WO2007076572A1 - A method of treatment - Google Patents

A method of treatment Download PDF

Info

Publication number
WO2007076572A1
WO2007076572A1 PCT/AU2006/001952 AU2006001952W WO2007076572A1 WO 2007076572 A1 WO2007076572 A1 WO 2007076572A1 AU 2006001952 W AU2006001952 W AU 2006001952W WO 2007076572 A1 WO2007076572 A1 WO 2007076572A1
Authority
WO
WIPO (PCT)
Prior art keywords
agent
systemic
sepsis
preferential
kidney failure
Prior art date
Application number
PCT/AU2006/001952
Other languages
French (fr)
Inventor
Clive N May
Rinaldo Bellomo
Original Assignee
Howard Florey Institute Of Experimental Physiology And Medicine
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 Howard Florey Institute Of Experimental Physiology And Medicine filed Critical Howard Florey Institute Of Experimental Physiology And Medicine
Priority to US12/159,196 priority Critical patent/US20090304818A1/en
Priority to AU2006332449A priority patent/AU2006332449B2/en
Priority to CA002633013A priority patent/CA2633013A1/en
Priority to JP2008547805A priority patent/JP2009521513A/en
Priority to EP06828056A priority patent/EP1971358A4/en
Publication of WO2007076572A1 publication Critical patent/WO2007076572A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/04Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08Peptides having 5 to 11 amino acids
    • A61K38/085Angiotensins
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365Lactones
    • A61K31/366Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37Coumarins, e.g. psoralen
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/02Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates generally to a method of treatment and in particular a method of treating a subject exhibiting symptoms of kidney failure or are at risk of developing same. Even more particularly, the present invention provides a method of treating kidney failure or reducing the risk of developing kidney failure in a subject such as following or during or prior to sepsis or a related condition including severe sepsis, septic shock and the systemic inflammatory response syndrome or any state of systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure, such as liver disease with associated kidney failure or kidney failure after cardiopulmonary bypass in patients in whom the systemic inflammatory syndrome which follows such cardiopulmonary bypass is associated with a high cardiac output and systemic or renal vasodilatation or kidney failure in other conditions which lead to the systemic inflammatory response syndrome with systemic or renal vasodilatation such as major trauma, major surgery and similar states which can induce the aforementioned systemic inflammatory response syndrome.
  • Sepsis is a systemic response to infection (American College of Chest Physicians, Society of Critical Care Medicine Consensus Conference, Critical Care Medicine 20(6):864-874, 1992). In the absence of infection, it is referred to as the systemic inflammatory response syndrome.
  • Severe sepsis is defined by the presence of likely or proven infection and at least two of the following: a temperature of greater than 38 0 C or less than 36 0 C; a heart rate greater than 90 beats per minute; a respiratory rate of more than 20/minute or a partial CO 2 pressure of less than 32 mm Hg; and/or an alteration in white blood cell count (such as >12,000/mm or ⁇ 4,000/mm 3 ) together with evidence of vital organ failure (Fitch and Gossage Postgrad Med 111(3) :53-66, 2002).
  • Septic shock is a subset of severe sepsis and is sometimes referred to as sepsis-induced hypotension that persists despite fluid resuscitation and is associated with vital organ malfunction.
  • Septic shock results from or is at least exacerbated by a cytokine cascade.
  • cytokine cascade In general, local inflammation and substances elaborated from or associated with pathogenic organisms and viruses such as endotoxins, activated neutrophils, monocytes and tissue macrophages. This results in a cascade of pro-inflammatory cytokines and other effector molecules such as IL-I, IL-8, IL-IO, TNF ⁇ , prostaglandin E 1 , endogenous corticosteroids and catecholamines.
  • This cascade leads to cellular chemotaxis, endothelial injury and activation of the coagulation cascade (Fitch and Gossage 2002 supra).
  • This inflammatory response induced by other forms of body injury can be indistinguishable form that of severe sepsis and septic shock and appear mediated by the same immune system cascade of cytokines and nitric oxide induced vasodilatation (Argenziano et al. J Thorac Cardiovasc Surg ;116:973-980, 1998)). If the initial cardiovascular response is uncompensated, it has been proposed that tissue hypoperfusion results, leading to cellular dysfunction, lactic acidosis and multi-organ failure, frequently ending in death.
  • the present invention is predicated in part on the surprising observation that, contrary to expectation, experimental subjects exhibiting symptoms of kidney failure, such as that induced by sepsis, systemic inflammation or other related condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure (including hepatorenal syndrome), require blood flow to the kidneys to be regulated through the use of agents that preferentially vasoconstrict the efferent arteriole of the glomerulus (the filtering apparatus of the kidney). This is contrary to current treatment of kidney failure in severe sepsis, which emphasizes the need to give fluids and kidney vessel vasodilators.
  • one aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure.
  • Said method comprises administering to said subject an effective amount of preferential efferent arteriolar vasoconstricting agent for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure.
  • preferential efferent arteriolar vasoconstriction means that the efferent arteriole constricts more than the afferent arteriole.
  • the kidney failure results from or is exacerbated by sepsis or systemic inflammation .
  • systemic inflammation and “sepsis” includes severe sepsis, septic shock and systemic inflammatory response syndrome after major trauma, surgery or cardiopulmonary bypass or any other condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure.
  • another aspect of the present invention provides a method of treating a subject with systemic inflammation, sepsis or other conditions leading to systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure or a risk thereof, said method comprising the administration to said subject of an effective amount of a preferential efferent arteriolar vasoconstrictor for a time and under conditions sufficient for urine output to increase.
  • a convenient vasoconstricting agent which has a preferential action on the efferent arteriole of the glomerulus is angiotensin II (Ang II) or a homolog, derivative, analog or functional equivalent or an agonist of Ang II- AT-I receptor interaction.
  • Ang II angiotensin II
  • a homolog, derivative, analog or functional equivalent or an agonist of Ang II- AT-I receptor interaction.
  • the vasoconstrictor may be given alone or in combination with, for example, a nitric oxide synthase inhibitor, an antibiotic, an anti- viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide).
  • a nitric oxide synthase inhibitor such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid
  • a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the
  • the present invention is further directed to the use of a preferential efferent arteriolar vasoconstrictor alone or in combination with another therapeutic agent in the generation of a therapeutic protocol to treat a subject with symptoms of kidney failure or who is at risk of developing same following , during or prior to systemic inflammation or sepsis or other conditions leading to states of systemic or renal vasodilatation characterized by low blood pressure and a high cardiac output and low blood pressure.
  • the present invention extends to any animal or mammal but is particularly directed to the treatment of human subj ects .
  • Figures IA through C are graphical representations of a reduction in mean arterial pressure (A); an increase in renal blood flow (B); and a reduction in urine output (C); in sepsis and the ability of Ang II infusion to return these variables to normal in four (4) conscious sheep: I, pre-sepsis control; II, sepsis control period; III, sepsis+Ang II infusion period.
  • vasoconstrictor includes a single vasoconstrictor, as well as two or more vasoconstrictors
  • agent includes a single agent, as well as two or more agents
  • method includes a single method or a combination of methods; and so on.
  • compound used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect that is, preferential efferent arteriole vasoconstriction causing an increase in glomerular filtration rate and restoring urine output.
  • agent used interchangeably to refer to a chemical compound that induces a desired pharmacological and/or physiological effect that is, preferential efferent arteriole vasoconstriction causing an increase in glomerular filtration rate and restoring urine output.
  • drug also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like.
  • references to a "compound”, “agent”, “active agent”, “chemical agent” “pharmacologically active agent”, “medicament”, “active”, “drug” and “pro-drug” includes combinations of two or more actives such as a vasoconstrictor and one or more of a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), another vasosuppressor, a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-niicrobial agent (microbicide) and/or an antiviral agent (virocide).
  • actives such as a vasoconstrictor and one or more of a
  • a “combination” also includes multi-part compositions such as a two-part composition where the agents are provided separately and given or dispensed separately or admixed together prior to dispensation.
  • a particular example includes angiotensin II (Ang II) and the vasosuppressor, noradrenaline.
  • a multi-part pharmaceutical pack may have two or more active agents separately maintained.
  • the pack may also be designed to facilitate administration of the active ingredients.
