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WO1994005287A1 - Prevention ou traitement de la septicemie avec du dantrolene ou de l'azumolene - Google Patents

Prevention ou traitement de la septicemie avec du dantrolene ou de l'azumolene Download PDF

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Publication number
WO1994005287A1
WO1994005287A1 PCT/US1993/007698 US9307698W WO9405287A1 WO 1994005287 A1 WO1994005287 A1 WO 1994005287A1 US 9307698 W US9307698 W US 9307698W WO 9405287 A1 WO9405287 A1 WO 9405287A1
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Prior art keywords
sepsis
sodium
dantrolene
dantrolene sodium
azumolene
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PCT/US1993/007698
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English (en)
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Richard Samuel Hotchkiss
Irene Elsie Karl
Joseph John Henry Ackerman
Sheng-Kwei Song
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Washington University
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Priority to AU50151/93A priority Critical patent/AU5015193A/en
Publication of WO1994005287A1 publication Critical patent/WO1994005287A1/fr

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    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles

Definitions

  • This invention relates to methods of preventing and treating sepsis in humans or other mammals.
  • this invention relates to methods of preventing and treating sepsis comprising the administration of compounds that inhibit the release of calcium from the sarcoplasmic and endoplasmic reticula, preferably dantrolene sodium and/or azumolene sodium.
  • Sepsis is the leading cause of death in surgical intensive care units and neonatal units. In the United States alone, four hundred thousand (400,000) patients per year develop sepsis. Approximately, one hundred thousand (100,000) of these patients ultimately expire.
  • the plethora of articles discussing the gravity of the sepsis problem is indicative of the need for more effective management of sepsis. See, e.g. Glauser, M. P., et al . , "Septic Shock: pathogenesis", 338 Lancet 732 (September 21, 1991); Fein, A. M., et al . , "Sepsis Syndrome", 10(11) Infect ious Disease News letter 89-96 (1991); Parillo, J.
  • Sepsis is a clinical syndrome characterized by leukocyte proliferation, altered mental state, tachypnea, tachycardia, metabolic acidosis, impaired renal and hepatic function, hypotension and hyperthermia or hypothermia. Sepsis results from infection with gram-positive or gram-negative bacteria, pathogenic viruses, fungi or rickettsia or the by-products of such infectious agents. If untreated, sepsis can progress to septic shock, wherein the patient manifests all the symptoms of sepsis plus hypotension (the systolic blood pressure drops below 90 mmHg or it decreases below the baseline systolic blood pressure by 40 mmHg).
  • the voltage sensitive calcium channel blockers such as verapa il (an anti-hypertensive), increase the survival rate of Escherichia col i (£. co l i) induced sepsis in dogs and mice. It is postulated that the calcium channel blockers act by decreasing calcium entry from the outside of the cell into the interior of the cell. Thus, increased intracellular calcium due to the influx of extracellular calcium is prevented by verapamil treatment, and, in those cells where verapamil acts effectively, it may diminish some of the deleterious effects of intracellular calcium overload. See, Bosson, S., et al .
  • dantrolene sodium and azumolene sodium to treat sepsis is undisclosed in the art. Nor does the art suggest that dantrolene sodium and azumolene sodium are useful for sepsis treatment. Furthermore, the use of dantrolene sodium and azumolene sodium to treat sepsis is superior to the proposed use of verapamil which also affects cellular calcium. Verapamil exerts its effects on the voltage sensitive calcium channels which predominate in smooth and skeletal and cardiac muscle cells. See , Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chap. 32 (8th Edition 1990).
  • Dantrolene sodium and azumolene sodium modulate, directly or indirectly, calcium regulation by the sarcoplasmic and/or endoplasmic reticula, which are intracellular organelles, where calcium is stored, found in abundance not only in cardiac muscle cells, smooth muscle cells, and skeletal muscle cells, but also in brain cells, liver cells, pancreas cells and osteoblasts.
