenant du paracétamol, emballage comprenant la composition et procédé pour la réduction de l'effet toxique sur le foie des compositions de paracétamol
EP0164036A1 (fr) * 1984-05-26 1985-12-11 Nissan Chemical Industries Ltd. Composition pour accélérer la récupération de la fonction des organes hématopoiétiques et son application
WO1992003138A1 (fr) * 1990-08-20 1992-03-05 Sandoz Ltd Composes organiques ameliores

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CHEM. RES. TOXICOL. vol. 4, no. 2, March 1991, pages 218 - 222 J.P. UETRECHT ET AL. 'N-chlorination and oxidation of procainamide by myeloperoxidase: toxicological implications' *
DATABASE WPIL Section Ch, Week 8333, Derwent Publications Ltd., London, GB; Class B03, AN 83-739020 *
DATABASE WPIL Section Ch, Week 9201, Derwent Publications Ltd., London, GB; Class B03, AN 92-000191 *
INVEST. OPHTHALMOL. VISUAL SCI. vol. 25, no. 5, 1984, pages 573 - 580 M.P. MERVILLE 'In vitro cross-linking of bovine lens proteins photosensitized by promazines' *
J. BIOL. CHEM. vol. 265, no. 2, 15 January 1990, pages 844 - 847 D.N.R. RAO ET AL. 'Glutathione and ascorbate reduction of the acetaminophen radical formed by peroxidase' *
MOL. PHARMACOL. vol. 40, no. 5, November 1991, pages 848 - 853 V. FISCHER ET AL. 'Possible role of free radical formation in clozapine (clozaril)-induced agranulocytosis' *
SCAND. J. HAEMATOL. vol. 34, no. 1, 1985, pages 35 - 38 I. SZCZEPANNSKA ET AL. 'Amelioration of hydroxyurea-induced suppression of phagocytosis in human granulocytes by free radical scavengers' *
THERAPIE DER GEGENWART vol. 106, no. 9, 1967, pages 1083 - 1093 W. STICH ET AL. 'Die Therapie der Agranulozytose' *
YAKUGAKU ZASSHI vol. 111, no. 10, October 1991, pages 600 - 605 Y. MATSUKI ET AL. 'Effects of ascorbic acid on the free radical formations of isoniazid and its metabolites' *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150010651A1 (en) * 2009-03-25 2015-01-08 Keshav Malshe Compositions and methods for the treatment of wounds

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