  • an agent as used herein mean a sufficient amount of the agent (e.g. a vasoconstrictor) to provide the desired therapeutic or physiological effect or outcome.
  • the desired outcome is a reduction in kidney failure as measured by an increase in urine output and an improved creatinine clearance to normal or premorbid levels.
  • Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount”.
  • the exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount”. However, an appropriate "effective amount” in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
  • pharmaceutically acceptable carrier excipient or diluent
  • a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction.
  • Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
  • a "pharmacologically acceptable" salt, ester, emide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.
  • treating and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms of the condition being treated, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms of the condition and/or their underlying cause and improvement or remediation or amelioration of damage following a condition.
  • Treating" a subject may involve prevention of a condition or other adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by ameliorating the symptoms of the condition. Conveniently, treatment may be initiated immediately a subject's urine output drops or an infection or other condition is diagnosed. It is proposed that treatment commence after diagnosis of sepsis or other related conditions leading to a state of systemic vasodilatation with low blood pressure and high cardiac output with evidence of kidney failure or risk thereof. Hence, the present invention encompasses treating a subject having a risk of developing kidney failure.
  • a "subject” as used herein refers to an animal, preferably a mammal and more preferably human who can benefit from the pharmaceutical formulations and methods of the present invention. There is no limitation on the type of animal that could benefit from the presently described pharmaceutical formulations and methods. A subject regardless of whether a human or non-human animal may be referred to as an individual, subject, patient, animal, host or recipient. The compounds and methods of the present invention have particular application in human medicine but also in veterinary medicine as well as in general, domestic or wild animal husbandry.
  • the preferred animals are humans or other primates such as orangutangs, gorillas, marmosets, livestock animals, laboratory test animals, companion animals or captive wild animals, as well as avian species.
  • laboratory test animals include mice, rats, rabbits, sheep, simian animals, guinea pigs and hamsters. Rabbits, rodent, sheep and simian animals provide a convenient test system or animal model. Livestock animals include sheep, cows, pigs, goats, horses and donkeys.
  • one aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure, said method comprises administering to said subject an effective amount of preferential efferent arteriolar vasoconstricting agent for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure.
  • preferential efferent arteriolar vasoconstriction means that the efferent arteriole constricts more than the afferent arteriole.
  • the kidney failure results from or is exacerbated by systemic inflammation or sepsis .
  • Reference herein to systemic inflammation or "sepsis” includes severe sepsis, septic shock and the systemic inflammatory response syndrome or any other condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure.
  • a preferential efferent arteriolar vasoconstrictor includes any agent which reduces blood flow, particularly to the kidneys.
  • An example of a particularly useful vasoconstrictor that has a preferential action on the efferent arteriole compared to the afferent arteriole is angiotensin II (Ang II) or a homolog, derivative, analog or functional equivalent thereof or an agonist of an Ang II interaction with its receptor, the AT-I receptor (angiotensin AT-I receptor agonist) or a combination of Ang II or Ang II AT-I receptor agonist and another vasosuppressor such as noradrenaline.
  • Ang II or "angiotensin AT-I receptor agonist” or “Ang II AT-I receptor agonist” includes derivatives or homologs which have a longer half-life such as a longer serum or tissue fluid half-life.
  • the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure, said method comprising administering to said subject an effective amount of Ang II or a homolog, derivative, analog or functional equivalent or an agonist of Ang II-AT-1 receptor interaction for a time and under conditions sufficient to facilitate an increase in urine output and reduce kidney failure.
  • the present invention provides a method of treating a subject with systemic inflammation or sepsis or other conditions leading to systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure or a risk thereof, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor for a time and under conditions for urine output to increase and kidney failure to resolve.
  • the subject may be any animal or mammal but is preferably a human.
  • the present invention further extends to unborn foetuses such as when a pregnant subject is diagnosed with sepsis or related conditions leading to a state of systemic and renal vasodilation.
  • the present invention provides a method of treating a subject with systemic inflammation, sepsis, septic shock or other related conditions leading to systemic and renal vasodilatation with low blood pressure and high cardiac output and a failing kidney or risk thereof, said methods comprising administering to said subject an effective amount of Ang II or a homolog, derivative, analog or functional equivalent or an agonist of Ang II- AT-I receptor interaction for a time and under conditions for urine output to increase and reduce kidney failure.
  • a further embodiment comprises the administration of Ang II and/or an Ang II AT-I receptor agonist and another vasosuppressor such as noradrenaline.
  • severe sepsis refers to an acute bacterial, microbial or viral infection leading to a cascade of cytokines and inflammatory mediators being activated including the complement system, the coagulation cascade, the fibrinolytic system, catecholamines, glucocorticoids, prekallikrein, bradykinin, histamines, ⁇ -endorphins, encephalins, adrenocorticoid hormone, circulating myocardial depressant factors, cachectin (tumor necrosis factor), interleukins, other cytokines and nitric oxide. Symptoms of severe shock include fever, chills, constitution malaise, anxiety and/or confusion.
  • the subject will exhibit a temperature of greater than 38°C or less than 36°C; a heart rate greater than 90 beats per minute; a respiratory rate of more than 20/minute or a partial CO 2 pressure of less than 32 mm Hg; and/or an alteration in white blood cell count (such as >12,000/mm 3 or ⁇ 4,000/mm 3 ).
  • the patient must also have evidence of vital organ failure (low urine output, high blood lactate levels, delirium, lung malfunction, low platelet count etc.). If the blood pressure is very low and does not improve with fluids the condition is called septic shock.
  • the active agents may be administered for therapy by any suitable route.
  • Suitable routes of administration may include oral, rectal, nasal, inhalation of aerosols or particulates, topical (including buccal and sublingual), transdermal, vaginal, intravesical and parenteral (including subcutaneous, intramuscular, intravenous, intrasternal, intrathecal, epidural and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the subject, the nature of the condition being treated, its location within the subject and the judgement of the physician or veterinarian. It will also be understood that individual active agents may be administered by the same or different distinct routes.
  • an "effective amount” refers to an amount of active agent that provides the desired therapeutic or physiological outcome such as reducing kidney failure as endured by returning urine output to normal levels. Dosing may occur at intervals of several seconds, minutes, hours, days, weeks or months. Suitable dosage amounts and regimes can be determined by the attending physician or veterinarian.
  • Ang II or an angiotensin AT-I receptor agonist or pharmaceutically acceptable salts, derivatives, homologs, analogs or functional equivalents thereof may be administered generally by infusion to a subject at a rate of between about 0.01 ⁇ g/kg/min to about 20 mg/kg/min continuously for from about 1 hour (or less) to up to about 500 or more hours, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84,
  • a preferential efferent arteriolar vasoconstrictor may be given with a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger
  • vasosuppressor such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid
  • another vasosuppressor such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid
  • a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus
  • an antibiotic or other anti-microbial agent microbicide
  • an anti- viral agent such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid
  • a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus
  • an antibiotic or other anti-microbial agent microbicide
  • an anti- viral agent
  • antibiotic is used in its broadest sense and includes cell-produced molecules as well as chemotherapeutic agents.
  • a convenient reference is MIMS Annual, CMPMedica Australia Pty Limited: 1-1700, 2005, Publisher C & C Offset Printing Co., Ltd, Hong Kong.
  • the two or more active agents may be administered simultaneously or sequentially. If simultaneously, the agents may be in the same or different formulations. If sequentially, they may be administered with nanoseconds, seconds, minutes, hours or days of each other.
  • another aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or at risk of developing same, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstricting agent and at least one other agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), another vasosuppressor, a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney
