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WO1996004012A1 - Utilisation de la chlorpromazine en combinaison avec l'interleukine-6 pour le traitement ou la prevention du choc septique - Google Patents

Utilisation de la chlorpromazine en combinaison avec l'interleukine-6 pour le traitement ou la prevention du choc septique Download PDF

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Publication number
WO1996004012A1
WO1996004012A1 PCT/US1995/009496 US9509496W WO9604012A1 WO 1996004012 A1 WO1996004012 A1 WO 1996004012A1 US 9509496 W US9509496 W US 9509496W WO 9604012 A1 WO9604012 A1 WO 9604012A1
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Prior art keywords
chlorpromazine
septic shock
combination
administered
body weight
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Application number
PCT/US1995/009496
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English (en)
Inventor
Beverly Barton
James V. Jackson
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Schering Corporation
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 Schering Corporation filed Critical Schering Corporation
Priority to AU32023/95A priority Critical patent/AU3202395A/en
Publication of WO1996004012A1 publication Critical patent/WO1996004012A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/204—IL-6

Definitions

  • This invention relates to methods for treating or preventing septic shock in mammals by administering a combination of chlorpromazine and Interleukin-6.
  • Septic shock is an often fatal condition usually resulting from gram-negative bacteremia.
  • gram-negative bacteremia Despite the use of potent antibiotics and intensive care, there is still a high mortality rate for sepsis as well as for cases of gram- negative bacteremia which result in septic shock (See, e.g., Ziegler et al.. New Eng. J. Med. 524:429 (1991); Bone et al.. New Eng. J. Med. 317:653 (1987); and Kreger et al.. Am. J. Med 65:344 (1980)).
  • Approximately 100,000-300,000 cases of sepsis-causing gram-negative bacteremia are reported per year, with the resulting deaths estimated at 30,000 to 100,000 (Wolff, New Eng. J. Med. 324:486 (1991)).
  • Sepsis requires prompt treatment,, since the patient's condition often deteriorates rapidly. It is a leading cause of morbidity and mortality among hospitalized
  • septic shock include fever or hypothermia, tachycardia, tachypnea, hypotension, peripheral hypoperfusion or systemic toxicity. (Ziegler et al., supra).
  • This invention fills the foregoing need by providing a method for treating septic shock in a mammal comprising administering an effective amount of a combination of chlorpromazine and Interleukin-6 (IL-6) to a mammal afflicted with septic shock.
  • This invention also provides a method for preventing septic shock in a mammal which comprises administering an effective amount of a combination of chlorpromazine and IL-6 to a mammal susceptible to or at high risk for developing septic shock.
  • a pharmaceutical composition comprising a combination of chlorpromazine and IL-6, and a physiologically acceptable carrier, is also provided by this invention.
  • septic shock as used herein is defined as a state of morbidity manifesting one or more of the following symptoms: fever or hypothermia; tachycardia; elevated serum TNF; tachypnea; and either hypotension or two of the following six signs of systemic toxicity or peripheral hypoperfusion: 1) unexplained metabolic acidosis; 2) arterial hypoxemia; 3) acute renal failure; 4) elevated prothrombin or partial thromboplastin time or reduction of the platelet count; 5) sudden decrease in mental acuity; or 6) cardiac index of more than 4 liters per minute per square meter of body-surface area. (See Ziegler et al., supra).
  • Zeigler et al. have further defined the above criteria as follows: fever or hypothermia where temperature is above 38.7 * C (101" F) or below 35.6 * C (96 * F); tachycardia where heart rate is above 90 beats per minute in the absence of a beta-blockade, tachypnea where respiratory rate is above 20 breaths per minute or there is requirement of mechanical ventilation; hypotension where systolic blood pressure is below 90 mm Hg or a sustained drop in systolic pressure is above 40 mm Hg in the presence of adequate fluid challenge and the absence of anti -hypertensive agents; unexplained metabolic acidosis where blood pH is below 7.3, a base deficit of greater than 5 mmol per liter, or an elevated plasma lactate level; arterial hypoxemia, where partial pressure of oxygen is below 75 mm Hg or ratio of the partial pressure of oxygen to the fraction of inspired oxygen is less than 250; acute renal failure where urinary output is less than 0.5 ml per kilogram of body
  • the symptoms listed above are illustrative of specific selection criteria to be used in determining candidates for the proposed method of treatment.
  • States of morbidity which can cause the foregoing symptoms include but are not limited to: acute gram-negative bacteria infections, endotoxemia, purpura fulminans, severe psoriasis, acute rheumatoid arthritis, burns, organ transplant rejection, and physical traumas, such as abdominal wounds.
  • Candidates for abdominal surgery are at high risk for developing septic shock (Debets et al., Crit Care Med. 77(6):489 (1989)) and could benefit from prophylactic administration of the combination of chlorpromazine and IL-6.