  • sarcoplasmic and/or endoplasmic reticula which are intracellular organelles, where calcium is stored, found in abundance not only in cardiac muscle cells, smooth muscle cells, and skeletal muscle cells, but also in brain cells, liver cells, pancreas cells and osteoblasts.
  • compounds such as dantrolene sodium and azumolene sodium can exert their effects not only in muscle tissue, but on other major organ systems that may be targets of damage in sepsis.
  • the use of dantrolene sodium and azumolene sodium to treat sepsis is clearly an advance in the art of sepsis management.
  • a method of preventing and treating sepsis in a human or other mammal afflicted with sepsis comprising the administration of a safe and effective amount of a compound that inhibits the release of calcium from the sarcoplasmic and/or endoplasmic reticula, preferably dantrolene sodium and azumolene sodium.
  • tachypnea means very rapid breathing usually at a rate of greater than twenty (20) breaths per minute.
  • tachycardia means very rapid beating of the heart, usually at a rate of greater than ninety
  • sarcoplasmic reticulum (plural - sarcoplasmic reticula), as used herein, means the intracellular organelle where calcium is stored. The sarcoplasmic reticulum predominates in cardiac, smooth, and skeletal muscle cells.
  • endoplasmic reticulum (plural - endoplasmic reticula), as used herein, means the intracellular organelle where calcium is stored.
  • the endoplasmic reticulum predominates in heart cells, liver cells, lung cells, pancreas cells, brain cells, muscle cells and osteoblasts.
  • skeletal muscle relaxants means those compounds which cause relaxation of the skeletal muscle, by acting directly on the muscle or by acting on the neuromuscular junction or by acting on the central nervous system.
  • Dantrolene sodium is an example of a skeletal muscle relaxant that acts directly on the muscle cell by inhibiting calcium release from the sarcoplasmic and endoplasmic reticulum.
  • Baclofen is a centrally acting muscle relaxant which acts by hyperpolarizing gamma-a ino butyric acid (GABA) receptors.
  • GABA gamma-a ino butyric acid
  • Succinylcholine acts at the neuromuscular junction by depressing excitatory postsynaptic potentials. Cyclobenzoprine acts on the central nervous system at the brain stem.
  • septicemia as used herein, means a blood borne infection which if untreated can lead to sepsis and eventually septic shock.
  • septic shock means that clinical condition wherein the sepsis has progressed to a state where heart and organ failure are eminent.
  • trauma means severe physical injury occurring as a result of, but not limited to, automobile accidents, airplane crashes, gun shots, nautical accidents, falls, knife wounds, puncture wounds, and burns.
  • sympathomimetic agent means a drug which mimics the effects of the sympathetic nervous system.
  • the sympathetic nervous system is stimulated in response to physical or psychological stress. Therefore, agents that mimic the activity of the sympathetic nervous system are useful in the treatment of a variety of clinical disorders, such as shock and heart failure.
  • a sympathomimetic drug such as dopamine exerts a positive inotropic effect on the heart due to stimulation of cardiac 3-receptors.
  • epinephrine and phenylephrine stimulate the heart through their actions on the cardiac J-receptors. Because a septic patient is physically stressed, and often suffering with a cardiac malfunction, such a patient may be administered a sympathomimetic agents such as dopa ine or phenylephrine.
  • antibody means the protein molecule which is formed in response to a stimulus by an antigen, and, is useful in neutralizing the toxic effects of said antigen.
  • antigen There are five (5) major classes of human antibodies, IgG, IgA, IgM, IgD and IgE.
  • the bacterial endotoxin is an antigen which stimulates antibody formulation.
  • the antibody formed in response to the endotoxin antigen can be administered to sepsis patients to interfere with the cellular destruction caused by the endotoxin antigen.