  • the present invention provides a method of treating a subject with systemic inflammation, sepsis including severe sepsis and septic shock, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor and at least one other agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti- viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) flavonoid for a time and under conditions for urine output to increase.
  • Still another aspect of the present invention contemplates a treatment protocol for systemic inflammation, sepsis including the systemic inflammatory syndrome, severe sepsis, septic shock and any condition characterized by a state of systemic or renal dilatation with low blood pressure and high cardiac output and kidney failure or a risk thereof in a subject, said protocol comprising the steps of identifying renal failure or a risk thereof, administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor and a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole
  • the vasoconstrictor is Ang II and/or Ang II AT-I receptor agonist and the other vasosuppressor is noradrenaline.
  • the present invention also relates to compositions comprising a preferential efferent arteriolar vasoconstrictor or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, optionally with another agent such as a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) together with one or more pharmaceutically acceptable additives and optionally other medicaments.
  • the pharmaceutically acceptable additives may be in the form of carriers, diluents, adjuvants and/or excipients and they include all conventional solvents, dispersion agents, fillers, solid carriers, coating agents, antifungal or antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and slow or controlled release matrices.
  • the active agents may be presented in the form of a kit of components adapted for allowing concurrent, separate or sequential administration of the active agents.
  • Each carrier, diluent, adjuvant and/or excipient must be "pharmaceutically acceptable” in the sense of being compatible with the other ingredients of the composition and physiologically tolerated by the subject.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.
  • compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
  • compositions of the present invention are suitable for intravenous administration such as a continual or intermittent infusion.
  • compositions such as for parenteral, oral, intraperitoneal, subcutaneous, intramuscular, nasal, intrathecal or intraocular administration.
  • the compounds of the subject invention may also be administered in a sustained (i.e. controlled) or slow release form.
  • a sustained release preparation is one in which the active ingredient is slowly released within the body of the subject once administered and maintains the desired drug concentration over a minimum period of time.
  • the preparation of sustained release formulations is well understood by persons skilled in the art. Dosage forms may include oral forms, implants and transdermal forms.
  • the active ingredients may be suspended as slow release particles or within liposomes, for example.
  • compositions of the present invention may be packaged for sale with other active agents or alternatively, other active agents may be formulated with Ang II or Ang II AT-I receptor agonistor its pharmaceutical salts, derivatives, homologs or analogs thereof alone or in combination with one or more of a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide).
  • a nitric oxide synthase inhibitor such as but not limited to vitamin E, vitamin C,
  • the present invention creates a tamper-proof vasoconstricting delivery system that provides for full delivery of a preferential efferent arteriolar vasoconstrictor (such as Ang II or an Ang II AT-I receptor agonist) and an agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an antiviral agent (virocide) while at the same time effectively eliminating the problem of tampering by diversion, adulteration, or
  • the formulation may also contain carriers, diluents and excipients. Details of pharmaceutically acceptable carriers, diluents and excipients and methods of preparing pharmaceutical compositions and formulations are provided in Remmingtons Pharmaceutical Sciences 18 th Edition, 1990, Mack Publishing Co., Easton, Pennsylvania,
  • the active agents for use in the present invention may also be presented for use in veterinary compositions. These may be prepared by any suitable means known in the art. Examples of such compositions include those adapted for:
  • oral administration e.g. drenches including aqueous and non-aqueous solutions or suspensions, tablets, boluses, powders, granules, pellets for admixture with feedstuffs, pastes for application to the tongue;
  • parenteral administration e.g. subcutaneous, intramuscular or intravenous injection as a sterile solution or suspension or through intra-nasal administration;
  • topical application e.g. creams, ointments, gels, lotions, etc.
  • the composition is adopted for intravenous infusion.
  • the present invention will now be further described with reference to the following examples, which are intended for the purpose of illustration only and are not intended to limit the generality of the subject invention as hereinbefore described.
  • a left-sided thoracotomy was performed.
  • the pericardium was opened, and a transit time flow probe (20 mm, Transonics Systems, Ithaca, N. Y.) was placed around the pulmonary artery to measure cardiac output.
  • a left-sided flank incision was made and a retroperitoneal dissection was performed to expose the left renal artery.
  • a transit time flow probe (4 mm, Transonics Systems, Ithaca, N. Y.) was placed around the renal artery.
  • a single carotid artery loop was created. The animals were allowed to recover for two weeks before experimentation.
  • the transit-time flow probes were connected to flow meters (Transonics Systems, Ithaca, NY). Before starting the experiment, a Tygon catheter (Cole-Parmers; Boronia, Australia, id 1.0 mm, od 1.7 mm) was inserted into carotid loop to measure arterial pressure. Two internal jugular venous polyethylene catheters (Critchley, Silverwater, Australia, id 1.2 mm, od 1.7 mm) were placed to measure central venous pressure and for infusion. The cannulae were connected to pressure transducers (TDXIII, Code, Lakewood, CO) tied to the wool on the back.
  • TDXIII Code, Lakewood, CO
  • a correction factor was added in the data acquisition program to correct for the height of the transducers above the heart (Labview National Instruments).
  • a urinary catheter was inserted for measurement of urine volume and for sample collection.
  • Analog signals of mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO), and renal blood flow (RBF) were collected using a PC using a customized data acquisition system (Labview National Instruments). Data were recorded at 100 Hz for 10 s at every minute throughout the experimental protocol.
  • TPC cardiac output / mean arterial pressure
  • RVC renal vascular conductance
  • MAP, CVP, CO, RBF and heart rate were measured continuously. Following a 12-hour baseline period, sheep were monitored for a 48 hour control period. After 7 days, sheep were monitored for a 2 nd baseline period, followed by induction of sepsis by intravenous administration of a bolus of live E. colt (3.9x10 9 colony forming units in 15mL saline), followed by a continuous infusion (1.7xlO 10 colony forming units at 5 mL/h) for 48 h.
  • E. coli bacteria had been originally isolated from blood cultures from a septic patient, were grown from a stock kept at -70°C and incubated overnight in broth. The culture medium was then adjusted by turbidometry to give the correct concentration of bacteria.
  • the E. co ⁇ i infusion was continued for 48 h.
  • the sheep developed tachypnea, tachycardia and a temperature of > 41 °C, and began to use the accessory muscles of respiration.
  • the white blood cells decreased after 48 h of E. coli infusion to 1,600 ⁇ 800 / ⁇ L compared with 5400 ⁇ 2900 / ⁇ L in the control group (PO.05).
  • One sheep died 12 h after the induction of sepsis.
  • E. coli induced hyperdynamic sepsis with a delayed onset.
  • CO had increased significantly and continued to increase throughout the infusion to a maximum of 9.8 ⁇ 1.1 L/min, compared with 3.8 ⁇ 0.4 L/min with the control treatment (p ⁇ 0.05).
  • Heart rate increased rapidly in response to administration of E. coli reaching a plateau at 9 hours that was maintained for the 48 hour infusion (65.0 ⁇ 7.3 vs 161.1
  • RBF increased transiently over the following 6 hours, returning to baseline by 12 hours. RBF then began to increase again after 19 h, reaching a maximum of 757.4 ⁇ 250.1 mL/min after 45 h compared to control value of 262.3 ⁇ 47.7 mL/min (p ⁇ 0.05). This change was dependent on increased renal vascular conductance (3.0 ⁇ 0.7 mL/min/mmHg vs 11.4 mL/min/mmHg; p ⁇ 0.05.
  • the serum creatinine significantly increased in the sepsis group, reaching a value of 325 ⁇ 153 ⁇ mol/L compared with 73 ⁇ 18 ⁇ mol/L during the control treatment.
  • the serum creatinine in the control group was unaltered during the experiment.
  • the glomerular filtration rate (GFR) decreased after E. coli infusion (20.1 ⁇ 19.3 mL/min) compared to the control group (95.5 ⁇ 25.9 mL/min) (p ⁇ 0.05).
  • Urinary output increased briefly after the induction of sepsis and then decreased after 21 hours to below 0.5 mL/h/kg. During the 24-48 hour period hourly urinary output was 1.4 ml/h/kg in controls compared to 0.3 ml/h/kg.
  • Figure 1 shows the effects of administering Ang II to a mammal.
  • the data show a reduction in mean arterial pressure, an increase in renal blood flow and a reduction in urine output in sepsis and the ability of Ang II infusion to return these variables to normal in four (4) conscious sheep.
  • Example 4 The experiment in Example 4 is repeated in a short-term sepsis experiment with likely similar results.
  • Example 5 The experiment in Example 5 is repeated in a long-term sepsis experiment with likely similar results.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Vascular Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