  • the effectiveness of treatment can be assessed by monitoring the above-mentioned manifestations of septic shock.
  • Chlorpromazine is a phenothiazine that was first developed as an antipsychotic drug. Chlorpromazine is known to act as a calcium antagonist and to inhibit phospholipase A2. At present it is prescribed as a tranquilizer and/or an antiemetic. Gadina et al., (J. Exp. Med 173:1350 (1991)) have reported that chorpromazine protects mice and guinea pigs from the lethality of LPS in endotoxic shock models.
  • Chlorpromazine can be administered orally, in tablet or liquid form, or parenterally from a reconstituted solublilized formulation. Both oral and injectible formulations are commerically available from SmithKline Beecham,
  • IL-6 also known as B cell stimulatory factor 2, IFN- ⁇ 2 , hybridoma/plasmacytoma growth factor, and hepatocyte stimulatory factor
  • CLP Chlorpromazine
  • IL-6 is a 26-kDa multifunctional cytokine.
  • Some of the known effects of IL-6 include: induction of terminal differentiation in B cells, stimulation of the proliferation of T cells and thymocytes, induction of acute phase protein synthesis by hepatocytes, and stimulation of proliferation of various hematopoietic stem cells (Aderka et al., J. Immunol. 745:3517 (1989)).
  • International Publication WO 93/11793 discloses a combination treatment for septic shock using anti- TNF antibodies plus IL-6.
  • IL-6 derived from various species of origin, including human IL-6, are commercially available, e.g., from Genzyme Corporation, Cambridge, MA.
  • IL-6 can also be prepared by known methods using natural sources or recombinant DNA methodologies. (See, e.g., Sambrook et al., in Molecular Cloning: A Laboratory Manual, 2d Edition, 1989, Cold Spring Harbor Press, Plainview, New York); Mattecucci et al., J. Am. Chem. Soc. 705:3185 (1981); and Yoo et al., J. Biol. Chem. 754:17078 (1989)).
  • IL-6 can be made by standard methods. For example, oligonucleotide probe mixtures based on known IL-6 nucleotide sequences can be used to identify DNA encoding IL-6 in genomic or cDNA libraries prepared by standard methods. (See e.g., Maniatis et al.. Molecular Cloning: A Laboratory Manual, 1982, Cold Spring Harbor).
  • DNA thus identified can be excised from the library by restriction endonuclease cleavage or prepared using appropriate primers and the polymerase chain reaction (PCR) method (Saiki et al., Science 259:487 (1988)), sequenced and expressed in a eukaryotic expression system or (following intron deletion by standard methods if necessary) in a prokaryotic or eukaryotic expression system.
  • PCR polymerase chain reaction
  • both cDNA and genomic DNA libraries can be screened by the application of standard expression cloning methods, instead of by the use of oligonucleotide probes or PCR.
  • IL-6 thus produced is detected through the use of known immunochemical or bioassay methods.
  • the IL-6 used will preferably be that of the mammalian species being treated (e.g., human recombinant IL-6 is preferred for treating human beings).
  • IL-6 is generally supplied in a lyophilized form that can be reconstituted just prior to use in a pharmaceutically acceptable carrier such as phosphate buffered saline or any of the other well known carriers.
  • a pharmaceutically acceptable carrier such as phosphate buffered saline or any of the other well known carriers.
  • the pharmaceutical compositions of the invention can be injected directly into the bloodstream intravenously or via an IV drip solution such as Ringer's lactate.
  • Parenteral preparations that can be used in accordance with the present invention include sterile solutions or suspensions. These preparations can be prepared with conventional pharmaceutically acceptable excipients and additives such as stabilizers and carriers.
  • the solutions to be administered may be reconstituted lyophilized powders which may additionally contain, e.g., preservatives, buffers and dispersants.
  • the compositions are administered by intravenous injection.
  • compositions that can be used in connection with the present invention are described e.g., in Gil man, et al. (eds.) (1990) The Pharmacological Bases of Therapeutics, 8th Ed., Pergamon Press; and Remington's Pharmaceutical Sciences, 17th ed. (1990), Mack Publishing Co., Easton, Penn. Methods for administartion are discussed therein and below, e.g., for oral, intravenous, intraperitoneal, or intramuscular adiministration, transdermal diffusion, and others.
  • Pharmaceutically acceptable carriers can include water, saline, buffers, and other compounds described, e.g., Merck Index, Merck & Co., Rahway, New Jersey.
  • Formulations typically comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof.
  • Each carrier should be both pharmaceutically and physiologically acceptable in the sense of being compatible with the other ingredients and not injurious to the patient.
  • Formulations include those suitable for oral, rectal, nasal, or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the formulations may conveniently be prepared in unit dosage form and may be prepared by any methods well known in the art of pharmacy. See, e.g., Gilman, et al. (eds.) (1990) The Pharmacological Bases of Therapeutics, supra; and Remington's Pharmaceutical Sciences, supra; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications Dekker, New York; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Dekker, New York; and Lieberman, et al. (eds.) Pharmaceutical Dosage Forms: Disperse Systems, Dekker, New York.