  • the active materials useful in the methods of this invention include certain skeletal muscle relaxants, most preferably those which inhibit the release of calcium from the sarcoplasmic and/or endoplasmic reticula and those compounds, not necessarily skeletal muscle relaxants, that inhibit calcium release from the sarcoplasmic and/or endoplasmic reticula.
  • the methods of this invention comprise the administration of a safe and effective amount of dantrolene sodium to a human or other mammal afflicted with sepsis.
  • Dantrolene sodium (l-[[5-p-nitrophenyl)furfurylidene]-amino]hydantoin sodium salt) has the following structure:
  • Dantrolene sodium and methods for preparation of dantrolene sodium are described in U.S. Patent 3,415,821 to Davis, et al., issued December 10, 1968, previously incorporated by reference herein.
  • Pharmaceutical compositions comprising dantrolene sodium are described in U.S. Patent 3,689,654 to Conklin, et al . , issued September 5, 1972, previously incorporated by reference herein.
  • Dantrolene sodium is known to those ordinarily skilled in the healing arts as a skeletal muscle relaxant. Dantrolene sodium inhibits the release of calcium from the sarcoplasmic reticulum. See , Physicians Desk Reference, 46th Edition (1992). Dantrolene sodium can also be used to treat the symptoms of malignant hyperthermia which include tachycardia, tachypnea, and muscle rigidity. See, Physicians Desk Reference, 46th Edition (1992). Additionally, it has been used clinically to treat the symptoms of tetanus which include hyperventilation, muscle rigidity and fever.
  • the methods of this invention comprise the administration of a safe and effective amount of azumolene sodium to a human or other mammal afflicted with sepsis.
  • Azumolene sodium (1-[[[5-4- bromophenyl-2-oxazolyl]methylene amino]-2,4-imidazolidine-dione,) has the following structure:
  • Azumolene sodium and methods for preparation of azumolene sodium are described in U.S. Patent 4,049,650 to White issued September 20, 1977, previously incorporated by reference herein.
  • Pharmaceutical compositions comprising azumolene sodium are described in U.S. Patent 4,822,629 to Pong, issued April 18, 1989, previously incorporated by reference herein.
  • the methods of this invention comprise the administration of a safe and effective amount of a compound that inhibits the release of calcium from the sarcoplasmic and/or endoplasmic reticula, preferably dantrolene sodium or azumolene sodium, to a human or other mammal susceptible to or afflicted with sepsis.
  • a compound that inhibits the release of calcium from the sarcoplasmic and/or endoplasmic reticula preferably dantrolene sodium or azumolene sodium
  • safe and effective amount means an amount of a compound or composition large enough to significantly positively modify the symptoms and/or condition to be treated, but small enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of active ingredient for use in the pharmaceutical compositions to be used in the method of the invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician. Sepsis is essentially a problem associated with critical care situations. Critical care situations arise when the patient's body is abnormally stressed.
  • the dantrolene sodium or azumolene sodium may be administered at a level of 0.01 mg/kg to 10.0 mg/kg.
  • the dantrolene sodium or azumolene sodium is preferably administered intravenously to a patient suffering from sepsis at a level of 0.01 mg/kg/hour to 0.50 mg/kg/hour.
  • the dantrolene sodium or azumolene sodium is administered at a level of 0.025 mg/kg/hour to 0.35 mg/kg/hour. Most preferably, the dantrolene sodium or azumolene sodium is administered at a level of 0.05 mg/kg/hour to 0.25 mg/kg/hour.
  • the dantrolene sodium or azumolene sodium may also be administered by any of a variety of known methods of administration, e.g., orally, dermatomucosally (for example, dermally, subl ingually, intranasally, and rectally), parenterally (for example, by subcutaneous injection, intramuscular injection, intra-articular injection, intravenous injection), and by inhalation.
  • specific modes of administration include, but are not limited to, for example, oral, transdermal , mucosal , sublingual, intramuscular, intravenous, intraperitoneal , subcutaneous administration, and topical application.
  • Dantrolene sodium or azumolene sodium may also be co-administered with antibiotics.