The present invention relates generally to a method of treatment and in particular a method of treating a subject exhibiting symptoms of kidney failure or are at risk of developing same. Even more particularly, the present invention provides a method of treating kidney failure or reducing the risk of developing kidney failure in a subject such as following or during or prior to sepsis or a related condition including severe sepsis, septic shock and the systemic inflammatory response syndrome or any state of systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure, such as liver disease with associated kidney failure or kidney failure after cardiopulmonary bypass in patients in whom the systemic inflammatory syndrome which follows such cardiopulmonary bypass is associated with a high cardiac output and systemic or renal vasodilatation or kidney failure in other conditions which lead to the systemic inflammatory response syndrome with systemic or renal vasodilatation such as major trauma, major surgery and similar states which can induce the aforementioned systemic inflammatory response syndrome.

Description

A METHOD OF TREATMENT
BACKGROUND OF THE INVENTION
FIELD OF INVENTION
The present invention relates generally to a method of treatment and in particular a method of treating a subject exhibiting symptoms of kidney failure or are at risk of developing same. Even more particularly, the present invention provides a method of treating kidney failure or reducing the risk of developing kidney failure in a subject such as following or during or prior to sepsis or a related condition including severe sepsis, septic shock and the systemic inflammatory response syndrome or any state of systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure, such as liver disease with associated kidney failure or kidney failure after cardiopulmonary bypass in patients in whom the systemic inflammatory syndrome which follows such cardiopulmonary bypass is associated with a high cardiac output and systemic or renal vasodilatation or kidney failure in other conditions which lead to the systemic inflammatory response syndrome with systemic or renal vasodilatation such as major trauma, major surgery and similar states which can induce the aforementioned systemic inflammatory response syndrome.
DESCRIPTION OF PRIOR ART
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in any country.
Sepsis is the most common cause of death in intensive care units in the United States
(Parillo et al. Ann Intern Med 113(3) /227 '-242, 1990). The incidence of sepsis appears to be rising due to an increase in the use of invasive procedures, immunosuppressive therapies and emerging antibiotic and virocide resistance. Sepsis is a systemic response to infection (American College of Chest Physicians, Society of Critical Care Medicine Consensus Conference, Critical Care Medicine 20(6):864-874, 1992). In the absence of infection, it is referred to as the systemic inflammatory response syndrome. Severe sepsis is defined by the presence of likely or proven infection and at least two of the following: a temperature of greater than 380C or less than 360C; a heart rate greater than 90 beats per minute; a respiratory rate of more than 20/minute or a partial CO2 pressure of less than 32 mm Hg; and/or an alteration in white blood cell count (such as >12,000/mm or <4,000/mm3) together with evidence of vital organ failure (Fitch and Gossage Postgrad Med 111(3) :53-66, 2002).
Septic shock is a subset of severe sepsis and is sometimes referred to as sepsis-induced hypotension that persists despite fluid resuscitation and is associated with vital organ malfunction.
Septic shock results from or is at least exacerbated by a cytokine cascade. In general, local inflammation and substances elaborated from or associated with pathogenic organisms and viruses such as endotoxins, activated neutrophils, monocytes and tissue macrophages. This results in a cascade of pro-inflammatory cytokines and other effector molecules such as IL-I, IL-8, IL-IO, TNFα, prostaglandin E1, endogenous corticosteroids and catecholamines. This cascade leads to cellular chemotaxis, endothelial injury and activation of the coagulation cascade (Fitch and Gossage 2002 supra).
An initial and often sustained cardiovascular response occurs during the systemic inflammatory response syndrome or sepsis, which results from decreased systemic vascular resistance due to agents produced by organisms, responses to viruses, and mediators such as nitric oxide (Parker et al. Crit Care Med 100(4):483-490, 1984). A similar response characterized by vasodilation and the systemic inflammatory response syndrome is also frequently induced by other forms of severe physical injury such as cardiopulmonary bypass for cardiothoracic surgery, major trauma, other major surgery. This inflammatory response induced by other forms of body injury can be indistinguishable form that of severe sepsis and septic shock and appear mediated by the same immune system cascade of cytokines and nitric oxide induced vasodilatation (Argenziano et al. J Thorac Cardiovasc Surg ;116:973-980, 1998)). If the initial cardiovascular response is uncompensated, it has been proposed that tissue hypoperfusion results, leading to cellular dysfunction, lactic acidosis and multi-organ failure, frequently ending in death.
Traditional treatment strategies for kidney failure in the settings described above have centered around the use of volume expansion and vasodilators with the aim of restoring renal blood flow and renal function (Schrier and Wang Engl J Med ; 8; 351: 159-169, 2004)
However, the continuing high incidence of death due to septic or inflammatory shock is indicative that these management practices are not optimal. Furthermore, the multiple organ failure syndrome resulting from sepsis remains a major and expensive problem in ICUs around the world for which no reliably effective treatment has yet been developed. There is a need, therefore, to develop improved intervention protocols to treat sepsis, including septic shock and systemic inflammatory response syndrome and to protect failing organs, in this case, the kidney from the adverse effects of sepsis and systemic inflammation including severe sepsis, septic shock or systemic inflammation or other conditions leading to systemic and renal vasodilatation.
SUMMARY OF THE INVENTION
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
All scientific citations, patents, patent applications and manufacturer's technical specifications referred to hereinafter are incorporated herein by reference in their entirety.
The present invention is predicated in part on the surprising observation that, contrary to expectation, experimental subjects exhibiting symptoms of kidney failure, such as that induced by sepsis, systemic inflammation or other related condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure (including hepatorenal syndrome), require blood flow to the kidneys to be regulated through the use of agents that preferentially vasoconstrict the efferent arteriole of the glomerulus (the filtering apparatus of the kidney). This is contrary to current treatment of kidney failure in severe sepsis, which emphasizes the need to give fluids and kidney vessel vasodilators.
Hence, one aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure. Said method comprises administering to said subject an effective amount of preferential efferent arteriolar vasoconstricting agent for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure. In this setting, preferential efferent arteriolar vasoconstriction means that the efferent arteriole constricts more than the afferent arteriole.
In one embodiment, the kidney failure results from or is exacerbated by sepsis or systemic inflammation . Reference herein to "systemic inflammation" and "sepsis" includes severe sepsis, septic shock and systemic inflammatory response syndrome after major trauma, surgery or cardiopulmonary bypass or any other condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure.
Accordingly, another aspect of the present invention provides a method of treating a subject with systemic inflammation, sepsis or other conditions leading to systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure or a risk thereof, said method comprising the administration to said subject of an effective amount of a preferential efferent arteriolar vasoconstrictor for a time and under conditions sufficient for urine output to increase.
A convenient vasoconstricting agent which has a preferential action on the efferent arteriole of the glomerulus is angiotensin II (Ang II) or a homolog, derivative, analog or functional equivalent or an agonist of Ang II- AT-I receptor interaction. The vasoconstrictor may be given alone or in combination with, for example, a nitric oxide synthase inhibitor, an antibiotic, an anti- viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide).
Hence, the present invention is further directed to the use of a preferential efferent arteriolar vasoconstrictor alone or in combination with another therapeutic agent in the generation of a therapeutic protocol to treat a subject with symptoms of kidney failure or who is at risk of developing same following , during or prior to systemic inflammation or sepsis or other conditions leading to states of systemic or renal vasodilatation characterized by low blood pressure and a high cardiac output and low blood pressure.
The present invention extends to any animal or mammal but is particularly directed to the treatment of human subj ects . BRIEF DESCRIPTION OF THE FIGURES
Figures IA through C are graphical representations of a reduction in mean arterial pressure (A); an increase in renal blood flow (B); and a reduction in urine output (C); in sepsis and the ability of Ang II infusion to return these variables to normal in four (4) conscious sheep: I, pre-sepsis control; II, sepsis control period; III, sepsis+Ang II infusion period.
DETAILED DESCRIPTION OF THE INVENTION
Before describing the present invention in detail, it is to be understood that unless otherwise indicated, the subject invention is not limited to specific formulations of components, manufacturing methods, dosage regimes, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
In describing and claiming the present invention, the following terminology is used in accordance with the definitions set forth below.
The singular forms "a", "an" and "the" include plural aspects unless the context clearly dictates otherwise. Thus, for example, reference to "a vasoconstrictor" includes a single vasoconstrictor, as well as two or more vasoconstrictors; reference to "an agent" includes a single agent, as well as two or more agents; reference to "the method" includes a single method or a combination of methods; and so on.
The terms "compound", "agent", "active agent", "chemical agent", "pharmacologically active agent", "medicament", "active" and "drug" are used interchangeably herein to refer to a chemical compound that induces a desired pharmacological and/or physiological effect that is, preferential efferent arteriole vasoconstriction causing an increase in glomerular filtration rate and restoring urine output. The terms also encompass pharmaceutically acceptable and pharmacologically active ingredients of those active agents specifically mentioned herein including but not limited to salts, esters, amides, prodrugs, active metabolites, analogs and the like. When the terms "compound", "agent", "active agent", "chemical agent" "pharmacologically active agent", "medicament", "active" and "drug" are used, then it is to be understood that this includes the active agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, metabolites, analogs and the like. Reference to a "compound", "agent", "active agent", "chemical agent" "pharmacologically active agent", "medicament", "active", "drug" and "pro-drug" includes combinations of two or more actives such as a vasoconstrictor and one or more of a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), another vasosuppressor, a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-niicrobial agent (microbicide) and/or an antiviral agent (virocide). A "combination" also includes multi-part compositions such as a two-part composition where the agents are provided separately and given or dispensed separately or admixed together prior to dispensation. A particular example includes angiotensin II (Ang II) and the vasosuppressor, noradrenaline.
For example, a multi-part pharmaceutical pack may have two or more active agents separately maintained. The pack may also be designed to facilitate administration of the active ingredients.