  • the therapy of this invention may be combined with or used in association with other chemotherapeutic or chemopreventive agents.
  • mammals that are in need of treatment for septic shock as defined above are administered an amount of chlorpromazine in combination with IL-6 to abate one or more of the above described clinical manifestations of septic shock.
  • a dose of from about 0.1 mg to about 100 mg chlorpromazine per kilogram of body weight and about 0.1 ⁇ g to about 300 ⁇ g IL-6 per kilogram of body weight is preferably administered. More preferably, mammals are administered a dose from about 3 mg to about 10 mg chlorpromazine per kilogram of body weight and from about 5.0 ⁇ g to about 30.0 ⁇ g IL-6 per kilogram of body weight.
  • the precise amount of the combination of the chlorpromazine and the IL-6 to be administered would be determined by the attending clinicians, taking into account the etiology and severity of the disease, the patient's condition, sex, age, and other factors.
  • a combination of chlorpromazine plus IL-6 was given intraperitoneally one hour prior to the administration of LPS and D-galactosamine (to induce shock).
  • Pre-treatment of the mice with mouse IL-6 and chlorpromazine was done in order to facilitate adequate circulating concentrations in the bloodstream at the time of LPS-gal administration, because intraperitoneal injection of therapeutics requires a longer diffusion period to enter the bloodstream than other routes of administration (such as intravenous injection).
  • Intraperitoneal injection was selected in this model due to the difficulty of intravenous injection in the mouse.
  • the preferred route of administration would normally be intravenous injection, where bioavailability of the circulating therapeutic agent would be as rapid as 10 minutes.
  • the actual timing of administration to a patient with or at risk for developing septic shock is not to be construed to be limited to the Example, however.
  • Administration of IL-6 and chlorpromazine to an individual demonstrating symptoms of or at high risk for developing septic shock can be before, during, or after the onset of any of the manifestations of clinical disease state as described above.
  • prevention of septic shock can be defined by the following parameters. Certain circumstances pre-dispose individuals to developing septic shock. For example, candidates for abdominal surgery, or any situation that would cause the rupture of or laceration of the 9
  • intestines i.e., ruptured appendix
  • Other examples include gun shot wounds, automobile accident victims with abdominal trauma, and the like.
  • Administration of chlorpromazine and IL-6 to such individuals at high risk for developing septic shock prior to the onset of symptoms would ameliorate such symptoms, preventing the actual onset of the full blown manifestations of the disease.
  • mice Male C57BL/6J mice (5 weeks of age) were obtained from Jackson Laboratories, Bar Harbor, ME. Endotoxin-free phosphate buffered saline (PBS) was purchased from GIBCO, Grand Island, NY. LPS (E. coli 0111.B4) was purchased from List Biological Laboratories, Inc., Campbell, CA. D-galactosamine was obtained from Sigma Chemicals, St. Louis, MO. Chlorpromazine was purchased from Sigma Chemicals, St. Louis, MO, and mouse IL-6 was purchased from Biosource, Camarillo, CA.
  • PBS phosphate buffered saline
  • LPS E. coli 0111.B4
  • D-galactosamine was obtained from Sigma Chemicals, St. Louis, MO.
  • Chlorpromazine was purchased from Sigma Chemicals, St. Louis, MO
  • mouse IL-6 was purchased from Biosource, Camarillo, CA.
  • LPS endotoxin
  • septic shock a component of the outer membrane of gram-negative bacteria
  • LPS was dissolved in PBS at 1 mg/ml and frozen at -80 * C until use. Prior to freezing, the LPS solution was sonicated for 5 minutes in a sonifying bath. The solution was re-sonicated for 5 minutes after thawing, just prior to use. Appropriate dilutions were made in PBS in polypropylene tubes. D-galactosamine was dissolved at 32 mg/ml in PBS and mixed with an equal volume of diluted, sonciated LPS. The LPS- galactosamine mixture was used immediately and fresh batches were made for each experiment. Each mouse received 0.5 ml of LPS-gal mixture intraperitoneally (i.p.) one hour prior to administration of therapeutic agents.
  • a suboptimal dose of chlorpromazine (3 mg kg) was injected alone or in combination with various doses of mouse IL-6.
  • a control group was injected with Dulbecco's phosphate buffered saline (DPBS). All therapeutic agents (or controls) were injected one hour prior to the LPS/D-galactosamine injection. All injections were given i.p. The percent mortality was determined 24 hours after the LPS/D-galactosamine injection.
  • DPBS Dulbecco's phosphate buffered saline
  • ELISA's immunosorbent assays
  • Shock was induced by intraperitoneal injection of a dose of 100 ng/mouse LPS with 8 mg/mouse D-glactosamine as described.
  • chlorpromazine plus IL-6 given intraperitoneally significantly reduces mortality in an animal model of septic shock. Mortality was reduced from 80% in untreated controls to values between 20% and 34.29% (depending on dosage) in animals treated with the combination of chlorpromazine and IL-6.