  • co-administered means dosing the subject utilizing all types of adjuvant (i.e. combination) therapies: concurrently (at the same time) and sequentially (one immediately after the other, or one after the other after some rest period).
  • adjuvant i.e. combination
  • dantrolene sodium or azumolene sodium may be co-administered with certain antibiotic agents, including, but not limited to the penicillins, cephalosporins, ciprofloxacin, erythromycin and the aminoglycosides.
  • antibiotic agents including, but not limited to the penicillins, cephalosporins, ciprofloxacin, erythromycin and the aminoglycosides.
  • Antibiotics known to those skilled in the art, and useful in the methods of this invention are described in Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapters 44-49 (8th Edition, 1990).
  • the quinolonyl lactam antibiotics may be co-administered with the dantrolene sodium or azumolene sodium.
  • the quinolonyl lactam antibiotics useful for co-administering with dantrolene sodium or azumolene sodium are described in World Patent Publications WO 91/16327 and WO 91/16310, both of Demuth, et al . , both published October 31, 1991; both incorporated by reference herein and also in EPO Publications 366,640; 366,193; 366,641; 366,189; 366,643, all of Demuth, et al . , all published May 2, 1990; and all incorporated by reference herein.
  • the dantrolene sodium and azumolene sodium may also be co-administered with antibodies to bacterial endotoxins produced by gram-negative bacteria.
  • the bacterial endotoxins produced by the gram-negative bacteria are bacterial membrane 1 ipopolysaccharides.
  • the 1 ipopolysaccharide endotoxin triggers the cascade of events that can lead to sepsis and subsequently to septic shock and death.
  • mediators of the inflammatory response including but not limited to, tumor necrosis factor, interleukins, platelet-activating factor, leukotrienes, prostaglandins, interferon, platelets, and bradykinin.
  • mediators of the inflammatory response causes cellular injury which eventually leads to cellular destruction, and ultimately organ death. See, e.g. Glauser, M. P., et al . , "Septic Shock: pathogenesis", 338 Lancet 732 (September 21, 1991); Fein, A.M., et al .
  • Anti -endotoxin antibodies useful in the methods of this invention are described in Barriere, et al . , "Therapy Reviews - Gram Negative Sepsis, the sepsis syndrome, the role of antiendotoxin monoclonal antibodies", 11(3), Cl in. Pharm. 223-225 (March 1992).
  • Specific anti -endotoxin antibodies include, but are not limited to, HA-IA and E5.
  • HA-IA is a monoclonal IgM antibody derived from a human cell line.
  • E5 is a monoclonal IgM antibody derived from a urine cell line. See, Ziegler, E.J., et al .
  • antibodies to tumor necrosis factor and the interleukins can be co-administered with the dantrolene or azumolene sodium.
  • the dantrolene sodium or azumolene sodium may also be co-administered with a sympathomimetic agent such as, but not limited to, dopamine, epinephrine, or phenylephrine.
  • sympathomimetic agents known to those skilled in the art, and useful in the methods of this invention, are described in Goodman and Gilman, The Pharmacological Basis of Therapeutics, Chapter 10 (8th Edition, 1990).
  • the dantrolene sodium or azumolene sodium is administered until the sepsis is resolved.
  • the dantrolene sodium or azumolene sodium may be administered, at a level of 0.01 mg/kg to 10 mg/kg, post-operatively after the sepsis resolves for up to five (5) days to prevent a recurrence of the damaging effects of sepsis.
  • Post-operative administration of dantrolene sodium or azumolene sodium is preferably via intravenous infusion at a level of 0.01 mg/kg/hour to 0.50 mg/kg/hour.