The terms "effective amount" and "therapeutically effective amount" of an agent as used herein mean a sufficient amount of the agent (e.g. a vasoconstrictor) to provide the desired therapeutic or physiological effect or outcome. The desired outcome is a reduction in kidney failure as measured by an increase in urine output and an improved creatinine clearance to normal or premorbid levels. Undesirable effects, e.g. side effects, are sometimes manifested along with the desired therapeutic effect; hence, a practitioner balances the potential benefits against the potential risks in determining what is an appropriate "effective amount". The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, mode of administration and the like. Thus, it may not be possible to specify an exact "effective amount". However, an appropriate "effective amount" in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.
By "pharmaceutically acceptable" carrier, excipient or diluent is meant a pharmaceutical vehicle comprised of a material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial adverse reaction. Carriers may include excipients and other additives such as diluents, detergents, coloring agents, wetting or emulsifying agents, pH buffering agents, preservatives, and the like.
Similarly, a "pharmacologically acceptable" salt, ester, emide, prodrug or derivative of a compound as provided herein is a salt, ester, amide, prodrug or derivative that this not biologically or otherwise undesirable.
The terms "treating" and "treatment" as used herein refer to reduction in severity and/or frequency of symptoms of the condition being treated, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms of the condition and/or their underlying cause and improvement or remediation or amelioration of damage following a condition.
"Treating" a subject may involve prevention of a condition or other adverse physiological event in a susceptible individual as well as treatment of a clinically symptomatic individual by ameliorating the symptoms of the condition. Conveniently, treatment may be initiated immediately a subject's urine output drops or an infection or other condition is diagnosed. It is proposed that treatment commence after diagnosis of sepsis or other related conditions leading to a state of systemic vasodilatation with low blood pressure and high cardiac output with evidence of kidney failure or risk thereof. Hence, the present invention encompasses treating a subject having a risk of developing kidney failure.
A "subject" as used herein refers to an animal, preferably a mammal and more preferably human who can benefit from the pharmaceutical formulations and methods of the present invention. There is no limitation on the type of animal that could benefit from the presently described pharmaceutical formulations and methods. A subject regardless of whether a human or non-human animal may be referred to as an individual, subject, patient, animal, host or recipient. The compounds and methods of the present invention have particular application in human medicine but also in veterinary medicine as well as in general, domestic or wild animal husbandry.
As indicated above, the preferred animals are humans or other primates such as orangutangs, gorillas, marmosets, livestock animals, laboratory test animals, companion animals or captive wild animals, as well as avian species.
Examples of laboratory test animals include mice, rats, rabbits, sheep, simian animals, guinea pigs and hamsters. Rabbits, rodent, sheep and simian animals provide a convenient test system or animal model. Livestock animals include sheep, cows, pigs, goats, horses and donkeys.
Hence, one aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure, said method comprises administering to said subject an effective amount of preferential efferent arteriolar vasoconstricting agent for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure.
In this context, preferential efferent arteriolar vasoconstriction means that the efferent arteriole constricts more than the afferent arteriole.
In one embodiment, the kidney failure results from or is exacerbated by systemic inflammation or sepsis . Reference herein to systemic inflammation or "sepsis" includes severe sepsis, septic shock and the systemic inflammatory response syndrome or any other condition leading to systemic or renal vasodilatation with low blood pressure and high cardiac output with kidney failure.
A preferential efferent arteriolar vasoconstrictor includes any agent which reduces blood flow, particularly to the kidneys. An example of a particularly useful vasoconstrictor that has a preferential action on the efferent arteriole compared to the afferent arteriole is angiotensin II (Ang II) or a homolog, derivative, analog or functional equivalent thereof or an agonist of an Ang II interaction with its receptor, the AT-I receptor (angiotensin AT-I receptor agonist) or a combination of Ang II or Ang II AT-I receptor agonist and another vasosuppressor such as noradrenaline.
Reference to "Ang II" or "angiotensin AT-I receptor agonist" or "Ang II AT-I receptor agonist" includes derivatives or homologs which have a longer half-life such as a longer serum or tissue fluid half-life.
Hence, the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or who are at risk of developing kidney failure, said method comprising administering to said subject an effective amount of Ang II or a homolog, derivative, analog or functional equivalent or an agonist of Ang II-AT-1 receptor interaction for a time and under conditions sufficient to facilitate an increase in urine output and reduce kidney failure.
In another embodiment, the present invention provides a method of treating a subject with systemic inflammation or sepsis or other conditions leading to systemic or renal vasodilatation with low blood pressure and a high cardiac output with kidney failure or a risk thereof, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor for a time and under conditions for urine output to increase and kidney failure to resolve.
As indicated above, the subject may be any animal or mammal but is preferably a human. The present invention further extends to unborn foetuses such as when a pregnant subject is diagnosed with sepsis or related conditions leading to a state of systemic and renal vasodilation.
Hence, in a preferred embodiment, the present invention provides a method of treating a subject with systemic inflammation, sepsis, septic shock or other related conditions leading to systemic and renal vasodilatation with low blood pressure and high cardiac output and a failing kidney or risk thereof, said methods comprising administering to said subject an effective amount of Ang II or a homolog, derivative, analog or functional equivalent or an agonist of Ang II- AT-I receptor interaction for a time and under conditions for urine output to increase and reduce kidney failure.
A further embodiment comprises the administration of Ang II and/or an Ang II AT-I receptor agonist and another vasosuppressor such as noradrenaline.
The term "severe sepsis" refers to an acute bacterial, microbial or viral infection leading to a cascade of cytokines and inflammatory mediators being activated including the complement system, the coagulation cascade, the fibrinolytic system, catecholamines, glucocorticoids, prekallikrein, bradykinin, histamines, β-endorphins, encephalins, adrenocorticoid hormone, circulating myocardial depressant factors, cachectin (tumor necrosis factor), interleukins, other cytokines and nitric oxide. Symptoms of severe shock include fever, chills, constitution malaise, anxiety and/or confusion. Generally, the subject will exhibit a temperature of greater than 38°C or less than 36°C; a heart rate greater than 90 beats per minute; a respiratory rate of more than 20/minute or a partial CO2 pressure of less than 32 mm Hg; and/or an alteration in white blood cell count (such as >12,000/mm3 or <4,000/mm3). For severe sepsis to exist, the patient must also have evidence of vital organ failure (low urine output, high blood lactate levels, delirium, lung malfunction, low platelet count etc.). If the blood pressure is very low and does not improve with fluids the condition is called septic shock.
The active agents may be administered for therapy by any suitable route. Suitable routes of administration may include oral, rectal, nasal, inhalation of aerosols or particulates, topical (including buccal and sublingual), transdermal, vaginal, intravesical and parenteral (including subcutaneous, intramuscular, intravenous, intrasternal, intrathecal, epidural and intradermal). It will be appreciated that the preferred route will vary with the condition and age of the subject, the nature of the condition being treated, its location within the subject and the judgement of the physician or veterinarian. It will also be understood that individual active agents may be administered by the same or different distinct routes. As discussed above, an "effective amount" refers to an amount of active agent that provides the desired therapeutic or physiological outcome such as reducing kidney failure as endured by returning urine output to normal levels. Dosing may occur at intervals of several seconds, minutes, hours, days, weeks or months. Suitable dosage amounts and regimes can be determined by the attending physician or veterinarian. For example, Ang II or an angiotensin AT-I receptor agonist or pharmaceutically acceptable salts, derivatives, homologs, analogs or functional equivalents thereof, may be administered generally by infusion to a subject at a rate of between about 0.01 μg/kg/min to about 20 mg/kg/min continuously for from about 1 hour (or less) to up to about 500 or more hours, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499 or 500 hours. Dosing of the efferent arteriolar vasoconstrictor, such as an Ang II, can be determined by the attending physician in accordance with dosing rates in practice.
The present invention further contemplates combination therapy. Hence, a preferential efferent arteriolar vasoconstrictor may be given with a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger
(such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), another vasosuppressor, a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti- viral agent (virocide).
The term "antibiotic" is used in its broadest sense and includes cell-produced molecules as well as chemotherapeutic agents. A convenient reference is MIMS Annual, CMPMedica Australia Pty Limited: 1-1700, 2005, Publisher C & C Offset Printing Co., Ltd, Hong Kong.
In combination therapy, the two or more active agents may be administered simultaneously or sequentially. If simultaneously, the agents may be in the same or different formulations. If sequentially, they may be administered with nanoseconds, seconds, minutes, hours or days of each other.
Hence, another aspect of the present invention contemplates a method of treating a subject exhibiting symptoms of kidney failure or at risk of developing same, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstricting agent and at least one other agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), another vasosuppressor, a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure. An example of another vasosuppressor is noradrenaline. Examples of a preferential efferent arteriolar vasoconstricting agent is Ang II or an Ang II AT-I receptor agonist.
In a related embodiment, the present invention provides a method of treating a subject with systemic inflammation, sepsis including severe sepsis and septic shock, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor and at least one other agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti- viral agent, an isotonic crystalloid, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) flavonoid for a time and under conditions for urine output to increase.
Accordingly, still another aspect of the present invention contemplates a treatment protocol for systemic inflammation, sepsis including the systemic inflammatory syndrome, severe sepsis, septic shock and any condition characterized by a state of systemic or renal dilatation with low blood pressure and high cardiac output and kidney failure or a risk thereof in a subject, said protocol comprising the steps of identifying renal failure or a risk thereof, administering to said subject an effective amount of a preferential efferent arteriolar vasoconstrictor and a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) effective to reduce the level or risk of renal failure.
In a particular embodiment, the vasoconstrictor is Ang II and/or Ang II AT-I receptor agonist and the other vasosuppressor is noradrenaline.
The present invention also relates to compositions comprising a preferential efferent arteriolar vasoconstrictor or a pharmaceutically acceptable salt, derivative, homolog or analog thereof, optionally with another agent such as a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide) together with one or more pharmaceutically acceptable additives and optionally other medicaments.