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Abstract

La présente invention concerne des procédés et des compositions de traitement et de prévention du choc septique chez un mammifère. Les procédés consistent en l'administration d'une quantité suffisante de chlorpromazine en combinaison avec l'IL-6 à un mammifère souffrant de choc septique ou fortement susceptible de développer ce type de choc.
PCT/US1995/009496 1994-08-05 1995-08-03 Utilisation de la chlorpromazine en combinaison avec l'interleukine-6 pour le traitement ou la prevention du choc septique WO1996004012A1 (fr)

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AU32023/95A AU3202395A (en) 1994-08-05 1995-08-03 Use of the combination of chlorpromazine plus interleukin-6 to treat or prevent septic shock

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US28631694A 1994-08-05 1994-08-05
US08/286,316 1994-08-05

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180016576A1 (en) * 2014-12-22 2018-01-18 Chugai Seiyaku Kabushiki Kaisha Novel Therapeutic Agent for Septicemia, and a Method for Screening for Same
US10550387B2 (en) 2015-06-30 2020-02-04 Chugai Seiyaku Kabushiki Kaisha Therapeutic agent for a lung disease and/or method for screening for the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011793A1 (fr) * 1991-12-17 1993-06-24 Schering Corporation Utilisation de la combinaison du facteur de necrose anti-tumeur et de l'interleukine-6 dans le traitement du choc septique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993011793A1 (fr) * 1991-12-17 1993-06-24 Schering Corporation Utilisation de la combinaison du facteur de necrose anti-tumeur et de l'interleukine-6 dans le traitement du choc septique

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
IMMUNOLOGY, Volume 82, Number 2, issued June 1994, MENGOZZI et al., "Chlorpromazine Specifically Inhibits Peripheral and Brain TNF Production and Up-Regulates IL-10 Production, in Mice", pages 207-210. *
INFECTION AND IMMUNITY, Volume 61, Number 4, issued April 1993, BARTON et al., "Protective Role of Interleukin 6 in the Lipopolysaccharide-Galactosamine Septic Shock Model", pages 1496-1499. *
J. EXP. MED., Volume 173, issued June 1991, GADINA et al., "Protective Effect of Chlorpromazine on Endotoxin Toxicity and TNF Production in Glucocorticoid-Resistant Models of Endotoxic Shock", pages 1305-1310. *
THE JOURNAL OF IMMUNOLOGY, Volume 143, Number 11, issued 01 December 1989, ADERKA et al., "IL-6 Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Production in Cultured Human Monocytes, U397 Cells and in Mice", pages 3517-3523. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180016576A1 (en) * 2014-12-22 2018-01-18 Chugai Seiyaku Kabushiki Kaisha Novel Therapeutic Agent for Septicemia, and a Method for Screening for Same
US10550387B2 (en) 2015-06-30 2020-02-04 Chugai Seiyaku Kabushiki Kaisha Therapeutic agent for a lung disease and/or method for screening for the same
US11279931B2 (en) 2015-06-30 2022-03-22 Tadamitsu Kishimoto Therapeutic agent for a lung disease and/or method for screening for the same

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