  • a diagnosis of sepsis may include, but is not limited to, the following symptoms; tachypnea, tachycardia, hypotension, hyperthermia or hypothermia, altered mental state, metabolic acidosis, impaired renal and hepatic function and eventual loss of muscle mass, as determined by elevated blood and urinary nitrogen. Blood cultures are used to determine the presence of infectious organisms. Infectious organisms, known to cause sepsis, include but are not limited to the gram negative bacteria, such as Escherichia coli (E. coli), Klebsiella, Pseudomonas aeruginosa, and Enterobacter; and the gram positive bacteria, such as Staphylococcus epidermidis and Streptococcus faecal is.
  • the arterial blood gas analysis includes:
  • plasma electrolytes include:
  • Renal Function a) 24 hour urine output - variable, minimum urine output 1/2 cc/kg/hr
  • Hepatic Function plasma enzymes indicative of hepatocellular injury a) SG0T 8 - 33 u/ml b) SGPT 1 - 36 u/ml c) 7 GT 2 - 39 u/ml 4.
  • Hematologic and Coagulation System a) hemoglobin 13 - 17 gm/dl b) hematocrit 38 - 45 % c) white blood cell count 4,500 - 11,000/ul neutrophils 56% bands 3% eosinophils 2.7% lymphocytes 34% platelet count 150,000 - 400,000/ul
  • Plasma etabol ites glucose 70 - 110 mg/dl lactate ⁇ 2.0 mg/dL
  • the methods of this invention also comprise the administration of dantrolene sodium or azumolene sodium pre-operatively to a patient.
  • a patient likely to be treated pre-operatively with dantrolene sodium can be a patient suffering from severe trauma or a patient who will be undergoing major surgery, such as, but not limited to open heart surgery and abdominal surgery, where the risk of infection is enhanced.
  • Such a patient is administered dantrolene sodium or azumolene sodium at a level of 0.01 mg/kg to 10.0 mg/kg.
  • Such a patient is preferably administered dantrolene sodium or azumolene sodium via intravenous infusion pre-operatively, one day prior to surgery, at a level of 0.01 mg/kg/hour to 0.05 mg/kg/hour.
  • Such A patient who will be undergoing major surgery, can also be administered dantrolene sodium or azumolene sodium pre-operatively, four hours prior to surgery, in a bolus intravenous dose of 2 mg/kg over a period of twenty minutes.
  • Administration of dantrolene sodium or azumolene sodium, at a level of 0.01 mg/kg - 10.0 mg/kg, to trauma patients can begin, upon entry into the emergency ward and prior to the surgery to treat the trauma injuries.
  • intravenous administration of dantrolene sodium or azumolene sodium, at a level of 0.01 mg/kg/hour - 0.50 mg/kg/hour can begin upon entry into the Emergency Ward and prior to the surgery to treat the trauma injuries.
  • the methods of this invention comprise the intravenous administration of dantrolene sodium or azumolene sodium.
  • Dantrolene sodium is commercially available as Dantrium ®
  • Dantrium ® Intravenous is supplied in 70 ml vials containing 20 mg dantrolene sodium, 3000 mg annitol and sufficient sodium hydroxide to yield a pH of approximately 9.5 when reconstituted with 60 ml of sterile water for injection USP.
  • the patient is a 74 year old white male who is admitted to the hospital because of acute abdominal pain and fever.
  • the patient is taken to the operating room and intra-operative findings reveal a ruptured appendix with spillage of bowel contents and foul -smell ing infected peritoneal fluid.
  • the patient is taken to the surgical intensive care unit (S.I.C.U.).
  • Vital signs on admission to the S.I.C.U. are: syste ic arterial blood pressure - 130/70 pulse - 125 beats per minute (sinus tachycardia) temperature - 39.5°C rectally respirations - 10 breaths per minute by mechanical ventilator
  • the patient Given the diagnosis of intra-abdominal sepsis, the patient is started on broad-spectrum antibiotics and an intravenous infusion of dantrolene sodium (0.025 mg/kg/hour) is begun.
  • an intravenous infusion of dantrolene sodium (0.025 mg/kg/hour) is begun.