The pharmaceutically acceptable additives may be in the form of carriers, diluents, adjuvants and/or excipients and they include all conventional solvents, dispersion agents, fillers, solid carriers, coating agents, antifungal or antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and slow or controlled release matrices.
The active agents may be presented in the form of a kit of components adapted for allowing concurrent, separate or sequential administration of the active agents. Each carrier, diluent, adjuvant and/or excipient must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the composition and physiologically tolerated by the subject. The compositions may conveniently be presented in unit dosage form and may be prepared by methods well known in the art of pharmacy.
Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents, adjuvants and/or excipients or finely divided solid carriers or both, and then if necessary shaping the product.
Generally, the compositions of the present invention are suitable for intravenous administration such as a continual or intermittent infusion.
The present invention does extend, however, to other forms of compositions such as for parenteral, oral, intraperitoneal, subcutaneous, intramuscular, nasal, intrathecal or intraocular administration.
The compounds of the subject invention may also be administered in a sustained (i.e. controlled) or slow release form. A sustained release preparation is one in which the active ingredient is slowly released within the body of the subject once administered and maintains the desired drug concentration over a minimum period of time. The preparation of sustained release formulations is well understood by persons skilled in the art. Dosage forms may include oral forms, implants and transdermal forms. For slow release administration, the active ingredients may be suspended as slow release particles or within liposomes, for example.
The pharmaceutical compositions of the present invention may be packaged for sale with other active agents or alternatively, other active agents may be formulated with Ang II or Ang II AT-I receptor agonistor its pharmaceutical salts, derivatives, homologs or analogs thereof alone or in combination with one or more of a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an anti-viral agent (virocide).
The present invention creates a tamper-proof vasoconstricting delivery system that provides for full delivery of a preferential efferent arteriolar vasoconstrictor (such as Ang II or an Ang II AT-I receptor agonist) and an agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other anti-microbial agent (microbicide) and/or an antiviral agent (virocide) while at the same time effectively eliminating the problem of tampering by diversion, adulteration, or pulverization of the medication for abuse by addicts.
The formulation may also contain carriers, diluents and excipients. Details of pharmaceutically acceptable carriers, diluents and excipients and methods of preparing pharmaceutical compositions and formulations are provided in Remmingtons Pharmaceutical Sciences 18th Edition, 1990, Mack Publishing Co., Easton, Pennsylvania,
USA.
The active agents for use in the present invention may also be presented for use in veterinary compositions. These may be prepared by any suitable means known in the art. Examples of such compositions include those adapted for:
(a) oral administration, e.g. drenches including aqueous and non-aqueous solutions or suspensions, tablets, boluses, powders, granules, pellets for admixture with feedstuffs, pastes for application to the tongue;
(b) parenteral administration, e.g. subcutaneous, intramuscular or intravenous injection as a sterile solution or suspension or through intra-nasal administration;
(c) topical application, e.g. creams, ointments, gels, lotions, etc.
Preferably, however, the composition is adopted for intravenous infusion. The present invention will now be further described with reference to the following examples, which are intended for the purpose of illustration only and are not intended to limit the generality of the subject invention as hereinbefore described.
EXAMPLE 1
Animal Model
Seven female Merino ewes weighing between 34.2 kg and 47.3 kg were procured for chronic instrumentation. The sheep were held and studied in metabolic cages, with free access to food and water. The animals underwent two separate operative procedures. For all procedures, anaesthesia was induced with sodium thiopentone (15 mg/kg) for endotracheal tube placement (cuff size 10). Maintenance anaesthesia was by means of oxygen/air/isoflurane (1 to 2 %). Fractional inspired oxygen was altered to maintain PaO2 at approximately 100 mm Hg, and ventilation was controlled to maintain PaCO2 at approximately 40 mm Hg.
First, a left-sided thoracotomy was performed. The pericardium was opened, and a transit time flow probe (20 mm, Transonics Systems, Ithaca, N. Y.) was placed around the pulmonary artery to measure cardiac output. After two weeks recovery, a left-sided flank incision was made and a retroperitoneal dissection was performed to expose the left renal artery. A transit time flow probe (4 mm, Transonics Systems, Ithaca, N. Y.) was placed around the renal artery. During the same operative procedure, a single carotid artery loop was created. The animals were allowed to recover for two weeks before experimentation.
The transit-time flow probes were connected to flow meters (Transonics Systems, Ithaca, NY). Before starting the experiment, a Tygon catheter (Cole-Parmers; Boronia, Australia, id 1.0 mm, od 1.7 mm) was inserted into carotid loop to measure arterial pressure. Two internal jugular venous polyethylene catheters (Critchley, Silverwater, Australia, id 1.2 mm, od 1.7 mm) were placed to measure central venous pressure and for infusion. The cannulae were connected to pressure transducers (TDXIII, Code, Lakewood, CO) tied to the wool on the back. A correction factor was added in the data acquisition program to correct for the height of the transducers above the heart (Labview National Instruments). A urinary catheter was inserted for measurement of urine volume and for sample collection. Analog signals of mean arterial pressure (MAP), central venous pressure (CVP), cardiac output (CO), and renal blood flow (RBF) were collected using a PC using a customized data acquisition system (Labview National Instruments). Data were recorded at 100 Hz for 10 s at every minute throughout the experimental protocol. Total peripheral conductance (TPC) (cardiac output / mean arterial pressure) and renal vascular conductance (RVC) (renal blood flow / mean arterial pressure) were calculated.
EXAMPLE 2 Protocol and Measurements
During the experimental periods MAP, CVP, CO, RBF and heart rate were measured continuously. Following a 12-hour baseline period, sheep were monitored for a 48 hour control period. After 7 days, sheep were monitored for a 2nd baseline period, followed by induction of sepsis by intravenous administration of a bolus of live E. colt (3.9x109 colony forming units in 15mL saline), followed by a continuous infusion (1.7xlO10 colony forming units at 5 mL/h) for 48 h. The E. coli bacteria, had been originally isolated from blood cultures from a septic patient, were grown from a stock kept at -70°C and incubated overnight in broth. The culture medium was then adjusted by turbidometry to give the correct concentration of bacteria.
In both treatments, after the 12-hour baseline period, normal saline (1 mL/kg/h) was infused to avoid hypovolemia. Urinary output was measured and urine sampled every 90 minutes. Arterial blood samples for analysis of creatinine and urine samples to measure creatinine were measured 12-hourly. No fluid boluses, inotropic support, mechanical ventilation, or antibiotics were administered. The animals were conscious and not sedated for the duration of the experiment. At the end of the septic period, the sheep were sacrificed using the intravenous administration of sodium pentobarbitone (150 mg/kg). EXAMPLE 3 Statistical Analysis
Data are presented as mean ± standard deviation. In the control and the sepsis group mean values for each hour were compared using non-parametric 2-way repeated measures ANOVA (Friedman's test). The control and septic group values for central and renal hemodynamics and renal functional variables were compared using ANOVA with the Bonferroni post-hoc test Ap < 0.05 was considered statistically significant.
EXAMPLE 4 Assessment of renal blood flow and renal vascular conductance in experimental septic acute renal failure (ARF)
In six of the seven sheep, the E. coϊi infusion was continued for 48 h. The sheep developed tachypnea, tachycardia and a temperature of > 41 °C, and began to use the accessory muscles of respiration. The white blood cells decreased after 48 h of E. coli infusion to 1,600 ± 800 /μL compared with 5400 ± 2900 /μL in the control group (PO.05). One sheep died 12 h after the induction of sepsis.
Systemic hemodynamic pattern
Administration of E. coli induced hyperdynamic sepsis with a delayed onset. After 10 h of E. coli infusion, CO had increased significantly and continued to increase throughout the infusion to a maximum of 9.8 ± 1.1 L/min, compared with 3.8 ± 0.4 L/min with the control treatment (p<0.05). Significant hypotension occurred at the same time and blood pressure continued to decrease during the infusion of E. coli (89.2 ± 3.2 mm Hg vs 64.3 ± 5.3 mm
Hg; P<0.05). Heart rate increased rapidly in response to administration of E. coli reaching a plateau at 9 hours that was maintained for the 48 hour infusion (65.0 ± 7.3 vs 161.1
±18.3 beats/min; p<0.05). There was marked peripheral vasodilatation as shown by the increase in total peripheral conductance (TPC), which reached significance 10 hours after
E. coli injection and reached a maximum of 153.7 ± 24.7 mL/min/mniHg, compared with
42.8 ± 3.5 mL/min/mmHg during the control treatment (p<0.05). The CVP tended to increase in both groups without reaching a significant difference. Renal hemodynamic and functional parameters
At 3 hours after the injection of E. coli, RBF increased transiently over the following 6 hours, returning to baseline by 12 hours. RBF then began to increase again after 19 h, reaching a maximum of 757.4 ± 250.1 mL/min after 45 h compared to control value of 262.3 ± 47.7 mL/min (p<0.05). This change was dependent on increased renal vascular conductance (3.0 ± 0.7 mL/min/mmHg vs 11.4 mL/min/mmHg; p<0.05.
After 24 hours, the serum creatinine significantly increased in the sepsis group, reaching a value of 325 ± 153 μmol/L compared with 73 ± 18 μmol/L during the control treatment. The serum creatinine in the control group was unaltered during the experiment. The glomerular filtration rate (GFR) decreased after E. coli infusion (20.1 ± 19.3 mL/min) compared to the control group (95.5 ± 25.9 mL/min) (p<0.05). Urinary output, increased briefly after the induction of sepsis and then decreased after 21 hours to below 0.5 mL/h/kg. During the 24-48 hour period hourly urinary output was 1.4 ml/h/kg in controls compared to 0.3 ml/h/kg.
EXAMPLE 5 Effects of Angiotensin II (Λng II)
Figure 1 shows the effects of administering Ang II to a mammal. The data show a reduction in mean arterial pressure, an increase in renal blood flow and a reduction in urine output in sepsis and the ability of Ang II infusion to return these variables to normal in four (4) conscious sheep.
EXAMPLE 6
Effects ofAng II in short term sepsis
The experiment in Example 4 is repeated in a short-term sepsis experiment with likely similar results.
EXAMPLE 7 Effects ofAng II in long term sepsis
The experiment in Example 5 is repeated in a long-term sepsis experiment with likely similar results.
EXAMPLE 8 Combination therapy
The experiments are repeated with a nitric oxide synthase inhibitor.
EXAMPLE 9 Determining renal ATP levels
Using the experimental methods described in Examples 1 through 8, magnetic resonance spectroscopy is used to determine changes in renal ATP in sepsis and following treatment with Ang II.
EXAMPLE 10
Clinical studies
Clinical trials are conducted using patients diagnosed with or suspected of having or at high risk of developing systemic inflammation, sepsis or a related condition. Renal blood flow is measured as are urine output and mean arterial pressure. Results similar to those shown in Figure 1 are expected. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
BIBLIOGRAPHY
American College of Chest Physicians, Society of Critical Care Medicine Consensus Conference, Critical Care Medicine 20(6):864-874, 1992
Argenziano M, Chen JM et al. JThorac Cardiovasc Surg 1998 116: 973-980, 1998
Fitch and Gossage Postgrad Med lll(3):53-66, 2002
MIMS Annual, CMPMedica Australia Pty Limited: 1-1700, 2005, Publisher C & C Offset Printing Co., Ltd, Hong Kong
Parillo et al. Ann Intern Med 113(3):227-242, 1990
Parker et al. Crit Care Med 100(4): 483-490, 1984
Remmingtons Pharmaceutical Sciences 18th Edition, 1990, Mack Publishing Co., Easton, Pennsylvania, USA.
Schrier RW, and Wang W. N Engl J Med 2004; 8; 351: 159-169, 2004

Claims

1. A method of treating a subject exhibiting symptoms of kidney failure or who is at risk of developing kidney failure, said method comprising administering to said subject an effective amount of a preferential efferent arteriolar vasoconstricting agent for a time and under conditions sufficient to facilitate an increase in urine output and to reduce kidney failure.
2. The method of Claim 1 wherein the kidney failure is associated with systemic inflammation, sepsis or other related conditions leading to systemic and renal vasodilatation with low blood pressure and high cardiac output.
3. The method of Claim 2 wherein the sepsis is septic shock or severe sepsis.
4. The method of Claim 2 wherein the sepsis is systemic inflammatory response syndrome.
5. The method of Claim 2 wherein the systemic inflammatory response syndrome is a condition capable of causing systemic inflammation and systemic or renal vasodilatation including but not confined to the systemic inflammatory syndrome after cardiopulmonary bypass, major trauma, major surgery or related conditions .
6. The method of Claim 1 or 2 or 3 or 4 or 5 wherein the subject is human.
7. The method of Claim 1 wherein the preferential efferent arteriolar vasoconstricting agent is angiotensin II (Ang II) or a pharmaceutically acceptable salt, derivative, homolog, analog or functional equivalent thereof.
8. The method of Claim 1 wherein the preferential efferent arteriolar vasoconstricting agent is an agonist of Ang II interaction with its receptor, AT-I.
9. The method of Claim 1 or 5 or 6 or 7 further comprising the administration of an agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other antimicrobial agent (microbicide) and/or an anti-viral agent (virocide).
10. The method of Claim 9 wherein the other vasosuppressor is noradrenaline.
11. Use of an efferent arteriolar vasoconstrictor alone or in combination with an agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C, selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other antimicrobial agent (microbicide) and/or an anti-viral agent (virocide) in the generation of a therapeutic protocol to treat a subject with symptoms of kidney failure or who is at risk of developing same following, during or prior to systemic inflammation, sepsis and related conditions leading to systemic or renal vasodilation.
12. Use of Claim 11 wherein the sepsis is septic shock or severe sepsis.
13. Use of Claim 11 wherein the sepsis is systemic inflammatory response syndrome.
14. Use of Claim 11 wherein systemic inflammation is the systemic inflammatory response syndrome including all conditions capable of causing systemic inflammation and systemic or renal vasodilatation including but not confined to the systemic inflammatory syndrome after cardiopulmonary bypass, major trauma, major surgery or related conditions.
15. Use of Claim 11 or 12 or 13 or 14 wherein the subject is human.
16. Use of Claim 11 wherein the preferential efferent arteriolar vasoconstricting agent is angiotensin II (Ang II) or a pharmaceutically acceptable salt, derivative, homolog, analog or functional equivalent thereof.
17. Use of Claim 11 wherein the preferential efferent arteriolar vasoconstricting agent is an agonist of Ang II interaction with its receptor, AT-I .
18. Use of Claim 11 wherein the other vasosuppressor is noradrenaline.
19. A formulation comprising a preferential efferent arteriolar vasoconstrictor and an agent selected from a nitric oxide synthase inhibitor, an antibiotic, an anti-viral agent, an isotonic crystalloid, another vasosuppressor, a colloid or a free radical scavenger (such as but not limited to vitamin E, vitamin C5 selenium, an NADPH oxidase inhibitor and/or a flavonoid), a calcium antagonist such as diltiazem or other agent which causes preferential vasodilatation of the afferent arteriole of the glomerulus, an antibiotic or other antimicrobial agent (microbicide) and/or an anti-viral agent (virocide for treating renal failure following or during sepsis.
20. The formulation of Claim 19 wherein the sepsis is septic shock or severe sepsis.
21. The formulation of Claim 19 wherein the sepsis is systemic inflammatory response syndrome.
22. The formulation of Claim 19 wherein systemic inflammation is the systemic inflammatory response syndrome including all conditions capable of causing systemic inflammation and systemic or renal vasodilatation including but not confined to the systemic inflammatory syndrome after cardiopulmonary bypass, major trauma, major surgery or related conditions .
23. The formulation of Claim 19 wherein the preferential efferent arteriolar vasoconstrictor is Ang II.
24. The formulation of Claim 19 wherein the preferential efferent arteriolar vasoconstrictor is an Ang II AT-I receptor agonist.
25. The formulation of Claim 19 or 23 or 24 wherein the vasosuppressor is noradrenaline.
PCT/AU2006/001952 2005-12-30 2006-12-20 A method of treatment WO2007076572A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US12/159,196 US20090304818A1 (en) 2005-12-30 2006-12-20 Method of treatment
AU2006332449A AU2006332449B2 (en) 2005-12-30 2006-12-20 A method of treatment
CA002633013A CA2633013A1 (en) 2005-12-30 2006-12-20 A method of treatment
JP2008547805A JP2009521513A (en) 2005-12-30 2006-12-20 Method of treatment
EP06828056A EP1971358A4 (en) 2005-12-30 2006-12-20 A method of treatment