  • dantrolene sodium 0.025 mg/kg/hour
  • a number of laboratory parameters are followed sequentially to determine the course of the sepsis (see Table 1).
  • the patient's symptoms include high fever, metabolic lactic acidosis, marked loss of muscle mass as determined by elevated blood and urinary nitrogen, deteriorating renal function, and bleeding abnormal ities.
  • the dantrolene sodium infusion is increased to 0.50 mg/kg/hour. Over the next two to three days, the patient's clinical condition improves as indicated by resolution of the fever, normal acid-base balance, decreased muscle protein breakdown (indicated by the positive nitrogen balance in the 24 hour urine collection), and increased platelet count and decreased bleeding. His dantrolene sodium infusion is continued for seven days until the septic process is resolved. However, the dantrolene sodium is administered for an additional thirty-six hours after the septic process is resolved. He continues to improve and is discharged from the hospital ten days after admission.
  • a 2 kg infant girl is born (one month premature) by cesarean delivery performed for fetal distress. She is cyanotic and respirations are irregular. She is intubated, resuscitated, and placed on mechanical ventilation. Two days later the infant is noted to have increased respiratory rate, decreased blood pressure, and a fall in temperature. Chest x-ray reveals an infiltrate in the right lower lung lobe. Broad spectrum antibiotics are started and a continuous intravenous infusion of dantrolene sodium is begun at 0.01 mg/kg/hour. Blood cultures taken at two days are positive for Escherichia coli. A battery of laboratory tests are performed daily to follow the course of the sepsis (see Table 1).
  • the patient's progress is marked by gradual improvement in the respiratory distress and resolution of the septic process.
  • the metabolic acidosis resolves; muscle protein breakdown diminishes (decreased urinary nitrogen excretion); the elevated white blood cell count returns to normal.
  • the infusion of dantrolene sodium is continued for five days until the sepsis is resolved. However, the dantrolene sodium is administered for an additional twenty-four hours after the septic process has resolved.
  • the infant requires two additional weeks of support on a mechanical respirator but eventually is able to be extubated and has a full recovery.
  • Example 3 The patient is a 45 year old black female who is admitted for evaluation of anemia and blood in the stool. Workup reveals a large bowel carcinoma which is resected at surgery. Three days post-operatively the patient is noted to be febrile (39.8°C), has shaking chills, and is in respiratory distress. She is transferred to the surgical intensive care unit (S.I.C.U.) and workup reveals a leak at the site of the bowel anastomosis. She is taken to the operating room and a diverting colostomy procedure is performed. The abdomen is noted to be grossly infected. She is returned to the S.I.C.U. after surgery and her hospital course is marked by the following: 1. hemodynamic instability - falls in arterial blood pressure
  • the patient is started on dopamine 5 mg/kg/min to increase arterial blood pressure and improve cardiac pump function.
  • a continuous intravenous infusion of dantrolene sodium (0.025 mg/kg/hour) is begun.
  • cardiac output and pump function is improving.
  • Cardiac output has increased from 4.0 to 5.5 liters/min and stroke volume has improved from 40 to 60 ml.
  • Example 4 The patient is a 24 year old white male, who six months previous had a cadaveric renal transplant for chronic renal failure. He is admitted to the hospital because of high spiking fevers and evidence of a urinary tract infection. Blood and urine cultures are obtained and he is started on broad spectrum antibiotics. Because of hemodynamic instability and decreasing renal function, a continuous intravenous infusion of dantrolene sodium (0.025 mg/kg/hour) is begun.
  • the patient is monitored closely in the intensive care unit and serial metabolic and physiologic parameters are followed (see Table 1). Renal function is decreasing as evidenced by a rising serum creatinine and decreasing urine output.
  • the serum creatinine stabilizes at 4.0 mg/dL and urine output is barely adequate at 30 ml/hr.
  • the patient has a steadily improving hospital course and has resolution of his fever and septic picture after four days of the dantrolene sodium infusion.