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75526605P 2005-12-30 2005-12-30
US60/755,266 2005-12-30

Publications (1)

Publication Number Publication Date
WO2007076572A1 true WO2007076572A1 (en) 2007-07-12

Family

ID=38227849

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2006/001952 WO2007076572A1 (en) 2005-12-30 2006-12-20 A method of treatment

Country Status (7)

Country Link
US (1) US20090304818A1 (en)
EP (1) EP1971358A4 (en)
JP (1) JP2009521513A (en)
CN (1) CN101351215A (en)
AU (1) AU2006332449B2 (en)
CA (1) CA2633013A1 (en)
WO (1) WO2007076572A1 (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2016008108A (en) * 2013-12-18 2017-03-09 The George Washington Univ A Congressional Chartered Not-For-Profit Cororation Angiotensin ii alone or in combination for the treatment of hypotension.
TW201733610A (en) 2016-01-07 2017-10-01 拉荷亞製藥公司 Methods for administering angiotensin II
US11583568B2 (en) 2017-04-14 2023-02-21 La Jolla Pharma, Llc Methods for administering angiotensin II

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002098906A1 (en) * 2001-06-04 2002-12-12 Human Genome Sciences, Inc. Methods and compositions for modulating ace-2 activity
US7899527B2 (en) * 2004-05-13 2011-03-01 Palo Alto Investors Treatment of conditions through modulation of the autonomic nervous system during at least one predetermined menstrual cycle phase

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BEALE R.J. ET AL.: "Vasopressor and inotropic support in septic shock: an evidence-based review", CRIT. CARE MED., vol. 32, no. 11, SUPPL., 2004, pages S455 - S465, XP003015359 *
DUCKWORTH A.J. ET AL.: "Pressor and intra-renal effects of angiotensins I and II, and noradrenaline, in anesthetized and conscious sheep. The effects of halothane anaesthesia on pressor sensitivity and electrolyte shifts: the proposed use of angiotensin I in treating in......", MEDICAL HYPOTHESES, vol. 64, no. 4, 2005, pages 833 - 847, XP004732712 *
HOLLENBERG S.M. ET AL.: "Impaired microvascular vasoconstrictive responses to vasopressin in septic rats", CRITICAL CARE MEDICINE, vol. 25, no. 5, 1997, pages 869 - 873, XP009131712 *
HU L. ET AL.: "Nitric oxide synthase inhibition accelerates the pressor response to low dose angiotensin II, exacerbates target organ damage, and induces renin escape", AM. J. HYPERTENS., vol. 17, no. 5, PART 1, 2004, pages 395 - 403, XP003015358 *
See also references of EP1971358A4 *
YUNGE M. ET AL.: "Angiotensin for septic shock unresponsive to noradrenaline", ARCHIVES OF DISEASE IN CHILDHOOD, vol. 82, no. 5, 2000, pages 388 - 389, XP003015357 *

Also Published As

Publication number Publication date
JP2009521513A (en) 2009-06-04
CN101351215A (en) 2009-01-21
AU2006332449B2 (en) 2008-05-15
CA2633013A1 (en) 2007-07-12
EP1971358A1 (en) 2008-09-24
EP1971358A4 (en) 2010-05-26
AU2006332449A1 (en) 2007-07-12
US20090304818A1 (en) 2009-12-10

Similar Documents

Publication Publication Date Title
TWI386203B (en) Pharmaceutical composition for treating brain cancer or reducing temozolomide-resistance of brain cancer cells and uses of the same
CA2641815C (en) Method of treatment for muscular dystrophy
Cobb et al. Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs
Memis et al. The influence of methylene blue infusion on cytokine levels during severe sepsis
JP2017537149A (en) Methods for limiting acute kidney injury
ES2425482T3 (en) Angiotensin II receptor antagonist for the treatment of systemic diseases in cats
EA022166B1 (en) Synthetic triterpenoids and methods of use in the treatment of disease
KR20180059582A (en) Therapeutic treatment for lung conditions
JP2020002167A (en) Methods and compositions for treating sepsis
US20170007577A1 (en) Method of treating or inhibiting the development of brain inflammation and sepsis
WO2018119262A1 (en) Methods of treating glioblastoma multiforme using ibudilast
Xu et al. Regulation of pericyte metabolic reprogramming restricts the AKI to CKD transition
AU2006332449B2 (en) A method of treatment
US11123349B2 (en) Method of treatment
WO2022051495A1 (en) Methods and compositions for the treatment of pulmonary hypertension and cancer
CN111450089A (en) Application of Bepridil or KB-R7943 in preparation of medicine for treating melanoma
EP4335451A1 (en) Prophylactic or therapeutic agent for acute renal failure
Rimpiläinen et al. Lamotrigine plus leukocyte filtration as a neuroprotective strategy in experimental hypothermic circulatory arrest
Brady et al. Postoperative management of the emergency surgery small animal patient
AU732441B2 (en) Treatment of sepsis-induced acute renal failure and renal vasoconstriction and catecholamine-induced renal and mesenteric vasoconstriction
KR102512550B1 (en) Pharmaceutical composition for treatment of sepsis and septic shock
Borer et al. The effect of hyoscine on dobutamine requirement in spontaneously breathing horses anaesthetized with halothane
CN117398372A (en) Application of Ostarine in inhibiting NLRP3 inflammatory body activation
KR20070014114A (en) A treatment for necrotizing enterocolitis
Tomaz et al. NLRP3 Inflammasome Inhibition Decreases NETosis in AKI: FR-PO167

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680050067.X

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006332449

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2006332449

Country of ref document: AU

Date of ref document: 20061220

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2006332449

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2633013

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2006828056

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2008547805

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWP Wipo information: published in national office

Ref document number: 2006828056

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12159196

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: PI0620818

Country of ref document: BR

Free format text: COMPROVE QUE O SIGNATARIO JOAO LUIS D'OREY TEM PODERES PARA ATUAR EM NOME DO DEPOSITANTE, UMA VEZ ESTE NAO FOI CONSTITUIDO E NOMEADO NA PROCURACAO APRESENTADA E QUE BASEADO NO ARTIGO 216 DA LEI 9.279/1996 DE 14/05/1996 (LPI) OS ATOS PREVISTOS NESTA LEI SERAO PRATICADOS PELAS PARTES OU POR SEUS PROCURADORES, DEVIDAMENTE QUALIFICADOS .

ENPW Started to enter national phase and was withdrawn or failed for other reasons

Ref document number: PI0620818

Country of ref document: BR