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Abstract

Procédé de prévention et de traitement de la septicémie chez un homme ou un autre mammifère souffrant de septicémie, selon lequel on administre une quantité inoffensive et efficace d'un composé qui inhibe la libération de calcium provenant du reticulum sarcoplasmique et/ou du réticulum endoplasmique, ce composé étant de préférence du sodium de dantolène ou du sodium d'azumolène.
PCT/US1993/007698 1992-09-09 1993-08-17 Prevention ou traitement de la septicemie avec du dantrolene ou de l'azumolene WO1994005287A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100267258B1 (ko) * 1997-12-27 2000-10-16 최동환 탄저독소로 인한 세포독성의 해독제
WO2005013919A2 (fr) 2003-03-04 2005-02-17 Lyotropic Therapeutics, Inc. Traitement au moyen de dantrolene
US7758890B2 (en) 2001-06-23 2010-07-20 Lyotropic Therapeutics, Inc. Treatment using dantrolene
WO2010126818A1 (fr) * 2009-04-27 2010-11-04 Usworldmeds Llc Système d'administration intranasale de dantrolène
EP2583670A1 (fr) * 2007-10-09 2013-04-24 US Worldmeds LLC Compositions de co-solvants et procédés servant à améliorer la fourniture d'agents thérapeutiques à base de dantrolène
WO2019095056A1 (fr) * 2017-11-14 2019-05-23 University Health Network Dantrolène et ses analogues pour le traitement et la prévention chroniques d'un dysfonctionnement cardiaque de type dyssynchronie
US10441574B2 (en) 2014-11-13 2019-10-15 Washington University Treatment for wolfram syndrome and other endoplasmic reticulum stress disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4861790A (en) * 1987-10-28 1989-08-29 Norwich Eaton Pharmaceuticals, Inc. Use of azumolene for the treatment of malignant hyperthermia

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4861790A (en) * 1987-10-28 1989-08-29 Norwich Eaton Pharmaceuticals, Inc. Use of azumolene for the treatment of malignant hyperthermia

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
D.S. BEEBE ET AL.: "Is dantrolene safe to administer in sepsis? The effect of dantrolene after endotoxin administration in dogs and rats", ANAESTH. ANALG., vol. 73, no. 3, 1991, pages 289 - 294 *
G.P. ZALOGA ET AL: "Low dose calcium administration increases morality during septic peritonitis in rats", CIRC. SHOCK, vol. 37, no. 3, July 1992 (1992-07-01), pages 226 - 229 *
J.C. TODD ET AL.: "Effect of sepsis on erythrocyte intracellular calcium homeostasis", CRIT. CARE MED., vol. 20, no. 4, April 1992 (1992-04-01), pages S48 *
J.R. LOPEZ: "Effects of dantrolene on myoplasmic free (ca2+) measured in vivo in patients susceptible to malignant hyperthermia", ANESTHESIOLOGY, vol. 76, no. 5, May 1992 (1992-05-01), pages 711 - 719 *
R.C. BOORSE ET AL.: "Neuroleptic malignant syndrome in a multiple trauma patient", ARCH. SURG., vol. 125, no. 2, 1990, pages 274 - 275 *
S. BOSSON ET AL.: "Increased survival with calcium antagonists in antibiotic-treated bacteremia", CIRCULATORY SHOCK, vol. 19, no. 1, 1986, pages 69 - 74 *
S.-K. SONG ET AL.: "Increased intracellular Ca2+: A critical link in the pathophysiology of sepsis", PROC. NATL. ACAD. SCI. USA, vol. 90, no. 9, 1 May 1993 (1993-05-01), pages 3933 - 3937 *
T.J. BALDWIN ET AL.: "Elevation of intracellular free calcium levels in HEp-2 cells infected with enteropathogenic Escherichia coli", INFECT. IMMUN., vol. 59, no. 5, 1991, pages 1599 - 1604 *

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